NHMRC Research Achievements - SUMMARY
END OF GRANT REPORTS
OUTCOMES OF NHMRC FUNDED RESEARCH INTO CARDIOVASCULAR DISEASE
ENDING 2000 TO 2013
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Alfred Hospital
Austin Hospital Medical Research Foundation
Austin Research Institute
Australian National University
Baker IDI Heart and Diabetes Institute
Bond University
Cancer Council Victoria
Centre for Eye Research Australia Ltd
Curtin University of Technology
Deakin University
Edith Cowan University
Flinders Medical Centre
Flinders University
Garvan Institute of Medical Research
Griffith University
Heart Research Institute
Institute for Breathing and Sleep
Institute of Medical and Veterinary Science
International Diabetes Institute Inc
James Cook University
La Trobe University
Ludwig Institute for Cancer Research
Macfarlane Burnet Institute for Medical Research and Public Health
Macquarie University
Melbourne Health
Menzies Research Institute
Menzies School of Health Research
Monash University
Murdoch Childrens Research Institute
Murdoch University
National Stroke Research Institute
Prince Henry's Institute of Medical Research
Queensland Institute of Medical Research
Queensland University of Technology
RMIT University
Royal Adelaide Hospital
Royal Melbourne Institute of Technology
Royal Prince Alfred Hospital
NHMRC Research Achievements - SUMMARY
Sir Charles Gairdner Hospital
St Vincent's Health
St Vincent's Institute of Medical Research
Sydney Dental Hospital
Sydney West Area Health Service
The Children's Hospital at Westmead
The George Institute for International Health
The Queen Elizabeth Hospital
University of Adelaide
University of Melbourne
University of New South Wales
University of Newcastle
University of Queensland
University of South Australia
University of Sydney
University of Tasmania
University of Technology Sydney
University of Western Australia
University of Western Sydney
University of Wollongong
Victor Chang Cardiac Research Institute
Victoria University
Walter and Eliza Hall Institute
NHMRC Research Achievements - SUMMARY
Grant ID: 156400
Start Year: 2001
CIA Name: A/Pr Matthew Naughton
End Year: 2002
Admin Inst: Alfred Hospital
Grant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $140,906
Title of research award:
Randomized Controlled Trial of CPAP on cardiac function in patients with heart failure and obstructive sleep
apnoeaRandomized Controlled Trial of CPAP on cardiac function in patients with heart failure and obstructive
sleep apnoea
Lay Description (from application):
Heart failure is a very common condition associated with disabling symptoms. The main symptoms are
breathlessness, usually during sleep or upon exercise, and fatigue. Recent research has identified that sleep
apnoea, a condition that occurs in about 50% of subjects with heart failure, is likely to be responsible for these
symptoms. Moreover, treatment specifically aimed at sleep apnoea, namely continuous positive airway
pressure (CPAP) delived via a small electric pump and nasal mask worn during sleep, may also improve the
symptoms of heart failure. The study will involve subjects with stable heart failure on optimal drug treatment
who have evidence of obstructive sleep apnea on an overnight sleep study. Obstructive sleep apnoea (OSA) is a
condition in which the throat intermittently narrows or blocks during sleep (often associated with snoring)
causing cessation of airflow or "apnoeas". Associated with the apnoeas are vigorous efforts by the chest
muscles to breathe (creating negative vacuum-like pressures within the chest - and around the heart) at a time
of falling oxygen levels. Previous research has suggested that these obstructive apnoeas are detrimental to the
heart. Volunteers will be randomized to either a control or a CPAP treated group for a three month period. The
control and CPAP groups will receive intensive advice about good eating and sleeping habits as weight gain
and sleep loss are factors known to aggravate heart failure and obstructive sleep apnoea. In addition to the
"lifestyle advice", the CPAP group will also be treated with nasal CPAP. The variables which we will measure
include severity of sleep apnoea, exercise capacity, heart function at rest and symptoms. Symptoms will be
measured using 4 very detailed and validated questionnaires.
Research achievements (from final report):
Heart failure is likely to affect 1 in 5 Australians, about half of whom will have associated sleep apnoea.
Treatment of the apnoea may prevent deterioration of heart condition and improve quality of life. Future
studies are required to determine whether our findings translate into improved and reduced healthcare costs.
Mechanisms of action of apnoea and CPAP on the heart are required.
Expected future outcomes:
N/A
Name of contact:
N/A
Email/Phone no. of contact:
N/A
NHMRC Research Achievements - SUMMARY
Grant ID: 262303
Start Year: 2003
CIA Name: Prof Rinaldo Bellomo
End Year: 2007
Admin Inst: Austin Hospital Medical Research Foundation Grant Type: Established Career
Fellowships
Main RFCD: Clinical Sciences not elsewhere classified
Total funding: $198,975
Title of research award:
Saline versus Albumin Fluid Evaluation and Medical Emergency Response and Intervention TrialSaline versus
Albumin Fluid Evaluation and Medical Emergency Response and Intervention Trial
Lay Description (from application):
Not Available
Research achievements (from final report):
Published >250 papers, Conducted several major randomized controled trials of international impact published
in the NEJM and Lancet, Conducted multiple animal experimental studies, Perfromed early trials for concept
development
Expected future outcomes:
Continued research in multiple aspects of intensive care medicine, Improived patient care as a result of trial
findings
Name of contact:
Rinaldo Bellomo
Email/Phone no. of contact:
rinaldo.bellomo@austin.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 156710
CIA Name: Prof David Power
Admin Inst: Austin Research Institute
Main RFCD: Nephrology and Urology
Total funding: $227,037
Start Year: 2001
End Year: 2003
Grant Type: NHMRC Project Grants
Title of research award:
Regulation of the Na-K-Cl co-transporter by the AMP-activated protein kinaseRegulation of the Na-K-Cl cotransporter by the AMP-activated protein kinase
Lay Description (from application):
The failure of the kidney to excrete enough salt is a major driving force behind high blood pressure, kidney
failure and heart disease. At present, it is not known, in any detail, how the kidney is able to recognise that it is
not excreting enough salt and how it changes the amount it excretes. This is important if, for example, someone
eats a salty meal. Unless the kidney recognises that there is an excess of salt and adjusts itself to excrete it, then
salt accumulates leading to high blood pressure, kidney and cardiac problems. In this study, we have identified
a new mechanism that the kidney uses to detect salt and to excrete it. This could be a major advance in our
understanding of high blood pressure and other common diseases.
Research achievements (from final report):
This project identified a relationship between metabolic diseases, such as diabetes and obesity, and
erabsorption of salt from the kidney. Since a close relationship is now known to exist between salt handling
and blood perssure, this study has helped to explain, for the first time why people who have metabolic diseaes
develop high blood pressure. Closer examination of the molecules involved in this relationship should, in the
future, permit the development of therapies designed to break the link between metabolic disease and some of
its most feared cardiovascular and kidney complications.
Expected future outcomes:
Identification of molecular targets for drug discovery in the area of obesity, diabetes and blood pressure.
Name of contact:
David Power
Email/Phone no. of contact:
david.power@austin.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 250398
CIA Name: A/Pr Denise Jackson
Admin Inst: Austin Research Institute
Main RFCD: Haematology
Total funding: $441,000
Start Year: 2003
End Year: 2005
Grant Type: NHMRC Project Grants
Title of research award:
Regulating platelet thrombus formation by inhibitory co-receptorsRegulating platelet thrombus formation by
inhibitory co-receptors
Lay Description (from application):
Platelets are a specialised adhesive cell essential for normal blood clotting. Following induction of blood
vessel injury, platelets stick to sites of injury and activation mediate platelet spreading, aggregation and stable
blood clot formation. Platelet adhesion to components of the blood vessel in flowing blood is central to blood
clot formation. We are studying the role of inhibitory receptors that regulate the platelet adhesion phase on the
blood vessel surface. We have knockout mice that lack a specific protein, Platelet Endothelial Cell Adhesion
Molecule-1 (PECAM-1) that we can use to study its functional role in blood clot models. We are developing
transgenic mice to examine the important structural domains in PECAM-1 that lead to regulation of blood
clots. The knowledge gained from this work will help to improve our understanding of the regulatory
processes which influence the formation of a stable blood clot. This information is relevant to many human
diseases including heart attack and stroke.
Research achievements (from final report):
Aim 1: To investigate the physical proximity and functional interplay of PECAM-1 negative regulation of
collagen GPVI receptor, Fc receptor, FcgammaRIIa and integrin alphaIIbbeta3 on the platelet membrane., o
We have shown that PECAM-1 and
FcgammaRIIa are co-localised on the platelet membrane and PECAM-1 down-regulates FcgammaRIIamediated platelet responses (DJ25), indeed PECAM-1 can abrogate FcgammaRIIa-mediated HITS antibodyinduced platelet aggregation., o
In platelets, FcgammaRIIa and
collagen receptor, (GPVI) are palmitoylated and are co-localised in membrane microdomains with PECAM-1;
C595A PECAM-1 is required for palmitoylation and co-localisation to membrane microdomains., o Identified
and characterised a novel calmodulin binding motif in PECAM-1 that is associated with receptor cleavage
(DJ24)., o
We have demonstrated that PECAM1 regulates the 'outside-in' signalling properties of integrin alphaIIbbeta3 in platelets (DJ33)., Aim 2: To
investigate the physiological significance of PECAM-1 in the dynamics of platelet aggregation using an in vivo
mouse thrombosis models., o
We initially established a ferric
chloride vascular injury model of in vivo mouse thrombosis using fluorescence intravital microscopy. Using
this model, we compared wild-type versus PECAM-1 knockout mice and found that PECAM-1 knockout mice
were equally susceptible to in vivo thrombosis as wild-type mice., Aim 3: To determine the role of PECAM-1
ITIMs in the regulation of platelet function in vitro and in vivo by establishing transgenic mice that express
normal and disabled PECAM-1 ITIM/PTP interactions., o
We generated transgenic constructs
containing wild-type and ITIM mutant forms of mouse PECAM-1 fused to the H-2Kb promoter. We have now
developed transgenic mouse lines containing ITIM mutant forms of mouse PECAM-1. We have confirmed
authenticity of the transgene. We are currently characterising these transgenic mouse strains.,
Expected future outcomes:
The importance of immune inhibitory receptor modulation has been demonstrated by fatal autoimmune
disorders observed in mice with targeted disruption of inhibitory receptors. Intracytoplasmic ITIMs are highly
conserved throughout evolution and are proving to be essential for terminating platelet activation. Our studies
will clarify the unique role of inhibitory co-receptors in thrombosis.
Name of contact:
A/Prof. Denise Jackson
NHMRC Research Achievements - SUMMARY
Email/Phone no. of contact:
d.jackson@burnet.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 224219
Start Year: 2003
CIA Name: Prof Caryl Hill
End Year: 2005
Admin Inst: Australian National University
Grant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $282,750
Title of research award:
Myoendothelial gap junctions: their composition and role in vasodilator responses attributed to
EDHFMyoendothelial gap junctions: their composition and role in vasodilator responses attributed to EDHF
Lay Description (from application):
Cardiovascular disease, including coronary heart disease and stroke, continues to be the major cause of death in
Australia and hypertension is a significant risk factor. The endothelium, which lines blood vessels of all sizes,
is critical to the control of blood flow to the organs of the body. Endothelial cells release factors which can
cause blood vessels to constrict or to relax, thus decreasing or increasing blood flow, respectively. Under
normal conditions, the endothelium is more important as a source of relaxing factors, while under hypertensive
conditions, the balance is shifted in favour of the release of constricting factors. Thus, restoration of the
vasodilatory function of the endothelium is seen as an important new therapeutic target in the treatment of
vascular disorders. Present data suggests that the action of one of the major endothelial derived vasodilatory
factors, the so-called endothelium-derived hyperpolarizing factor, EDHF, requires the presence of particular
structures within the vascular wall, but little is known about the molecules of which they are comprised. We
have identified two unique situations, during development and during hypertension, when these structures are
present in vessels in which they are absent in normal adults. We will use gene microarrays to identify the
specific molecules involved in these structures and use physiological studies to test the role of these proteins
and structures in vasodilatory responses. The results of these studies may identify new targets for therapeutic
intervention to restore the action of EDHF in hypertension.
Research achievements (from final report):
The coordinated behaviour of small arteries is fundamental to the regulation of blood flow, blood pressure and
adequate tissue perfusion. Arteries consist of two layers: an inner lining of endothelial cells, surrounded by
layers of muscle. Arteriolar tone is therefore determined by a balance between stimuli promoting constriction
and those promoting relaxation of the muscle cells. Disruption of this balance in favour of vasoconstriction
occurs during hypertension and ageing, often resulting from endothelial dysfunction and decrease in the release
of potent relaxing factors. , Our studies provide evidence that cell coupling links the muscle cells with the inner
endothelium through myoendothelial gap junctions and that this coupling is essential for the activity of an
important vasodilatory factor called endothelium derived hyperpolarising factor (EDHF). We have shown that
the incidence of these myoendothelial gap junctions decreases during development and changes in
hypertension in line with the ability of EDHF to induce vasodilation suggesting that modulation of these
junctions might improve relaxation. However, such alteration was not effected by antihypertensive treatment
even though EDHF activity was restored suggesting that other target molecules may be involved. , We
therefore sought to identify new targets for the treatment of hypertension by comparing the gene changes that
occur in arteries during two different forms of hypertension. Although the majority of changes varied between
the two models, we found similar changes in three important molecules which could contribute to hypertension
through disruption of the balance in favour of vasoconstriction. These molecules provide potential targets for
future drug treatment.
Expected future outcomes:
Our studies have identified three novel targets which may contribute to hypertension. Further studies are
required to validate the role that these molecules could have in the development of hypertension.
Name of contact:
Caryl Hill
NHMRC Research Achievements - SUMMARY
Email/Phone no. of contact:
caryl.hill@anu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 268015
CIA Name: Prof Niels Becker
Admin Inst: Australian National University
Main RFCD: Applied Statistics
Total funding: $212,250
Start Year: 2004
End Year: 2006
Grant Type: NHMRC Project Grants
Title of research award:
Improved ways to study the effect of transient exposures on the risk of an illness, with application to flying and
DVTImproved ways to study the effect of transient exposures on the risk of an illness, with application to
flying and DVT
Lay Description (from application):
Improved methods of analysis will be developed to estimate the extent to which certain short-term activities
trigger a particular illness and to determine who is most at risk. The new methods of analysis have many
potential applications, including study of the effect of periods of intense exercise or intense alcohol
consumption on the risk of a heart attack. Here we apply them to study the effect of air travel on illness due to
blood clots in a vein (deep vein thrombosis, DVT), and the factors that put individuals at greatest risk. The
extra understanding that our improved analysis of the data provides will accelerate research into ways to
minimise the risk of flight-induced DVT and implementation of preventative measures in the travel industry.
This has the potential to prevent many cases, and deaths, because the number of flights taken, globally, by
individuals in a year is now in the billions. Specifically, dependence of flight-induced DVT on age, sex, being
pregnant, recent fractures and having certain cancers will identify individuals at greatest risk, while dependence
on the duration of the flight will identify flights that present greater risk. The development of these new
methods of analysis will make a lasting contribution to public health research, because they can be used to
study many short-term-activity / illnesses combinations. The methods will see increasing applications because
the type of data they rely on, namely the complete history of exposures over time periods, will increasingly
become available as electronic recording of activities becomes more common place. For example, electronic
records of flights are now almost universal and bookings at squash courts and other sporting venues are
increasingly recorded electronically. The computer software to apply the new methods of analysis will be made
available to other researchers, to promote studies of this type.
Research achievements (from final report):
This project has provided the strongest evidence so far of an association between Deep Vein Thrombosis and
long-haul air travel, because it is based on a unique and very large data set obtained by linking hospitalisation
and travel data. As a consequence the findings have informed policy on the risks associated with flying and the
need to inform the travelling public on the need to take precautions known to ameliorate the risk. In the course
of this work new methods were developed for the analysis of data on short-term exposures that might trigger
acute adverse health outcomes. These methods apply to investigation of a range of other associations and have
already been applied to establish triggers of Menière's disease.
Expected future outcomes:
The methodology for analysis will see further applications. For example, it is being considered for use in
studying associations between acute infection and relapse for individuals with Multiple Sclerosis.
Name of contact:
Professor Niels Becker
Email/Phone no. of contact:
niels.becker@anu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 268027
Start Year: 2004
CIA Name: Prof Philip Board
End Year: 2006
Admin Inst: Australian National University
Grant Type: NHMRC Project Grants
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $402,000
Title of research award:
CLICs and GSTs: New Ion Channel ModulatorsCLICs and GSTs: New Ion Channel Modulators
Lay Description (from application):
Controlling the concentration of calcium inside cells is extremely important for normal cell function. For
example, a brief increase in calcium concentration inside muscle cells is essential for muscle contraction and
the normal heart beat. This calcium is kept stored in sacs inside cells and is rapidly released when needed
through calcium channels known as ryanodine receptors. We have discovered that some proteins (glutathione
transferases and intracellular chloride channel proteins) inside cells can affect how much calcium flows
through these calcium channels. The proteins were thought to have other functions and our discovery of their
effect on ryanodine receptor calcium channels has caused considerable excitement. We now plan to explore
how they do this. We will mutate specific regions of the proteins to discover which regions are important and
which are not. We will also look at whether closely related proteins have similar effects. The new class of ion
channel modulator that we are studying has the capacity to alter not only respiration, movement and cardiac
contraction, but also other aspects cardiovascular function, neuronal activity and immune responses.
Understanding the way in which soluble proteins can interact with ion channels may reveal a novel target for
drugs that affect ryanodine receptor calcium channel function and allow the rational design of specific drugs to
regulate ion channels or ion channel modulators.
Research achievements (from final report):
We studied the effects of different members of the glutathione transferase structural family on the function of
ryanodine receptors (RyR)., We completed studies on the structure of CLIC-2 and its effects on cardiac RyR
calcium channels. The effects CLIC-2 on Ca2+ release from skeletal and cardiac SR under oxidising and
reducing conditions show a critical dependence on redox conditions. CLIC-2 inhibits Ca2+ release from
cardiac SR under oxidising conditions, but increases Ca2+ release under reducing conditions. , The distribution
of GSTM2-2 in skeletal and cardiac muscle and its action on RyRs from each muscle type were also
investigated. We compared the effects of GSTM2-2 and calsequestrin (CSQ) on the luminal side of RyRs. CSQ
is the luminal Ca2+ binding protein contains 3 thioredoxin folds. GSTM2-2 has a distinctly different action
when added to the luminal or cytoplasmic side of RyR channels. The actions of GST and CSQ are different
suggesting that they do not depend on the common thioredoxin fold structure. Unexpectedly we found that the
C-terminal helical domain of GSTM2 was responsible for its inhibitory action on cardiac RyR. Further studies
allowed us to narrow down the inhibitory region to peptides containing helix 6. This new knowledge will be
used to develop novel inhibitors to regulate the cardiac RyR during heart failure.
Expected future outcomes:
We will be able to identify the region of the C-terminal of GSTM2 that is responsible for the modulation of
cardiac ryanodine receptors. We will also be able to identify the GSTM2 binding site. We hope this knowledge
will contribute to the development of drugs to inhibit cardiac ryanodine receptors in heart failure.
Name of contact:
Philip Board
Email/Phone no. of contact:
Philip.Board@anu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 316907
CIA Name: Dr Shin-Ho Chung
Admin Inst: Australian National University
Main RFCD: Biophysics
Total funding: $381,000
Start Year: 2005
End Year: 2007
Grant Type: NHMRC Project Grants
Title of research award:
Theoretical Studies on the Dynamics of Ion Permeation Across Membrane ChannelsTheoretical Studies on the
Dynamics of Ion Permeation Across Membrane Channels
Lay Description (from application):
All electrical activities in the brain are regulated by opening and closing of ion channels. Thus, understanding
their mechanisms at a molecular level is a fundamental problem in biology. There are many different types of
ion channels, each type fulfilling a different role. We now know the exact atomic structures of several types of
the proteins forming ion channels. Using this newly unveiled information, we propose to build exact physical
models of many different types of ion channels. Then, making use of powerful supercomputers, we propose to
follow the motion of ions as they move through the channel, study how a channel can select only the correct
type of ions to traverse it and determine how many ions a single channel is capable of processing per second.
The predictions made by our theory and computer simulations will be checked experimentally. Once we fully
understand how these channels work, we will be able to understand the causes of, and possibly find the cures
for, many neurological, muscular and renal disorders.
Research achievements (from final report):
We have provided a comprehensive physical description of several important classes of biological ion
channels. The theoretical models we constructed are capable of predicting channel function from channel
structure, capable of revealing certain aspects of atomic structures of protein macromolecules, and link the
macroscopic observables to the details of the inter-molecular potential operating between ions, water molecules
and atoms that form the channel. , Among the channel models we constructed are two classes of anionic
channels and two classes of cationic channels. We built atomic models of two eukaryotic ClC channels, the
GABA receptor, and several classes of potassium and calcium channels. The channels are important for the
control of membrane excitability in nerves and muscles. Genetic alterations of these channels are known to be
associated with muscular and renal disorders, epilepsy and hypertension. The properties of each model so
constructed were examined, using macroscopic calculations, semi-microscopic Brownian dynamics and fully
microscopic molecular dynamics. Each virtual channel we created was then modified and refined until the
salient properties deduced from computer simulations reproduce those obtained experimentally. With these
theoretical model channels, we could test highly detailed hypotheses about the mechanisms of ion permeation
across the membrane. Our studies not only provided a detailed mechanistic understanding of ion conduction in
these highly selective pores, but also they have unraveled new information on the mechanism of action of small
molecule blockers and basis of selectivity. Our technique of building and studying virtual channels can be
readily extended for designing and screening potential drugs.
Expected future outcomes:
New theoretical tools we have devised and the virtual biological channels we have constructed will provide
quantitative physical explanations of the mechanisms of ion permeation, selectivity and gating. Computational
approaches we have adopted will lead to hosts of pharmaceutical products, specifically targeted at biological
ion channels.
Name of contact:
Shin-Ho Chung
Email/Phone no. of contact:
shin-ho.chung@anu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 316911
CIA Name: Dr Shin-Ho Chung
Admin Inst: Australian National University
Main RFCD: Biophysics
Total funding: $651,750
Start Year: 2005
End Year: 2009
Grant Type: Established Career Fellowships
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
, The cell membrane is the ultimate unit of the physiology of life. Its task is to confine ions and molecules on
one side of the membrane and exchange them with others on the opposite side. This delicate task of regulating
the transport of ions across the membrane is carried out by biological nanotubes, known as ion channels. They
play crucial roles in the existence of living organism. In the past five years, we have successfully built exact
virtual models of several different types of ion channels. The physical models of the ion channels we
constructed enable us to trace the motion of ions as they move through the narrow pore, study how a channel
can select only the correct type of ions to traverse it and visualize how the gate of a channel opens and closes.
Also, we are able to make several precise and quantitative predictions about how the function of these channels
will be modified when certain specific changes on their structures are brought about. To study how drugs,
toxins and other small channel blockers interact with ion channels, we devised and extensively tested two novel
computational tools. With these new innovatations and utilizing modern high performance supercomputers, we
are now able to search for compounds that will modulate the activities of one specific voltage-gated channel,
while having no effect on all other channels. Such compounds, once identified and designed, can potentially be
used as pharmaceutical compounds for combating certain types of cardiac disorders and autoimmune diseases.
Expected future outcomes:
The state-of-the-art methodology we devised, combining the two powerful current techniques, will become the
method of choice for studying biomolecules. We can construct accurate structural models, and rapidly screen
potential compounds in modulating channel function. Theses studies will facilitate the development of new and
better agents for combating life-threatening disorders.
Name of contact:
Shin-Ho Chung
Email/Phone no. of contact:
shin-ho.chung@anu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 418017
CIA Name: Dr Shin-Ho Chung
Admin Inst: Australian National University
Main RFCD: Biophysics
Total funding: $517,243
Start Year: 2007
End Year: 2009
Grant Type: NHMRC Project Grants
Title of research award:
Theoretical Investigations into Permeation Dynamics in Calcium- and Potassium-Selective Membrane Ion
ChannelsTheoretical Investigations into Permeation Dynamics in Calcium- and Potassium-Selective Membrane
Ion Channels
Lay Description (from application):
All electrical activities in the brain are regulated by opening and closing of ion channels. Thus, understanding
their mechanisms at a molecular level is a fundamental problem in biology. There are many different types of
ion channels, each type fulfilling a different role. We now know the exact atomic structures of several types of
the proteins forming ion channels. Using this newly unveiled information, we propose to build exact physical
models of two important classes of ion channels, namely, the calcium channels and potassium channels, using
the technique known as 'homology' modelling. Then, making use of powerful supercomputers and the special
computer programs we have devised, we propose to follow the motion of ions as they move through the
channel and study how some chemical compounds or drugs interfere with the normal functioning of the
channel. Specifically, we will attempt to understand how verapamil, which is used to treat irregular heart beats
and high blood pressure, interact with the calcium channel. Once we fully understand how these channels
work, we will be able to understand the causes of, and possibly find the cures for, many neurological and
muscular disorders, such as cardiac arhythmia and hypertension.
Research achievements (from final report):
Ionic channels of excitable membranes play a crucial role in the existence of all living organisms. All electrical
activities in the nervous system, including communication btween cells and the influence of drugs on cell
function, are regulated by opening and closing of membrane ion channels. Understanding how these channels
work will ultimately help us find the causes of, and possibly cures for, several neurological, muscular and
cardiac disorders. In the past few years, we have successfully built exact virtual models of several different
types of ion channels. The physical models of the ion channels we constructed enable us to trace the motion of
ions as they move through the narrow pore, study how a channel can select only the correct type of ions to
traverse it and visualize how the gate of a channel opens and closes. Also, we are able to make several precise
and quantitative predictions about how the function of these channels will be modified when certain specific
changes on their structures are brought about. To study how drugs, toxins and other small channel blockers
interact with ion channels, we devised and extensively tested two novel computational tools. With these new
innovatations and utilizing modern high performance supercomputers, we are now able to search for
compounds that will modulate the activities of one specific voltage-gated channel, while having no effect on all
other channels. Such compounds, once identified and designed, can potentially be used as pharmaceutical
compounds for combating certain types of cardiac disorders and autoimmune diseases.
Expected future outcomes:
The state-of-the-art methodology we devised, combining the two powerful current techniques, will become the
method of choice for studying biomolecules. We can construct accurate structural models, and rapidly screen
potential compounds in modulating channel function. Theses studies will facilitate the development of new and
better agents for combating life-threatening disorders.
Name of contact:
Shin-Ho Chung
Email/Phone no. of contact:
shin-ho.chung@anu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 418026
Start Year: 2007
CIA Name: Dr Yi Zhang
End Year: 2009
Admin Inst: Australian National University
Grant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $341,210
Title of research award:
Nitroso-redox imbalance in glucocorticoid-induced hypertensionNitroso-redox imbalance in glucocorticoidinduced hypertension
Lay Description (from application):
High blood pressure (hypertension) affects 20-30 % of Australian adults and in about 90-95 % of these
individuals the hypertension is considered essential (cause unknown). Globally, it is the number 1 risk factor
for death, and number 3 for disability (World Health Report 2002). The major consequences of hypertension
are heart attack and stroke. Glucocorticoid (adrenal steroid hormone) induced hypertension and consequent
cardiovascular morbidity/mortality is an important clinical problem. Although naturally occurring
glucocorticoid (GC) hypertension (Cushing's syndrome) is relatively rare, synthetic GC are widely used in
clinical practice (in numerous inflammatory and autoimmune diseases and transplantation) and produce
substantial cardiovascular morbidity and mortality. Further, abnormal GC breakdown (metabolism) and
sensitivity to GC have been reported in around a third of essential hypertensive patients.
We therefore need
to understand how GC raise blood pressure and whether we can prevent and/or reverse these blood pressure
raising effects. In the proposed studies, we will explore the role of relative deficiency of blood vessel dilating
nitric oxide and nitric oxide inhibition by excess superoxide (nitroso-redox imbalance) in the genesis of GC
hypertension. Further, we will identify agents known to be suitable for clinical use which are effective in
preventing/reversing GC hypertension in the rat and are thus appropriate for clinical trials to prevent/reverse
GC hypertension in humans. These studies will help answer the question of how GC raises blood pressure so
that safer steroids can be designed, as well as identify agents that can potentially prevent or treat GC
hypertension in humans.
Research achievements (from final report):
We completed all experiments listed in the grant application except the rotenone study (as its effects on
mitochondrial superoxide production are now unclear) and the experiments using gp91phox KO mice (mice not
available), and damonstrated glucocorticoid-induced hypertension is associated with nitric oxide deficiency and
oxidative stress. , Neither chronic glucocorticoid treatment altered mitochondrial superoxide production, alphalipoic acid prevents but did not reverse both adrenocorticotrophic hormone (ACTH)- and dexamethasoneinduced hypertension. Alpha-lipoic acid decreased plasma F2-isoprostane concentrations but had no effect on
mitochondrial superoxide production. Propranolol did not affect ACTH or dexamethasone-induced
hypertension, although it decreased heart rate. We have exclued xanthine oxidase as a major souce of in
dexamethasone-induced superoxide overproduction. Arginase inhibition by alpha-difluoromenthylornithine
prevented ACTH- and dexamethasone-induced hypertension and reversed dexamethasone-induced
hypertension indicating that arginase may play a role in glucocorticoid-hypertension associated L-arginine
deficiency. , In genetically modified mice with functional changes in nitroso-redox imbalance, basal BP was
higher in eNOS KO mice and lower in eNOS Tg mice compared with WT (C57BL6J) mice. Dexamathasone
up to dose of 4 mg/kg/day s.c. had no effect on BP in WT, eNOS KO or eNOS Tg mice. High dose ACTH (2
mg/kg/day s.c.) tended to increase BP in eNOS Tg mice. Both ACTH and dexamethasone failed to raise blood
pressure in eNOS KO mice. High dose ACTH also increased BP in P47phox KO mice. , The antioxidant Nacetylcysteine prevented but did not reverse dexamethasone induced hypertension. Losartan prevented and
reversed while ramipril prevented but did not reverse ACTH- and dexamethasone-induced hypertension. These
drugs can be use for human studies. Fenofibrate worsened ACTH- but not dexamethasone-induced
hypertension.
Expected future outcomes:
Complete the following manuscripts:, The role of angiotensin II in glucocorticoid-induced hypertension,
Effects of arginase inhibitors on glucocorticoid-induced hypertension, Mitochondrial superoxide production in
NHMRC Research Achievements - SUMMARY
glucocorticoid-hypertensive rats. , Effects of Fenofibrate on glucocorticoid-induced hypertension. , Effects of
glucocorticoid in blood pressure of p47phox KO, eNOS KO and eNOs Tg mice.
Name of contact:
Yi Zhang
Email/Phone no. of contact:
yi.zhang@act.gov.au
NHMRC Research Achievements - SUMMARY
Grant ID: 466009
Start Year: 2007
CIA Name: Dr Rebecca Haddock
End Year: 2013
Admin Inst: Australian National University
Grant Type: Early Career Fellowships (Australia)
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $394,886
Title of research award:
Obesity and diabetes: Understanding cardiovascular risk factors and identification of novel targets for
treatmentObesity and diabetes: Understanding cardiovascular risk factors and identification of novel targets for
treatment
Lay Description (from application):
Media Summary not available
Research achievements (from final report):
Blood vessels consist of an inner layer of endothelial cells and an outer layer of smooth muscle cells which are
surrounded by nerves. These cells all release substances that cause the vessel diameter to increase (relax) or
decrease (contract). Blood pressure is regulated by the balance of the smooth muscle cell relaxation and
contraction and cardiovascular disease and hypertension occurs when this balance is upset, such as in people
who are obese. By correlating anatomical and functional observations, the studies conducted during the tenure
of my Doherty Fellowship focussed on determining the effect of obesity on the mechanisms that underlie blood
pressure control; specifically that which related to the effect of obesity on endothelium derived
hyperpolarisation (relaxation) and sympathetic nerve-mediated vasoconstriction (contraction). These studies
showed that obesity alters the mechanism by which endothelium derived relaxation occurs - causing vessels to
become more contracted. They also showed that obesity increases the amplitude of sympathetic nerve-mediated
contractions as a consequence of increased growth of the sympathetic nerves over the surface of blood vessels.
Excitingly, we also showed that growth of the sympathetic nerves was caused by abnormal interactions
between the sympathetic nervous system and cells of the immune system. By identifying new therapeutic
targets, these discoveries will lead to improved therapeutic management of hypertension in obese patients and
reduce the need for invasive surgical intervention.
Expected future outcomes:
Future studies will examine the effect of obesity on the interaction between the immune and sympathetic
nervous systems. The results will translate into clinically improved therapeutic treatments aimed at reducing
hypertension in the obese.
Name of contact:
Rebeccca Haddock
Email/Phone no. of contact:
rebecca.haddock@anu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 471400
Start Year: 2008
CIA Name: Dr Nicole Beard
End Year: 2010
Admin Inst: Australian National University
Grant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $265,987
Title of research award:
Identification of cardiac sarcoplasmic reticulum targets for cardiotoxic drugsIdentification of cardiac
sarcoplasmic reticulum targets for cardiotoxic drugs
Lay Description (from application):
Anthracyclines are drugs which are used successfully in chemotherapy. Unfortunately, these drugs can lead to
serious heart problems which sometimes result in death, and the mechanisms behind this remain elusive.
Finding the specific targets of these drugs and how these drugs affect heart contraction may lead to designing
drug cocktails which protect the heart from side effects.
Research achievements (from final report):
, My objective was to examine the interaction between chemotherapeutic agents (anthracyclines) and protein
targets in muscle, to determine how anthracycline treatment affects cardiac contraction/heartbeat.
Anthracyclines are powerful anti-cancer drugs, but can cause cardiac damage and death. Calcium ions released
from intracellular stores through the ryanodine receptor (RyR) are central to cardiac contraction. The efficacy
of calcium release depends on the capacity of the intracellular calcium stores, the ability of calcium release
channels to release calcium during contraction, and restitution of the intracellular calcium store load during
relaxation. Disturbing these pathways has dire consequences, including arrhythmia and dilated
cardiomyopathy., , We found anthracyclines bind to proteins essential for controlling cardiac calcium release .
Anthracyclines cause a long-term inhibition of the intracellular calcium release channel (RyR). Such inhibition
may induce arrhythmia. The more toxic anthracycline metabolites (which build up in the heart), induce a more
rapid inhibition of calcium release through the RyR, which would cause greater dysfunction in the heart than
the parent compounds. The calcium binding protein CSQ was shown to be an anthracycline target and we
found that CSQs capacity for storing calcium was impaired by anthracyclines. This is likely to impair the
intracellular store load which would severely disrupt cardiac contraction. We identified a new anthracycline
target -triadin- which may be important for maintaining cardiac store load and contraction/heartbeat. This work
has uncovered protein targets and mechanisms which lead to cardiac damage induced by anthracycline
treatment and may contribute to the future design of chemotherapeutics with less toxic side effects.
Expected future outcomes:
Expected future outcomes include a further definition of the basic mechanisms leading to cardiac contraction
and heart beat. This work has lead to a new grant proposal to examine pathways linking anthracycline
treatment to the induction of the currently untreatable fraction cardiomyopathy, experienced by a significant
number of patients.
Name of contact:
Nicole Beard
Email/Phone no. of contact:
nicole.beard@anu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 471420
CIA Name: Prof Caryl Hill
Admin Inst: Australian National University
Main RFCD: Basic Pharmacology
Total funding: $597,682
Start Year: 2008
End Year: 2011
Grant Type: NHMRC Project Grants
Title of research award:
Voltage dependent calcium channels and vascular function: do microdomains determine function?Voltage
dependent calcium channels and vascular function: do microdomains determine function?
Lay Description (from application):
Blood flow depends on arterial diameter which can change with contraction of muscle in the vessel wall.
Calcium influx through one type of channel in the muscle cells has been considered critical, but drugs targeting
these channels have not succeeded in treating the arterial spasm which occurs after stroke and head injury. Our
study will investigate the existence and role of other calcium channels in brain arteries. Knowledge gained will
likely lead to development of new drug targets for stroke.
Research achievements (from final report):
Blood flow and blood pressure are regulated by the capacity of the smooth muscle cells of arteries and
arterioles to contract and relax in response to neural, humoral and physical stimuli. Vasoconstriction depends
on a rise in calcium inside the muscle cells and the most important mechanism for this increase occurs through
voltage dependent calcium channels, in response to a change in transmembrane voltage. One subtype of these
channels, the L-type channels, are an established clinical drug target for the treatment of hypertension and
angina, however, blockade of these channels has consistently failed to alleviate cerebral ischaemia following
subarachnoid haemorrhage., In this project we investigated whether a different member of the voltage
dependent calcium channel family, the T-type channels, are expressed in cerebral arteries and whether these
channels could contribute to cerebrovascular function., We have found that T-type channels are expressed in
cerebral vessels and that they occupy a location in the cell membrane of the smooth muscle cells, which is
separate from that of the normal L-type channels. We have also discovered that these channels contribute to
vasoconstriction of small, but not large, cerebral arteries, suggesting that they could contribute to the control of
blood flow to organs. Importantly, we have found that arteries express a modified form of these channels
compared to that expressed in nerve cells and that this helps to explain their involvement in vascular function. ,
These data demonstrate a potential new target for the treatment of cerebral vasospasm.
Expected future outcomes:
This project has provided new data showing that T-type channels are upregulated under pathophysiological
conditions associated with cardiovascular disease. This result paves the way for additional experimentation to
test whether the involvement of these novel channels in vasoconstriction could explain why 30% of
hypertensive patients are resistant to current drug therapies.
Name of contact:
Professor Caryl Hill
Email/Phone no. of contact:
caryl.hill@anu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 471421
CIA Name: Prof Caryl Hill
Admin Inst: Australian National University
Main RFCD: Basic Pharmacology
Total funding: $583,767
Start Year: 2008
End Year: 2011
Grant Type: NHMRC Project Grants
Title of research award:
The role of connexins in blood pressure regulation: Use of a conditional gene expression systemThe role of
connexins in blood pressure regulation: Use of a conditional gene expression system
Lay Description (from application):
Cell coupling through gap junctions is said to play an important role in regulating blood flow and blood
pressure. However data obtained from mice, in which specific gap junctions are deleted, may be compromised
by compensatory changes in other junctions. We have validated a new method for rapidly and reversibly
altering gap junctions in adult mice with oral sugar. This technique will enable us to directly determine whether
interference with cell coupling affects blood flow and blood pressure.
Research achievements (from final report):
Cell coupling through gap junctions and their component connexins is a prominent feature of the
cardiovascular system. In the heart, cell coupling is essential for the generation and rhythm of the heart beat,
however, the role of cell coupling in the vasculature in the control of blood flow and blood pressure is less
clear. A role for connexin40 in blood pressure regulation has been suggested by hypertension experienced by
mice in which Cx40 has been deleted. However, Cx40 is prominently expressed in the heart, kidneys and
vascular endothelium and so the location of the effect on blood pressure is unknown., In this project we have
developed and validated a new expression system in which specific genes can be controlled in a temporal and
tissue specific manner. We developed mice in which Cx40 expression in the vascular endothelium is either
reduced or increased, without affecting expression in the heart and kidneys. We have shown that we can
control these changes in expression in time by simple oral administration of a non toxic sugar analogue.,
Importantly, we have found that we can increase vascular contractility and blood pressure by decreasing Cx40
expression in the endothelium, and we can decrease these parameters by increasing Cx40 expression. We also
show that these effects result from changes in the vasodilatory factors normally released by the endothelium to
homeostatically control excessive vasoconstriction., These data demonstrate directly that cell coupling in the
vascular endothelium plays an important part in the regulation of vascular tone and blood pressure.
Expected future outcomes:
, This project has provided three unique animal models to enable further detailed investigation of the role of
endothelial cell coupling in the control of vascular tone and regulation of blood pressure.
Name of contact:
Professor Caryl Hill
Email/Phone no. of contact:
caryl.hill@anu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 471462
Start Year: 2008
CIA Name: Prof Philip Board
End Year: 2011
Admin Inst: Australian National University
Grant Type: NHMRC Project Grants
Main RFCD: Pharmacology not elsewhere classified
Total funding: $418,517
Title of research award:
Glutathione transferase-derived compounds as therapeutic agentsGlutathione transferase-derived compounds as
therapeutic agents
Lay Description (from application):
Inhibition of cardiac calcium ion channels may be an effective new way of improving heart performance in
patients with heart failure. This project will investigate how a glutathione transferase enzyme inhibits calcium
ion channels in the heart and if small fragments of a muscle specific glutathione transferase can be used to
specifically modify cardiac ryanodine receptor function. These fragments will provide the basis for the
development of a new therapeutic approach.
Research achievements (from final report):
The regulated release of calcium through ryanodine receptors from intracellular calcium stores in the the
sarcoplasmic reticulum is required for normal muscle function and is therefore essential for life. We have made
the remarkable discovery that a muscle specific enzyme termed glutathione transferase M2 (GSTM2) is a
potent inhibitor of ryanodine receptors in the heart (RyR2). Since specific inhibitors of the heart ryanodine
receptors could be used to treat heart failure we have investigated the nature of the interaction between GSTM2
and RyR2. We discovered that the inhibitory activity of GSTM2 was confered by a small region containing
helix 6. Mutation of several structurally important aminoacids in helix 6 reduced the inhibitory activity of
GSTM2 and confirmed the functional importance of this region. , We then used the yeast two hybrid system to
identify regions of RyR2 that bind to GSTM2-2. These experiments indicated that GSTM2 binds specifically to
divergent region 3 (D3) of RyR2 and not to the D3 region of skeletal muscle ryanodine receptors (RyR1). This
is an exciting observation because it is entirely consistent with the specific action of GSTM2 on the cardiac
RyR. Our results indicate that the D3 region of the cardiac ryanodine receptor is a novel drug target and that
fragments of GSTM2 that contain helix 6 may provide the basis for RyR2-specific compounds for
experimental and therapeutic use in heart failure
Expected future outcomes:
Compounds that specifically inhibit the cardiac ryanodine receptor are potentially useful in the treatment of
heart failure. Future studies arising from the results obtained in this project will develop peptides or small
molecules that can bind to the D3 region of cardiac the ryanodine receptor and regulate its function.
Name of contact:
Philip Board
Email/Phone no. of contact:
Philip.Board@anu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 471512
Start Year: 2008
CIA Name: Dr Ross Stephens
End Year: 2009
Admin Inst: Australian National University
Grant Type: NHMRC Development Grants
Main RFCD: Radiotherapy and Nuclear Medicine
Total funding: $170,717
Title of research award:
Novel nanoparticle composites for molecular probes in diagnostic imagingNovel nanoparticle composites for
molecular probes in diagnostic imaging
Lay Description (from application):
Isotope labelled protein probes, eg. antibodies, are a valuable imaging tool in investigating patient disease.
Their biological specificity is their great strength, however, detection sensitivity often limits their use. A novel
nanoparticle developed at ANU can increase this signal by a million-fold in comparison with conventional
methods of labelling. This approach suits a range of probes and will accommodate many of the isotopes already
used in patient diagnostics and therapy.
Research achievements (from final report):
The grant from NHMRC has enabled initial development studies of our novel radiolabelled nanoparticle
technology for applications in nuclear medicine. The principal outcomes sought were discovery and testing of
reliable new methods for attaching macromolecules and especially biological substances to the outside surface
of graphitic nanoparticles that have radioactive cores, such that the biological coatings do not detach from the
radiolabelled nanoparticles under conditions experienced inside the body. We have been successful in
achieving this outcome for proteins, notably antibody coatings, and also in developing methods for attaching
the protein coated nanoparticles to synthetic polymers, such as those used in oncology as devices for
administering internal radiation therapy. The development studies have employed a clinical gamma camera to
image the biodistribution of radiolabelled nanoparticle composites in animal models, and their accumulation at
different organ sites., , The positive outcomes obtained in this study have strengthened our collaboration with a
commercial partner active in the medical oncology field, so that it is planned that the technology will be further
developed and tested for its potential application in the assessment of cancer patients prior to their cancer
treatment.
Expected future outcomes:
The future outcomes from this project may include novel nanoparticle composites enabling better imaging of
tumours that will improve assessment of staging and treatment efficacy for cancer patients. Further
development of the nanoparticle technology may also lead to better targeted therapy.
Name of contact:
Dr Ross Stephens
Email/Phone no. of contact:
ross.stephens@anu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 585453
Start Year: 2010
CIA Name: Prof Shin-Ho Chung
End Year: 2013
Admin Inst: Australian National University
Grant Type: NHMRC Project Grants
Main RFCD: Neurosciences not elsewhere classified
Total funding: $427,797
Title of research award:
Theoretical and Computational Studies on Voltage-Gated Potassium (Kv) ChannelsTheoretical and
Computational Studies on Voltage-Gated Potassium (Kv) Channels
Lay Description (from application):
The primary aim of the proposed projects is to understand how biological ion channels work. All electrical
activities in the nervous system, including communication between cells and influences of hormones and drugs
on cell function, are regulated by the opening and closing of ion channels. We will study, applying rigorous
physical principles and engineering methods and using powerful supercomputers, a class of biological ion
channels, known as the voltage-activated potassium channels.
Research achievements (from final report):
We have successfully elucidated the precise mechanisms by which many toxins isolated from venomous
animals interfere with the conduction properties of different subfamilies of potassium ion channels, which are
highly relevant to human health. Some among the subfamilies of ion channels we studies have been important
targets for the treatment of autoimmune diseases, cardiac arrhythmia, chronic pain, and sickle cell diseases.
Making use of the state-of-the-art computational tools and the fast supercomputers, we have elucidated the
precise mechanisms by which the polypeptide toxins we studied inhibit the flow of currents across various ion
channels, and identified the key pairs of interacting toxin-channel amino acid residues. Also, we have been able
to predict the binding affinity between each toxin and a specific subfamily of ion channels we studied. The
predictions of binding affinities we made from molecular dynamics simulations closely mirrored those
determined experimentally. We have also studied how small drug molecules, such as lidocaine and its
analogues, which are used as local anesthetics. We showed that they inhibit a voltage-gated sodium channel,
known as Kv1.7, by binding to a small cavity just below the selectivity filter, thus making it hard to sodium
ions to move across the channel. Using the knowledge we gained from our computational studies, we have
been able to design a new class of ion channel blockers, known as dendrimers, mimicking the action of toxins
from venomous animals, and several small molecules which are more potent and longer-lasting than the local
anesthetics currently being used.
Expected future outcomes:
Using the knowledge we gained from computational studies, we will construct and test a new class of potent
blockers of voltage-gated ion channel which mimic the action of toxins from venomous animals. Also, we will
synthesize new compounds which will be more potent than the local anesthetics currently being used.
Name of contact:
Shin-Ho Chung
Email/Phone no. of contact:
shin-ho.chung@anu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 585474
Start Year: 2010
CIA Name: Prof Angela Dulhunty
End Year: 2013
Admin Inst: Australian National University
Grant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $421,161
Title of research award:
Unique isoform-specific regulation of cardiac ryanodine receptors by calcium store proteinsUnique isoformspecific regulation of cardiac ryanodine receptors by calcium store proteins
Lay Description (from application):
The importance of proteins that regulate calcium stores of heart muscle is graphically illustrated by massive
changes in cell structure and function, which lead to ventricular fibrillation and fatality when the proteins are
disrupted. We recently made the remarkable discovery that the proteins have a unique action in the heart which
enhances cardiac contraction. We will discover the interaction sites between the proteins and will define novel
therapeutic targets for heart failure.
Research achievements (from final report):
Four manuscripts have been published including reviews which are based on results obtained during this grant.
Two major manuscripts containing the bulk of the experimental results are in final preparation for publication.
This work has been presented at major national and international meetings and it was selected for an invited
platform presentation at the most recent Gordon Conference of excitation-contraction coupling. The results
have defined the very complex way in which junctin allows the calcium binding protein calsequestrin to
regulate the cardiac ryanodine receptor calcium release channel in response to changes in luminal calcium
concentration that occur during diastole in the heart. Small changes in this regulation by luminal calcium can
lead to a "leaky" ryanodine receptor phenotype in which cytoplasmic calcium increases and causes
depolarization and unregulated electrical activity, known delayed after depolarizations, which trigger
arrhythmia and sudden cardiac death. We have come a long way towards defining the residues in the ryanodine
receptor and in junctin that allow calsequestrin to determine the ryanodine receptors response to luminal
calcium. Understanding the molecular mechanisms involved in arrhythmia generation that we have discovered
will allow the design of drugs that are specifically targeted to sites in the myocyte that are disrupted by this
aberrant calcium signaling. There is a present lack of specific drugs for treating this form of arrhythmia.
Expected future outcomes:
In the long term, the results of this proposal and future research will provide a molecular basis for the design of
therapies to target calcium release mediated arrhythmias. In the shorter term, the results provide a firm
background for understanding ryanodine receptor dysregulation can cause sudden cardiac death.
Name of contact:
Angela Dulhunty
Email/Phone no. of contact:
angela.dulhunty@anu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 182810
Start Year: 2002
CIA Name: Prof Murray Esler
End Year: 2004
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Research Fellowships
Main RFCD: Autonomic Nervous System
Total funding: $404,250
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
Media Summary not available
Research achievements (from final report):
Achievements were made in several areas relevant to health:1. The way in which blood pressure is elevated in
overweight people has been worked out. A stimulant division of the automatic section of the nervous system,
the sympathetic nervous system, is activated in obesity, particularly involving the nerves passing to the
kidneys. Through changing the kidney's control of how much salt is in the body, this raises blood pressure. The
research illustrates the potential value of two non-drug hypertension treatments in obesity, exerise training and
dietery calorie restriction, both of which inhibit the excessive activity of the nerves to the kidney such as to
lower blood pressure. Further, the research suggests that a new class of blood pressure lowering drug, the
"Imidazoline-binding agents", which inhibit the sympathetic nervous system, are ideally suited for use in
overweight people with high blood pressure. At present the entry of this class of antihypertensive drug into use
in Australia is inexplicably being prevented by the Government.2. The importance of mental stress and
psychiatric illness of several types (including depressive illness) as a cause of heart attack was proven.
Depressive illness is now regarded as an important heart "risk factor", right up there with high blood
cholesterol, diabetes , smoking and high blood pressure in its importance. Treating depression well has become
part of heart attack prevention clinical care.
Expected future outcomes:
1. Knowledge of the body stress processes conveying heart risk in patients with panic disorder should lead to
better preventive care of panic sufferers, by allowing specific drug targeting of these abnomal nervous system
mechanisms which damage the heart.2. The new class of blood pressure-lowering drugs, Imidazilone binding
agents, will specifially target obesity-related hypertension.
Name of contact:
Professor Murray Esler
Email/Phone no. of contact:
murray.esler@baker.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 182813
Start Year: 2002
CIA Name: Prof Tony Dart
End Year: 2004
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: Established Career Fellowships
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $419,250
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
At the time of my initial involvement there was very limited activity world-wide in large artery function which
is now the subject of numerous articles and of dedicated research meetings. I believe the important new
findings from our group (particularly in relation to coronary disease and the introduction of novel
methodologies) have played a significant role in promoting this interest.
Expected future outcomes:
N/A
Name of contact:
Professor Anthony Dart
Email/Phone no. of contact:
a.dart@alfred.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 182815
Start Year: 2002
CIA Name: A/Pr Elizabeth Woodcock
End Year: 2004
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: Established Career Fellowships
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $357,500
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
We have identified a novel mechanism of arrhythmogenesis associated with rapidly elevated
inositol(1,4,5)trisphosphate (Ins(1,4,5)P3) in heart tissue. Our studies have been instrumental in initiating
further work on the electrophysiological consequences of heightened Ins(1,4,5)P3 and how this may cause
arrhythmias, especially atrial fibrillation. In addition, we have begun studies on signalling pathways in
cardiomyocyte protection and have identified the members of the FOXO family of transcription factors as
being involved in myocardial apoptosis following ischaemic injury. We have developed novel adenoviral
vectors that allow efficient delivery of short hair-pin cDNA in cardiomyocytes and provide a GFP marker of
transfection efficiency.
Expected future outcomes:
We plan to identify the subtype and splice variant of phospholipase C responsible for generation of
Ins(1,4,5)P3 under pathological circumstances. We plan to establish a role for Ins(1,4,5)P3 in arryhtmias in
heart failure.
Name of contact:
Elizabeth A. Woodcock
Email/Phone no. of contact:
liz.woodcock@baker.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 182816
Start Year: 2002
CIA Name: Prof Geoffrey Head
End Year: 2005
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: Established Career Fellowships
Main RFCD: Pharmacology not elsewhere classified
Total funding: $482,750
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
We now have greater understanding of how brainstem pathways influence sympathetic neural patterns and how
angiotensin and nitric oxide in the hypothalamus and brainstem mediate sympathetic responses to stress and
baroreflexes.
Studies of sympathetic recordings in
renal hypertensive rabbits have resulted in a new concept in the understanding of how the sympathetic nervous
system influences blood pressure in the long term.
In our work on centrally-acting
antihypertensive agents, we have characterised the link between imidazoline and alpha2 receptors which
involves a 42kDa imidazoline binding protein located on brain noradrenergic terminals.
We have also
patented a new analysis for human ambulatory 24-hour blood pressure recordings and found that there is a
greater rate of "arousing" increase in blood pressure in hypertensive patients, an important potential risk factor.
We patented and are commercializing novel peptides for treatment of heart failure through the first Baker spinout company Elacor PtyLtd for which I am the sole Baker Institute investigator/inventor. The outcomes will
provide detailed information on the CNS systems contributing to sympathetic overactivity in hypertension, an
understanding of the role of the sympathetic nervous system in patients at risk from a morning surge in blood
pressure and a new orally active peptide for heart failure patients.
Expected future outcomes:
N/A
Name of contact:
Geoffrey Head
Email/Phone no. of contact:
geoff.head@baker.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 182817
Start Year: 2002
CIA Name: Dr Jaye Chin-Dusting
End Year: 2005
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: Established Career Fellowships
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $399,000
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
N/A
Expected future outcomes:
N/A
Name of contact:
Dr Jaye Chin Dusting
Email/Phone no. of contact:
jaye.chin-dusting@baker.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 182818
Start Year: 2002
CIA Name: Prof Bronwyn Kingwell
End Year: 2005
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: Established Career Fellowships
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $420,750
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
A/Prof Kingwell's skill base as a clinical physiologist has facilitated translation of experimental research to
clinical practise. Over the past 5 years she has had a lead role in 60 publications including 37 original
publication involving patients. She has made key contributions to knowledge which have or are in the process
of being translated to clinical applications. Examples over the past 5 years include:, - Discovery of key
mechansisms mediating the benefits of exercise in diabetes and cardiovascular disease which have identified
potential new therapeutic targets., - Identification of a novel mechanism for stimulation of glucose and fat
metabolism, with potential therapeutic application in type 2 diabetes, - Ramipril, a drug commonly used to treat
high blood pressure, markedly improves walking ability in patients with peripheral arterial disease, - Chief
invesigator on numerous clinical trials examining the utility of arterial stiffness as a risk marker for
cardiovascular disease including the Australian National Blood Pressure trial (ANBP2), - Chief investigatior on
numerous trials identifying therapeutic intervention (pharmacological and lifestyle) which improve large artery
stiffness and cardiovascular risk
Expected future outcomes:
- Identification of new therapeutic targets and therapies for atherosclerosis and for prevention of its major
complications, - Improved prediction, using blood borne markers and imaging, of 'coronary prone' individuals
allowing a shift from treatment to prevention, - Development and clinical evaluation of promising new
therapeutic modalities including pharmacotherapy for peripheral arterial disease
Name of contact:
Bronwyn Kingwell
Email/Phone no. of contact:
bronwyn.kingwell@baker.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 182819
Start Year: 2002
CIA Name: A/Pr Dmitri Sviridov
End Year: 2004
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: Established Career Fellowships
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $326,750
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
Heart diseases are the biggest single cause of preventable death in the developed countries. Burden of heart
diseases is the major challenge for the health systems of these countries. And yet recent advances in medical
science demonstrated that heart diseases are by large preventable. About half of the heart diseases are caused
by atherosclerosis. Atherosclerosis is a formation of plaques inside the arteries. These plaques narrowing the
vessels and limit blood flow to the target organ, most often heart or brain, causing hypoxia and dystrophy of
these organs. Moreover, the surface of these plaques is prone to cause a formation of thrombi, which can
subsequently detach and block a smaller vessel downstream, causing an infarction or a stroke. The key element
in the development of atherosclerotic plaque is accumulation of cholesterol in the cells of vessel wall, most
importantly macrophages. By definition an accumulation is a misbalance between delivery of cholesterol to
cells and its removal from cells. Hence, to reduce accumulation of cholesterol either delivery of cholesterol to
cells should be reduced or its removal enhanced. Reduction of cholesterol delivery to cells was explored for the
last 20 years and brought a tremendous result. It translated into 30% fall in cardiovascular diseases and increase
of longevity by about 5 years. Further reduction of cardiovascular diseases is however possible. One of the new
strategies is to target removal of cholesterol from cells. The rationale is that combining decreased delivery with
enhanced removal will further reduce accumulation of cholesterol and prevent or even reverse the development
of atherososis. We developing stratagies to ehnahce eviction of excessive cholesterol from cells thus preventing
and possibly even reversing development of atherosclerosis.
Expected future outcomes:
The major outcome would be developing treatments able to enhance egress of cholesterol from vessels and
slow down, halt or reverse development of atherosclerosis
Name of contact:
Dmitri Sviridov
Email/Phone no. of contact:
Dmitri.Sviridov@Baker.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 182820
Start Year: 2002
CIA Name: Prof Walter Thomas
End Year: 2004
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: Established Career Fellowships
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $295,500
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
Our bodies generate a hormone called angiotensin II in response to a decrease in blood pressure (or salt in our
bloodstream). This hormone increases blood pressure by causing blood vessels to constrict, by making us
thirsty, and by inducing salt and fluid retention via an effect on the kidneys. In some cardiovascular diseases,
the generation of angiotensin II or our sensitivity to this hormone is elevated. It is therefore crucial that we
understand how angiotensin II works and how its actions in the body are mediated. For angiotensin II to act it
must first bind to a receptor. Receptors are proteins and behave like locks that are "opened" by the hormone
"keys". Thus, cellular receptors for angiotensin II are engaged and activated by increases in angiotensin II in
our blood. These receptors then produce "signals" which initiate a response (e.g. constriction of a blood vessel).
Subsequently, the receptors are "switched-off" to prevent over-stimulation., The experiments in our laboratory
investigate how angiotensin II receptors are regulated or "switched-on and -off". A major way for receptors to
be turned off is for them to be ear-marked by a modification known as phosphorylation. These modified
receptors are then bound by proteins termed arrestins, which as indicated by their name play a role in
preventing further receptor signalling. These arrestins also help remove activated receptors from the cell
surface to the inside of the cell. How arrestins interact with receptors and regulate their function is poorly
understood and is the focus of our experiments. We also study how angiotensin receptors activate other
receptors to cause inappropriate growth of the heart. Results from these studies will further our understanding
of angiotensin II receptors and their role in cardiovascular control.
Expected future outcomes:
Drugs that block receptors are the most common form of therapy and will continue to be pharmaceutical
targets. Understanding how receptors work at the molecular level will provide logical strategies for their
improved development.
Name of contact:
Walter Thomas
Email/Phone no. of contact:
walter.thomas@baker.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 182824
Start Year: 2002
CIA Name: A/Pr Xiao-Jun Du
End Year: 2004
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: Established Career Fellowships
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $295,500
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
The research focus in my laboratory has been to elucidate the mechanisms responsible for the pathogenesis
involving the myocardium and the extracellular matrix ultimately leading to cardiomyopathy and heart failure,
and to test experimentally novel therapies based on these findings. My group has been functioning as a
bridging laboratory by conducting research using experimental disease models and integrated approaches to
investigate clinically fundamental questions. This group is the first within Australia to use, since 1995,
genetically modified mouse models for heart research in vitro and in vivo. With the establishment of a range of
techniques, we now provide a core facility within the Baker Institute to support research that involves
determination of cardiovascular phenotypes in mouse models and animal models of various cardiac diseases.
Expected future outcomes:
N/A
Name of contact:
N/A
Email/Phone no. of contact:
N/A
NHMRC Research Achievements - SUMMARY
Grant ID: 182830
Start Year: 2002
CIA Name: Dr Stephen Duffy
End Year: 2006
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: Career Development Fellowships
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $475,000
Title of research award:
The relationship of iron status to oxidative stress in vivo, nitric oxide bioactivity and coronary artery disease
activiThe relationship of iron status to oxidative stress in vivo, nitric oxide bioactivity and coronary artery
disease activi
Lay Description (from application):
Not Available
Research achievements (from final report):
We have been seeking to determine novel markers of vulnerable plaque in patients with coronary artery
disease. To this end, we have developed a program of comprehensive clinical assessment of patients with stable
and unstable coronary artery disease, along with detailed examination of anatomical aspects of the coronary
plaque using coronary angiography and intracoronary ultrasound (for example, vessel remodelling, plaque
burden and lesion characteristics), and trans-lesional (stenotic) coronary blood sampling. This latter technique
will aid in the identification of novel biomarkers of acute coronary syndromes., I am a foundation member of
the Melbourne Interventional Group, which is a collaboration of like-minded interventional cardiologists who
have established a large registry (already including more than 6,300 patients) of percutaneous coronary
interventions. This is in collaboration with the Department of Epidemiology and Monash University. We are
able to determine long-term outcomes, and this group is fosterering investigator- and sponsor-initiated
randomised clinical trials., Percutaneous treatment of functional mitral regurgitation in patients with heart
failure. I am the principal investigator of the "first-in-human" clinical trial of the permanent device.
Expected future outcomes:
My research experience has evolved from a focus on applied vascular biology to address important questions,
in clinical cardiology. Nevertheless, we are continuing to address fundamental questions within the context, of
clinical research in collaboration with scientific colleagues.
Name of contact:
Dr. Stephen J. Duffy
Email/Phone no. of contact:
s.duffy@alfred.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 183099
Start Year: 2002
CIA Name: Prof Garry Jennings
End Year: 2006
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Block Funding
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $1,001,560
Title of research award:
Infrastructure support for Dr Stephen Duffy and Baker/Alfred Gene BankInfrastructure support for Dr Stephen
Duffy and Baker/Alfred Gene Bank
Lay Description (from application):
Not Available
Research achievements (from final report):
The Alfred & Baker Gene Bank is the most comprehensive collection of samples from patients with
cardiovascular disease in Australia. A key objective is to facilitate research into the genetic basis of heart
disease by developing a repository of well-characterised samples. In addition to contributing to the
understanding of genetic markers of heart disease, studying these samples may also assist in the development
of novel therapies for heart disease. Genetic and biochemical analysis may also provide information on whether
an individual is likely to benefit from a particular treatment. , As envisaged in the original application other
achievements have included the establishement and set ups of several new clinical cardiovascular
investigations in Australia, the development of international links including a laboraory in Singagpore.
Expected future outcomes:
N/A
Name of contact:
Professosr Garry Jennings
Email/Phone no. of contact:
garry.jennings@baker.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 210413
Start Year: 2002
CIA Name: Prof Simon Stewart
End Year: 2006
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: Career Development Fellowships
Main RFCD: Not Allocated
Total funding: $475,000
Title of research award:
Optimising the therapeutic management of individuals with chronic cardiac diseaseOptimising the therapeutic
management of individuals with chronic cardiac disease
Lay Description (from application):
Not Available
Research achievements (from final report):
The successful activities funded via this CDA have focussed on the following:, a) Developing innovative and
cost-effective health care solutions to manage an evolving epidemic of cardiovascular disease in our ageing
Australian population and heart failure programs that are community based and multidisciplinary in nature., b)
Further developing the role of the
specialist chronic heart failure nurse in providing the "gold standard" of care for chronic heart failure., c)
Supporting a new generation of health care researchers from a range of disciplines (including my "home"
discipline of cardiovascular nursing) to undertake pragmatic multidisciplinary research.
Expected future outcomes:
A number of innovative studies examining the burden of cardiovascular disease in Australia (the ARC-funded
CARDIAC-ARIA Study), better ways to manage individuals with heart disease and depression (the NHMRCfunded Take-Heart Study) and optimsing the care of individuals with chronic heart failure (the NHMRCfunded WHICH? Study) will influence health care policy and practice in the next 5 years.
Name of contact:
Simon Stewart
Email/Phone no. of contact:
simon.stewart@baker.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 217023
Start Year: 2002
CIA Name: Dr Rebecca Ritchie
End Year: 2006
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: Career Development Fellowships
Main RFCD: Not Allocated
Total funding: $425,000
Title of research award:
New Targets for the preventio of Cardiac Hypertrophy and IschaemiaNew Targets for the preventio of Cardiac
Hypertrophy and Ischaemia
Lay Description (from application):
Not Available
Research achievements (from final report):
My core activities focus on prevention and treatment of heart muscle structure and function, both in the
absence and presence of diabetes. I pioneered the discovery that a functional lining of the blood vessels
(endothelium) plays a key role in regulation of myocardial growth. I have shown that the endogenous
bradykinin/nitric oxide/cGMP hormone system is a powerful mechanism for limiting abnormal heart muscle
growth, and that part of this protection is via suppression of enzymes that generate free radicals in the heart.
This has implications for the diabetic heart, in which this hormone system is ineffective, and as a result, some
of the actions of ACE inhibitors (current treatment for diabetic heart disease) are lost. I have also fully
characterised diabetic heart disease, demonstrated the role of free radicals in this disorder, and identified
treatment strategies that differentially ameliorate functional versus structural abnormalities in the diabetic
heart. I have also demonstrated that the male sex hormone testosterone induces abnormal heart muscle growth
(but the female sex hormone estrogen does not), explaining at least some of the increased risk of heart failure in
men versus pre-menopausal women. As part of my secondary activities, I have identified endogenous (annexin1, urocortin, nitric oxide) and synthetic (resveratrol) treatments that limit damage t the heart induced by heart
attack. These compounds are particularly effective when administered after the heart attack has commenced, of
significant clinical relevance.
Expected future outcomes:
Heart failure currently affects >300,000 Australians, with many more at risk. I am developing new strategies to
minimise impairment of heart pumping function induced by cardiac hypertrophy (abnormal heart muscle
growth), fibrosis (scarring), diabetes and heart attack. This will ultimately delay progression to heart failure and
death our community.
Name of contact:
Rebecca Ritchie
Email/Phone no. of contact:
rebecca.ritchie@baker.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 219283
Start Year: 2003
CIA Name: Prof Garry Jennings
End Year: 2007
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: Centre of Clinical Excellence
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $2,000,000
Title of research award:
Alfred and Baker Medical Unit Centre for Clinical Cardiovascular ResearchAlfred and Baker Medical Unit
Centre for Clinical Cardiovascular Research
Lay Description (from application):
This Centre has three objectives: to create clinical research platforms; to provide time and training for
advanced cardiology trainees, young clinical academics, research nurses, allied health staff and non-medical
science graduates; and to translate previously established local and international research outcomes into
knowledge, education and health benefits for the wider Australian community.
Research achievements (from final report):
Development of a genebank incorporating linkage with key research and clinical databases provides a valuable
resource to study the genetic causes of diabetes and heart disease. The Alfred and Baker Genebank is the most
comprehensive collection of cardiovascular samples in Australia. Achievements include identification of key
genes involved in stiffening of the large arteries, unstable coronary syndromes and cardiac failure., Other
significant clinical discoveries include:, - the blood pressure lowering drug, ramipril dramatically improves
walking distance and quality of life in patients with peripheral arterial disease. Given that peripheral arterial
disease affects approximately 12% of people over the age of 50, this work is likely to have widespread impact,
- fish oil supplementation is an effective treatment for high blood fat levels in patients with HIV, - raising good
cholesterol may also have beneficial effects on metabolism by lowering blood glucose and via its monocytic
anti-inflammatory effects, - new devices for measurement of blood pressure near the heart offer no advantage
over conventional blood pressure measurements using an arm cuff in elderly individuals, - the milk proteins
caesin A1 and A2 have identical effects on cardiovascular risk factors
Expected future outcomes:
Linkage of the Alfred-Baker genebank with the Baker IDI Heart and Diabetes Institute Risk Profiling Facility
will facilitate identification of new biomarkers for metabolic and cardiovascular disease which will improve
risk assessment and clinical management of these conditions.
Name of contact:
Prof Garry Jennings
Email/Phone no. of contact:
garry.jennings@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 225108
Start Year: 2003
CIA Name: Prof Garry Jennings
End Year: 2007
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: Programs
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $9,061,084
Title of research award:
Heart failure and its Antecedents: Pathophysiology, Prevention and treatmentHeart failure and its Antecedents:
Pathophysiology, Prevention and treatment
Lay Description (from application):
Heart failure is mainly a result of coronary artery disease. It is a major cause of disability and mortality in
Australia and is projected to increase markedly over the next two decades. This program brings together
clinical and basic science expertise to address aspects of the prevention and control of coronary disease and
heart failure. The outcomes that will arise will provide a better understanding of the mechanisms involved in
the progression from stable heart disease to failure.
Research achievements (from final report):
Over 300,000 Australians have heart failure and it is estimated that this number will increase two to three-fold
over the next 10 years. Severe heart failure has a mortality rate of up to 80% by one year. The outcomes of the
program include a better understanding of the mechanisms involved in the progression of heart failure and have
identified new targets for therapy. Major findings include:, , Risk Prediction and Prevention, We have
identified novel cardiovascular disease markers which may help to improve risk prediction. These include
genetic markers which predict the risk of sudden heart attack and markers of mental stress which may have
particular application in individuals with high blood pressure. Importantly, we have also shown that new tools
to estimate blood pressure in the arteries close to the heart offer no advantage in risk prediction over
conventional arm cuff assessment of blood pressure., , Mechanisms, Understanding disease mechanisms
underpins better risk prediction and treatment. This program of research has substantially increased our
knowledge of how HDL or 'good' cholesterol protects from cardiovascular disease through its antiinflammatory actions. An extensive series of projects in mice has elucidated how high pressure causes damage
to the heart and revealed a variety of new treatment strategies for further investigation., , Treatment, A number
of therapies including nutritional supplements (folate) and conventional blood pressure lowering therapies
(ACE inhibitors) were shown to reduce the stiffness of the large arteries. This was associated with a significant
improvement in walking ability in patients with peripheral arterial disease and reduced aortic diameter in
Marfan syndrome. Several complementary studies identified the potential pharmacogenomic value of certain
genetic polymorphisms. An important interaction between genes and heart failure treatment was also identified
with implications for patient management.
Expected future outcomes:
Novel insights gained from this research program characterise mechanims that drive the progression of
cardiovascular disease from initial vascular and cardiac injury through to heart failure. This information now
informs formal studies of new therapeutic strategies for heart failure, heart attack and vascular disease.
Name of contact:
Prof Garry Jennings
Email/Phone no. of contact:
garry.jennings@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 225111
Start Year: 2003
CIA Name: Prof David Kaye
End Year: 2007
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: Established Career Fellowships
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $572,000
Title of research award:
Congestive Heart Failure (CHF)Congestive Heart Failure (CHF)
Lay Description (from application):
Not Available
Research achievements (from final report):
As a clinician-scientist the principle aim of the research supported by my fellowship has been to investigate the
pathophysiologic basis of cardiovascular disease. In particular the development of new strategies for the
treatment and prevention of disease has been a key objective. Work on the lining layer of blood vessels, the
endothelium, has identified several new insights including a genetically determined aleteration in the
endothelial mechanism that may predispose to hypertension. In a similar way we have found that metabolism
of arginine is impaired in the setting of heart attack. Together these findings can be readily translated to the
clinic. As a part of studies on the function of blood vessels I have identified and tested a novel series of
chemicals that boost blood vessel function. These have been patented and may ultimately lead to a new class of
drugs for the treatment of hypertension and heart failure., Together with disorders of the endothelium,
abnormalities of heart muscle function contribute to the pathophysiology of heart failure. Several major
disturbances of gene and cellular function have been idientified. Accordingly, we sought to develop a system
for the delivery of therapeutic genes and cells-thereby solving a key roadblock in the translation of gene and
cell therapy to heart failure. This system has been patented and led to the creation of a spin-off company, with
clinical trials of the system underway.
Expected future outcomes:
N/A
Name of contact:
Ebru Yaman
Email/Phone no. of contact:
ebru.yaman@baker.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 225118
Start Year: 2003
CIA Name: Prof Geoffrey Head
End Year: 2005
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $488,250
Title of research award:
Central regulation of blood pressure : role of angiotensin and nitric oxideCentral regulation of blood pressure :
role of angiotensin and nitric oxide
Lay Description (from application):
High blood pressure is a major public health problem in Western society with approximately 20% of adults
affected. If left untreated serious damage to organs can occur and the risk of sudden cardiac death or stroke is
greatly increased. While many factors contribute to the development of hypertension such as lifestyles, genes,
diet, weight and exercise levels, a common feature in the early stages is an overactive nervous system in the
kidney and in the heart which is most likely due to altered signals from the brain. A major question has been to
understand why this occurs. One possibility is angiotensin (a hormone released from the kidney that is known
to control body fluid) also acts in the brain to increase nerve activity to the kidney and heart and in this way
contribute to high blood pressure. Our research has shown that normally brain angiotensin has relatively little
activity but can be switched on by specific situations such as stress or a high salt. This may be by depleting
anti-oxidants and producing an "oxidative stress" in the brain. With aging, stress, lack of exercise and other
various environmental influences our body is less able to cope with "oxidative stress" which is the result of
the normal cells function. The major thrust of this project is to determine whether the long term contribution of
angiotensin in the brain to high blood pressure is caused by a high level of oxidative stress in the brain. We will
see whether experimental animals still develop high blood pressure if angiotensin is blocked in the brain and
see whether changing the "oxidative stress" levels in the brain affects this role. We will be able to better
understand the interplay between these molecules in the brain which opens the way for the development of new
highly specific drugs that can prevent the high level of nerve activity to the heart and kidney and hence the
development of high blood pressure.
Research achievements (from final report):
N/A
Expected future outcomes:
N/A
Name of contact:
Geoffrey Head
Email/Phone no. of contact:
geoff.head@baker.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 225123
Start Year: 2003
CIA Name: Prof Walter Thomas
End Year: 2007
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $710,625
Title of research award:
EGF receptor transactivation in GPCR-mediated cardiac hypertrophyEGF receptor transactivation in GPCRmediated cardiac hypertrophy
Lay Description (from application):
Soon after birth, the muscle cells of the human heart stop dividing and subsequent growth of the heart occurs
through enlargement of pre-existing muscle cells in a process referred to as hypertrophy. This normal growth
accounts for the difference in size between juvenile and adult human hearts. In certain people, heart cell
growth is accelerated as a consequence of complex genetic, hormonal and environmental factors. In others, it
occurs as an adaptive response to high blood pressure or damage/disease of the heart muscle, such as occurs
following a heart attack. As hearts grow inappropriately, they function less efficiently and eventually fail.
Cardiac hypertrophy is therefore a major risk factor for heart failure and death. Hormones like adrenalin,
angiotensin, and endothelin affect cells of the heart and blood vessels to regulate blood pressure and volume.
In addition, these hormones also act directly on heart cells to cause growth, particularly during the accelerated
phase associated with cardiac hypertrophy. One attribute shared by these hormones is that they act through Gprotein coupled receptors (GPCRs), a superfamily of cell surface proteins. How binding of hormone to its
specific GPCR triggers cell growth has been the focus of extensive research. Based on studies of angiotensin
receptors in cultured muscle cells, we have observed that the growth action of angiotensin receptors requires
them to first "hijack" another receptor - the epidermal growth factor receptor. By commandeering the EGF
receptor, the angiotensin hormone in effect usurps growth-signalling pathways. This application proposes
experiments that will investigate the mechanism and consequence of GPCRs stimulation of EGF receptors in
heart cells and whole animals. By understanding the mechanism by which angiotensin promotes growth, better
therapeutic regimens against abnormal growth of the heart during human cardiovascular disease will evolve.
Research achievements (from final report):
We studied how a hormone in our bodies (angiotensin), that regulates blood pressure and the function of our
heart and blood vessels, is able to cause heart cells to grow. The way angiotensin does this is to hijack another
hormone receptor system usually associated with growth of cancer cells - the so-called epidermal growth factor
receptor system. We studied in detail how angiotensin "talks " to the epidermal growth factor receptor and we
made some interesting observations. 1) We found that the heart contains various types of EGF receptor and that
these are all made in the heart cell (the cardiomyocyte); 2) angiotensin acts to activate the EGF receptor by
shedding an EGF hormone from the cell surface; 3) the main EGF receptor is the so-called type 4 EGF receptor
and hormones that specificially activate this receptor type are very good at causing heart growth; 4) we have
developed new tools to block these receptors using a technique called RNA intereference; 5) we are
incorporating these inhibitors into viruses and hope to deliver them into mice with various heart problems to
see if they alleviate their conditions.
Expected future outcomes:
If we can better understand this system we may be able to develop new strategies and drugs to treat cardic
growth and failure
Name of contact:
Walter Thomas
Email/Phone no. of contact:
w.thomas@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 244622
Start Year: 2003
CIA Name: Dr Karen Andrews
End Year: 2007
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: Early Career Fellowships
(Australia)
Main RFCD: Endocrinology
Total funding: $267,150
Title of research award:
Endothelial control of vascular tone in microvessels of diabetic ratsEndothelial control of vascular tone in
microvessels of diabetic rats
Lay Description (from application):
Not Available
Research achievements (from final report):
Nitric oxide (NO) is an important and potent compound produced by the endothelium. NO acts on the smooth
muscle layer allowing blood vessels to dilate. NO is produced by a catalyst (enzyme) called endothelial nitric
oxide synthase (eNOS) in the endothelial cells from an amino acid, L-arginine. L-arginine is also broken down
by another enzyme called arginase.Where the two enzymes (arginase and eNOS) are found together, arginase
may potentially interfere with the conversion of L-arginine to NO. Several conditions and diseases such as high
cholesterol, high blood pressure, diabetes, stroke and heart failure have reduced NO production. This reduction
in NO contributes to abnormal endothelial (vascular) function. Treatment of alleviating impaired endothelial
function is by administration of a drug called GTN (glyceryl trinitrite). GTN is an organic nitrate, which
increases NO availability in the blood vessel and therefore enhances the relaxation of blood vessels. However,
a limitation with this drug is the development of tolerance (the effects of the drug are diminished) that occurs
after long-term use. We have found that inhibiting arginase II prevents the development of tolerance.
Furthermore we have also investigated another potential drug which we have found does not develop tolerance,
Angeli's salt, which acts by donating nitroxyl (HNO), a compound that differs from NO by only one electron.
Expected future outcomes:
Further investigation into nitric oxide signalling may result in better therapeutic agents for cardiovascular
disease
Name of contact:
Karen Andrews
Email/Phone no. of contact:
karen.andrews@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 268904
Start Year: 2004
CIA Name: A/Pr Terri Allen
End Year: 2007
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: Career Development Fellowships
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $352,000
Title of research award:
The role of the AT2 receptor in diabetes associated atherosclerosis: novel interventions and human studiesThe
role of the AT2 receptor in diabetes associated atherosclerosis: novel interventions and human studies
Lay Description (from application):
Not Available
Research achievements (from final report):
We were able to determine that some of the commonly used drugs for treating high blood pressure may also
give good results for other end organ disease such kidney and large blood vessel disease. I was also able ot
show that a treatmetn fo rcancer ws laso useful in preventing diabetic blood vessel disease. Since getting the
CDA I have now been successful in obtaining a NHMRC Senior research fellowship
Expected future outcomes:
More combinatin therpay may be used for treating patients with cardiovascular disease and diabetes
Name of contact:
Terri Allen
Email/Phone no. of contact:
terri.allen@baker.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 268916
Start Year: 2004
CIA Name: A/Pr Josephine Forbes
End Year: 2006
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Endocrinology
Total funding: $431,700
Title of research award:
Interactions between advanced glycation and oxidative stress in diabetic renal and cardiac
complicationsInteractions between advanced glycation and oxidative stress in diabetic renal and cardiac
complications
Lay Description (from application):
Kidney and heart disease are serious complications of diabetes. These complications are the major cause of
disability and premature death in the western world. Studies from our group and others have shown that
diabetic complications appear to be a consequence of a number of different processes. These pathways include
a sugar dependent pathway of irreversible interactions between proteins such as collagen and sugar known as
advanced glycation. The process of advanced glycation alters the body's ability to renew these protein, hence
causing accelration of the ageing process. In fact, it is estimated that this process occurs almost fifty times
faster in diabetes. These sticky complexes accumulate in tissues causing disruption ot the normal tissue
structure. Our group has a drug which can act as scissors and cut the sticky sugar off the proteins allowing it to
be turned over. Unfortunately this does not fix all of the damage. These AGE molecules are involved in a
number of other harmful processes including the production of toxic oxygen derived molecules which are
harmful byproducts of diabetes. While these oxygen 'radicals' have been implicated in heart attack and stroke
their source has remained a mystery in diabetes. Previously, the only way to remove these molecules was to
mop them up with antioxidants such as Vitamin E. Antioxidants work slowly and so some damage is already
done before they 'detoxify' these oxygen radicals. We propose to use combinations of medicines to see if we
can achieve more effective protection against these processes in experimental diabetes. This may provide new
therapies for threatment of kidney and heart disease in diabetes.
Research achievements (from final report):
More than 1 million Australians have diabetes. Although diabetes per se is an enormous burden on our health
system it is in fact the complications of diabetes which are the most costly to both the patient themselves in
terms of quality of life and to our national health care budgets. In particular kidney disease as a consequence of
diabetes affects up to 40% of persons with diabetes. Diabetic kidney disease eventually leads to a lifetime of
kidney replacement therapy with dialysis (artificial blood filtration/cleaning) or transplants. In addition kidney
disease is the major predictor of heart attacks and strokes which are the prominent causes of death in diabetic
patients. Current first line therapy for patients with diabetic kidney disease is with drugs that bklock the actions
of the hormone angiotensin. Although these drgus have improved kidney outcomes in these patients, their
kidney disease is only slowed down but not cured. Therefore it is clear that other complimentary strategies are
required to combat this epidemic of kidney disease as a consequence of diabetes., Our research has focussed on
medicines which have the capacity to decrease specific abormalities seen in the kidney as the result of high
sugar. These include the formation of toxic oxygen free radicals and "toffee like" additions on proteins called
advanced glycation end products (AGEs). Over the course of this project we discovered a number of
detrimental events which affect kidney cell function caused specifically by AGEs and oxygen free radicals
which are not normalised by the currently used clinical therapy for diabetic kidney disease. In particular these
are abnormalities in the energy producing systems within the cells in "powerstation" compartments known as
mitochondria. We have identified two significant targets for new medicines which will likely lead to a
reduction in diabetic kidney disease.
Expected future outcomes:
We anticipate that follow up studies of these medicines both preclinically and then subsequently in humans will
produce promising new therapies for patients with diabetic kidney disease.
Name of contact:
NHMRC Research Achievements - SUMMARY
Josephine Forbes
Email/Phone no. of contact:
josephine.forbes@baker.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 268918
Start Year: 2004
CIA Name: Prof Mark Cooper
End Year: 2006
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Endocrinology
Total funding: $414,000
Title of research award:
Role of advanced glycated end products in mediating diabetes associated atherosclerosisRole of advanced
glycated end products in mediating diabetes associated atherosclerosis
Lay Description (from application):
Diabetes is on the increase in the Western world and with this increase comes the burden of increased
complications. One of these is atherosclerosis which leads to heart attacks, strokes and gangrene. In this grant
we consider the role of a biochemical reaction where sugar attaches to proteins called advanced glycation and
how it may promote atherosclerosis. We will use novel drugs to block vessel damage in a model of diabetic
mice prone to atherosclerosis. We will also inject these sugar-attached proteins (AGEs) into mice to see how
they directly influence the vessel wall. We will characterise molecular and cellular changes in response to
these AGEs. These studies will ultimately lead to better treatments to prevent, slow down or reverse blood
vessel damage in diabetes.
Research achievements (from final report):
Our studies have provided further evidence that the AGE/RAGE axis plays a pivotal role in diabetes associated
macrovascular disease. We could demonstrate that inhibition of AGE formation with aminoguanidine and the
cross link breaker ALT 711 (alagebrium) were able to significantly reduce plaque area in a model of diabetes
accelerated atherosclerosis, the diabetic apoE knockout mouse. More recntly, we have also shown that AGE
inhibition in established atherosclerosis was able to attenuate progression of preexisting atherosclerosis. The
anti-atherosclerotic effect of AGE inhibitors was associated with attenuation of inflammatory and pro-fibrotic
pathways. Specifically, we were able to demonstrate potential molecular mediators of vascular injury including
CTGF, VCAM-1 and MCP-1 which appeared to be directly regulated via the AGE/RAGE axis.
Expected future outcomes:
These studies have provided further evidence that the AGE receptor RAGE plays a critical role in
macrovascular disease in the presence and absence of diabetes. Therefore, RAGE has become a potential target
in the prevention and treatment of diabetes associated atherosclerosis. Further studies will now investigate
RAGE knockout and transgenic mice, overeexpressing RAGE in endothelial cells.
Name of contact:
Professor Mark Emmanuel Cooper
Email/Phone no. of contact:
mark.cooper@baker.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 268921
Start Year: 2004
CIA Name: A/Pr Elizabeth Woodcock
End Year: 2006
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Pharmacology not elsewhere classified
Total funding: $399,750
Title of research award:
Inositol polyphosphate 1-phosphatase, a novel anti-hypertrophic factorInositol polyphosphate 1-phosphatase, a
novel anti-hypertrophic factor
Lay Description (from application):
Growth of the heart muscle cells occurs after heart attack and in people with high blood pressure or who suffer
from diseases such as diabetes. Such growth leads eventually to the development of heart failure, a major
cause of death and disability in western societies. We have identified a novel inhibitor of this growth, an
enzyme that destroys a signalling intermediate called inositol(1,4)bisphosphate (or IP2). We now need to
define how reduction in IP2 reduces growth and whether it provides a useful target for therapy.
Research achievements (from final report):
The project investigated the mechanisms by which inositol polyphosphate phosphatases reduce hypertrophic
signalling pathways and the possibility that inositol(1,4,5)trisphosphate (Ins(1,4,5)P3) or its metabolite
inositol(1,4)bisphosphate (Ins(1,4)P2) act directly to activate myocardial growth signalling. Expression of
hypertrophic marker genes, including atrial natriuretic peptide (ANP) and myosin light chain 2v, were
suppressed by overexpression of the 1-phosphatase that degrades Ins(1,4)P2 to Ins(4)P1. Using adenoviruses
expressing the 1-phosphatase we have found that even though there were reductions in ANP expression there
was no demonstrable change in protein/DNA ratio or cell size responses. We cloned IP3-5-phosphatase into
both conventional and adenoviral vectors to address the question of the role of Ins(1,4,5)P3 in limiting ANP
expression. We found that overexpression of the 5-phosphatase caused reduced ANP expression without any
change in cardiomyocyte size. This suggested the likelihood that the effects of the 1-phosphatase were caused
by reductions in Ins(1,4,5)P3. Overexpression of IP3-5-phosphatase caused selective loss of the Ins(1,4,5)P3
response to a1-adrenergic agonists immediately after stimulation, 15-30 sec. However, with prolonged
stimulation, Ins(1,4,5)P3 levels were normalised, and overall phospholipase C activity was heightened. This
was found to be caused by an increased expression of phospholipase Cb1, the enzyme responsible for
generation of Ins(1,4,5)P3. Thus, the heart responds to factors that reduce Ins(1,4,5)P3 levels by increasing its
generation. In cardiomyocytes, we found that the b splice variant was solely responsible for the observed
activation by G protein coupled receptors. This suggests the possibility of selectively inhibiting Ins(1,4,5)P3
responses in heart, a scenario that may prove useful in treating arrhythmia under some conditions.
Expected future outcomes:
This work has defined phospholipase Cb1b as the mediator of a1-adrenergic receptor mediated signalling.
Activation of this phospholipase requires targeting to the sarcolemma apparently using its unique C-terminal
proline-rich domain. Targeting this interaction provides a mechanism of inhibiting these responses in a tissuespecific manner.
Name of contact:
Elizabeth A. Woodcock
Email/Phone no. of contact:
liz.woodcock@baker.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 268925
Start Year: 2004
CIA Name: Prof Walter Thomas
End Year: 2006
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Basic Pharmacology
Total funding: $349,500
Title of research award:
Arresting type 1 angiotensin receptorsArresting type 1 angiotensin receptors
Lay Description (from application):
Our bodies generate a hormone called angiotensin II in response to a decrease in blood pressure (or salt in our
bloodstream). This hormone increases blood pressure by causing blood vessels to constrict, by making us
thirsty, and by inducing salt and fluid retention via an effect on the kidneys. In some cardiovascular diseases,
the generation of angiotensin II or our sensitivity to this hormone is elevated. It is therefore crucial that we
understand how angiotensin II works and how its actions in the body are mediated. For angiotensin II to act it
must first bind to a receptor. Receptors are proteins and behave like locks that are "opened" by the hormone
"keys". Thus, cellular receptors for angiotensin II are engaged and activated by increases in angiotensin II in
our blood. These receptors then produce "signals" which initiate a response (e.g. constriction of a blood
vessel). Subsequently, the receptors are "switched-off" to prevent over-stimulation. The experiments proposed
in this application continue our investigations into how angiotensin II receptors are regulated or "switched-on
and -off". A major way for receptors to be turned off is for them to be ear-marked by a modification known as
phosphorylation. These modified receptors are then bound by proteins termed arrestins, which as indicated by
their name play a role in preventing further receptor signalling. These arrestins also help remove activated
receptors from the cell surface to the inside of the cell. How arrestins interact with receptors and regulate their
function is poorly understood. This application proposes experiments to investigate the molecular mechanisms
of arrestin action as it relates to the angiotensin II receptor. Results from these studies will further our
understanding of angiotensin II receptors and their role in cardiovascular control.
Research achievements (from final report):
In some cardiovascular diseases, the generation of a hormone, angiotensin II, or our sensitivity to this hormone
is elevated. It is therefore crucial that we understand how angiotensin II works and how its actions in the body
are mediated. For angiotensin II to act it must first bind to a receptor. Receptors are proteins and behave like
locks that are "opened" by the hormone "keys". Thus, cellular receptors for angiotensin II are engaged and
activated by increases in angiotensin II in our blood. These receptors then produce "signals" which initiate a
response (e.g. constriction of a blood vessel). Subsequently, the receptors are "switched-off" to prevent overstimulation., In this project grant, we continued our investigations into how angiotensin II receptors are
regulated or "switched-on and -off". A major way for receptors to be turned off is for them to be bound by
proteins termed arrestins, which as indicated by their name play a role in preventing further receptor signalling.
Our studies determined how these arrestins work (at the mechanistic level) to remove activated receptors from
the cell surface to the inside of the cell. We also development a new screening assay to identify proteins that
interact with arrestins and regulate their funciton
Expected future outcomes:
Results from these studies will further our understanding of angiotensin II receptors and the molecular
mechanisms of arrestin action as it relates to the angiotensin II receptor and their role in cardiovascular control.
Name of contact:
Walter Thomas
Email/Phone no. of contact:
walter.thomas@baker.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 268928
Start Year: 2004
CIA Name: A/Pr Peter Little
End Year: 2006
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $500,750
Title of research award:
Inhibition of c-Abl as a target for shortening glycosaminoglycan length on proteoglycans and preventing
atherosclerosisInhibition of c-Abl as a target for shortening glycosaminoglycan length on proteoglycans and
preventing atherosclerosis
Lay Description (from application):
The major health issue developing in Australia is vascular and cardiovascular disease resulting from obesity
and diabetes. Whilst prevention strategies based on lifestyle changes are preferable, treating cardiovascular risk
factors with the latest drugs has been shown to produce significant benefits but there is a large remaining
component of disease. New therapies are required and these will most likely target blood vessels directly. We
are working on the basic cause of atherosclerosis with the aim of finding a mechanism and developing a drug
to prevent the process - we have recently identified such a target and it is the subject of this research grant
proposal. A group of very large molecules which have recently received increasing attention are the
proteoglycans, combined protein-sugar molecules which are heavily coated with negatively charged groups. It
has recently been published in the prestigious journal, Nature, that the binding of lipids in the blood to the wall
of the blood vessel is the main cause of atherosclerosis. Proteoglycans are the molecules which cause the lipids
to be stuck in blood vessels. Specifically, the length of the sugar (GAG) chains on the proteoglycan determines
the binding of the lipids. We have now discovered a pathway and have one drug candidate which prevents the
elongation of the GAG chains on proteoglycans. The exciting possibility is use of this agent with existing
agents, for example, to use a "statin" drug to lower blood cholesterol and a new GAG elongation inhibitor to
prevent the cholesterol sticking in the wall. The outcome will be the proof of the potential of a target for the
direct therapy of atherosclerosis and a clear pathway for the development of a drug to be used in people
susceptibility to atherosclerosis which is particularly people with diabetes.
Research achievements (from final report):
Cardiovascular disease is the largest cause of premature death in the developed world. Most of the treatments
for cardiovascular disease are targeted at changes in blood borne factors and blood pressure. This strategy has
limited effectiveness with only 30 per cent of disease being prevented. We are working on targets within the
wall of the blood vessel that directly affect of course of the disease. Our specific target is the sugar chains
(glycosaminoglycans) on molecules known as proteoglycans where the sugar chains have increased stickiness
for lipids (Low Density Lipoprotein cholesterol). A definitive study of human vessel has recently shown that
the binding of lipids to the sugar chains of proteoglycans is an initiating step in atherosclerosis. In this study we
have fully characterised several new drugs which can reduce the stickiness of glycosaminoglycan chains for
lipids. The studies have progressed as far as to demonstrate that a molecule highly characterised in the
laboratory in cell based studies can reduce lipid deposition in the wall of the blood vessel of high fat fed
animal. The hypotheses of targeting proteoglycans is new and our initial studies provide evidence that this
might be a valid target for the prevention of atherosclerosis.
Expected future outcomes:
The studies provide a pathway to the ultimate development of a product which includes a statin drug to lower
blood cholesterol and a proteoglycan inhibitor to block the binding of the cholesterol in the vessel wall. Further
studies will further characterise the target of the new drugs, describe the changes in proteoglycan occurring in
the vessel wall of animals and provide a pathway for the testin
Name of contact:
Peter Little
Email/Phone no. of contact:
NHMRC Research Achievements - SUMMARY
peter.little@baker.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 317800
Start Year: 2005
CIA Name: Prof Tony Dart
End Year: 2009
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: Established Career Fellowships
Main RFCD: Clinical Sciences not elsewhere classified
Total funding: $811,500
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
Clinical studies have examined methods for determining the stiffness of human large arteries, factors affecting
this stiffness, its relation to arterial disease and elevated blood pressure and its response to several treatments.
Of particular significance was the demonstration of a beneficial effect of perindopril treatment on arterial
stiffness and aortic dilatation in Marfan's syndrome. Other studies indicated different characteristics of
atherosclerotic plaque in the coronary arteries of subjects with diabetes and the effects of HDL infusion on the
inflammation found in atherosclerotic plaque of subjects with peripheral vascular disease. In relation to
hypertension the contributions of arterial dimensions and stiffness to pulse pressure have been delineated. A
number of studies have been conducted in particular patient groups susceptible to increased chance of
atherosclerotic cardiovascular disease. In particular we have shown important change in the circulating lipids
of patients infected with HIV as well as effects due to antiretroviral treatment. , Work in the animal laboratory
has particularly been concerned with the pathophysiology of acute myocardial infarction. Particular attention
has been given to the role of inflammation with evidence that the extent of inflammation in the heart following
an infarct is critical for both the short term and long term mechanical complications. The demonstration of
changes in enzymes that break down collagen also has important implications for future therapy. In addition to
studying inflammatory cells within the heart we have also examined their activation in the circulation and
recent studies have now extended these observations to the clinical field.
Expected future outcomes:
Recent work on the effects of the hormone relaxin on large artery stiffness in older hypertensive animals have
yielded very positive results and it is planned to undertake clinical studies to see if this may be a valuable
treatment option.
Name of contact:
Prof Anthony M Dart
Email/Phone no. of contact:
a.dart@alfred.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 317801
Start Year: 2005
CIA Name: A/Pr Elizabeth Woodcock
End Year: 2007
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Pharmacology not elsewhere classified
Total funding: $354,375
Title of research award:
FOXO proteins and protection from cardiac ischaemic injuryFOXO proteins and protection from cardiac
ischaemic injury
Lay Description (from application):
Reduced blood supply to the heart can initiate a heart attack that results in damage to the heart muscle. Loss of
muscle tissue under these conditions initiates pathological growth of the heart and can eventually lead to the
development of heart failure, a major cause of death and disability in western countries. Treatment with
growth factors can prevent the acute damage and loss of cells, but these cause detrimental effects on other
tissues. For these reasons, it is necessary to establish ways to activate protective pathways in the heart without
causing unwanted effects on other tissues. To this end, we have identified for the first time in the heart
members of a newly described family of gene regulators that can cause cell death by increasing expression of
cytotoxic factors. We showed that these FKHRor FOXO family members are regulated in the heart and that
they are active in generating cytotoxic factors. We now plan to establish whether FOXO proteins are involved
in causing cell death during heart attack and whether manipulating their activities can be cardioprotective.
Research achievements (from final report):
We have shown that Foxo1 is directly apoptotic in cardiomyocytes. Foxo1 mediated apotposis is unusual in
cardiomycoytes in that it uses the extrinsic pathway of apoptosis rather than the intrinsic mitochondrial
pathway that usually mediates apoptosis in heart. Currently cytotoxic agents used to treat cancers are often
limited in their usefullness by damaging effects on the myocardium. The finding that cardiomycoyte apoptosis
can be mediated by the extrinsic pathway, measn that cardiomyocyte apoptosis is likely a bigger problem than
previously appreciated.
Expected future outcomes:
We expect to show that Foxo contributes substantially to cardiomyocyte death under ischameic conditions.
Name of contact:
Elizabeth Woodcock
Email/Phone no. of contact:
liz.woodcock@baker.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 317802
Start Year: 2005
CIA Name: A/Pr Elizabeth Woodcock
End Year: 2007
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $468,750
Title of research award:
Ischaemia-induced sarcolemmal changes and their role in Ins(1,4,5)P3 generation and
arrhythmogenesisIschaemia-induced sarcolemmal changes and their role in Ins(1,4,5)P3 generation and
arrhythmogenesis
Lay Description (from application):
Studies in our laboratory at the Baker Heart Research Institute over the last several years have identified a
novel mechanism causing the development of arrhythmias, a primary cause of sudden cardiac death in heart
failure as well as during an acute heart attack caused by acutely reduced blood flow. The reduced blood flow
leads to lowered oxygen and nutrients and thus the beating heart cells have insufficient energy to properly
maintain function. Under these stressed conditions, cardiac myocytes produce large amounts of a small
molecule called IP3, which interferes with the normal electrical balance of the cells. Blocking IP3 generation
prevents arrhythmias under these acutely ischaemic conditions. In more recent studies, we have identified
many of the enzymes responsible for generation of IP3 in heart cells and have defined the properties of the
regions of the cell responsible for this response. We now want to establish exactly how a period of ischaemia
alters the localization or functioning of the enzymes that are responsible for this pathological change that leads
to fatal arrhythmias.
Research achievements (from final report):
We have shown that brief periods of ischaemia cause dramatic changes in the functional properties of defined
regions within the sarcolemma that are important for the regulation of Ins(1,4,5)P3 generation and for the
synthesis of the lipid PIP2 itself an important regulator of cardiac rhythm. We showed that ischaemia and postischaemic reperfusion cause a marked generation of PIP2 within sarcolemmal lipid rafts. This is in marked
contrast to changes udner normoxia where descreses in PIP2 are associated with generation of Ins(1,4,5)P3. , In
addition we showed that a1a-adrenergic receptors were not responsible for generation of Ins(1,4,5)P3 durign
reperfusion, but rather that these had a preconditioning effect that protected the heart from ischaemia-induced
changes.
Expected future outcomes:
It is now clear that both Ins(1,4,5)P3 and its precursor lipid PIP2 can have major influences on cardiac rhythm.
The finding that PIP2 increases rather than decreases under reperfusion conditionins even though it is beign
degraded to Ins(1,4,5)P3 will lead to a better understanding as to how arrhythmias are initiated under these
conditions.
Name of contact:
Elizabeth Woodcock
Email/Phone no. of contact:
liz.woodcock@baker.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 317803
Start Year: 2005
CIA Name: A/Pr Elizabeth Woodcock
End Year: 2009
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: Established Career Fellowships
Main RFCD: Basic Pharmacology
Total funding: $651,750
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
Dilated atria are associated with atrial fibrillation and provide a worsened prognosis. We have shown that
dilated atria from human, mouse and sheep have heightened expression and activity of one splice variant of one
subtype of phospholipase C, specifically PLCbeta1b. Furthermore, activity correlated with the degree of atrial
distension. In parallel studies, we showed that PLCbeta1b was exclusively responsible for pathological
cardiomyocyte growth and apoptotic death downstream of the receptor coupling protein, Gq. PLCbeta1b was
shown to be the only functional PLC that was localized to the cardiac sarcolemma, where it can function in
signalling. This selective binding to the sarcolemma was dependent on the splice variant-specific C-terminal
tail that contains two proline-rich domains. Expression of the unique C-terminal tail of PLCbeta1b reduced
PLC activation and furthermore prevented hypertrophy and apoptosis downstream of Gq. We next identified
the SH3 domain containing protein responsible for the selective binding of PLCbeta1b to the sarcolemma and
showed that this was the high MW scaffolding protein Shank3. Transgenic mice are being generated to express
PLCbeta1b and PLCbeta1b-C-terminal inhibitory peptide in hearts of mice under a conditional promoter. In
addition, AAV9 constructs have been prepared in order to express PLCbeta1b and the inhibitory peptide in
vivo in mouse and sheep hearts. These will extend our findings to the in vivo situation.
Expected future outcomes:
Our current and future plans involve in vivo studies to demonstrate the usefulness of the PLCbeta1b-Shank3
interface as a drugable target. We will also demonstrate that the proline-rich domain of PLCbeta1b binds to the
SH3 domain of Shank3. We will then screen for suitable inhibitors of this interaction.
Name of contact:
Elizabeth Woodcock
Email/Phone no. of contact:
liz.woodcock@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 317808
Start Year: 2005
CIA Name: A/Pr Xiao-Jun Du
End Year: 2010
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: Established Career Fellowships
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $811,601
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
I am a medical scientist specialized in the area of cardiac pathophysiology determining the mechanism of heart
diseases and testing novel therapies.
Research achievements (from final report):
Cardiac inflammation following ischemic heart attack:, I have demonstrated that cardiac inflammation evoked
by ischemia and infarction promotes cardaic muscle injury and development of severe complications (cardiac
wall rupture leading to sudden death, ventricular dilatation, formation of thrombus in cardiac chamber). I have
documented significance of inflammation mediated damage of the non-cellular structure of heart tissues (i.e.
extracellular matrix) leadign to these adverse consequences. I have identified key factors (e.g. male gender,
ageing, platelets, macrophage migration inhibitory factor-MIF) contributing to the inflammatory responses. I
have provided evidence for both platelets and MIF as good therapeutic targets in the setting of cardiac ischemia
and infarction., Development of a new anti-fibrotic drug relaxin: accumulation of excessive scar tissues
(fibrosis) in the heart and blood vessels is a key component of cardiovascular disease and yet we are short of
effective and specific drugs. A series of studies from my group in cultured cardiac cells or in animal models of
cardiovascular disease have documented that relaxin as a natural occurreing peptide hormone is potent in the
reversal of established fibrosis and holds the potential of developling as clinical drug., The sympathetic
nervous system and signaling through adrenergic recpetors in heart disease: I have demonstrated the distinct
function of subtypes of adrenergic receptors in mediating structural and fucntional adaptation of the heart under
diseased conditions and the biochemical signals invovled.
Expected future outcomes:
Novel scientific discoveries from models of human cardiovascular diseases with great potential of clincal
translation in terms of new therapies or diagnostic tools.
Name of contact:
Xiao-Jun Du
Email/Phone no. of contact:
xiao-jun.du@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 317810
Start Year: 2005
CIA Name: A/Pr Dmitri Sviridov
End Year: 2009
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: Established Career Fellowships
Main RFCD: Medical Biochemistry: Lipids
Total funding: $595,500
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
Major achievements of our research are in the area or understanding the mechanisms and treating heart
diseases. Specifically, a substantial progress has been made in testing various forms of therapy aimed in raising
levels of good cholesterol. These studies were conducted on the laboratory level as well as in clinic. Two
approaches were tested, direct infusion of high density lipoprotein (good cholesterol) that was made in a tube,
and creating small molecules that can mimic the properties of good cholesterol. Both approaches are
progressing to clinical trials and may become a widely used therapy in few years. Another direction of our
research was investigating a connection between infectious diseases and heart diseases. Specifically we
established mechanisms of how HIV infection causes heart diseases and went further establishing new class of
compounds that may treat both HIV and heart disease. Further, we investigated the basic mechanisms of how
cells handle cholesterol and established new principles that can then be targeted for prevention and treating of
heart disease. Finally we conducted research establishing the mechanisms causing high risk of heart disease at
diabetes and obesity. Our finding would lead to new paradigms in treating and preventing heart disease.
Expected future outcomes:
In the future we will continue to develop new treatments for heart disease, new prevention measures and new
predictive testing methods for heart disease and conditions that are associated with high risk of heart disease.
The priority will be given to infectious diseases, diabetes and obesity.
Name of contact:
Dmitri Sviridov
Email/Phone no. of contact:
Dmitri.Sviridov@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 317811
Start Year: 2005
CIA Name: A/Pr Dmitri Sviridov
End Year: 2007
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Medical Virology
Total funding: $339,375
Title of research award:
Impact of HIV infection and treatment with highly active retroviral therapy on reverse cholesterol
transportImpact of HIV infection and treatment with highly active retroviral therapy on reverse cholesterol
transport
Lay Description (from application):
HIV has been found to be associated with increased risk of cardiovascular diseases. The introduction of new
treatment for HIV resulted in a dramatic improvement in morbidity and mortality of HIV-infected patients, but
paradoxically cardiovascular complications became more frequent and severe. It is not currently clear whether
increased cardiovascular risk is due to long lasting HIV or due to the impact of therapy. In both cases a major
complication of HIV and/or therapy is rapid development of atherosclerosis. Atherosclerosis is the cause of
more than half of heart diseases, which is a leading cause of death in Western societies. Atherosclerosis
develops when cholesterol is deposited within artery walls, causing the formation of a fatty plaque and
restricting blood flow. The mechanism behind the effect of HIV and its treatment on development of
atherosclerosis is unknown. This project is designed to investigate how and why HIV infection and its
treatment results in this increased risk of cardiovascular disease.
Research achievements (from final report):
Our study investigated a relationship between HIV infection, its treatment and cardiovascular risk factors. It
was previously believed that most of the cardiovascular risk in HIV-positive subjects is due to the adverse
effects of antiretroviral treatment. The major achievement of our study is that we firmly established that HIV
infection itself has great impact on cardiovascular risk. We investigated the effect of HIV infection on the
ability of cells to release excessive cholesterol and found that this ability is significantly impaired by HIV
virus. The consequence of that is that HIV-infected individuals have no protection against high levels of blood
cholesterol and are therefore are very susceptible to heart disease. In contrast, antiretroviral compounds have
very limited effect on atheroprotective mechanisms. In a clinical study we established that another pathway,
"good cholesterol" also responsible for protection is damaged as well and, as with cellular mechanisms, most of
the damage is done by HIV infection, not by the treatment. Both in basic and clinical studies we established the
exact biochemical and molecular mechanisms of how HIV is damaging protective pathways. As a result of
these studies we begin to develop a new kind of medication that would affect both HIV and its cardiovascular
complications.
Expected future outcomes:
The main outcome of our studies is a realization that targeting cardiovascular complications of HIV requires
targeting HIV itself. Further it leads to development of a new concept of treatment that can simultaneously
target HIV and cardiovascular complications.
Name of contact:
A/Prof. Dmitri Sviridov
Email/Phone no. of contact:
Dmitri.Sviridov@Baker.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 317821
Start Year: 2005
CIA Name: Prof Geoffrey Head
End Year: 2007
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Systems Physiology
Total funding: $450,750
Title of research award:
Sympathetic nervous system contribution to hypertension : CNS pathways, neurotransmitters and neuroeffector
mechanismsSympathetic nervous system contribution to hypertension : CNS pathways, neurotransmitters and
neuroeffector mechanisms
Lay Description (from application):
High blood pressure (hypertension) is a major public health problem in Western society with approximately
20% of adults affected. If left untreated, serious damage to organs can occur and the risk of sudden cardiac
death or stroke is greatly increased. While many factors contribute to the development of hypertension such as
lifestyle, genes, diet, weight and exercise levels, a common feature in the early stages is an overactive nervous
system in the kidney and in the heart which is most likely due to altered signals from the brain. We need to
understand why this occurs. One possibility is that renin (a chemical released from the kidney) that is known
to control body fluid, also acts in the brain to increase nerve activity to the kidney and heart and in this way
contributes to high blood pressure. It does this indirectly by producing another hormone called angiotensin.
Our research has shown that in conditions where the kidney releases excess of the hormone renin, which may
occur if the blood supply to the kidney is reduced, a change occurs in the way in which the nervous system
affects blood pressure. The nervous system is "activated" to increase the release of renin from the kidney. The
effect of this is to make blood pressure increase further in what can become a vicious circle. At present it is not
understood why and how this change occurrs. The major thrust of this project is to determine the mechanims
by which the renal hormones signal the central nervous system to change the nature of the nervous activity
back to the kidney. We want to know what parts of the brain are involved, how the nature of the activity in the
nerves changes and also how the nervous control of the kidney changes (i.e. how the kidney changes its
responsivness to the nerve activity). Because similar processes probably occur in nearly all forms of high
blood pressure, our results will greatly improve our understanding of how this dangerous condition develops.
Research achievements (from final report):
Renovascular hypertension constitutes 2-4 % of all hypertension and is increasing as the population ages and
the incidence of renal artery atheroma increases. Our studies have shed new light on the way in which the SNS
contributes to the development of Ang II dependent hypertension via renal nerves and changes to specific renal
neuroeffector mechanisms. Importantly we have shown that renal nerves become more controlling of the inner
kidney blood flow in angiotensin dependent hypertension. This mechanism would be expected to increase
blood pressure further. At present there is no preferred long term antihypertensive medication for renovascular
hypertension. We have identified a number of key CNS nuclei activated by low levels of the renal hormone
angiotensin. This could potentially offers new possibilities for therapeutic intervention in hypertension.
Expected future outcomes:
Our studies are also relevant to other pathologies where sympathetic nerves and kidney are implicated (e.g.
heart failure, obesity, diabetes) and to oedematous states associated with sodium retention (nephrotic
syndrome, renal failure, cirrhosis). In these cases the same CNS pathways may be activated by other
inappropriate signals resulting in a change to the renin neuroeffector mechanism.
Name of contact:
A/Prof Geoff Head
Email/Phone no. of contact:
geoff.head@baker.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 317826
Start Year: 2005
CIA Name: Prof Geoffrey Head
End Year: 2007
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $399,450
Title of research award:
Characterisation of the morning surge of blood pressure as a risk factor for cardiovascular
disease.Characterisation of the morning surge of blood pressure as a risk factor for cardiovascular disease.
Lay Description (from application):
Cardiovascular events occur more frequently in the early morning transition between the asleep and awake
state. This parallels the period where the rise in blood pressure and heart rate is at its greatest and hence may
be a potential risk marker for cardiovascular events. We have developed a new mathematical way of
measuring the morning surge in blood pressure and heart rate in patients using ambulatory monitoring which
has been patented. The main aim of the grant is to determine if morning blood pressure surge is a risk factor
and to determine the underlying mechanisms. Using both clinical and experimental studies we aim to a)
characterise the rate of morning rise in hypertension and normotension b) determine whether subjects with an
exaggerated morning surge in blood pressure also have an over responsive nervous system, c) determine
whether the rate of rise in blood pressure is a risk factor and d) determine in stroke prone animals whether
preventing the waking blood pressure surge is beneficial. This will be achieved via a novel analysis method of
continuous BP recording over the 24hr period. These studies are important since identification of new risk
markers or predictors of sudden cardiac death, stroke and myocardial infarction is a national health priority.
Understanding the mechanisms that are responsible for the increased risk of a cardiovascular event in the
morning is the first step to devising appropriate treatment and risk management. Our study will shed light on
both the mechanism and the therapy aspects.
Research achievements (from final report):
Cardiovascular events occur more frequently in the early morning transition between the asleep and awake
state. This parallels the period where the rise in blood pressure and heart rate is at its greatest and hence may be
a potential risk marker for cardiovascular events. We developed a new mathematical way of measuring the
morning surge in blood pressure and heart rate in patients using ambulatory monitoring which has been
patented. The main aim of the grant was to determine if morning blood pressure surge is a risk factor and to
determine the underlying mechanisms. Using both clinical and experimental studies found that the the rate of
morning rise is greater in subjects with high blood pressure and that those with a high cholesterol level have a
higher surge in morning blood pressure. These studies are important since identification of new risk markers or
predictors of sudden cardiac death, stroke and myocardial infarction is a national health priority. Understanding
the mechanisms that are responsible for the increased risk of a cardiovascular event in the morning is the first
step to devising appropriate treatment and risk management.
Expected future outcomes:
One future direction would be to establish whether loweing cholesterol (by diet or treatment) could reduce the
morning rise in blood pressure.
Name of contact:
A/Prof Geoff Head
Email/Phone no. of contact:
geoff.head@baker.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 317829
Start Year: 2005
CIA Name: Prof Murray Esler
End Year: 2009
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: Established Career Fellowships
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $736,500
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
The major achievement was the development and testing, with Melbourne colleagues, of a new method of
treatment for severe high blood pressure, not controlled with combinations of multiple antihypertensive drugs.
The theoretical research underpinning the therapeutic advance was my demonstration that the stimulant nerves
to the kidneys (sympathetic nerves) are markedly activated in many patients with high blood pressure. With a
California-based bioengineering company, Ardian Corporation, as research partner, a device to silence these
sympathetic nerves was developed and tested. The device is a purpose-developed catheter which delivers
radiofrequency energy (high energy radio waves). The catheter, after insertion under local anaesthesia into an
artery in the groin, is advanced to lie, in turn, in both kidney arteries where energy is delivered to ablate
(destroy) the sympathetic nerves to the kidneys, which lie in the wall of the kidney arterie, which lie within
reach of the delivered energy. The trial was very successful, leading to publications in 2009 in The Lancet and
The New England Journal of Medicine. This revolutionary treatment of severe high blood pressure has now
received (May 2010) regulatory approval by the EU and the Australian TGA.
Expected future outcomes:
Future testing will determine whether this treatment method for high blood pressure can be applied in patients
with milder disease, and ascertain if the effect is durable enough (to this point persistence of full therapeutic
benefit has been documented out to 24 months) to actually cure high blood pressure.
Name of contact:
Professor Murray Esler
Email/Phone no. of contact:
murray.esler@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 317832
Start Year: 2005
CIA Name: Prof Mark Cooper
End Year: 2007
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Endocrinology
Total funding: $453,750
Title of research award:
Understanding vasoactive hormone pathways in diabetic complicationsUnderstanding vasoactive hormone
pathways in diabetic complications
Lay Description (from application):
High blood pressure damages tissues. In clinical practice blood pressure is measured in large arteries, such as
the brachial artery in the arm. However, it is the pressure within the organ such as the kidney that actually
causes the damage. In particular, the sieving apparatus of the kidney (called the glomerulus), is especially
sensitive to the effects of pressure. In diabetes, the pressure within the glomerulus is high because its outflow
valve (called the efferent arteriole) is tightly constricted. Therefore even if blood pressure is thought to be
normal when measured in the arm, it may still be excessively high within the kidney. Studies have already
shown that lowering within-kidney pressure may have a major impact on the progression of kidney disease in
diabetes. However, to date this reduction of within-kidney pressure has been sub-maximal. The planned
studies will involve the use of new compounds which have more powerful effects in reducing the formation or
action of hormones which promote constriction of vessels in the kidney leading to elevated pressure within the
kidney. Furthermore, some of these very new agents can open up or dilate these kidney vessels thereby
achieving excellent reductions in the pressure inside the kidney. The proposed studies aim to examine new
strategies for preferentially lowering pressure within the kidney down to these ideal levels. These hormones
also have other effects which could be relevant to non-kidney sites of injury in diabetes including blood vessels
and the retina.
Research achievements (from final report):
Activation of the renin angiotensin system (RAS) is considered to be among the most important mediators of
renal damage in diabetes. Traditionally, the RAS has been viewed as simply a vasoconstrictor pathway, arising
from the formation of angiotensin II (Ang II) and the subsequent activation of the AT1 receptor. While
blocking the actions of Ang II attenuates renal damage, it does not prevent renal hypertrophy or hyperfiltration
in experimental models of type 1 diabetes. Similarly, in individuals with diabetes, the protection afforded by
angiotensin converting enzyme (ACE) inhibitors is only partial and, despite their treatment, many patients with
diabetes ultimately develop diabetic renal disease, albeit at a slower rate. Recently, the traditional view of the
RAS has been challenged by the discovery of novel components that regulate vasodilator and trophic pathways
in the kidney, in a balancing and complementary manner to traditional vasoconstrictor actions. Specifically,
these novel components include the angiotensinase ACE2, the vasodilatory angiotensin peptide, Ang 1-7 and
the AT2 receptor subtype, which act to counterbalance the actions of ACE, Ang II and the AT1 receptor
respectively in the kidney., , The major finding from our study was that the expression of ACE2 is significantly
modified by diabetes, which impacts on the pathogenesis of kidney disease. Of clinical importance is the fact
that for ACE inhibitors (therapy used in diabetic kidney disease) to work maximally a normal functioning level
of ACE2 is required. Indeed, this may explain why not all people with diabetes respond well to ACE inhibitor
therapy.
Expected future outcomes:
It is now possible for patients with diabetic kidney disease to have their levels of ACE2 measured. This will
allow us to predict patients who will respond well to ACE inhibitor therapy. The non-responders can then be
treated with other treatment regimes.
Name of contact:
Professor Mark E Cooper
Email/Phone no. of contact:
NHMRC Research Achievements - SUMMARY
mark.cooper@baker.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 317835
Start Year: 2005
CIA Name: Dr Julie McMullen
End Year: 2009
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: Career Development Fellowships
Main RFCD: Medical Physiology not elsewhere classified
Total funding: $453,500
Title of research award:
Differences between physiological and pathological hypertropy offer new strategies for the treatment of heart
failureDifferences between physiological and pathological hypertropy offer new strategies for the treatment of
heart failure
Lay Description (from application):
Not Available
Research achievements (from final report):
-Demonstrated that activating a gene that is elevated in the heart in response to exercise is beneficial when it is
activated in a setting of cardiac stress. Activation of this gene improved life span and heart function in mouse
models of heart failure. This gene also protects the heart against atrial fibrillation (the most common cardiac
arrhythmia seen in cardiology clinics worldwide)., -I have also identified other novel genes that are critical for
the beneficial effects of exercise.
Expected future outcomes:
New and improved therapeutics for patients with heart failure and atrial fibrillation
Name of contact:
Julie Mcmullen
Email/Phone no. of contact:
julie.mcmullen@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 317838
Start Year: 2005
CIA Name: Dr Tanya Medley
End Year: 2010
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: Early Career Fellowships
(Overseas)
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $325,101
Title of research award:
Potential of Transgenic mice derived vascular progenitor cills for myocardial revascularisationPotential of
Transgenic mice derived vascular progenitor cills for myocardial revascularisation
Lay Description (from application):
Not Available
Research achievements (from final report):
This project idenitified the presence of a cell type within the adult thymus that has potential for organ
regeneration., The potenial of these cells was then tested and shown to be able to contribute to multiple
components of the developing thymus. To our knowledge, this is the first demonstration of prospective
isolation of functionally validated progenitors from the adult thymus and thus opens prospect of propagating
these cells for therapeutic purposes.
Expected future outcomes:
Further analyses will be required to determine the extent to which these progentior cells contribute to
maintenance of the adult thymus. The candidate developed a transgenic mouse to test such a hypothesis. These
mice are currently being bred.
Name of contact:
Clare Blackburn
Email/Phone no. of contact:
c.blackburn@ed.ac.uk
NHMRC Research Achievements - SUMMARY
Grant ID: 332510
Start Year: 2005
CIA Name: Dr Peter Kistler
End Year: 2008
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: Early Career Fellowships
(Overseas)
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $389,799
Title of research award:
Simultaneous use of electroanatomical and non contact mapping to investigate the mechanisms of chronic atrial
fibrillatiSimultaneous use of electroanatomical and non contact mapping to investigate the mechanisms of
chronic atrial fibrillati
Lay Description (from application):
Not Available
Research achievements (from final report):
Atrial fibrillation had been identified as an emerging epidemic of cardiovascular disease. Catheter ablation
which involves the passage of wires form a patients groin into the heart allows the ability to deliver discrete
burns which may form barriers the abnormal electrical currents. This is the sole current possiblity to provide
"cure" for atrial fibrillation as currently available drugs have limited efficacy and are largely palliative. On my
arrival at St bartholomews Hospital in London a new 3D mapping system had become available which allowed
a highly detailed image aquired by cardiac CT or MRI to be integrated into the mapping system and be used to
guide manipulation of the wires real time within the heart. We were the first in the world to validate this
technology in humans and went on to publish extensively in this area. The use of image integration has become
the mainstay of catheter ablation for atrial fibrillation world wide., On return to Australia I have taken up a
position with the Baker Heart Reseach Institute as head of Clinical Electrophysiology research and Senior
Lecturer at Melbourne University supervising a PhD student continuing research into the responsible
mechanisms of atrial fibrillation and the therapeutic implications of these findings.
Expected future outcomes:
Improved understanding of the responsible mechanisms of atrial fibrillation and the therapeutic impact of these
findings with respect to new targets for medication and catheter ablation.
Name of contact:
Peter Kistler
Email/Phone no. of contact:
peter.kistler@baker.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 342115
Start Year: 2005
CIA Name: Prof Mark Febbraio
End Year: 2007
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $360,750
Title of research award:
Novel therapeutic interventions to increase blood flow to skeletal muscleNovel therapeutic interventions to
increase blood flow to skeletal muscle
Lay Description (from application):
Over the past decade it has become clear that the cytokine interleukin (IL)-6 is produced in and released from
tissues such as fat and muscle to mediate metabolic processes. In this respect, it acts in a "hormone like"
manner. During this period it has also become apparent that the hormone insulin increases blood flow to
skeletal muscle. There is emerging evidence that IL-6 plays a role, not only in metabolic and signalling
processes within skeletal muscle, but also in blood flow. This project will determine whether the cytokine IL-6
is a viable therapeutic target in the treatment of blood flow disorders in patients with type 2 diabetes. This has
major ramifications since type 2 diabetes has reached pandemic levels in Australia and is estimated to cost the
community approximately 800 million dollars per year.
Research achievements (from final report):
We hypothesised that IL-6 may promote endothelial cell signaling and capillary recruitment leading to
enhanced insulin stimulated glucose uptake. Contrary to our hypothesis, we observed that IL-6 blunted insulin
stimulated endothelial cell signalling and capillary recruitment via the activation of TNFalpha. However, IL-6
alone did not negatively affect either endothelial cell signalling or capillary recruitment. This is significant
because the data demonstrate that insulin can act in a pro-inflammatory manner
Expected future outcomes:
The future outcomes may be that, from a clinical perspective, one should be cautious when prescribing insulin
as a glucoselowering therapy in obesity since circulating IL-6 is elevated in obesity and these two proteins act
in a synergistic manner to promote inflammation in endothelial cells
Name of contact:
Mark A Febbraio
Email/Phone no. of contact:
mark.febbraio@baker.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 367600
Start Year: 2006
CIA Name: Dr Julie McMullen
End Year: 2008
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $335,473
Title of research award:
Differences between physiological and pathological cardiac hypertrophy offer new strategies for treating heart
failureDifferences between physiological and pathological cardiac hypertrophy offer new strategies for treating
heart failure
Lay Description (from application):
The heart becomes large both in athletes as well as in patients with heart disease and failure. In the first
instance, the large (hypertrophied) heart has normal or even increased pumping ability (function) whereas in
the patient with heart disease the function is depressed and the heart may fail. My studies are directed towards
finding out what is the difference in these 2 situations and what mechanisms are responsible for making one big
heart pump well and the other big heart pump poorly. Specifically my project hopes to identify the genes and
proteins responsible for the differences. I have already identified one such gene and I now plan to manipulate
this gene by overexpressing it in animals (transgenic mice) with heart failure. I predict that overexpression of
this gene will improve heart function in models of heart failure. If the hypothesis is correct, activating genes
that are activated in the "athlete's heart" maybe a potential tool for improving heart function, quality of life and
life span in patients with heart failure.
Research achievements (from final report):
-Demonstrated that activating a gene that is critical for the cardioprotective properties of exercise can improve
heart function and life span in heart failure mouse models, and protects the heart against atrial fibrillation., Identified novel genes critical for the protective effects of exercise
Expected future outcomes:
New and improved therapeutics for patients with heart failure and atrial fibrillation
Name of contact:
Dr Julie McMullen
Email/Phone no. of contact:
julie.mcmullen@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 367606
Start Year: 2006
CIA Name: Prof Murray Esler
End Year: 2008
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Mental Health
Total funding: $456,657
Title of research award:
Panic disorder: neurobiology and mechanisms of cardiac riskPanic disorder: neurobiology and mechanisms of
cardiac risk
Lay Description (from application):
Some people are subject to episodes of recurring, often inexplicable anxiety which are very unpleasant and
accompanied by physical symptoms such as sweating, palpitations, tremor and a sensation of suffocation.
Recurring attacks over a period of months, or years, forms the basis for the diagnostic of "panic disorder". It
has until recently been felt that although panic disorder was distressing and disabling, it did not constitute a risk
of life. Sufferers often fear that they have heart disease, because of the nature of their symptoms, but have been
reassured that this is not the case. Recent epidemiological studies, however, indicate that there is an increased
risk in patients with panic disorder. Our hypotheses in this research project are as follow: That some specific
genes predispose to the development of panic disorder - through actions on the nervous system and blood
vessels and that drug treatment (selective serotonin uptake blockers) and psychological treatment (cognitive
behaviour therapy, CBT) reduce cardiac risk in panic disorder. We will test these hypothesis using state of the
art clinical scientific methods. Panic disorder has an important cardiological dimension which needs to be
better understood for cardiac protection to be achieved in panic disorder patients.
Research achievements (from final report):
Panic disorder is a psychologically disabling condition, but additionally, in some sufferers carries a risk of
heart attack, disorders of heart rhythm and sudden death. This research was directed at trying to understand the
mechanisms of heart risk. The findings are: (i) An automatic stimulant system of the nervous system, the
sympathetic nervous system, is markedly activated during panic attacks; (ii) Panic disorder sufferers have a
problem of gene control, an "epigenetic" disorder, involving the noradrenaline transporter gene, which controls
the body mechanism for neutralizing the chemical messenger when is released from sympathetic nerves. This
intensifies the stimulation of the heart during panic attacks, adversely enhancing the stress response in the
heart; (iii) Panic disorder patients have very high rates of release of serotonin by brain neurons (the presumed
chemical basis of the disorder)
Expected future outcomes:
Identification of panic disorder sufferers at heart risk (these are a minority of patients) and provision of
pharmacological cardiac protection, directed at these demonstrated mechanisms of heart risk.,
Name of contact:
Professor Murray Esler
Email/Phone no. of contact:
murray.esler@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 367611
Start Year: 2006
CIA Name: Prof David Kaye
End Year: 2008
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Pharmacology not elsewhere classified
Total funding: $476,265
Title of research award:
Manipulation of intracellular arginine content in endothelial cellsManipulation of intracellular arginine content
in endothelial cells
Lay Description (from application):
The lining layer of blood vessels (termed the 'endothelium') plays a vital role in the control of blood vessel
function. Recently it has been shown that risk factors for heart and vascular disease (smoking, high blood
pressure, high cholesterol and diabetes), heart attack and heart failure are associated with an abnormally
functioning endothelium. In particular, the endothelium maintains blood vessels in a relaxed state, prevents the
formation of blood clots (which may cause heart attack and stroke) and prevents the thickening of blood
vessels. These important actions of the endothelium are explained by the production of nitric oxide (NO) a
small chemical messenger that is derived from an amino acid, L-arginine, which circulates in blood. The
amount of NO produced by endothelial cells is very dependent on the amount of arginine available, and this is
determined by a careful balance between the amount of arginine taken (transported) into cells and the amount
that is destroyed (metabolized) by an enzyme called arginase. Research undertaken in our laboratory is
directed at understanding the important balance between arginine transport and arginase activity, as a basis for
identifying new ways to prevent and treat cardiovascular disease. The current proposal describes a series of
studies which will critically examine the importance of arginine transport and arginase activity, using
transgenic models of over-activity and under-activity of these systems. Once established we will test the
possibility that manipulating these systems may prevent atherosclerosis.
Research achievements (from final report):
Our study identified several novel mechanisms that are responsible for the regulation of intracellular arginine
levels in endothelial cells. Endothelial cells and the level of arginine they have available is very important for
the control of blood vessel function.
Expected future outcomes:
These findings have the potential to improve health by better understanding the control of vascular health and
disease
Name of contact:
Professor David Kaye
Email/Phone no. of contact:
david.kaye@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 367612
Start Year: 2006
CIA Name: Dr Gavin Lambert
End Year: 2008
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Autonomic Nervous System
Total funding: $490,797
Title of research award:
Sympathetic nervous system activation in renal failure. Its contribution to pathogenesis and
progression.Sympathetic nervous system activation in renal failure. Its contribution to pathogenesis and
progression.
Lay Description (from application):
Cardiovascular morbidity and mortality is exceedingly high in patients with chronic renal failure and
particularly end stage renal disease. Recent studies suggest that sympathetic activation contributes substantially
to the development of hypertension, progression of renal disease and cardiovascular prognosis in these patients.
Increased sympathetic nerve firing has been demonstrated in end stage renal disease by the use of clinical
microneurography, which has been attributed to uremia-related toxins. However, renal transplant recipients
with excellent graft function and no signs of uremia still exhibit increased sympathetic nerve firing. Most
interestingly, bilateral nephrectomized patients have nerve firing rates comparable to that of normal control
subjects without renal disease. These data suggest that the diseased kidneys exert excitatory effects on the
sympathetic nervous system independent of correction of uremia. The proposed study aims to comprehensively
investigate the pattern of sympathetic activation both centrally (microneurography) and regionally (radiotracer
dilution methodology) in patients with chronic renal failure and end stage renal disease . The effect of the
centrally acting sympatholytic drug rilmenidine on sympathetic activity in the setting of renal disease will be
assessed. Patients with ESRD waitlisted for kidney transplantation will be studied before and after
transplantation. Some of the transplant recipients will also have undergone uni- or bilateral nephrectomy before
transplantation which will enable us to further explore the role of the diseased kidneys in sympathetic
activation. The results of this study may prove to have significant implications for treatment and prevention of
cardiovascular morbid events frequently associated with renal disease.
Research achievements (from final report):
Measurements of muscle sympathetic nerve activity in patients with chronic (CRF) and end stage renal disease
(ESRD) have generated evidence for the involvement of sympathetic activation in the progression of renal
disease and the associated increase in blood pressure. Furthermore, regional spillover of noradrenaline from the
kidneys is elevated in a substantial number of patients with CRF and particularly in those with ESRD. Most
interestingly, in the context of the substantially elevated cardiovascular risk in these patients, cardiac
noradrenaline spillover is significantly related to the degree of renal impairment, indicating that the high
cardiovascular risk in this patient group is possibly mediated, at least in part, via a specific activation of the
cardiac sympathetic nervous outflow. Furthermore, echocardiographic and MRI assessment of left ventricular
structure provides clear evidence of left ventricular hypertrophy in both ESRD and CRF compared to healthy
subjects. Importantly, inhibition of sympathetic activation in our patients does not only lower blood pressure
but also results in regression of LV hypertrophy. An important development from this project is our
involvement in a novel treatment approach to selectively inhibit renal sympathetic nerve activation by a
catheter based ablation procedure via the renal arteries. The procedure is safe and effective in that it reduces
renal noradrenaline spillover by 35-65%. Most importantly, renal nerve ablation is associated with a
pronounced and sustained reduction in mean arterial blood pressure with typical changes ranging between 2030 mmHg, despite concurrent antihypertensive treatment with typically more than 3 drugs.
Expected future outcomes:
Data from these studies may serve as the ultimate proof for a substantial involvement of renal sympathetic
nerves in the blood pressure rise and possibly the poor prognosis associated with CRF, ESRD and the
associated elevated blood pressure. Selective, catheter-based sympathetic renal denervation offers hope in
improving morbidty in these patient groups.
NHMRC Research Achievements - SUMMARY
Name of contact:
A/Prof Markus Schlaich
Email/Phone no. of contact:
markus.schlaich@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 367621
Start Year: 2006
CIA Name: Prof Mark Cooper
End Year: 2008
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Endocrinology
Total funding: $438,521
Title of research award:
Role of epigenetic mechanisms in diabetic vascular complicationsRole of epigenetic mechanisms in diabetic
vascular complications
Lay Description (from application):
Diabetic complications including heart attacks, strokes, kidney disease and blindness appear to be related to the
high glucose (sugar) level but how glucose itself induces end-organ injury remains to be fully determined. In
this proposal it is suggested that the long-term damaging effects of glucose relate to its ability to damage the
regulation of genes by directly affecting DNA and its covering known as histones. Specifically glucose,
possibly by altering certain biochemical pathways called oxidation pathways, interferes with enzymes which
affect the structure of DNA and related molecules resulting in altered expression of many proteins. One of
these proteins known as NF kappa B is activated in diabetes, probably by mechanisms involving regulation of
these enzymes which play a central role in modifying gene structure. By clarifying the exact mechanisms at a
molecular level that mediate the effect of glucose on genes and proteins it will be possible to target these
molecules and develop new treatments to prevent, retard or reverse the blood vessel complications that are so
common in diabetes.
Research achievements (from final report):
Diabetic complications including heart attacks, strokes, kidney disease and blindness appear to be related to the
high glucose (sugar) level but how glucose itself induces end-organ injury remains to be fully determined. In
this study we defined how long-term damaging effects of glucose are related to the regulation of genes by
directly affecting DNA and its covering known as histones. Specifically glucose, by altering certain
biochemical pathways called oxidation pathways, interferes with enzymes which affect the structure of DNA
and related molecules resulting in altered expression of many proteins. One of these proteins known as NF
kappa B is activated in diabetes, probably by mechanisms involving regulation of a particular enzyme which
play a central role in modifying gene structure. By clarifying the exact mechanisms at a molecular level that
mediate the effect of glucose on genes and proteins it will now be possible to target these molecules and
develop new treatments to prevent, retard or reverse the blood vessel complications that are so common in
diabetes.
Expected future outcomes:
By clarifying the exact mechanisms at a molecular level that mediate the effect of glucose on genes and
proteins it will now be possible to target these molecules and develop new treatments to prevent, retard or
reverse the blood vessel complications that are so common in diabetes.
Name of contact:
Assam El-Osta
Email/Phone no. of contact:
assam.el-osta@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 367625
Start Year: 2006
CIA Name: A/Pr Merlin Thomas
End Year: 2008
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Nephrology and Urology
Total funding: $297,523
Title of research award:
Circulating low -molecular weight AGEs in the development and progression of diabetic
complicationsCirculating low -molecular weight AGEs in the development and progression of diabetic
complications
Lay Description (from application):
High levels of sugars seen in patients with diabetes leads to damage of many organs including the heart, the
eyes and the kidneys. These high sugars cause damage through a number of mechanisms, one being the
formation of advanced glycation end products or AGEs, formed by the irreversible reaction between proteins
and glucose. This reaction leads to a change in the shape and function of AGE-modified molecules that
progressively contributes to organ damage. AGEs also bind and activate specific receptors that promote the
damage and scarring of tissue. Where the glucose concentration is high, AGEs accumulate much more quickly.
This is one reason why patients with good sugar control do better than those who are unable to control their
blood sugars. The importance of this AGE pathway is illustrated by the fact that blocking the formation of
AGEs is able to prevent kidney damage in animals with diabetes. In addition, exposure to AGEs can cause
diabetes-like changes in the absence of high sugars. Our laboratory is a world leader in the study of the
advanced glycation and methods blocking this process. The research proposed will investigate circulating
levels of AGEs in experimental animals and patients with diabetes, and correlate them with the development
and progression of complications of diabetes
Research achievements (from final report):
AGEs are formed when sugars bind to protein, making it sticky, sweet and brown. In food like chocolate and
caramel, this reaction is appetizing. But when sugar accumulates in diabetes, this same process contributes to
blindness, kidney failure and heart disease. This grant has examined the damage caused by AGEs and ways of
measuring their accumulation. In diabetes, tissue such as lens, skin and cartilage as well as circulating proteins
become fluorescent. I have shown that this correlates with the development and severity of diabetic
complications. This increase in fluorescence has been attributed to the accumulation of AGEs. In this work, we
describe the chemical identity of the major 'AGE- fluorophores' in the circulation. I have used this data to
develop quantitative assays that will increase understanding of this chemistry. I have also been able to measure
each these fluorophores in over 300 blood samples and determined which peaks are best associated with
cardiovascular and kidney (dys)function. The potential utility of this methodology can be illustrated by my
studies in children with type 1 diabetes, that showed that a gluten-free diet also reduced the accumulation of
fluorophores. I have also completed in experimental studies some of their potential regulators. For example,
mice deficient in the receptor for advanced glycation (RAGE) do not increase circulating levels of
fluorophores, paralleling their protection from diabetes associated vascular complications. Similarly animals
that do not increase their kidney function in response to diabetes, actually have an increase in circulating
fluorophores and a worse outcome.
Expected future outcomes:
It is anticipated that a better understanding of the mediators of circulating fluorescence will lead to improved
risk assessment not only in diabetes but also cardiovascular disease and ageing. It will also facilitate new trials
of interventions whose focus is to reduce advanced glycation.
Name of contact:
A/Prof Merlin Thomas
Email/Phone no. of contact:
mthomas@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 367626
Start Year: 2006
CIA Name: Prof Jaye Chin-Dusting
End Year: 2011
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: Established Career Fellowships
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $735,472
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
As a basic scientist in a clinical environment, I have successfully developed the capacity to bring advances that
are usually limited to the basic sciences into the clinical arena. Much of my work starts at cellular and preclinical discoveries which are then validated and progressed in man. A recent example is our novel work on the
anti-inflammatory aspects of high density lipoprotein which identifies a new functional mechanism for HDL,
findings which were validated in patient groups and where a robust, high throughput assay was developed
which is currently used for lead candidate selection in collaboration with NIH and separately with Hoffmann
La Roche (Basel, Switzerland) and Lipid Sciences, Inc. (California, US)., Another proven translational
outcome of my previous research has been in the management of hepatic cirrhosis. This involved successfully
re-dressing the gut flora/nitric oxide imbalance which then returned cardiovascular function to normal in
cirrhosis. Since then, international editorial comments, independent clinical trials and successful case studies
have followed evidencing a direct contribution towards health practice.
Expected future outcomes:
My Future Research Plans are aimed at 3 Deliverables:, successfully manipulating
intracellular L-arginine concentrations for restoration of endothelium function in vascular disease , novel therapy focused on
inflammation and exploiting the original finding that HDL have potent monocytic anti-inflammatory effects , identifying new biomarkers and mediators in cardiovascular disease (CVD)
Name of contact:
Jaye Chin-Dusting
Email/Phone no. of contact:
jaye.chin-dusting@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 367627
Start Year: 2006
CIA Name: Prof Alexander Bobik
End Year: 2011
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: Established Career Fellowships
Main RFCD: Medical and Health Sciences not elsewhere classified
Total funding: $805,133
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
Demonstrated the importance of the immune system for the development and progression of atherosclerosis,
defining the importance of different B cell subtypes and their roles in either promoting or protecting from
atherosclerosis. Demonstrating the importance of cell necrosis and rlease of HMGB1 for progression of
atherosclerosis, the importance of CD4+ NKT cells as well as regulatory CD4+CD25+ T cells and CD8+ T
cells.
Expected future outcomes:
Expect to translate some of the findings to prevent development/progression of human atherosclerosis and its
complications.
Name of contact:
Alexander Bobik
Email/Phone no. of contact:
alex.bobik@baker.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 367628
Start Year: 2006
CIA Name: Prof Peter Little
End Year: 2011
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: Established Career Fellowships
Main RFCD: Medical and Health Sciences not elsewhere classified
Total funding: $639,194
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
The focus of the work was cardiovascular disease and the underlying process of atherosclerosis.
Atherosclerosis in humans commences with a pre-inflammatory stage involving the trapping of lipids in the
vessel wall by modified proteoglycans followed by an inflammatory stage involving multiple immune cells
resulting in the formation of atherosclerotic plaques. Treatments for atherosclerosis are directed at the above
risk factors but even in clinical trials these strategies only prevent one third of the cardiovascular events. What
is required is a greater understanding of the mechanisms of plaque formation and determinants of stability and
liability in the vessel wall and the generation of novel therapeutic agents which address these drivers of the
atherosclerotic process. My laboratory worked on modified proteoglycans and we discovered a process and a
drug that could inhibit the modifications to proteoglycans in the vessel wall that makes it stickier for
cholesterol - this drug reduced lipid deposition in a mouse model of atherosclerosis. We following work will be
aimed at identifying the exact target of the action of the drug and developing new agents suitable for use in
humans. Such as agent would be used with a lipid lowering statin drug with the aim of greatly reducing
cardiovascular events.
Expected future outcomes:
These studies have contribuited to the understanding of the disease process of atherosclerosis and provided a
patwhay to the development of new targetted drugs to prevent this disease and reduce heart attacks.
Name of contact:
Prof Peter Little Am
Email/Phone no. of contact:
peter.little@rmit.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 367629
Start Year: 2006
CIA Name: Prof Bronwyn Kingwell
End Year: 2008
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: Established Career Fellowships
Main RFCD: Clinical Sciences not elsewhere classified
Total funding: $357,250
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
Since award of the fellowship in 2006 my laboratory has made significant progress in three main, clinically
relevant areas., 1. HDL and metabolism, Demonstration that HDL cholesterol lowers blood glucose in patients
with type 2 diabetes through a variety of novel mechanisms including both increased glucose uptake into
skeletal muscle and increased secretion of insulin from pancreatic beta cells. This work has implications for the
use of HDL-raising agents for treatment of type 2 diabetes., 2. Peripheral Arterial Disease, Demonstration that
the ACE inhibitor, ramipril has efficacy in controlling claudication more effectively than current therapies. Our
work demonstrates that ramipril has benefits beyond reduction in vascular events in this high-risk population,
and provides substantial improvement in clinical symptoms and quality of life. , 3. Marfan Syndrome, In
patients with Marfan syndrome, therapy with the ACE inhibitor, perindopril for 24 weeks reduced aortic
stiffness by up to 60% and aortic diameter by between 3 and 7 mm. These are substantial changes over a
relatively short intervention period and are highly clinically significant. It is likely that ACE inhibitor therapy
would delay the need for surgery and reduce the incidence of aortic rupture. , ACE inhibitors are now
recommended in the latest guidelines for patients with peripheral arterial disease and Marfan Syndrome as a
result of my work.
Expected future outcomes:
All three areas listed above will move into further clinical trials in 2010 and will make important contributions
to the evidence base for treatment of type 2 diabetes, peripheral arterial disease and abdominal aortic aneurysm.
Name of contact:
Prof. Bronwyn Kingwell
Email/Phone no. of contact:
bronwyn.kingwell@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 367630
Start Year: 2005
CIA Name: Prof David Kaye
End Year: 2006
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Development Grants
Main RFCD: Gene Therapy
Total funding: $187,000
Title of research award:
Mechanically-restricted percutaneous gene therapeutic solutions for heart failure.Mechanically-restricted
percutaneous gene therapeutic solutions for heart failure.
Lay Description (from application):
We have developed a novel system for the localized delivery of specialised genes to the heart in order to
improve contractility and function of a failing heart. Many genes, for reasons of toxicity, clearance, or uptake,
require direct delivery to the target region without spillover to the systemic circulation. Our system addresses
these issues by isolating the local circulation of the target organ and directly delivering the agent with minimal
systemic loss and improved delivery and uptake efficiency, while minimizing potentially dangerous and toxic
systemic effects.
Research achievements (from final report):
The V-Focus system demonstrated in this project is a non-surgical delivery system for the selective delivery of
agents to the heart. The system isolates the heart circulation from the rest of the body, avoiding the toxicity
associated with delivery to non-targeted regions and enables higher dose rates and prolonged exposure for
increased uptake and efficacy. The system enables a safe and reliable method for the delivery of genes and
cells to the heart with minimal loss to the systemic circulation and expression in other organs., The first
application for the system is the delivery of agents for the treatment of congestive heart failure (CHF).
Approximately 500,000 people in Australia and 23 million people worldwide suffer from CHF with 50,000 and
2 million new cases diagnosed annually in Australia and worldwide respectively. CHF has a five year survival
rate of 50% in moderate heart failure, whilst in severe cases the 1 year survival rate may be as low as 20%. Use
of the V-Focus system is expected to enable targeted delivery and high uptake of therapeutic agents to treat
CHF. Globally the direct and indirect costs for CHF are estimated to be as high as US$56 billion, with costs for
medication in the US alone as high as US$2.7 billion in 2004.
Expected future outcomes:
This device is currently at a pre-clinical, proof of concept stage. Clinical use of the device is expected to
capture a significant proportion of the CHF market.
Name of contact:
David Kaye
Email/Phone no. of contact:
david.kaye@baker.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 367631
Start Year: 2006
CIA Name: Prof Geoffrey Head
End Year: 2010
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: Established Career Fellowships
Main RFCD: Basic Pharmacology
Total funding: $714,574
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
The main thrust of my research is in the understanding of the role of brain pathways and neurotransmitters
regulating the cardiovascular system through the autonomic nervous system. In a major study using a
chronically instrumented rabbits we have been able to unravel the contribution of the sympathetic nervous
system to cardiovascular regulation in renovascular hypertensive rabbits. Together with Roger Evans from
Monash University we have found subtle changes to the regulation of kidney medullary blood flow which may
promote hypertension. We have shown that chronic elevation of angiotensin in rabbits leads to long term
activation of specific autonomic regions in the hypothalamus. In our most recent study we have shown changes
to the integration of responses to stress and hypoxia which may be directly related to the CNS changes we have
observed. We are now pursuing the effects of chronic stress and its interaction with CNS actions of angiotensin
in our new NHMRC grant starting this year. , A second major area has been a clinical translational study which
has applied a new mathematical algorithm to ambulatory blood pressure recordings to calculated the rate of rise
in morning blood pressure. We showed that hypertensives have a greater rate of rise than normotensives. I have
further developed the concept by calculated a novel measure of the effective power of the blood pressure rise
given by the product of the rate and amplitude and related these measures to clinical predictors. I am now
assessing the relationship between morning surge in blood pressure and the reactivity of the sympathetic
nervous system in selected patients. Other research areas of interest involve collaborations with other
laboratories (7 within the Baker Institute, 11 with international and national research laboratories and 2 with
industry). In additional, a collaboration with Professor Elena Lukoshkova (Moscow) and Dr Simon Malpas
Expected future outcomes:
My research into the activity of natriuretic peptides isolated from the venom of the Taipan snake by Dr Paul
Alewood from the Institute of molecular Bioscience at the university of Queensland resulted in a profile of
activity of some peptides which was suitable for development of a compound to treat heart failure. We have
patented the work and formed a company Elacor to commercialize the findings.
Name of contact:
Prof. Geoffrey Head
Email/Phone no. of contact:
geoff.head@baker.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 367643
Start Year: 2006
CIA Name: A/Pr Assam El-Osta
End Year: 2008
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $474,518
Title of research award:
Transcriptional regulatory complexes associated with cardiac hypertrophyTranscriptional regulatory complexes
associated with cardiac hypertrophy
Lay Description (from application):
Following the success in decoding human genome, i.e. DNA sequence, a major task is to understand how the
activity of genes with consequent changes in respective proteins. As proteins are an important component for
cell structure and function, such changes in quantity and quality of proteins will play a pivotal role to affect
disease development and progression. It has been well known that a group of genes are altered (up or down)
in the heart under conditions such as heart muscle overgrowth (ie hypertrophy), aging or of abnormal beating
function. The reasons for such altered gene activity remain poorly understood. Although recent studies from
research on genetics or cancer have revealed the important role of the DNA and DNA-bound proteins (called
histone) in the control of gene activity, this has rarely been studied in the heart. In this project, we will test our
hypothesis that DNA-histone structure is a key factor that control gene activities in ageing and diseased heart.
This proposal is supported by our recent findings showing that in the hypertrophied heart, such DNA-histone
structure did alter in such a way that fits well with alterations in gene activity. We have planned a series of
studies to test this hypothesis in a systematic fashion. A number of sophisticated and cutting-edge techniques
and experimental models of heart hypertrophy will be used. We will analyse changes in activities of a number
of selected genes in the heart and also analyse changes in DNA-histone structures and chemical modifications
at particular regions. These changes will then be linked together. We will also explore the possibility of
modulating DNA-histone structure, thereby controlling the degree of cardiac hypertrophy. This project is the
joint efforts of scientists with substantial experience in research on gene activity and heart diseases, and is
highly likely to generate novel information to and hold significant therapeutic potential.
Research achievements (from final report):
This is a new area of research in both the epigenetics and cardiology fields. We believe the landmark findings
of this work will have a significant impact on our understanding of transcriptional events associated with heart
disease. This work challenges the textbook descriptions of gene expression in the hypertrophied heart and thus
deals with reassessing current dogma.
Expected future outcomes:
A better understanding on the epigenetic factors in controlling gene transcription in the compromised heart will
advance the current knowledge of the mechanism responsible for molecular remodeling in the hypertrophic and
failing heart.
Name of contact:
A/Prof Assam El-Osta
Email/Phone no. of contact:
assam.el-osta@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 367645
Start Year: 2006
CIA Name: Prof Karlheinz Peter
End Year: 2008
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $496,518
Title of research award:
Novel selective anti-platelet and clot-specific anticoagulant strategies targeting conformational states of
GPIIb/IIIaNovel selective anti-platelet and clot-specific anticoagulant strategies targeting conformational states
of GPIIb/IIIa
Lay Description (from application):
The inhibition of platelets and the inhibition of coagulation factors are among the most widely used drugs in
medicine and provide major benefits for numerous patients. Prevention and treatment of thrombosis, emboli,
stroke and heart attack are examples of the many diseases where anti-platelet and anticoagulant drugs are
administered. However, the downsides of these drugs are bleeding complications, which can result in death or
disability. The consequences of these drug-associated bleeding complications are also a major financal burden
for our health care system. Thus, progress towards therapeutic strategies with less bleeding complications is
highly sought-after. The proposed project aims to generate new antibody-based agents for platelet inhibition.
One group of these agents do only block platelets when they are activated. Furthermore, these agents allow an
enrichment of potent inhibitors of coagulation factors at the site of the clot. Thus, these inhibitors should
predominatly act at the site where they are needed. At the same time the overall concentration of inhibitors of
coagulation factors can be kept low and the functions of non-activated platelet can be left intact. Overall, the
proposed project aims for the development of novel anti-platelet and anticoagulant strategies with high antithrombotic efficacy and low bleeding risks.
Research achievements (from final report):
Achievements: 1) We were able to define a mechanism by which clinically used GPIIb/IIIa blockers, which are
all ligand-mimetics, cause paradoxical platelet activation. We found that con-comitant ADP receptor blockade
prevents these paradoxical platelet-activating effects. This finding has direct clinical implications. , 2) We
could prove that activation-specific antibodies against GPIIb/IIIa are effective anti-platelet agents in an in vivo
mouse model of thrombosis. Most importantly this anti-platelet effect could be achieved without prolongation
of bleeding times. , 3) We further developed/tested a single-chain antibody that only binds to a ligand-induced
binding site (LIBS) of GPIIb/IIIa. This antibody allows unique targeting to activated platelets and thereby
targeting towards clots. Using this antibody in a therapeutic approach, we constructed a recombinant fusion
protein with the highly potent factor Xa inhibitor, TAP (tick anticoagulant peptide). This resulted in a highly
efficient anticoagulation without bleeding time prolongation. , 4) Based on our data demonstrating highly
specific binding of anti-GPIIb/IIIa single-chain antibodies to activated platelets, we started using these
antibodies for diagnostic targeting of magnetic resonance contrast agents. We were able to image vessel injury,
thrombosis and vascular inflammation. Imaging activated platelets with activation-specific anti-GPIIb/IIIa
antibodies even allowed to demonstrate the involvement of platelets and the early detection of cerebral malaria.
In addition, we could demonstrate that these antibodies can image thrombus development and thrombolysis in
mice., 5) We also targeted another integrin, Mac-1, which is expressed on leukocytes and which is involved in
coagulation, inflammation and pathogen defense. We were able to generate single-chain antibodies that are
specific for the active conformation of Mac-1. We could demonstrate its diagnostic as well as its therapeutic
application.
Expected future outcomes:
The ultimate goal is the development of diagnostic and therapeutic applications in humans. We will further
develop molecular imaging approaches for the identification of thrombi/emboli, vulnerable plaques and
inflammatory processes. In addition, we will follow a commercial development of novel anticoagulative and
anti-platelet approaches that come with less bleeding complications.
Name of contact:
NHMRC Research Achievements - SUMMARY
Karlheinz Peter
Email/Phone no. of contact:
karlheinz.peter@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 367647
Start Year: 2006
CIA Name: A/Pr Assam El-Osta
End Year: 2008
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: Career Development Fellowships
Main RFCD: Medical Biochemistry: Nucleic Acids
Total funding: $272,000
Title of research award:
The generlaity of the SWI/SNF regulatory complex in mental health and cardiovascular diseaseThe generlaity
of the SWI/SNF regulatory complex in mental health and cardiovascular disease
Lay Description (from application):
Media Summary not available
Research achievements (from final report):
The human epigenome regulates critical nuclear events involved in normal cell development, however, these
molecular processes are deregulated in human disease. During the development of the heart it is known that a
complex repertoire of inductive molecular signals and cardiogenic specific transcription factors are essential
for heart development. The hypertrophied and failing myocardium is characterized by profound changes in
gene transcription. However, it is not known whether an epigenetic program is implicated in gene regulation
during heart failure. I have exciting experimental evidence that SWI/SNF is critical in regulating gene activity
associated with heart disease. In heart disease we have identified specific regulatory proteins central to the
expression of genes associated with left ventricular hypertrophy.We have defined components of the
corepressor and coactivator complexes that are required for gene activity, our results suggest the demonstrable
exchange of coactivator and corepressors dictates the level of gene expression.As a result of ongoing work
initiated in the CDA, I have hypothesized that one of the critical functions of these complexes is to integrate
transcriptional output in response to input from multiple signaling pathways. The presence of SWI/SNF
associated components in multiple complexes, coupled with their biological roles in development, presents an
ideal model for elucidation of basic principles of regulatory gene expression and the generality of this
regulation.
Expected future outcomes:
A better understanding of the underlying mechanism regulatoing gene expression critical to hypertrophy and
potential gene targets for therapy.
Name of contact:
A/Prof Assam El-Osta
Email/Phone no. of contact:
assam.el-osta@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 367648
Start Year: 2006
CIA Name: Dr Elisabeth Lambert
End Year: 2010
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: Career Development Fellowships
Main RFCD: Autonomic Nervous System
Total funding: $462,290
Title of research award:
Physiological, biological and genetic abnormalitities associated with the postural tachycardia
syndromePhysiological, biological and genetic abnormalitities associated with the postural tachycardia
syndrome
Lay Description (from application):
Postural Orthostatic Tachycardia Syndrome (POTS) is a clinical syndrome characterized by the development of
excessive tachycardia (heart rate increases by 30 beats or more per min) when the upright position is assumed.
The condition is accompanied by weakness, dizziness, presyncope or fainting. POTS has only recently come to
international medical attention as the number of patients with the condition is steadily rising. The symptoms
and ongoing disability in POTS appear to primarily result from a supernormal reflex sympathetic activation on
standing, in ways which are readily apparent for some symptoms, such as tachycardia, but obscure for others,
such as postural syncope in the absence of postural hypotension. Poorly defined diagnostic criteria and the
likelihood of multiple causes have made it difficult to clarify the underlying pathophysiology of POTS. In this
project I will investigate the sympathetic nervous system response to head-up tilt in patients with POTS as well
as possible genetic and epigenetic mechanisms which might underpin the syndrome. Preliminary results are
encouraging and merit to be taken further.
Research achievements (from final report):
, My first aim was to understand the physiological, biological and genetic abnormalities associated with the
condition Postural tachycardia syndrome (POTS). I investigated how the sympathetic nerves responded to the
upright position by using a number of techniques including noradrenaline (NA) plasma kinetics and muscle
sympathetic nerve activity (MSNA) . Results indicate that sympathetic activity is excessive during standing in
POTS patients. Subcutaneous forearm vein biopsy allowed to extract sympathetic nerves for measurement of
the expression of noradrenaline transporter (NET) protein, which is essential for the termination of the nerve
firing signal. Results indicate that this protein is very low in the patients. Last, we performed some genetic
analysis and discovered that a specific epigenetic mechanism underlies the impairment of NET function in
POTS and is a causal factor in the disorder., My second aim was to understand how the sympathetic nerves
impacts on the heart, renal, and vessels in obesity and to assess the benefit of a low calorie diet. I demonstrated
that the activationof the sympathetic nerves in obesity was a major cause for damaging various organs and that
diet improved the condition by reducing the activity of the nerves.
Expected future outcomes:
In POTS indicate that NET function is crucial in the sympathetic response associated with posture and that
targeting NET activity may represent a novel target in the treatment of POTS. In obesity, sympathetic nerves
are also crucial in generating damages to the organs indicating that sympathetic ihnibition should be a goal in
the treatment of obesity to alleviate the cardiovascular risks.
Name of contact:
.Elisabeth Lambert
Email/Phone no. of contact:
elisabeth.lambert@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 367650
Start Year: 2006
CIA Name: A/Pr Markus Schlaich
End Year: 2009
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: Career Development Fellowships
Main RFCD: Autonomic Nervous System
Total funding: $299,500
Title of research award:
Role of sympathetic activation for pathogenesis and cardiovascular complications of patients with chronic renal
failureRole of sympathetic activation for pathogenesis and cardiovascular complications of patients with
chronic renal failure
Lay Description (from application):
Not Available
Research achievements (from final report):
My findings indicate that the activity of specific nerves in the kidney is elevated in chronic renal disease and
contributes substantially to the elevation in blood pressure comonly seen in these patients.Perhaps more
important is the finding of a concomitant increased central sympathetic nerve outflow, which also adversely
affects other organs such as the heart and the peripheral blood vessels. Based on these findings we have
explored strategies to alter both efferent and afferent nerve activity including a newly developed catheter based
renal denervation approach to silence these nerves. Therapeutic renal denervation has been explored in man
with surgical removal of native kidneys and radical surgical removal of sympathetic nerves, and has been
shown to be an effective means of blood pressure control. In an on-going "first-in-human" research project we
have looked into the safety and feasibility of a novel catheter based device to functionally denervate the
kidneys in patients with resistant hypertension and also in patients with end stage renal disease. Preliminary
results are very promising with regards to both safety and effectiveness of the procedure, with an average
reduction of ~25-30 mmHg in systolic blood pressure in patients who are on at least 3 different
antihypertensive drugs. This novel approach may have wide ranging implications for future treatment of
hypertension, chronic renal disease and potentially other condition characterized by heightened sympathetic
tone.
Expected future outcomes:
I expect that our catheter based approach to denervate the human kidney will become routine clinical practice
within the next 3-4 years and will provide new hope for many patients suffering from severe forms of
hypertension and renal disease.
Name of contact:
A/Prof Markus Schlaich
Email/Phone no. of contact:
markus.schlaich@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 367651
Start Year: 2006
CIA Name: A/Pr Karin Jandeleit-Dahm
End Year: 2008
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: Career Development Fellowships
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $272,000
Title of research award:
Elucidating the metabolic & inflammatory pathways in diabetic macrovascular disease: experimental and
clinical studies.Elucidating the metabolic & inflammatory pathways in diabetic macrovascular disease:
experimental and clinical studies.
Lay Description (from application):
Not Available
Research achievements (from final report):
During the time of the NHF/NHMRC CDA I have made significant discoveries in terms of the role of
inflammation and oxidative stress in diabetes related vascular complications. For example, I could show that
the AGE/RAGE axis plays an important role in diabetes assictaed atherocslerosis. RAGE deletion in diabetic
apoE KO mice was associated with reduced plaque area via effects on inflammation and ROS generation.
Furthermore, I could demonstrate that oxidative stress related pathways play a major role in diabetic vascular
comlications. Specific NOX KO mice demonstrate less plaque area and microvascular disease in diabetes. I
have also been able to confirm findings obatined in our expetimental animal models in human atherosclerotic
plaques from patients with and without diabetes.
Expected future outcomes:
The results of my ongoing research will further delineate the role of inflammation and oxidative stress in
diabetes associated vascular complications. Furthermore, based on our experimental findings, we have
identified novel treatment targets. These findings need to be translated to the clinical context.
Name of contact:
Karin Jandeleit-Dahm
Email/Phone no. of contact:
karin.jandeleit-dahm@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 367660
Start Year: 2006
CIA Name: Dr Anna Calkin
End Year: 2012
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: Early Career Fellowships
(Australia)
Main RFCD: Endocrinology
Total funding: $241,125
Title of research award:
Diabetes-Associated Atherothrombosis: Characterisation of Platelet Activation andDiabetes-Associated
Atherothrombosis: Characterisation of Platelet Activation and
Lay Description (from application):
Not Available
Research achievements (from final report):
Stroke and heart attack are the major causes of death amongst individuals with diabetes, which is of great
concern given that over 1 million Australians are estimated to have diabetes. Small blood cells known as
"platelets" stick to diseased areas of the blood vessel, accumulating at the site of injury to form a blood clot.
However, excessive accumulation of platelets can lead to a clot that may block blood flow resulting in a stroke
or heart attack. It has been suggested that individuals with diabetes have platelets which are "hyper-reactive" or
"stickier" and thus are more likely to form larger blood clots, leading to a greater risk of stroke and heart attack.
It is known that high levels of HDL "good" cholesterol are associated with a reduced risk of heart disease but
little is known about its effects on platelet reactivity. My studies focused on the effect of a particular type of
HDL called reconstituted HDL (rHDL) which is cholesterol "poor". We demonstrated that individuals with
type 2 diabetes remarkably had a greater than 50% reduction in the reactivity of their platelets after a 4-hour
infusion of rHDL. Further studies demonstrated that the cholesterol poor rHDL was able to accept cholesterol
from the platelets themselves which made them less reactive and behave more like platelets seen in nondiabetic individuals. This suggests that raising levels of rHDL may be a promising therapy to reduce the risk of
stroke and heart attack in individuals with diabetes., , CAVEAT: If this summary and future outcomes is to be
made available to the public please contact bronwyn.kingwell@bakeridi.edu.au to comply with MTA
agreements with CSL.
Expected future outcomes:
Future studies are required to investigate therapies that can raise levels of "cholesterol poor" HDL in both the
short- and long-term as well as examine whether raising cholesterol poor HDL has benefit above and beyond
current anti-clotting therapies.
Name of contact:
Anna Calkin
Email/Phone no. of contact:
acalkin@mednet.ucla.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 418902
Start Year: 2007
CIA Name: Prof Gavin Lambert
End Year: 2012
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Research Fellowships
Main RFCD: Clinical Sciences not elsewhere classified
Total funding: $677,718
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
I am a neurochemist-clinical research scientist investigating the interaction between, in particular, brain
monoaminergic activity, autonomic function and physiological responses. My studies are largely focussed on
determining the aetiology and consequenc
Research achievements (from final report):
My projects are associated with three research themes: psychological stress, obesity and hypertension. These
projects are fundamentally linked in terms of the significant co-morbidity that they share and that the
underlying pathologies are initiated and sustained by disturbances in sympathetic regulation. Studies in
depression aimed to identify the consequences of sympathoexcitation and to develop novel cardioprotective
strategies in this high risk patient group. In obesity and the metabolic syndrome we investigated sympathetic
dysfunction along the diabetic continuum and continue to examine the benefits of weight loss within different
strata of metabolic risk. In hypertension our work was pivotal in the development of new treatment approaches
targeting the renal sympathetic nerves.
Expected future outcomes:
Development of novel therapeutic approaches for the treatment of clinically important diseases such as
depression, obesity and high blood pressure.
Name of contact:
Gavin Lambert
Email/Phone no. of contact:
gavin.lambert@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 418916
Start Year: 2007
CIA Name: Prof Mark Cooper
End Year: 2009
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $389,522
Title of research award:
Role of advanced glycation end products and their receptors in diabetes accelerated atherosclerosisRole of
advanced glycation end products and their receptors in diabetes accelerated atherosclerosis
Lay Description (from application):
Diabetes is on the increase in the Western world and with this increase comes the burden of increased
complications. One of these is atherosclerosis which leads to heart attacks, strokes and gangrene. In this grant
we consider the role of a biochemical reaction where sugar attaches to proteins called advanced glycation and
how these advaced glycated proteins (AGEs) interact with specific receptors to promote atherosclerosis. We
will use novel animal models overexpressing the receptor RAGE or with deletion of the gene for this receptor.
We will investigate if these animals are protected against blood vessel disease when made diabetic and will
unravel the mechanisms involved. Furthermore we will investigate novel drugs to block vessel damage in a
model of diabetic mice prone to atherosclerosis. One of these interventions will involve giving a free form of
the receptor RAGE which will trap the circulating AGEs and prevent them from binding to RAGE in the blood
vessel wall. This therpeutic principle has been shown in animals to prevent blood vessel disease in diabetes.
We will also feed the sugar-attached proteins (AGEs) to these mice prone to atherosclerosis and to the
genetically modified mice to see how these proteins directly influence the vessel wall even if diabetes is not
present. These studies will ultimately lead to better treatments to prevent, slow down or reverse blood vessel
damage in diabetes.
Research achievements (from final report):
The findings of this grant showed that RAGe deletion protected form diabetes associated atherosclerosis via
effects on inflammation and fibrosis. Furthermore, there was attenuation of vascular macrophage and
lymphocyte infiltration suggetsing that RAGE expression on immune cells mat play an important part in
diabetes related atherosclerosis.
Expected future outcomes:
These findings further support the ongoing drug discovery program to develo RAGE antagonists for clinical
use in diabetci vacsular complications.
Name of contact:
Prof Mark Cooper
Email/Phone no. of contact:
mark.cooper@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 418920
Start Year: 2007
CIA Name: Prof Bronwyn Kingwell
End Year: 2009
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Endocrinology
Total funding: $349,683
Title of research award:
Novel Metabolic Actions of HDL with Potential Therapeutic Implications for Type 2 Diabetes and the
Metabolic Syndrome.Novel Metabolic Actions of HDL with Potential Therapeutic Implications for Type 2
Diabetes and the Metabolic Syndrome.
Lay Description (from application):
There are currently in excess of 170 million patients diagnosed with type 2 (late onset) diabetes in the world
and this figure is expected to double by 2030. Almost one in four Australians 25 years and over has either
diabetes or a condition of impaired glucose metabolism. These conditions pose significant problems in terms
of both individual suffering and economic burden. Poor diet, sedentary lifestyles with resultant weight gain
and increased obesity rates underlie the escalating prevalence of type 2 diabetes. Our proposal investigates a
novel approach to treat these conditions. We have identified an important link between HDL (good)
cholesterol and glucose and fat metabolism in human muscle cells. We have shown that HDL increases
glucose uptake into muscle cells. This process would be expected to remove glucose from blood vessels
where it causes damage which ultimately contributes to heart attack and stroke. Furthermore, we have shown
that HDL increases the amount of fat the body uses. HDL may therefore not only remove damaging fat from
blood vessels, but also help to reduce body weight. Our study seeks to determine the relevance of these
mechanisms in both healthy individuals and patients with type 2 diabetes. At the conclusion of this grant we
expect to understand whether HDL raising strategies may be a an effective new therapy for type 2 diabetes.
Specifically, we will understand: 1. how HDL exerts its beneficial effects and 2. whether acute and chronic
HDL elevation using drugs improves glucose and fat metabolism in humans.
Research achievements (from final report):
, This research concerned HDL (good cholesterol) which is well known for its protective actions in the context
of cardiovascular disease. The most significant outcome was the discovery that HDL elevation over a 4 hour
period lowers blood glucose in patients with type 2 diabetes. Studies in cells have uncovered novel
mechanisms in both muscle and the pancreas to explain our observation. This work represents a paradigm shift
from low HDL being a bystander to active player in the glucose intolerance of the metabolic syndrome, and is
highly relevant to the rising epidemic of diabetes and its dramatic impact on cardiovascular disease. These
findings suggest that HDL elevation could represent a novel therapeutic approach to preventing and treating
type 2 diabetes., , , , , , , .
Expected future outcomes:
This work is being further developed through a subsequent NHMRC project grant to determine whether
elevation of HDL over a period of weeks results in sustained blood glucose reduction. Chronic HDL raising
therapies are already in advanced clinical development for vascular disease so this work is primed for rapid
translation should the outcome of our subsequent investigations be positive.
Name of contact:
Prof. Bronwyn Kingwell
Email/Phone no. of contact:
bronwyn.kingwell@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 418935
Start Year: 2007
CIA Name: A/Pr Elizabeth Woodcock
End Year: 2009
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Protein Targeting and Signal Transduction
Total funding: $449,878
Title of research award:
Signalling pathways activated by atrial dilatation and their relationship to atrial fibrillationSignalling pathways
activated by atrial dilatation and their relationship to atrial fibrillation
Lay Description (from application):
Atrial fibrillation (AF) is an abnormality of cardiac rhythm that affects a large percentage of the population,
especially the ageing population, and causes increases in morbidity and mortality. AF is associated with
structural heart disease, and especially with atrial dilatation. Current treatments are designed to treat symptoms
rather than underlying causes, and most have undesirable side effects. It is our long term goal to study the
involvement of the calcium-releasing messenger inositol(1,4,5)trisphosphate (Ins(1,4,5)P3) and its immediate
precursor phosphatidylinositol(4,5)bisphosphate (PIP2) in atrial fibrillation with a view to providing targets for
therapy that are well tolerated. There is recent evidence that Ins(1,4,5)P3 and PIP2 can contribute to atrial
fibrillation. Over the next 3 years we will study cellular signalling responses to acute and chronic dilatation of
the atria and examine the relationship of these findings to clinical atrial fibrillation. We will identify the G
protein and phospholipase C subtypes involved in responses to stretch and use tools developed in these studies
in experiments with atrial fibrillation models.
Research achievements (from final report):
Dilated atria are associated with atrial fibrillation and provide a worsened prognosis. We have shown that
dilated atria from human, mouse and sheep have heightened expression and activity of one splice variant of one
subtype of phospholipase C, specifically PLCbeta1b. Other PLC subtypes were not altered. Furthermore,
activity correlated with the degree of atrial distension. In parallel studies, we showed that PLCbeta1b was
exclusively responsible for pathological cardiomyocyte growth and apoptotic death downstream of the receptor
coupling protein, Gq. We currently have a mouse model with dilated atria and atrial fibrillation. These mice
have high PLCbeta1b expression and activity as well as heightened IP3-receptor expression. Thus they have
high IP3 generation and high IP3 receptors. Experiments are underway to delete the IP3-receptors in order to
establish whether or not IP3 contributes to atrial fibrillation in this model.
Expected future outcomes:
We expect to identify IP3 as a contributing factor to atrial fibrillation in the mouse model. We are underway
with developing drugable targets for this dialtation-activated pathway.
Name of contact:
Elizabeth Woodcock
Email/Phone no. of contact:
liz.woodcock@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 418937
Start Year: 2007
CIA Name: A/Pr Karin Jandeleit-Dahm
End Year: 2009
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Endocrinology
Total funding: $460,397
Title of research award:
The role of specific Nox isoforms in diabetic renal disease and atherosclerosisThe role of specific Nox
isoforms in diabetic renal disease and atherosclerosis
Lay Description (from application):
Diabetes is increasing worldwide and in Australia. The majority of patients with diabetes eventually will
develop kidney disease and will die of blood vessel complications such as heart attacks and stroke. Oxidative
stress (the generation of free oxygen radicals that react quickly with other proteins in the body causing tissue
damage) has been suggested to play an important role in kidney and blood vessel disease observed in diabetic
patients. This proposal will try to identify and measure specific proteins in the kidney and vessels that are
involved in the production of oxidative stress. We aim to define which one of these proteins is the most
important. We will assess in detail how these proteins work and which other factors are activated leading to
tissue damage. The ultimate goal of these studies is to find new treatment options to decrease the production of
harmful molecules in the kidney and blood vessel wall thereby reducing kidney failure, heart attacks, stroke
and gangrene in diabetes. In our studies, we will use medications already used in patients to treat high blood
pressure in diabetes. In preliminary studies we have shown that these drugs also reduce oxidative stress.
Furthermore, we will use novel, more specific treatments that the harmful ptoteins. Through a collaboration
with Professor Harald Schmidt and his group from Germany who have recently moved to Monash University
in Melbourne we will have access to mice in which specific genes for harmful proteins have been knocked out.
These mice when made diabetic will most likely develop less or no kidney and blood vessel damage. Our
studies will help to identify the most important oxidative stress producing protein associated with kidney and
vessel disease. This knowledge will lead to more effective and more potent treatments for patients with
diabetes to prevent, stop or even improve kidney and blood vessel disease thereby reducing disability and death
in this high risk group of patients.
Research achievements (from final report):
We have investigated the role of oxidatie stress in diabetic kidney disease and atherosclerosis. We showed that
there is significant upregulation of oxidative stress parameters in the kidney and vasculature and that treatments
which redcue oxidative stress such as apocynin or the ARB candesartan were associated reduced end-organ
injury in diabetes. Furthermore we have successfully generated mice with specific deletions of the various
NOX isoforms (NOX1, 2 and 4) on the C57 and apoE -/- background and have induced diabetes in these mice.
Expected future outcomes:
In our ongoing studies we are now investigating the mechanisms how the NOX isoforms mediate renal and
vascular injury. Furthermore, we have now established floxed NOX knockout mice and are in process of
generating cell specific NOX knockout mice which will be investigated in the context of diabetes.
Name of contact:
Karin Jandeleit-Dahm
Email/Phone no. of contact:
karin.jandeleit-dahm@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 418967
Start Year: 2007
CIA Name: Prof Simon Stewart
End Year: 2012
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Strategic Awards
Main RFCD: Public Health and Health Services not elsewhere classified
Total funding: $921,641
Title of research award:
Which heart failure intervention is most cost-effective and consumer friendly in reducing hospital care: the
WhichWhich heart failure intervention is most cost-effective and consumer friendly in reducing hospital care:
the Which
Lay Description (from application):
Chronic heart failure (CHF) is a costly, debilitating and deadly condition that has reached near epidemic
proportions in Australia. In the absence of a permanent cure for CHF, the number of people affected by CHF
has risen beyond 350,000 and is expected to increase by 20-30% in the next 20 years. We recently reviewed the
benefits of applying nurse-led, CHF management programs (CHF-MPs) to typically old and fragile patients, in
whom recurrent hospital admissions and a premature death are common. We confirmed the results of
pioneering Australian research that CHF-MPs dramatically improve health outcomes in CHF. CHF-MPs now
form part of the recommended gold-standard management of CHF. However, we also have evidence that only a
small proportion of patients are exposed to a CHF-MP in Australia. Residual issues such as consumer
preference and the cost of applying these programs are hindering their wide-spread application. The WHICH?
Study addresses this “road block” to implementing a potentially valuable health care service by tackling a
number of critical issues: which form of CHF-MP (home or specialist clinic-based follow-up), will produce the
best health outcomes, save the most money and meet the needs of consumers at the same time? To answer this
question, we will undertake a randomised, head-to-head study of a home versus clinic-based CHF-MP, in 1000
recently hospitalised CHF patients recruited from SA, VIC, NSW and QLD. Patterns and of health care and
consumer preferences and quality of life will then be compared for these two different forms of CHF-MP from
a combined health economic, health policy and consumer perspective to determine the best form of CHF-MP to
be applied. A “consensus” vision for applying an Australia-wide service will then be developed. The potential
impact of the results of the study will then be modelled on the status of Australian CHF-MPs in the year 2010
and a blue-print for action devised.
Research achievements (from final report):
The was a propsective multi-centre randomised controlled trial (RCT) with blinded endpoint adjudication
comprising 280 hospitalised chronic heart failure (CHF) patients randomised to home-based intervention (HBI)
or specialised CHF clinic-based interventation (CBI). Primary endpoint was all-cause, unplanned
hospitalisation or death during 12-18 month follow-up. Secondary endpoint included type/duration of
hospitalisation and health care costs.The project has now been completed with the publications of the primary
report from the study in the prestigious Journal of the American Collegue of Cardiology that supplements a
number of other peer-reviewed international journals from the study including the European Journal of Heart
Failure, Journal of Cardiovascualr Nursing and PLoS One. A new $1.8 million grant was awarded by the
NHMRC to continue research into multidisciplinary chronic heart failure management in regional/rural areas.
Expected future outcomes:
All collaborating CIs and AIs (across three States) have built a close complementary collaborative framework
underlying the study and are committed to incorporate the outcomes of the WHICH? Study into expert clinical
guideline and health policy with opportunities for further evaluation of other forms of clinical health care
services.
Name of contact:
Prof Simon Stewart
Email/Phone no. of contact:
simon.stewart@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 472600
Start Year: 2008
CIA Name: Prof Garry Jennings
End Year: 2012
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: Programs
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $13,017,057
Title of research award:
A Program of Research Addressing the Transition from Health to Advanced Cardiovascular Disease.A
Program of Research Addressing the Transition from Health to Advanced Cardiovascular Disease.
Lay Description (from application):
Cardiovascular disease (CVD) is the major cause of death and disability in Australia and worldwide. This
burden will increase without new knowledge. We will address knowledge gaps that delay more effective
prevention and control. Our team has a strong track record of influencing clinical practice of CVD prevention,
treatment and technology transfer. For many, the first indication of a heart problem is sudden heart attack or
death. By understanding mechanisms we aim to develop new tests and treatments that prevent heart attack,
heart failure and other serious consequences of atherosclerosis.
Research achievements (from final report):
This clinically based cardiology Program addressed three critical stages in the progression from health to
advanced cardiovascular disease. These were (i) obesity, high blood pressure and diabetes risk, (ii) heart
attacks and (iii) end stage heart failure.Important outcomes with relevance to patient care include:Development of a technique to block nerve activity in kidney blood vessels to cure high blood pressure-Risk
prediction blood tests to identify those at most risk for sudden heart attacks-New diagnostic blood markers for
heart attacks which indicate the extent of heart damage-Large multinational study of the effects of angiotensin
receptor blockers (ARBs) and angiotensin converting enzyme inhibitors (ACEIs) which have altered
international guidelines on their use.-Demonstration that an ACE inhibitor (ramipril) improves walking ability
in patients with leg artery disease (peripheral artery disease) to an extent unmatched by present drug therapiesDemontsration of the utility of gene therapy as a treatment for heart failureOur clinical research has direct
implications for patient care. In addition, the international scientific community is a beneficiary of our
molecular work through our contributions to fundamental knowledge.
Expected future outcomes:
The novel biological mechanisms, risk prediction tools, new diagnostics and novel therapies in development as
part of this Program will be progressed under our new Program grant (2013-2017). This is likely to result in
impact on strategies to prevent and manage cardiovascular risk disease as well as to improve patient outcomes.
Name of contact:
Garry Jennings
Email/Phone no. of contact:
garry.jennings@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 472604
Start Year: 2008
CIA Name: Dr Nora Straznicky
End Year: 2010
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $328,195
Title of research award:
Neurogenic mechanisms of cardiovascular risk in the metabolic syndrome: benefits of lifestyle
interventionsNeurogenic mechanisms of cardiovascular risk in the metabolic syndrome: benefits of lifestyle
interventions
Lay Description (from application):
One in four adult Australians has the 'metabolic syndrome' (MetS), a clustering of metabolic and heart disease
risk factors associated with abdominal obesity. Sympathetic nervous system (SNS) activity is increased in the
MetS resulting in enhanced release of the stress hormone 'noradrenaline' . This project will examine the
biological and genetic determinants of enhanced SNS activity and the benefits of lifestyle interventions (weight
loss, weight loss maintenance and aerobic exercise).
Research achievements (from final report):
, This project examined the benefits of dietary weight loss alone or together with aerobic exercise training on
risk factors associated with abdominal obesity, collectively known as the "metabolic syndrome". A major focus
was the sympathetic nervous system (SNS) which plays an important role in both metabolic and blood pressure
regulation. This is relevant to health status because chronic activation of the SNS is a feature of obesity that
increases risk of heart disease and organ damage. Key findings were:, (1) That weight loss averaging 8-9% of
body weight improved all aspects of the metabolic syndrome (blood pressure, cholesterol profile, insulin
sensitivity, inflammation, kidney and liver function) and reduced resting SNS activity by 22%. Whilst the
combined weight loss and exercise group had a greater reduction in waist circumference than the group
randomised to weight loss alone, we failed to identify significant additive benefits of exercise training,
suggesting that weight loss is the prime mover for improvement in metabolic, cardiovascular and SNS
function. , (2) With successful weight loss maintenance, we observed rebound in some parameters (blood
cholesterol and muscle sympathetic nerve activity) whereas benefits on other parameters (insulin sensitivity,
blood pressure) were retained. , (3) A further finding of interest arising from this project was the demonstration
that insulin resistant obese subjects have a delayed and blunted sympathetic neural responsiveness to food
ingestion compared with insulin sensitive obese subjects and that this abnormality is reversed by weight loss.
This is relevant to the obese state because the increase in caloric expenditure following food intake is mediated
in part by the SNS, and a blunted response would favour weight gain., Overall our results underscore the
importance of lifestyle interventions as first-line treatment for obesity and the metabolic syndrome.
Expected future outcomes:
We are currently investigating the determinants of successful weight loss in order to understand why some
people lose weight easily whilst other people struggle.
Name of contact:
Nora Straznicky
Email/Phone no. of contact:
Nora.Straznicky@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 472606
Start Year: 2008
CIA Name: Prof David Kaye
End Year: 2012
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Research Fellowships
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $690,082
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
I am a cardiovascular clinician-scientist involved in characterising the cellular and molecular pathogenesis of
heart failure. My goal is to translate these findings into clinical solutions.
Research achievements (from final report):
Professor Kaye's research has led to major advances in the understanding of the causation of cardiovascular
disease, particularly in regard to heart failure. In particular he has identified new targets for the prevention of
cardiac fibrosis and potential therapeutic means to stimulate cardiac regeneration. His research has also
generated a substantial portfolio of intellectual property, a large body of which provided the foundation for the
creation of Osprey Medical which listed on the ASX in 2012. Prof Kaye's success in translational research was
recognized in 2012 with the award of the Eureka Prize for Medical Research Translation.
Expected future outcomes:
Professor Kaye's continuing research aims to improve life expextancy and quality of life in patients with
advanced cardiovascular disease.
Name of contact:
David Kaye
Email/Phone no. of contact:
david.kaye@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 472609
Start Year: 2008
CIA Name: Prof David Kaye
End Year: 2009
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Development Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $266,427
Title of research award:
Development of non-surgical approach to treating tricuspid regurgitationDevelopment of non-surgical
approach to treating tricuspid regurgitation
Lay Description (from application):
Heart failure is a common problem in which the heart enlarges and contracts poorly. In association with
enlargement of the heart, the heart valves also begin to fail causing further worsening of quality and length of
life. Failure of the tricuspid valve occurs in up to 87% of patients with heart failure and presently the only
treatment option is high risk heart surgery. We are developing a way of dealing with tricuspid valve failure that
does not require cardiac surgery.
Research achievements (from final report):
This research allowed further iterations of a percutaneous non-surgical device to be developed for the
treatement of tricuspid regurgitation. The prototypes continue to be evaluated in ongoing research and are the
subject of additional patent application. In conjunction, the clinical importance of tricuspid regurgitation for
patients with heart failure was further defined by clinical research conducted in conjunction with the
developmental work.
Expected future outcomes:
Optimization of the percutaneous approach/device for correction of functional tricuspid regurgitation.
Name of contact:
David Kaye
Email/Phone no. of contact:
david.kaye@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 472611
Start Year: 2008
CIA Name: Prof Peter Little
End Year: 2010
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Pharmacology not elsewhere classified
Total funding: $342,865
Title of research award:
KIT as a target for the modification of vascular proteoglycans and prevention of atherosclerosisKIT as a target
for the modification of vascular proteoglycans and prevention of atherosclerosis
Lay Description (from application):
Heart disease occurs when arteries supplying blood to the heart become blocked. One aspect of this blockage is
the capture of fats from the blood, by artery wall structures called proteoglycans. Proteoglycans are made up of
a core protein and sugar chains (GAGs). The stickier the GAGs, the more fats that are captured. No drug
treatment acts directly on the artery wall to prevent heart disease. This project aims to identify steps that lead to
stickier GAGs and therefore a potential drug target.
Research achievements (from final report):
Not Available
Expected future outcomes:
N/A
Name of contact:
Peter J. Little
Email/Phone no. of contact:
peter.little@rmit.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 472628
Start Year: 2008
CIA Name: Dr Xiao-Ming Gao
End Year: 2010
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $547,577
Title of research award:
Macrophage Migration Inhibitory Factor (MIF): Pathological and Therapeutic Significance in Post- Infarct
InflammationMacrophage Migration Inhibitory Factor (MIF): Pathological and Therapeutic Significance in
Post- Infarct Inflammation
Lay Description (from application):
Ischemic heart injury mediated by the inflammatory response has a significant impact on the prognosis. MIF is
a central factor mediating and amplifying the inflammatory response but its role in heart disease remains
largely untested. This project will study, for the first time, the crucial role of MIF in ischemic heart disease and
will establish important experimental evidence for developing new anti-inflammation therapeutic strategies
against ischemic heart injury.
Research achievements (from final report):
The proposed project represents an integrated clinical correlative and mechanistic study to examine the role of
MIF in mediating local inflammatory response in ischemic myocardial injury. Using genetic modified mouse
stain together with integrated physiological, molecular, biochemical and histological approaches, this project,
for the first time, demonstrated the crucial role of MIF in promoting systemic and regional inflammation
following severe cardiac ischemic insult and the contribution of MIF to cell death, cardiac dysfunction and
adverse remodeling. Further, this project has identified the significance of MIF in activation of peripheral
blood mononuclear cells and in amplification of inflammatory response in the setting of acute myocardial
infarction and established a critical linkage between MIF and MMP9 activation in tissue injury in this context.
Results from this project advance our understanding on the role of MIF in inflammatory response after
ischemic insult, and provide important experimental evidence for developing a new anti-inflammatory strategy
against ischemic myocardial injury and possible support for future clinical trials. Notably, convincing evidence
from this project shows that MIF is an important biomarker for myocardial injury and will have significant
potential to guide and improve clinical management for acute myocardial infarction.
Expected future outcomes:
The potential for developing a new anti-inflammatory strategy targeting MIF against ischemic myocardial
injury and a novel biomarker to guide clinical management for acute myocardial infarction will significantly
reduce healthcare cost and improve clinical outcome.
Name of contact:
Xiao-Ming Gao
Email/Phone no. of contact:
xiaoming.gao@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 472632
Start Year: 2008
CIA Name: Prof Alexander Bobik
End Year: 2010
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $519,715
Title of research award:
HMGB1, a Cytokine Linking Inflammation, Lipid Accumulation, and Platelet Activation in
AtherosclerosisHMGB1, a Cytokine Linking Inflammation, Lipid Accumulation, and Platelet Activation in
Atherosclerosis
Lay Description (from application):
Atherosclerosis, or hardening of large arteries is the underlying cause of up to 50% of deaths in Western
communities, primarily from heart attacks and strokes. Today it is considered a chronic inflammatory disease
arising from the accumulation of fats such as cholesterol into the inner lining of blood vessels including those
supplying vital organs such as the heart and brain. This study focuses on understanding how a major
inflammatory factor, HMGB1, influences this disease process.
Research achievements (from final report):
We identified HMGB1 in human atherosclerotic lesions and here we proposed to investigate whether HMGB1
contributed to the development of atherosclerosis and the mechanisms by which it might exter such effects. We
demonstrated using a specific HMGB1 monoclonal neutralising antibody developed by us that HMGB1
promoted the development of atherosclerosis. We also demonstrate that it did this by stimulating the
accumulation of macrophages in atherosclerotic lesions, by enhancing their migration. We also investigated the
receptor systems through which it might exert such effects, specifically TLR2, TLR4 and TLR9. We generated
double knockout ApoE-deficient mice in whom these receptors were deleted. We showed that TLR9 was not
the receptor through which HMGB1 exerted it pro-atherogenic effects as deletion of this receptor was
associated with augmented rather than reduced atherosclerosis. This was due to increased interferon-alpha
expression. Our results suggest that targeting HMGB1 may be a useful therapeutic strategy to attenuate
development of atherosclerosis.
Expected future outcomes:
We expect that it may be possible to develop better approaches to inhibit HMGB1 during development of
atherosclorosis using small molecule inhibitors and by completing our experiments defining the receptors
through which HMGB1 exerts its pro-atherogenic effects.
Name of contact:
Alexander Bobik
Email/Phone no. of contact:
alex.bobik@baker.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 472633
Start Year: 2008
CIA Name: Prof Alexander Bobik
End Year: 2010
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $535,333
Title of research award:
Atherosclerosis: Molecular Mechanisms of Suppression by CD4+CD25+ Regulatory T-cellsAtherosclerosis:
Molecular Mechanisms of Suppression by CD4+CD25+ Regulatory T-cells
Lay Description (from application):
Atherosclerosis, or hardening of large arteries is the underlying cause of up to 50% of deaths in Western
communities, primarily from heart attacks and strokes. Today it is considered a chronic inflammatory disease
arising from the accumulation of fats such as cholesterol into the inner lining of blood vessels including those
supply vital organs such as the heart and brain. This study focuses on understanding how to use the body's own
anti-inflammatory cells suppress inflammation.
Research achievements (from final report):
We examined ways to increase CD4+CD25+ regulatory T cell numbers during development and progression of
atherosclerosis. We found the most effective way to increase these T cells was by injecting into mice
recombinant IL-2/anti-IL-2 monoclonal antibody (clone JES6-1) complex. This antibody stablised IL-2 in vivo
and marked increased plasma concentrations resulting in increased CD4+CD25+ regulatory T cell
proliferation. Its administration during development of atherosclerosis markedly prevented atherosclerosis and
when administered to mice with already developed atherosclerosis attenuated further progression of disease.
The study offers a novel therapeutic approach to inhibtion inflammation and associated atherosclerosis.
Expected future outcomes:
The approach of targeting inflammation by expanding CD4+CD25+Foxp3+ regulatory is novel and with
further refinement may be applicable as a cotherapy with cholesterol lowering agents to prevent strokes and
heart attacks.
Name of contact:
Alexander Bobik
Email/Phone no. of contact:
alex.bobik@baker.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 472634
Start Year: 2008
CIA Name: Prof Alexander Bobik
End Year: 2010
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $434,135
Title of research award:
Roles of Interleukins, Chemokines and Circulating Cells in Cardiac FibrosisRoles of Interleukins, Chemokines
and Circulating Cells in Cardiac Fibrosis
Lay Description (from application):
Cardiac fibrosis is a disease of the heart in which large amounts of collagen are deposited within the heart
tissue. This leads to poor heart function and may also lead to sudden death due to arrhythmias (abnormal
electrical pulses). This study sets out to define the role of substances called interleukins and special circulating
cells called lymphocytes, macrophages and progenitor cells in the development of cardiac fibrosis.
Research achievements (from final report):
In these studies we indentified previously unrecognised mechanisms of cardiac fibrosis in the hypertensive
heart. We found that inflammation associated with development of cardiac hypertrophy in hypertension-influx
of macrophages and CD4+ T cells and activation of mast cells were essential for development of cardiac
fibrosis. We also found that cardiac fibrosis was in part dependent of interleukin-4 secretion by mast cells
which were activated via increased oxidative stress. Transforming growth factor-beta probably produced by
macrophages also contributed to cardiac fibrosis. Neutralizing interleukin-4 effectively prevented about 50% of
the fibrosis. Also, administration of in vitro expanded CD4+CD25+Foxp3+ regulatory T cells marked
attenuated fibrosis by reducing macrophage, myofibroblast and T cells numbers also also probably preventing
mast cell activation. The studies provide novel insights not only into mechanisms of cardiac fibrosis but also
potential therapies to prevent cardiac fibrosis.
Expected future outcomes:
It is expected that further development of the novel aspects of these studies may lead to novel experimental
therapies to prevent cardiac fibrosi and impairment in cardiac function associated with fibrosis.
Name of contact:
Alexander Bobik
Email/Phone no. of contact:
alex.bobik@baker.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 472635
Start Year: 2008
CIA Name: Prof Alexander Bobik
End Year: 2010
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $429,393
Title of research award:
Understanding the pharmacology of G-CSF for treating myocardial infarctionUnderstanding the pharmacology
of G-CSF for treating myocardial infarction
Lay Description (from application):
Heart attacks remain the most common cause of heart failure. Unlike many other tissues the heart is unable to
repair itself. Recently it has been recognised that bone marrow cells promote to a small degree repair. Our
research confirms these findings and indicates that these can be affected by substances that increase the
circulating bone marrow cell numbers. This project will explore how bone marrow cells improve repair and
ways to further improve efficacy.
Research achievements (from final report):
The experiments demonstrate that the ability of G-CSF to attenuate adverse effects of myocardial infarctionreperfusion injury is dependent on the expression of G-CSF receptors on bone marrow cells. G-CSF therapy
altered the type of monocytes that invaded infarcted myocardium from Ly-6C(hi) to Ly-6C(lo), i.e, from and
inflammatory to a healing phenotype. This was associated with marked attenuated production of inflammatory
cytokines. These effects were complexed and could not be mediated by depletion of monocytes but were in part
replicated using darbepoietin. Also, anti-GM-CSF therapy appeared to also attenuate adverse effects of
myocardial infarction on heart function and remodeling. Drugs that mimic such effects, e.g. target
inflammatory monocytes but are more efficacious may be useful to treat myocardial infarction.
Expected future outcomes:
Further development of cytokine mediated anti-inflammatory therapies maybe useful to prevent deterioration
of cardiac function and adverse cardiac remodeling after myocardial infarction.
Name of contact:
Alexander Bobik
Email/Phone no. of contact:
alex.bobik@baker.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 472642
Start Year: 2008
CIA Name: A/Pr Rebecca Ritchie
End Year: 2010
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Basic Pharmacology
Total funding: $533,433
Title of research award:
NOVEL cGMP-BASED THERAPIES PREVENT LEFT VENTRICULAR REMODELLINGNOVEL cGMPBASED THERAPIES PREVENT LEFT VENTRICULAR REMODELLING
Lay Description (from application):
Over 300,000 Australians are affected by heart failure. Current drugs for cardiac remodelling (the decline in
heart pumping function and changed structure that precede heart failure) slow but not reverse disease
progression. We have identified a new, nitrovasodilator-based therapy superior to those currently available. We
propose it represents a more effective treatment for reversing abnormalities in both structure and function in the
remodelled heart, preventing or delaying heart failure.
Research achievements (from final report):
Heart failure is a major cause of death and disability, affecting 300,000 Australians. Current drugs for treating
heart failure slow the decline in cardiac contractile function, but do not reverse or cure the disorder. The
development of new treatments for heart failure remains disappointing. We have identified a naturallyoccurring molecule called nitroxyl which has unique advantages over current therapies. We have obtained
exciting new evidence that novel nitroxyl donors as well as other soluble guanylyl cyclase (sGC) ligands
prevent abnormal changes in cardiac structure, particularly in terms of pathological growth responses and its
triggers (levels of toxic free radicals and activity of cell damage enzymes in the heart). These actions are all
mediated by the endogenous molecule, cGMP. This work has attracted 2 international and 2 national
conference speaking invitations, and has been presented at several national and international conferences.
Three publications have directly resulted fromm this work, plus another currently in review and two additional
manuscripts are in preparation. We have recently demonstrated the acute effects of nitroxyl donors on the
normal heart, enhancing both its contractile function and its blood flow. Furthermore, in studies nearing
completion data, we also have preliminary evidence that, in the setting of heart failure, chronic low-dose
nitroxyl donors may retain the ability to suppresses pathological growth responses and protect cardiac
contractile function. Ultimately, the benefits of this work may include the potential development of nitroxylbased therapies for the chronic treatment of cardiac pathologies where oxidative stress is high, such as heart
failure.
Expected future outcomes:
The combined properties of chronic nitroxyl treatment (suppression cardiac hypertrophy, hypertension and free
radicals, with enhanced cardiac function) are unique from current treatments and are attractive for managing
heart failure. Our research studies may ultimately facilitate the development of novel, nitroxyl-based therapies
for the CHRONIC treatment of heart failure.
Name of contact:
A/Prof Rebecca H Ritchie
Email/Phone no. of contact:
rebecca.ritchie@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 472658
Start Year: 2008
CIA Name: Prof Simon Stewart
End Year: 2012
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Research Fellowships
Main RFCD: Health and Community Services
Total funding: $630,275
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
I am a clinical health researcher who combines the principles of public health and multidisciplinary research
(from the “platelet to population”) in order to: 1. Identify key issues arising from an evolving epidemic of
cardiovascular disease within our ag
Research achievements (from final report):
During the course of the Fellowship, Professor Stewart completed a number of large surveillance studies to
better understand the evolving epidemic of heart disease. In Australia, this included reporting on Australia's
largest ever studies of blood pressure levels in the community (involving >13,000 individuals) and primary
care setting (>500,000 patients) Australia-wide, as well as completion of the unique Heart of the Heart Study in
Central Australia. These led to key intervention trials in BP management in primary care (including Australia's
largest ever primary management of blood pressure - the VIPER-BP Study) and the ongoing Central Heart
Protection Study. In Africa, Professor Stewart continued his research via the seminal Heart of Soweto Study in
South Africa - leading to a number of new initiatives around the continent. Reports have been published in
highly prestigious international (e.g. Lancet and Circulation) positively influence clinical guidelines and health
policy.As the Principal Investigator of an NHMRC Program Grant, Project Grant and Health Services Research
Grant, Professor Stewart has led and continues to lead a suite of pragmatic trials examining the best ways to
prevent and manage chronic forms of heart disease. In particular, the WHICH? Trial of home versus clinicbased management (reported in the J Am Coll Cardiol) identified the benefits of home management of the
syndrome (including prolonged survival) and has led to the NHMRC funded WHICH? II Trial. All activities
are underpinned by national and international collaborations now supported by the NHMRC CRE to Reduce
Inequality in Heart Disease led by Professor Stewart.
Expected future outcomes:
The results of key trials such as the VIPER-BP Study and the WHICH? Trial have led to further research to
refine the prevention and management of heart disease and its common antecedents. They are also influential in
positively changing clinical practice in Australia and beyond.
Name of contact:
Simon Stewart
Email/Phone no. of contact:
simon.stewart@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 472662
Start Year: 2008
CIA Name: Prof Simon Stewart
End Year: 2012
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Health and Community Services
Total funding: $1,166,160
Title of research award:
A randomised controlled trial of a Nurse-led Intervention for Less Chronic Heart Failure: The NIL-CHF
StudyA randomised controlled trial of a Nurse-led Intervention for Less Chronic Heart Failure: The NIL-CHF
Study
Lay Description (from application):
The overall aim of the unique NIL-CHF Study is to examine the benefits of applying a specialist nurse-led,
home and clinic-based intervention to optimise the care of recently discharged hospital patients with heart
disease. Involving 950 patients, it will explore whether more flexible and individualised care to apply the best
possible medical treatments is able to PREVENT the most deadly and disabling form of heart disease (chronic
heart failure - CHF) and save money in the process.
Research achievements (from final report):
This was a prospective designed randomised controlled trial (RCT) with blinded endpoint adjudication
comprising 624 hospitalised individuals at risk of developing chronic heart failure (70% men, mean age 66 +/11 years) randomised to either NIL-CHF intervention (309) or usual discharged care (315). A total of 307
(97%) of subjects received tailor-designed NIL-CHF intervention. Overall, a total of 497 (80%) surviving
individuals have completed final clinical assessment at three-years follow-up. The RCT phase of the study was
completed in the first quarter of 2013 and we are currently analysing the primary end point data.
Expected future outcomes:
A series of four to five reports will be produced in the next 12 months from interim data. Overall, we expect to
generate ten or more clincially important reports from the present study that remains unique in the field of
disease management programs.
Name of contact:
Prof Simon Stewart
Email/Phone no. of contact:
simon.stewart@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 472665
Start Year: 2008
CIA Name: Prof Karlheinz Peter
End Year: 2009
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Development Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $460,798
Title of research award:
Novel single-chain antibody-targeted nanoparticles for diagnosis of vascular diseases in magnetic resonance
imagingNovel single-chain antibody-targeted nanoparticles for diagnosis of vascular diseases in magnetic
resonance imaging
Lay Description (from application):
The aim of this project is to develop targeted imaging agents that seek out specific markers for various states of
cardiovascular disease.These agents would provide a method for detecting the presence and level of
atherosclerosis and thrombotic events. The targeted nanoparticles may provide a unique opportunity to detect
very early plaques, the vulnerability of existing plaques and difficult to diagnose vessel blockages such as
pulmonary embolism.
Research achievements (from final report):
We achieved our aim to develop novel targeted imaging agents that target specific markers of various states of
cardiovascular disease. We successfully conjugated our specific single-chain antibodies to magnetic resonance
imaging contrast agents with high efficiency. We could demontrate that these agents are suitable for the
detection of thrombosis in vivo. These imaging agents could help identifying atherosclerotic plaques that are
prone to rupture and thus could define patients at risk for myocardial infarction or stroke allowing early
intervention and preventative treatment.
Expected future outcomes:
This project demonstrated that antibody targeted dendrimer nanoparticles are feasible for non-invasive
magnetic resonance imaging. This imaging agent will be valuable for the detection of atherosclerosis,
pulmonary embolism and inflammation in a clinical setting. This diagnostic method will ultimately be of direct
benefit for patients.
Name of contact:
Prof Karlheinz Peter
Email/Phone no. of contact:
karlheinz.peter@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 472666
Start Year: 2008
CIA Name: Prof Karlheinz Peter
End Year: 2010
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $674,881
Title of research award:
Monomeric C-reactive protein as pathogenic factor and therapeutic target in atherothrombotic
disease.Monomeric C-reactive protein as pathogenic factor and therapeutic target in atherothrombotic disease.
Lay Description (from application):
CRP is a plasma marker that can identify individuals at high risk for heart attack and stroke. Our preliminary
data suggests that plasma CRP is not only an innocent marker, but can also be "activated" and thereby become
a strong inflammatory stimulus by changing from a five unit to a single unit form on the surface of activated
platelets. We will investigate this CRP "activation" in vitro, in animal models and in patients, and aim to
develop new drug therapies for diseases such as heart attack.
Research achievements (from final report):
C-reactive protein (CRP) is a blood marker that reports on inflammatory reactions in the body. CRP circulates
in blood as a molecule consisting of five subunits (pentameric (p)CRP). Our studies could demonstrate that this
5 subunit format is dissociated/transferred to a single subunit format (monomeric (m)CRP) by activated cell
membranes such as on the surface of activated platelets. We could demonstrate that thereby a relatively inert
pCRP is transferred to a highly proinflam-matory and procoagulatory molecule that is a strong activator of
leukocytes, platelets and many other cells. We therefore established a new pathomechanism of how
inflammation is localised and at the same time massively amplified. We could show that mCRP plays a major
role in atherosclerosis. In addition, mCRP is a strong amplifier of thrombotic events. In a proteomic approach
we could confirm that mCRP differs strongly from pCRP in its induction of inflammatory proteins. We could
also show that mCRP plays a central role in stem cell differentiation. Overall, we could thus define a novel
pathomechanism that plays a crucial role in many diseases. Our data also define mCRP and the conversion of
pCRP to mCRP as potential therapeutic targets for anti-atherosclerotic, anti-inflammatory and anti-thrombotic
therapy. , As a side result we discovered a novel pathomechanism in Alzheimer disease. We could show that
Alzheimer plaques cause localised inflammation in the brain of the affected patients and this inflammation is
driven by mCRP that is generated by dissociation of pCRP to mCRP on the surface of Alzheimer plaques. .
Expected future outcomes:
After defining a novel pathomechanism that drives inflammatory reactions, we are now developing novel antiinflammatory reagents. We already successfully tested the first prototype that prevents dissociation/conversion
of pCRP to mCRP in a model of myocardial infarction. Based on this lead reagent we are currently testing
various reagents for anti-inflammatory potency.
Name of contact:
Karlheinz Peter
Email/Phone no. of contact:
karlheinz.peter@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 472667
Start Year: 2008
CIA Name: Prof Karlheinz Peter
End Year: 2010
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $596,677
Title of research award:
Single-chain antibodies for directed stem cell homing and targeting of effector cells in vascular diseaseSinglechain antibodies for directed stem cell homing and targeting of effector cells in vascular disease
Lay Description (from application):
Regenerative cellular therapy e.g. with adult stem cells is a promising novel medical therapy. However, until
now there is no reliable method to direct cells to areas where they are needed. We aim to develop a
biotechnological approach based on genetically tailored antibody molecules that will allow cell targeting. As a
pilot project we will test whether this approach improves lipid deposition and "hardening" of arteries.
Research achievements (from final report):
1) Major progress has been made in the generation and large-scale production of recombinant molecules.
Bispecific single-chain antibodies (scFv) have been generated in a tandem format and produced in a drosophila
and a mammalian cell expression system., 2) It proved to be difficult to obtain sufficient numbers of Sca-1
expressing murine stem cells for experiments, so we cloned the cDNA of Sca-1 and expressed the protein in a
stable cell line. In static adhesion assays using a monolayer of activated platelets the scFvSca-IIb/IIIa construct
increased adhesion of this cell line significantly (up to 17-fold)., 3) To obtain sufficient numbers of human
stem cells we developed a cell culture method that allows expanding CD34-selected cord blood cells over
30fold. We have performed an extensive characterisation of the cells and confirmed their progenitor properties.
, 4) Using a flow chamber system we assessed scFvSca-IIb/IIIa under conditions of laminar shear stress using
human platelets and Sca-1 expressing cells. We found a 54-fold increase of cell adhesion at physiological flow
conditions compared to untreated cells. In addition we tested the adhesion of Sca-1 expressing cells to the
murine VCAM-1 expressing cell line SVEC4-10 at physiological flow conditions. ScFvSca-VCAM treatment
increased adhesion 24-fold compared to scFvSca-cont treated cells. , 5) We have developed a novel
bioconjugation technique based on the enzyme Sortase which allows the site specific modification of proteins
for cell homing or antibody fusion. We could demonstrate the specific delivery of cells to microthrombi and
laser-injured vessels in vitro and in vivo., 6) Using intravital microscopy we tested the properties of scFvScaIIb/IIIa in vivo. Small vascular injuries with thrombi lining mesenterial arteries were induced and could
confirm in vivo cell targeting with stem cells. Final ongoing experiments are assessing the ability of our
tandem scFvs and scFv-cells to attenuate atherosclerosis.
Expected future outcomes:
The potential future outcome of our work will be highly significant in two aspects. Firstly, we can use the
developed strategies to deliver benefits for the growing number of patients with atherosclerosis and its
associated complications. Secondly, the technology might be used for the rapidly developing area of
regenerative cell therapies in many areas of human disease.
Name of contact:
Karlheinz Peter
Email/Phone no. of contact:
karlheinz.peter@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 472668
Start Year: 2008
CIA Name: Dr Christoph Hagemeyer
End Year: 2012
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: Career Development Fellowships
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $380,559
Title of research award:
Novel Single-chain antibody-targeted nanoparticles for diagnosis of vascular diseasesNovel Single-chain
antibody-targeted nanoparticles for diagnosis of vascular diseases
Lay Description (from application):
The aim of this project is to develop targeted imaging agents that seek out specific markers for various states of
cardiovascular disease. These agents would provide a method for detecting the presence and level of
atherosclerosis, fatty tissue build up in the vessel wall. The nanoparticles may provide a unique opportunity to
detect very early plaques, the vulnerability of existing plaques and difficult-to-diagnose vessel blockages such
as clots in lung vessels (pulmonary embolism).
Research achievements (from final report):
The clinical consequences of atherosclerosis such as acute myocardial infarction, stroke or pulmonary
embolism are major causes of death and disability in Australia. The aim of this project was to develop targeted
imaging agents that seek out specific markers for various states of cardiovascular disease. These agents should
provide a method for detecting the presence and level of atherosclerosis, fatty tissue build up in the vessel wall.
The identification of unstable, rupture-prone plaques allows the prevention, instead of treatment of myocardial
infarction, resulting in a major impact on individual health and the health care system in general. Over the
course of the research we successfully developed nano-particles that were able to detect thrombosis and
inflammation. These targeted imaging agents are based specific antibodies that can selectively target activated
endothelium, activated monocytes and macrophages, fibrin and activated platelets. These antibodies were
covalently coupled to Gadolinium and near infrared fluorochrome-loaded dendrimers to generate new contrast
agents. They were successfully tested in in vitro and in vivo models of disease. Our work will be translated in
the future from the bench to the bedside delivering direct benefits to patients.
Expected future outcomes:
If approved for clinical use, the developed particles have the potential to detect very early plaques, the
vulnerability of existing plaques and difficult-to-diagnose vessel blockages such as clots in lung. Our research
on improved diagnostics for cardiovascular disease could have a major impact on the health care system.
Name of contact:
Dr Christoph Hagemeyer
Email/Phone no. of contact:
christoph.hagemeyer@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 472669
Start Year: 2008
CIA Name: Prof Markus Schlaich
End Year: 2010
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Medical Physiology not elsewhere classified
Total funding: $510,871
Title of research award:
Noradrenaline transporter dysfunction in neural circulatory disorders: clinical, molecular and therapeutic
implicationsNoradrenaline transporter dysfunction in neural circulatory disorders: clinical, molecular and
therapeutic implications
Lay Description (from application):
We will investigate the clinical relevance of "noradrenaline transporter" (NET) dysfunction and its molecular
and genetic regulation in (1) essential hypertension, (2) postural tachycardia syndrome where the heart rate
increases abnormally when the patient assumes an upright position and (3) syncope where subjects experience
recurrent blackouts. In a therapeutic approach, we will explore whether NET inhibition can reduce the number
of episodes and alleviate the symptoms associated with syncope.
Research achievements (from final report):
The understanding of the pathophysiologic basis of neural circulatory disorders such as postural orthostatic
tachychardia syndrome (POTS) and neurogenic mediated syncope (NMS) is not completely understood. In this
project we aimed to test the proposition that alterations in noradrenaline transporter (NET) function are
critically involved in the pathophysiology of these conditions and investigated the underlying molecular and
epigenetic mechanisms. We were able to demonstrate that indeed expression of the NET is regulated
differentially, in that it is downregulated in POTS, thereby potentially explaining the elevated heart rate due to
reduced clearance of the pacing molecule noradrenaline. In contrast, NET is upregulated in patienst with NMS,
thereby reducing the amount of noradrenaline available to counteract changes in posture, presidposing these
patienst to faint while standing.
Expected future outcomes:
Ongoing studies are aimed at determining whether the NET can be targeted therapeutically in both POTS and
NMS to normalize its functin and therefore alleviate the symptoms associated with impaired NET function.
Name of contact:
A/Prof Markus Schlaich
Email/Phone no. of contact:
markus.schlaich@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 472672
Start Year: 2008
CIA Name: A/Pr Peter Meikle
End Year: 2012
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Research Fellowships
Main RFCD: Medical Biochemistry: Lipids
Total funding: $581,968
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
My research activity is focused on the application of metabolomics to understand the role of lysosomes in
health and disease. I have a major interest in understanding the molecular mechanisms of pathology resulting
from lysosomal dysfunction. The outcomes
Research achievements (from final report):
Obesity, type 2 diabetes and cardiovascular disease are major health problems in Australia and result in many
tens of thousands of deaths each year. Changes in our metabolism lead to an imbalance in lipids (fats)
circulating in our blood (dyslipidemia) which contributes to the disease process. Over the past five years we
have developed lipid profiling technology that enables us to and are able to quantitatively profile over 400 lipid
species within 20 minutes from 10 uL plasma. We have used this technology to measure the plasma lipid
profiles from different patient groups. We have been able to demonstrate the patients with unstable coronary
artery disease have a different profile from patients with stable coronary artery disease. These profiles can
improve on traditional risk factors for theidentification of those individuals with unstable coronary artery
disease.We have performed plasma lipid profiling on individuals with type 2 diabetes and demonstrated that
again the plasma lipid profile is able to improve on traditional risk factors to correctly identify those with type
2 diabetes or those at high risk of developing type 2 diabetes. From these studies we have identifies new lipid
classes and individual lipid species that are associated with these disease states. This information is providing
insight into disease pathogenesis and new directions for future research.
Expected future outcomes:
We are now in the process of validating the plasma lipid profiles for their predictive ability in type 2 diabetes
and cardiovascular disease. We are working to translate this technology into new clinical test to identify those
at high risk of developing type 2 diabetes or having a cardiovascular event.
Name of contact:
Peter Meikle
Email/Phone no. of contact:
peter.meikle@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 472673
Start Year: 2008
CIA Name: A/Pr Rebecca Ritchie
End Year: 2013
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Research Fellowships
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $690,502
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
I am a cardiac pharmacologist investigating new therapies for the precursors of, and preventing their transition
to, heart failure. My core activities focus on factors that control cardiac hypertrophy and ventricular function,
in both the absence and pres
Research achievements (from final report):
Heart failure is a major cause of death, with >3 million Australians at risk of developing, or already affected
by, heart failure. The achievements of this six year fellowship include significant contributions to knowledge
regarding the causes of heart failure, and identification of new potential means for delaying its onset, and its
progression. With her particular focus on identifying new drug strategies for maintaining myocardial function
in response to myocardial infarction (heart attack), diabetes, and other causes of abnormal cardiac remodelling,
A/Prof Ritchie's work thus has the potential to enrich the quality and length of life for Australians at risk of, or
already affected by, heart failure. Her contributions to knowledge over the fellowship duration included
identification (and mechanisms) of innovative mechanisms for targeting diabetic cardiomyopathies, abnormal
cardiac muscle growth, and myocardial infarction, some of which are derived from novel endogenous factors.
She has achieved a reputation for her contributions, recognised by 64 career publications (33 during the term of
the fellowship), the prestigious 2013 Millennium Award for Type 1 Diabetes (awarded once/yr) and the 2012
ASCEPT Achievement Award and significant, ongoing research support. Ritchie has been invited to 8
prestigious world congresses (6 symposium speaker, 7 chair), with 10 invitations to other international
conferences and 15 to international institutions. Nationally, she has 24 and 14 national symposium speaker &
session chair career invitations, served on 9 organizing committees, and 37 invited seminars. Ritchie has also
made significant contributions to scientific discipline, mentoring, policy and public awareness of science.
Expected future outcomes:
Ritchie's vision is obtaining key scientific breakthroughs in understanding causes of heart failure, particularly
myocardial infarction and diabetes, via her paradigm-shifting discoveries. By continuing to identify new targets
for heart failure precursors and development of innovative pharmacotherapies for delaying their progression,
her research addresses a clear area of clinical need.
Name of contact:
A/Prof Rebecca H Ritchie
Email/Phone no. of contact:
rebecca.ritchie@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 472674
Start Year: 2008
CIA Name: Prof Geoffrey Head
End Year: 2009
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Development Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $389,534
Title of research award:
Development of Oral Natriuretic-like Peptides for Chronic Treatment of Congestive Heart FailureDevelopment
of Oral Natriuretic-like Peptides for Chronic Treatment of Congestive Heart Failure
Lay Description (from application):
Congestive heart failure is fatal disease and a major disease burdon for the community affecting nearly half a
million Australians. Current therapies are inadequate and very limited in prolonging life. We seek to develop a
new peptide therapy based on the effectivness of human B type natriuetic peptide which has to be given by
injection. Our aim is to produce an orally active and effective treatment based on peptides discovered in snake
venom. The program involves testing in animals and cells.
Research achievements (from final report):
The development grant was designed to synthesised novel group of peptide chimeras based on snake venom
peptides that are based on the end sections of a Tapan peptide and the central section of the Dendroaspis
natriuretic peptide (DNP). These peptides have natruietic (salt losing) properties that make them suitable for
treatment of heart failure. Several of these peptides have significant activity improvements over human
naturally occurring peptides and previously tested analogues using an in vitro, cell-based assay to compare
potency at the human natriuretic peptide receptor (NPR-A), which is primarily responsible for the activity of
these peptides. The breakthrough development was to make these potent stable peptides orally active which
was achieved by adding amphiphilic moieties which are small polyethylene glycol chains which we have
shown gives approximately 6% bioavailability when given orally to animals. Importantly, these substitutions
do not affect the potency or the stability with over 6 hours of activity demonstrated after a single oral dose.
Thus we have developed a rrange of very active and stable peptides formulations that can be further developed
into a viable human drug treatment for heart failure. The major limitation is the limited bioavailability which
can be addressed by optimising the glcol chains.
Expected future outcomes:
The future outcome will be a viable treatment for heart failure once the glycol formulation has been optimised.
Name of contact:
Geoffrey A Head
Email/Phone no. of contact:
geoff.head@baker.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 472680
Start Year: 2008
CIA Name: Prof Geoffrey Head
End Year: 2010
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $535,333
Title of research award:
Role of the hypothalamus, oxidative stress and angiotensin in chronic stressRole of the hypothalamus,
oxidative stress and angiotensin in chronic stress
Lay Description (from application):
Stress can trigger life threatening cardiovascular events and its impact is much greater when blood pressure is
raised. We seek to determine which chemical type of brain neuron and which region is responsible for
amplifying the responses to repeated stress in an animal model that closely resembles the human form of the
disease. We will focus specifically on the hypothalamus which controls the sympathetic nervous system.
Research achievements (from final report):
Our studies have shed new light on the role of the sympathetic nervous system in hypertension dependent on
the renin-angiotensin system. In marked hypertension induced by angiotensin (AngII) infusion, renal
sympathetic nerve activity (RSNA) is not elevated but responses to stress are exaggerated. In long-term lowlevel hypertension, RSNA is markedly increased at rest and during stress and hypoxia, possibly due to
activation of hypothalamic pathways. These mechanisms may contribute to sympathetic activation in
conditions associated with chronic activation of the renin angiotensin system such as in obesity or renovascular
disease. Our findings also provide a mechanistic basis for the sympatho-excitatory effects of intermittent
hypoxia due to sleep apnea to be enhanced by chronic renin-angiotensin system activation. Chronic exposure to
stress is closely linked to hypertension and heart disease and we have shown a marked desensitisation of
sympathetic responses with repeated exposure. This process, which involves increased activation of AT1
receptors, is stressor-specific and does not appear to have an impact on novel aversive stimuli. Brain nitric
oxide plays a lesser role in the responses to novel stressors but makes an increasingly important contribution to
chronic stress.
Expected future outcomes:
Our studies are relevant to other pathologies where sympathetic nerves and kidney are implicated, eg obesity,
heart failure, diabetes.
Name of contact:
Prof. Geoffrey Head
Email/Phone no. of contact:
geoff.head@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 472700
Start Year: 2008
CIA Name: A/Pr Anne Abbott
End Year: 2012
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: Early Career Fellowships
(Australia)
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $200,062
Title of research award:
Prevention of Stroke Caused by Carotid AtherosclerosisPrevention of Stroke Caused by Carotid
Atherosclerosis
Lay Description (from application):
Stroke is a leading cause of death and disability and a huge drain on health resources in Australia and
worldwide. Carotid artery atherosclerosis (vascular disease) is an important cause of stroke. Currently surgery
(with a significant risk of stroke-death) is commonly performed to prevent carotid stroke. My aim is to show
that current best practice medical intervention is superior to surgery and to identify high risk patients for whom
additional stroke prevention strategies may be justified.
Research achievements (from final report):
This half-time (27 month FTE) fellowship allowed me to be first in the world to test and prove correct the
hypothesis that stroke risk associated with clinically silent (asymptomatic), severe (50-99%) atherosclerotic,
narrowing (stenosis) of the internal carotid artery origin is now best reduced with medical (non-invasive)
intervention alone. Medical intervention refers to identification of risk factors for heart and vascular disease
(including high blood pressure, diabetes and smoking) and risk reduction using healthy lifestyle habits and
appropriate medication. This lesion (asymptoamtic carotid stenosis) is common in older people and casues
about 10% of all strokes. Until my discovery carotid surgery (or recently stenting) have been the standards of
care. However, I discovered that medical intervention alone is now best because of its improved stroke
prevention efficacy over the last 3 decades, it protects against other complications of heart and vascular disease
(caused by carotid artery surgey or stenting) , it is cheaper than invasive carotid procedures and because high
stroke risk patients who benefit from current medical intervention and additional invasive carotid proocedures
have not been identified. I have also used my fellowship salary to put my discoveries into practice with my
successful efforts improve standards of stroke prevention globally. Highlights include a significant impact on
international stroke prevention expert opinion, research agendas and literature (> 170 citations to my metaanalysis of stroke risk associated with asymptomaitc carotid stenosis published in Stroke, 2009). Other
highlights; my work leading to updates in USA and UK stroke prevention guidelines and mysuccessful lead of
international stroke experts to prevent US Medicare from funding routine practice carotid stenting for
asymptomatic (and 'symptomatic') carotid stenosis in 2012 (simultaneously discouraging poor medical service
funding policies in other countries).
Expected future outcomes:
The impacts described above will be long-lasting. However, I am no longer funded academically which makes
it near impossible for me to continue the paradigm shift in stroke prevention methods I have begun or to
capitalise on my academic skills and current academic momentum.
Name of contact:
Anne Abbott
Email/Phone no. of contact:
Anne. L. Abbott@gmail.com
NHMRC Research Achievements - SUMMARY
Grant ID: 472705
Start Year: 2008
CIA Name: A/Pr Chiew Wong
End Year: 2011
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: Early Career Fellowships
(Australia)
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $210,055
Title of research award:
Effect of laparoscopic gastric banding and angiotensin converting enzyme inhibitor on metabolic myocardial
diseaseEffect of laparoscopic gastric banding and angiotensin converting enzyme inhibitor on metabolic
myocardial disease
Lay Description (from application):
The proposed research studies will add novel information about the effects of drug acting on ReninAngiotensin-Aldosterone system and substantial weight reduction by key hole surgery on heart muscle
stiffening and scar tissue formation due to obesity and diabetes. The knowledge gained will be essential to
gain important insights into the underlying process of heart failure due to over-nutrition, high blood pressure,
diabetes and define strategies aimed at reducing future heart failure.
Research achievements (from final report):
Assessment of cardiac function to include measures linked with the syndrome of 'Heart Failure with Normal
Ejection Fraction' is an important area for clinical research given the contribution that HFNEF makes to
clinical heart failure presentation. We found that defining the HFNEF can be difficult in clinical trials based on
the current best available cardiac imaging techniques. Assessing myocardial torsion dynamics using the latest
advanced echocardiography imaging provided a new dimension in assessing myocardial function dynamic. LV
torsion dynamics acquired immediately after exercise stress test can be a good indicator of exercise capacity,
and an useful tool for assessing myocardial mechanics beyond the non inasive measure for myocardial filling
pressure. We also found that substantial weight reduction by gastric banding improved myocardial function in
early stage of disease process, hence therapeutic implication for both surgical and non surgical interventions to
control weight in morbid obesity.
Expected future outcomes:
encourage ongoing studies in the growing epidemic of HFNEF, new preventive measures to curb HFNEF to be
developed in parellel with new sensitive method of assessing myocardial torsional dynamics.
Name of contact:
Chiew Wong
Email/Phone no. of contact:
chiew.wong@wh.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 472707
Start Year: 2008
CIA Name: Dr Melinda Carrington
End Year: 2011
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: Early Career Fellowships
(Australia)
Main RFCD: Health Promotion
Total funding: $287,321
Title of research award:
Advanced non-invasive cardiovascular risk screening in the community: Practical and cost effective?Advanced
non-invasive cardiovascular risk screening in the community: Practical and cost effective?
Lay Description (from application):
This research focuses on the practicalities and cost of mobile, advanced, non-invasive cardiovascular
assessments to determine the extent of CVD and clinical risk factors and its likely impact on patterns of
treatment and care to “disadvantaged” individuals living in rural and remote regions and Indigenous
Australians. The advantage of directly acquiring risk profile information has not been fully explored and its
potential to address an “epidemic” of CVD world-wide cannot be overstated.
Research achievements (from final report):
This postdoctoral research program focused on the practicalities and cost of applying mobile, advanced risk
assessments to determine the extent of cardiovascular risk factors and clinical disease and the likely impact on
patterns of treatment and care to "disadvantaged" individuals and communities. There is clear evidence that the
public health burden of cardiovascular disease (CVD) is unevenly distributed in Australia, particularly in
vulnerable communities (i.e. rural and/or aboriginal communities)., The major discovery was that mobile
screening with echocardiography and automated data collection and analysis to determine the presence/absence
of symptoms in remote communities can provide rapid estimation of CVD risk. This has the potential impact of
better access to optimal risk management and care and an improvement in longer term cardiovascular
outcomes. As part of the Healthy Hearts Beyond City Limits research program, high CVD risk factor levels
were confirmed from 2125 participants in four regional Victorian communities and we found a strong need for
more pro-active prevention. In the second major project of this postdoctoral research program, the landmark
Heart of the Heart study identified in 436 Aboriginal people from geographically dispersed regions of Central
Australia a high burden of risk factors and psycho-social contributors to the presence of diabetes, renal disease,
heart disease and CVD overall. These represent probable antecedents and characteristics of chronic heart
failure in affected individuals.
Expected future outcomes:
In addressing cardiovascular risk factors and established CVD in thousands of vulnerable Australians, close
engagement with individuals and communities provides scope for the application of regional risk management
clinics and outreach models of nurse-led intervention programs to reduce the burden of CVD risk in
disadvantaged individuals and communities.
Name of contact:
Melinda Carrington
Email/Phone no. of contact:
melinda.carrington@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 472708
Start Year: 2008
CIA Name: Prof David Kaye
End Year: 2009
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Development Grants
Main RFCD: Pharmacology not elsewhere classified
Total funding: $137,685
Title of research award:
Development of guanylate cyclase activators for the treatment of pulmonary arterial hypertensionDevelopment
of guanylate cyclase activators for the treatment of pulmonary arterial hypertension
Lay Description (from application):
Pulmonary arterial hypertension (PAH) is a life threatening condition with few treatment options. It is marked
by shortness of breath and reduced energy as a result of an unexplained constriction of the blood vessels in the
lung. This results in reduced life expectancy. We are developing a new treatment that will relax the blood
vessels in the lung to improve quality and length of life.
Research achievements (from final report):
This grant allowed re-screening of a novel set of compounds that modulate blood vessel function. Completion
of this work allowed the formal granting of a European patent and provide a sound foundation for ongoing
work into the potential use of these drugs for the treatment of pulmonary hypertension.
Expected future outcomes:
Development of a new drug to treat pulmonary hypertension and other forms of heart disease
Name of contact:
N/A
Email/Phone no. of contact:
N/A
NHMRC Research Achievements - SUMMARY
Grant ID: 519823
Start Year: 2009
CIA Name: Prof Simon Stewart
End Year: 2013
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: Programs
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $5,162,176
Title of research award:
Integration of Risk Evaluation in Cardiovascular Disease Management Programs.Integration of Risk
Evaluation in Cardiovascular Disease Management Programs.
Lay Description (from application):
This study will determine the feasibility of a coordinated health care team approach to the treatment of
cardiovascular disorders. It will examine a range of issues – who would most benefit from this approach, its
value for money, the relative importance of health care services to consumers, and where to invest additional
health funds. Built on strong collaborations between expert researchers in advanced diagnostic techniques,
coordinated health care, community health care and health economics, this provides a unique opportunity to
benefit millions of Australians.
Research achievements (from final report):
We have developed a strong program of research projects to examine the cost-benefits of multidisciplinary
disease management program (DMP) to delay the onset and slow the progression of different forms of CVD in
high-risk individuals (from subclinical to heart failure). Our team have successufully designed/completed a
series of pragmatic national multicentre randomised controlled trials (RCTs) relevent to the underlying
hypotheses. Key outcomes include:, 1. Completion and presentation of the primary and longer-term outcomes
from the multicentre, randomised WHICH? Trial of home- versus clinic-based management of heart failure the results of which will significantly impact on the future management of chronic heart failure., 2. Completion
and presentation of the Young @ Heart study, a multicentre, randomised trial of secondary prevention in
privately insured cardiac patients with key implications for sex-specific programs of care., 3. Completion of
two other key studies in secondary prevention (the NIL-CHF study) and atrial fibrillation management (the
SAFETY study) that will be presented (late-breaking trial sessions and research articles) in 2014/2015 - with
profound translational implications for clinical practice., 4. Completion and presentation of Australia's largestever blood pressure management trial in primary care., 5. Ongoing trials in primary prevention (the IMPRESS
study), secondary prevention (the Central Australia Heart Protection study) and chronic heart failure
mangement (the WHICH?II study)., There is significant potential for all findings of our RCTs to direct future
reserarch into optimal DMP of patients with different forms of CVD and for further improving or enhancing
risk factor delineation and management strategies.
Expected future outcomes:
We are currently drafting a series (>20 papers) of primary and secondary endpoint reports from the above
described RCTs (including comprehensive health economic analyses) of targeted preventative DMPs. These
will facilitate their implementation in delivering maximal optimisation of CVD risk delineation and
management in the next 5-10 years.
Name of contact:
Professor Simon Stewart
Email/Phone no. of contact:
simon.stewart@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 526604
Start Year: 2009
CIA Name: Prof Bronwyn Kingwell
End Year: 2013
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Research Fellowships
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $702,604
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
I am a translational, human physiologist which places me in a unique position to address important clinical
questions. My current interests centre on: • Identification of novel predictors of unstable coronary heart disease
• Novel treatment approaches in:
Research achievements (from final report):
HDL and Diabetes, Low HDL cholesterol has long been known as risk factor for heart and blood vessel
disease, but Professor Kingwell and her team have discovered that HDL also plays a pivotal role in glucose
metabolism. , They have identified that HDL influences both glucose uptake into muscle and insulin secretion
from the pancreas. Through industry collaboration (Roche, CSL and Resverlogix) this work is now informing
clinical development of HDL-raising therapies for those with type 2 diabetes who are at high risk of
cardiovascular complications. , ?????, Professor Kingwell's vascular studies have translated to new medical
management strategies for arterial diseases, including Marfan syndrome and peripheral artery disease, , ,
Peripheral artery disease, During the current fellowship, Professor Kingwell focused on lower limb peripheral
artery disease, which is a growing health burden as a result of Australia's aging population and accelerating
rates of obesity and diabetes. Approximately ~15% of adults aged over 40 suffer from this condition, and
intermittent claudication (severe leg muscle pain on walking) significantly impairs mobility and quality of life
in one third of these individuals. , Professor Kingwell and her team have shown that the cardiovascular drug,
ramipril, increases walking time by 5-fold more than the only therapy currently indicated in Australia to
manage intermittent claudication (cilostazol). Mechanistic investigations suggest that a combination of
vasodilatation, angiogenesis, anti-thrombotic and anti-inflammatory actions may contribute. Importantly, the
changes in walking time were accompanied by highly significant improvement in quality of life. Given that
ramipril is 4 times cheaper than cilostazol, it represents a highly effective and inexpensive therapy for this
prevalent condition.
Expected future outcomes:
- Current studies in Professor Kingwell's laboratory are testing the efficacy of a novel HDL therapy to improve
glucose control in patients with prediabetes, - Professor Kingwell is currently working with the TGA and
industry who are likely to use her ram
Name of contact:
Professor Kingwell is currently woBronwyn Kingwell
Email/Phone no. of contact:
bronwyn.kingwell@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 526605
Start Year: 2009
CIA Name: Prof Karin Jandeleit-Dahm
End Year: 2013
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Research Fellowships
Main RFCD: Endocrinology
Total funding: $580,752
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
I am a clinician scientist and fully trained nephrologist. My research involves preclinical and clinical
translational approaches to identify new targets and to develop new treatments to prevent, reverse and retard
diabetes related micro-and macrovascular
Research achievements (from final report):
During the course of the fellowship I have made significant contributions in the major research areas as
outlined in the felloship application. I have published on endothelin-receptor antagonism showing simultaneous
reno-and atheroprotection (published in Diabetologia). Furthermore my work has shown atheroprotection with
urotensin antagonists and with AT2 receptor antagonists (both published in Diabetologia). I have produced
seminal papers on the role of RAGE in diabetes associated atherosclerosis and renal disease (both published in
Diabetes). More recently my work has identified Nox1 as the most important Nox isoform in diabetes
associated atherosclerosis (published in Circulation 2013) and the role of Nox4 in diabetic nephropathy
(published in JASN, 2014). The work is ongoing with several other publications in progress. Furthermore, this
work has been widely communicated as invited presentations at the major international and national diabetes,
heart and kidney conferences. We have submitted an ongoing project grant to continue this work. We have
established and expanded collaborations with the top groups in the world in this field and have an ongoing
collaboration with industry to investigate novel more specific Nox inhibitors initially preclinically and
ultimately in the clinical context.
Expected future outcomes:
My future research includes identification of new targets to inhibit early dicarbonyls such as methylglyoxal and
its interaction with RAGE. We also work on innovative approaches to increase glyoxalase activity.
Furthermore, we continue to assess and validate novel Nox inhibitors targeting specific Nox isoforms.
Name of contact:
Karin Jandeleit-Dahm
Email/Phone no. of contact:
karin.jandeleit-dahm@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 526614
Start Year: 2009
CIA Name: Prof Dmitri Sviridov
End Year: 2011
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Medical Biochemistry: Proteins and Peptides
Total funding: $372,472
Title of research award:
Impact of advanced glycation on anti-atherogenic properties of high density lipoproteinImpact of advanced
glycation on anti-atherogenic properties of high density lipoprotein
Lay Description (from application):
Type 2 diabetes is a rapidly growing medical problem in Australia and around the world. Diabetes affects
human health through its complications and the cardiovascular complications are a cause for major concern.
One of the complications is the effect on plasma lipids: it makes cholesterol carrying particles to accumulate in
the blood vessels, causing atherosclerosis. We intend to investigate how diabetes modify these particles making
them atherogenic.
Research achievements (from final report):
Diabetes is associated with elevation of plasma levels of glucose and that leads to modification of many
proteins and impairment of their function. This study has established that severe modification of a protein
apolipoprotein A-I, the main protein of HDL ("Good Cholesterol") impairs its functions and as a result Good
Cholesterol is no longer good. It loses its capacity to remove cholesterol from cells and it also loses its capacity
to reduce inflammation. In cases of severe atherosclerosis this may be a significant factor contributing to the
development of atherosclerosis and elevation of the risk of heart attack in patients with diabetes and may
requires a specific treatment. On the other hand we established in animal models and in patients, that if diabetes
is controlled, the levels of modification of apoA-I are less severe and changes in functional capacity of good
cholesterol in this situation are fully compensated. We conclude that if diabetes is controlled, that may be
sufficient to eliminate the effects of this specific modification on risk of cardiovascular disease; however in
uncontrolled diabetes a specific treatment is needed. We also established that other diabetes-related
modifications of HDL may also contribute to the impairment of HDL functional properties.
Expected future outcomes:
In this study we investigated only one diabetes-related factor that reduces protection against atherosclerosis.
We now are focusing on other factors to establish those that contribute the most and on treatments capable of
modifying these factors.
Name of contact:
Prof. Dmitri Sviridov
Email/Phone no. of contact:
Dmitri.Sviridov@Bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 526615
Start Year: 2009
CIA Name: Prof Dmitri Sviridov
End Year: 2011
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $379,418
Title of research award:
Atherosclerosis and HIVAtherosclerosis and HIV
Lay Description (from application):
Atherosclerosis is an underlying cause of majority of cardiovascular diseases. The key element in the
pathogenesis of atherosclerosis is impairment of cholesterol metabolism. Current treatment reduces
cardiovascular disease by 30-40%, but the remaining risk is unacceptably high. A new idea how to treat
atherosclerosis came from unexpected source, HIV infection. We propose to investigate how HIV causes
atherosclerosis and if similar mechanisms are involved in "common" atherosclerosis.
Research achievements (from final report):
This project was about relationship between HIV infection and atherosclerosis. Atherosclerosis, a hardening of
blood vessels, is the major cause of cardiovascular disease. Current treatment of HIV disease is capable to
efficiently control immunodeficiency. So much so that secondary consequences of HIV becoming the major
cause of morbidity and mortality in HIV patients. One of such secondary consequences is increased risk of
cardiovascular disease in HIV infected subjects. It was believed that this results from adverse effects of drugs
used to treat HIV. We however demonstrated that HIV infection itself increases risk of atherosclerosis. In this
study we investigated mechanisms of this connection. We have established that one of the proteins of HIV
reduces the capacity of cells to release excessive cholesterol and as a result cholesterol accumulates in the
macrophages causing formation of foam cells, a hallmark of atherosclerosis. HIV uses a unique mechanism to
inhibit the key molecule responsible for the removal of excessive cholesterol. Moreover, this HIV protein can
be secreted from the infected cells to blood and affect cells that are not infected. In this study we also tested
how this HIV protein affects atherosclerosis in animal model of this disease. We found that HIV protein caused
an unusual accumulation of cholesterol-loaded cells in various parts of the vessel, quite differently to what
happens in classical atherosclerosis indicating that atherosclerosis in HIV-infected patients may be different to
that in HIV-negative subjects. We also found that several compounds that inhibit development atherosclerosis
also inhibit HIV infection.
Expected future outcomes:
Our findings target two future outcomes. One is a development of a medication that would explore common
metabolic pathways in HIV and atherosclerosis to treat both diseases. Second to explore our mechanistically
findings to establish a connection between atherosclerosis and infections beyond HIV, a general connection
between infection and atherosclerosis.
Name of contact:
Prof. Dmitri Sviridov
Email/Phone no. of contact:
Dmitri.Sviridov@Bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 526618
Start Year: 2009
CIA Name: Prof Geoffrey Head
End Year: 2011
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $358,035
Title of research award:
A neurogenic basis of obesity hypertension: Role of adipokines and ghrelin in regulating sympathetic
vasomotor activityA neurogenic basis of obesity hypertension: Role of adipokines and ghrelin in regulating
sympathetic vasomotor activity
Lay Description (from application):
During the development of obesity, brain centres are inappropriately activated by factors such as leptin which
are released by excess fat accumulation. This reults in high blood pressure. We seek to determine which
chemical type of brain neuron is responsible for receiving these signals in a specific brain region in an animal
model that closely resembles the human form of the disease. We will focus specifically on areas known to
control the sympathetic nervous system.
Research achievements (from final report):
Our studies have shed new light on the role of the sympathetic nervous system in hypertension caused by
obesity. Chronic obesity is a worldwide epidemic and is associated with high risk of cardiovascular disease but
the events that occur during the establishment of obesity are poorly understood. We showed that consumption
of a high fat diet (HFD) by rabbits results in increased blood pressure, heart rate and nerve activity to the
kidney within 1 week and these values remain high even after the diet is withdrawn. The marked nerve
activation is related to increased responsiveness of the brain to the effects of the hormone leptin. A study of the
time-course for the development of the high blood pressure showed that nerve activity increases rapidly (within
48h) after starting a HFD and can be accounted for by disturbances to the daily rhythm of blood pressure and
nerve activity. Using drugs that block the feeding-related hormones leptin and insulin we have shown that the
hypertension and high nerve activity induced by a HFD is predominantly mediated by actions of leptin in the
brain. Insulin contributes a smaller proportion of the hypertension, but is responsible for all of the high heart
rate due to feeding a HFD. There is greater neural activation in the region of the ventromedial hypothalamus
following direct injection of one of the components of the signalling pathway involved and this is likely to be
the region of the hypothalamus involved in the onset of obesity related hypertension.
Expected future outcomes:
Our studies are relevant to other pathologies where sympathetic nerves and kidney are implicated, eg stress,
heart failure, diabetes.
Name of contact:
Prof. Geoff Head
Email/Phone no. of contact:
geoff.head@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 526622
Start Year: 2009
CIA Name: A/Pr Elizabeth Woodcock
End Year: 2011
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $413,936
Title of research award:
A novel cardiac inotropic mechanism that provides functional benefitA novel cardiac inotropic mechanism that
provides functional benefit
Lay Description (from application):
Patients with heart failure are often treated with an inotropic agent to increase the force of the heart's
contraction and thus improve quality of life for these patients. Most inotropic agents have deleterious effects
that limit their usefullness. Mice that have increased alpha1-A receptor expression in their hearts have
heightened contactility that is not associated with hypertrophy or arrhythmias. We will use microarray, and siRNA delivery and signalling studies to identify the mechanism.
Research achievements (from final report):
These studies investigated the importance of signalling pathways downstream of alpha1A-adrenergic receptors
in mediating pathological Ca2+ responses and subsequent disease. We have discounted any role for PLC
epsilon, because crossing alpha1A-AR cardiac transgenic mice with PLC epsilon-/- mice did not educe either
PLC or inotropic responses. Instead, we identified one subtype of phospholipase C (PLCbeta1b) as being
specifically responsible. PLCbeta1b generates two products that initiate different downstream signalling
pathways. We investigated the contribution of inositol(1,4,5)trisphosphate and its receptors (IP3-R) by crossing
with mice in which the gene encoding the cardiomyocyte IP3-R subtype (IP3-R(2)) had been deleted (IP3R(2)-/-). Deletion of IP3-R(2) did not alter cardiac responses in vivo, arguing against a contribution of this arm
of the pathway. In contrast, the sn-1,2-diacylglycerol signalling response downstream of alpha1A-receptors
was demonstrated to be of importance in the observed Ca2+ responses. This will enable us to identify targets
for the development of inotropic agents that are well tolerated.
Expected future outcomes:
We hope to pin point nodal points in the inotropic response signalling pathway. These should provide excellent
therapeutic targets.
Name of contact:
Elizabeth Woodcock
Email/Phone no. of contact:
liz.woodcock@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 526623
Start Year: 2009
CIA Name: A/Pr Elizabeth Woodcock
End Year: 2011
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Pharmacology not elsewhere classified
Total funding: $542,684
Title of research award:
Cardiac-specific therapy targeting hypertrophy and apoptotisCardiac-specific therapy targeting hypertrophy
and apoptotis
Lay Description (from application):
We have discovered that certain pathological responses in the heart are mediated by an unusual type of
signalling protein. The aim of the proposed studies is to determine whether this unusual signalling mechanism
can provide a good target for development of new therapeutic approaches to prevent or treat heart failure.
Research achievements (from final report):
Over the period of this grant we identified the specific phospholipase C subtype (PLCbeta1b) associated with
cardiac pathologies in human and rodent models. PLCbeta1b is not active in most tissues sand so this provides
a potential therapeutic target that should be heart selective. We also identified the reason for this exclusive
activity. We identified the protein responsible for the activity of PLCbeta1b in heart and demonstrated that this
was Shank3. Selective inhibitors of the interaction between PLCbeta1b and Shank3 were developed and these
were shown to prevent pathological growth of cardiomyocytes. This opens up the possibility of developing
cardiac-specific agents to inhibit cardiac hypertrophy.
Expected future outcomes:
In vivo studies need to be finalised and then we will commence screening for inhibitors of the PLCbeta1bShank3 interaction.
Name of contact:
Elizabeth A. Woodcock
Email/Phone no. of contact:
liz.woodcock@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 526624
Start Year: 2009
CIA Name: Prof David Kaye
End Year: 2011
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $525,661
Title of research award:
Mitochondrial L-arginine transport and its role in the pathogenesis of heart failureMitochondrial L-arginine
transport and its role in the pathogenesis of heart failure
Lay Description (from application):
Heart failure is a common disorder that is marked by significant symptoms and reduced survival. Reduced
cardiac performance is the key responsible mechanism. At the tissue level, altered energy metabolism is a
major contributor. Mitochondria are the cellular elements that produce energy and in this project we aim to
study how a key process that regulates mitochondrial activity behaves in the setting of heart failure.
Research achievements (from final report):
Mitochondria are the key site of energy metabolism for all cells, and in particular they play a critical role in the
function of those cells that are very active metabolically, such as the heart. In this context it is known that the
metabolic activity of cadiac cells is impaired in heart failure, a condition characterised by heart muscle
weakness. In patients with heart failure, the quality and length of life are substantially reduced. Our series of
studies sought to better understand the changes that occur in mitochondria in the setting of heart failure. By
obtaining mitochondria from animal models of heart failure we demonstrated that the uptake of a key amino
acid, L-arginine, is reduced in heart failure and this impacts on the function of the mitochondria. Subsequently
we developed novel methods of restoring the levels of a key transport protein for L-arginine in mitochondria,
and observed that this protected the heart from damage.
Expected future outcomes:
Our studies provide new insights into potential therapeutic targets to improve mitochondrial function in the
setting of heart failure and heart attack.
Name of contact:
Prof David Kaye
Email/Phone no. of contact:
david.kaye@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 526626
Start Year: 2009
CIA Name: Prof Karlheinz Peter
End Year: 2011
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $515,986
Title of research award:
Platelet-Activating and Proinflammatory Effects of Proteins Secreted by Staphylococcus aureusPlateletActivating and Proinflammatory Effects of Proteins Secreted by Staphylococcus aureus
Lay Description (from application):
Skin or other Staphylococcus aureus (SA, golden Staph.) infections are common in Aboriginal Australians.
We address the question whether atherosclerotic disease is accelerated by this bacterial infection. We will
investigate whether a class of newly described toxins secreted by SA activates blood cells and leads to clot
formation and potentially heart attack. We will evaluate plasma samples from cardiac patients and Aboriginal
Austr. and will develop and test therapeutics in vitro and in mice.
Research achievements (from final report):
S.aureus infections are a major health problem often resulting in death with a combination of bleeding and
thrombosis. As we have increasing numbers of S. aureus infections that do not respond to antibiotic treatment
in Australia and worldwide. S. aureus superantigen-like (SSL) proteins are a family of toxins secreted by S.
aureus. We have investigated whether one member of this exotoxin family, SSL5, causes thrombosis and
bleeding complications. , We have made the following discoveries:, SSL5 causes platelet activation and
aggregation and thereby induces clot formation., Identification of the receptors on platelets that SSL5 binds to.,
Successful screening of SSL5 binding against a library of glycan structures, from which we identified two
glycans as having highest binding affinity and the ability to reduce overall SSL5-platelet binding and
subsequent activation., The glycan-based therapeutic, Bimosiamose, which is currently in phase two clinical
trials for inflammatory diseases, can inhibit SSL5-induced platelet activation, making it a lead investigational
compound for in vivo studies. , Successful generation of anti-SSL5 mAbs, which have been found to detect
SSL5 in plasma and to inhibit the SSL5 effect. , SSL5 can induce thrombosis but also thrombocytopenia and
bleeding in mice. It may thus play an important role in disseminated intravascular coagulation caused by S.
aureus infections. , Monoclonal antibodies against SSL5 and Bimosiamose can prevent SSL5-induced
thrombosis and bleeding in mice., Overall, this project contributes to the understanding of S. aureus infections
and describes novel therapeutic strategies to combat one of the most deadliest infections in humans.
Expected future outcomes:
The most important outcome would be the proof of concept that in a Staphylococcus aureus induced sepsis,
which is associated with disseminated intravascular coagulation, the newly described therapeutic strategies and
reagents are effective in preventing thrombosis and bleeding and are thus live saving.
Name of contact:
Prof Karlheinz Peter
Email/Phone no. of contact:
karlheinz.peter@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 526635
Start Year: 2009
CIA Name: Prof Assam El-Osta
End Year: 2012
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $476,258
Title of research award:
Understanding the opposing roles of SWI-SNF in the control of gene programs for pathological cardiac
hypertrophyUnderstanding the opposing roles of SWI-SNF in the control of gene programs for pathological
cardiac hypertrophy
Lay Description (from application):
Following the success in decoding human genome, i.e. DNA sequence, a major task is to understand how the
activity of genes with consequent changes in respective proteins. As proteins are an important component for
cell structure and function, such changes in quantity and quality of proteins will play a pivotal role to affect
disease development and progression.
Research achievements (from final report):
Despite the advance in our understanding about signaling pathways and transcription factors that mediate gene
transcription and molecular remodeling in diseased hearts, the underlying molecular mechanism remains
poorly defined. This project addressed a key issue regarding how pathological stimuli are converted into altered
gene expression patterns that lead to hypertrophy and heart failure. These studies characterized epigenetic
changes mediated by SWI/SNF. In addition, we report that histone deacetylase inhibiton as a potential of novel
therapeutic targeting specific epigenetic factors thereby expression and reversing cardiac hypertrophy.
Expected future outcomes:
Characterizing the therapeutic benefit of histone deacetylase inhibition for the treatment cardiac hypertrophy
and failure.
Name of contact:
Assam El-Osta
Email/Phone no. of contact:
assam.el-osta@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 526638
Start Year: 2009
CIA Name: A/Pr Rebecca Ritchie
End Year: 2011
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Basic Pharmacology
Total funding: $487,670
Title of research award:
TARGETING ROS-INDUCED DAMAGE RESCUES THE DIABETIC HEARTTARGETING ROSINDUCED DAMAGE RESCUES THE DIABETIC HEART
Lay Description (from application):
Over 1 million Australians have diabetes. Many of these patients die from cardiovascular disease. We have
identified free radicals as a major cause of decreased pumping function and impaired recovery from each
heartbeat in the diabetic heart. Stronger antioxidant approaches and-or activation of protective protein
pathways is a more effective treatment for reversing impaired function in the diabetic heart, preventing or
delaying heart failure in patients with diabetes.
Research achievements (from final report):
Patients with diabetes are 2.4-fold more likely to develop heart failure, even when adjusted for age and
coronary artery disease. The onset of heart failure occurs earlier in diabetes, with heart failure prevalence
increased 5- 8-fold in adults <65yrs old. In particular, how the heart recovers from each heart beat (cardiac
muscle relaxation, known as diastolic function) in diabetic patients takes longer, and is less efficient, than in
people without diabetes. This impaired recovery is directly related to patient prognosis over the longer term.
The alarming global epidemic of diabetes thus gives rise to an ever-increasing heart failure burden. We have
now identified two different signalling pathways that regulate cardiac function in the diabetic heart. One of
these pathways is detrimental for cardiac function, the generation of toxic chemicals (known as free radicals)
by the heart muscle, which is triggered by high blood glucose levels. The other pathway isprotective. We now
demonstrate that a novel protective protein called PI3K? (previously identified by Dr McMullen in other
cardiac pathologies) preserves cardiac function in diabetes. This work has attracted 2 major conference
speaking invitations (Cardiac Society of Australia and New Zealand 2012; International Society of Heart
Research World Congress 2010), as well as 7 national and 4 international university seminar programs. Ten
publications have resulted , plus another currently in review and two additional manuscripts are in preparation.
Our research may ultimately facilitate the development of exciting new ways to treat diabetic cardiac disease,
and hence increase survival, in humans suffering diabetes.
Expected future outcomes:
Diabetes is Australia's fastest-growing chronic disease, affecting ~1000000 Australians; many more await
diagnosis. Cardiovascular complications represent their major cause of death. We have identified detrimental
and protective signals that regulate diabetic heart function. Targeting the interaction between these signals may
reduce progression to heart failure and death in diabetic patients.
Name of contact:
A/Prof Rebecca H Ritchie
Email/Phone no. of contact:
rebecca.ritchie@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 526642
Start Year: 2009
CIA Name: Prof Merlin Thomas
End Year: 2011
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Nephrology and Urology
Total funding: $453,145
Title of research award:
The role of angiotensin converting enzyme 2 in diabetic complicationsThe role of angiotensin converting
enzyme 2 in diabetic complications
Lay Description (from application):
Most heart attacks and strokes arise from narrowing of the arteries. This process is regulated by a number of
hormonal pathways. One of the most important is the renin angiotensin system. Our group has demonstrated
important changes in this pathway which play a pivotal role in regulating the development of atherosclerosis
and its response to treatment. It is predicted that these studies will provide critical information to develop
innovative treatment strategies for cardiovascular disease.
Research achievements (from final report):
The RAS is a common target for drug interventions for the prevention of cardiovascular and kidney disease.
However, it complexities are still poorly understood. Our research has focused on the ACE2/A1-7 axis,
particularly in the context of diabetes. We have demonstrated that suppression of ACE2 is required for diabetes
associated complications and that ACE2 deficiency is able to cause a range of problems in the heart, kidneys
and blood vessels. We believe that these findings will directly lead to improved therapeutic approaches that
target ACE2 to achieve superior renal and vascular protection than occurs currently with conventional blockade
of the RAS, as well as identifying new strategies to retard or reverse micro- and macrovascular damage
associated with diabetes.
Expected future outcomes:
It is expected that better understanding of the renin angiotensin system and its players will lead to the
identification of more effctive ways to modulate its activities than are currently available.
Name of contact:
Merlin Thomas
Email/Phone no. of contact:
mthomas@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 526647
Start Year: 2009
CIA Name: A/Pr Julie McMullen
End Year: 2011
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $512,947
Title of research award:
Targeting critical nodes on the IGF1-PI3K pathway to improve function of the failing heartTargeting critical
nodes on the IGF1-PI3K pathway to improve function of the failing heart
Lay Description (from application):
Heart failure is a major clinical problem which is becoming worse as our population grows older and
comorbidities such as obesity and diabetes become more prevalent. Current heart failure therapeutics largely
delay disease progression. This research proposal focuses on strategies designed to improve function of the
failing heart, as opposed to simply delaying disease progression. This approach will lead to the development of
new therapeutics.
Research achievements (from final report):
There is no cure for heart failure. Current therapies largely slow down disease progression. The beneficial
effects of regular physical activity/exercise on cardiovascular health are well established. Exercise is one of
only a few interventions with the capacity to improve heart function rather than just delaying disease
progression in heart failure patients. In this project we identified a key gene called PI3K that is essential for
exercise-induced heart protection.We then used a gene therapy approach to increase PI3K in hearts of mice
with pre-existing heart disease. We demonstrated for the first time, that increasing PI3K in the hearts of mice
can improve heart function., , We have also examined the role of other genes that have been linked with PI3K
and may also provide protection in the heart.
Expected future outcomes:
A gene therapy approach incorporating a different gene (i.e. not PI3K) recently entered a phase 2 trial in heart
failure patients with promising findings. Our results suggest that gene delivery of PI3K in the human failing
heart could improve heart function.
Name of contact:
Dr Julie Mcmullen
Email/Phone no. of contact:
julie.mcmullen@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 526656
Start Year: 2009
CIA Name: Dr Judy de Haan
End Year: 2011
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $358,319
Title of research award:
Antioxidant glutathione peroxidase (GPx) mimetics and atherosclerosis: a role for targeted antioxidant
therapy.Antioxidant glutathione peroxidase (GPx) mimetics and atherosclerosis: a role for targeted antioxidant
therapy.
Lay Description (from application):
This proposal investigates the use of antioxidant therapy, targeted at increasing the function of the body's
important antioxidant enzyme GPx1, to reduce atherosclerosis both in a non-diabetic and diabetic setting.
Strong clinical evidence and our recently published data support an important role for GPx1 in limiting
atherosclerosis. We will now investigate the molecular mechanisms involved in mediating these effects and
whether compounds that mimic GPx1 function reduce atherosclerosis.
Research achievements (from final report):
Diabetic complications such as atherosclerosis remain a significant health issue despite intensive glucose and
blood pressure lowering therapeutics. The quest for additional treatment regimens remains a highly desirable
aim. Therapies to lessen oxidative stress is a major focus of many health programs; however no clear
cardiovascular benefits have emerged in clinical trials using standard antioxidants. We believe a targeted
antioxidant approach is more likely to yield clinical benefits. Research undertaken as part of NHMRC project
#526656 focussed on the use of mimetics of the antioxidant enzyme, GPx1, to reduce the burden of diabetesasociated atherosclerosis (DAA). This study was built on our very significant earlier findings that showed an
important anti-atherogenic role for GPx1 in diabetic mouse models. GPx1 is responsible for the removal of
damaging reactive oxygen species such as peroxynitrite and hydrogen and lipid peroxides. The data generated
in NHMRC grant #526656 showed that GPx1 mimetics that removed these particular ROS, were able to lessen
atherosclerosis, as well as pro-inflammatory and pro-atherogenic pathways in diabetic mouse models. Our data
also revealed that this class of antioxidant (we investigated both the parent compound ebselen as well as
modifications of ebselen that rendered the compound more efficacious) was able to reduce inflammation via
the inhibition of key modifications to pro-inflammatory mediators such as p-JNK and p-IKK. Our results
therefore highlight the important anti-atherogenic potential of synthetic GPx1 mimetic compounds, making this
class of compound an attractive therapeutic option in the treatment of DAA.
Expected future outcomes:
It is anticipated that our results, published in prestigious journals such as ATVB and Diabetes, will lead to
clinical investigations of synthetic GPx1 mimetics to lessen diabetes-associated atherosclerosis. Our results
therefore have the potential to significantly impact treatment options to lessen atherosclerosis in diabetics as
well as the general population.
Name of contact:
Judy De Haan
Email/Phone no. of contact:
judy.dehaan@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 526662
Start Year: 2009
CIA Name: Prof Geoffrey Head
End Year: 2011
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $475,917
Title of research award:
Neurogenic hypertension in the spontaneously hypertensive mouse : Role of the hypothalamic-brainstem
sympathetic axisNeurogenic hypertension in the spontaneously hypertensive mouse : Role of the hypothalamicbrainstem sympathetic axis
Lay Description (from application):
In human high blood pressure, particularly in the young, an overactive nervous system is thought to be a major
underlying cause. Using a unique mouse model of high blood pressure which closely resembles this aspect of
the human disease, we will examine which brain cells and neuro- chemicals are involved, particularly in a
small area that is involved in regulating the hormonal and nervous system response to stress. From this we
hope to be able to target these chemicals with specific therapy.
Research achievements (from final report):
Our studies have shed new light on the role of the sympathetic nervous system in hypertension. Hypertension is
associated with many risk factors for cardiovascular disease. Until now it has been difficult to determine the
role the sympathetic nervous system plays but the development of the Schlager hypertensive mouse has meant
that this can be studied. We have determined the contribution of the autonomic nervous system to the high
blood pressure which is evident in the Schlager mouse. We have shown an important role for the sympathetic
nervous system in the development of hypertension in both young and adult mice independent of their levels of
physical activity or the renin angiotensin system. In addition, we found that the hypertension in Schlager mice
is associated with greater responsiveness of blood pressure to aversive stress but not to appetitive arousal. The
hypertension in the Schlager mice appears to be associated with greater responses of blood pressure to
stimulation of certain brain pathways. These pathways mediate the arousal responses to stress, and involve
regions of the brain such as the amygdala, hypothalamus and rostral ventrolateral medulla. We have also found
that angiotensin type 1 receptors in the brain are important for the hypertension in Schlager mice. The present
study has identified a diversity of genes and possible mechanisms involved in the etiology and maintenance of
hypertension in the Schlager mouse, highlighting both common and divergent processes in the early and adult
phases of the condition.
Expected future outcomes:
Our studies are relevant to other pathologies where sympathetic nerves and kidney are implicated, eg stress,
heart failure, obesity and diabetes.
Name of contact:
Prof. Geoff Head
Email/Phone no. of contact:
geoff.head@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 526664
Start Year: 2009
CIA Name: Prof Jaye Chin-Dusting
End Year: 2011
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Basic Pharmacology
Total funding: $243,946
Title of research award:
Targeting arginase in peripheral arterial occlusive diseaseTargeting arginase in peripheral arterial occlusive
disease
Lay Description (from application):
Peripheral artery occlusive disease causes narrowing of large peripheral blood vessels which can result in
severe pain, gangrene and stroke. Its prevalence is steadily increasing in western countries. This proposal aims
to characterize the role of an enzyme (arginase) in PAOD and determine whether it may be a new drug target
for treatment of this disease.
Research achievements (from final report):
We demonstrated that an enzyme called arginase plays a very important role in the cardio-profile;
demonstrating cardio-benefit with one isoform and cardio-risk with another.
Expected future outcomes:
We expect to see future therapies targeting these enzyme isoforms in the future.
Name of contact:
Jaye Chin-Dusting
Email/Phone no. of contact:
jaye.chin-dusting@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 586603
Start Year: 2010
CIA Name: A/Pr Julie McMullen
End Year: 2012
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $532,593
Title of research award:
Targeting PI3K-regulated microRNAs to treat heart failureTargeting PI3K-regulated microRNAs to treat heart
failure
Lay Description (from application):
Current therapeutics largely delay heart failure progression rather than regressing it. New therapeutic strategies
with the capability of improving function of the failing heart are thus greatly needed. The primary goal of this
study is to determine whether novel regulatory genes can enhance cardiac function in a setting of heart failure.
Ultimately, technologies that target these genes may lead to innovative pharmacotherapies in the clinical
management of heart failure.
Research achievements (from final report):
Existing therapies for heart failure typically slow, rather than prevent or reverse disease progression. New welltolerated therapies with the ability to improve function of the failing heart are greatly needed. We discovered
that inhibiting a family of tiny molecules called microRNAs can prevent heart failure in mice and improve the
pumping performance of the heart. MicroRNAs are important for the normal function of cells, but when
microRNAs are dysregulated they can cause heart disease. The researchers had observed that the microRNA 34
family was elevated in the heart after a cardiac stress (e.g. heart attack or high blood pressure). When they gave
mice a drug that inhibits the miR-34 family they were able to prevent or reduce the adverse effects of a heart
attack or high blood pressure. Most importantly, they were also able to improve heart function. This research is
significant for a number of reasons. First, a number of other research groups have inhibited single microRNAs
in settings of heart disease. The current study differs in that it has used a new approach which inhibits a whole
family of microRNAs simultaneously in mice with established heart disease. The scientists found that
inhibiting the entire miR-34 family which contains three members was far more effective than inhibiting just
one family member. Second, no evidence of toxicity was observed with the treatment. Third, the translation of
a microRNA-based therapy from mice to primates and into clinical trials has already been demonstrated with a
drug for the treatment of Hepatitis C. ?????
Expected future outcomes:
With a microRNA-based therapy already in clinical trials for the treatment of Hepatitis C, we are working
towards the same for heart failure patients.
Name of contact:
A/Prof Julie Mcmullen
Email/Phone no. of contact:
julie.mcmullen@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 586626
Start Year: 2010
CIA Name: Prof Bronwyn Kingwell
End Year: 2012
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Endocrinology
Total funding: $559,472
Title of research award:
Novel Metabolic Actions of HDL with Therapeutic Potential for Type 2 DiabetesNovel Metabolic Actions of
HDL with Therapeutic Potential for Type 2 Diabetes
Lay Description (from application):
Our proposal investigates a novel approach to treat type 2 (late onset) diabetes. We have identified an
important link between HDL (good) cholesterol and glucose metabolism. The current proposal is to conduct
studies in humans to determine whether therapies which increase HDL result in sustained reduction of blood
glucose. Given the escalating global prevalence of obesity and type 2 diabetes, this work is potentially of great
significance.
Research achievements (from final report):
Recent clinical studies by our laboratory and others indicate that high-density lipoprotein (HDL) cholesterol
('good' cholesterol) exerts beneficial actions beyond protection from heart and blood vessel disease, which may
extend to type 2 diabetes. Many drugs are now in development to raise HDL and are being tested for their
ability to prevent heart and blood vessel disease. One of these HDL-raising drug classes in advanced clinical
trials is cholesteryl ester transfer protein (CETP) inhibitors. Based on our previous work showing that HDL has
multiple effects on glucose metabolism through both effects on muscle (which is where most glucose in the
body is used) and in the pancreas (which makes and releases insulin) we examined the effects of CETP
inhibition on pancreatic function. Our work shows that a novel CETP inhibitor has potentially favourable
effects on plasma insulin levels after a meal. Furthermore we showed that plasma from patients in this clinical
trial directly stimulated insulin release from pancreatic cells grown in culture. This effect occurred in the
presence of glucose which mimics meal consumption, but not under basal (low glucose or fasting) conditions.
This suggests that HDL elevation may potentially protect against large exursions in post meal blood glucose
levels which are known to harm blood vessels.These studies will support therapeutic approaches to raise levels
of circulating HDL for indications beyond vascular disease to manage type 2 diabetes. Given the escalating
global prevalence of metabolic syndrome and type 2 diabetes, therapies targeting both glycaemic control as
well as cardiovascular complications have the potential for significant impact.This grant resulted in 12
publications in leading cardiovascular and diabetes journals inlcuding (Circulation Research, European Heart
Journal, Diabetes and Nature Reviews (Endocrinology)).
Expected future outcomes:
N/A
Name of contact:
Bronwyn Kingwell
Email/Phone no. of contact:
bronwyn.kingwell@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 586653
Start Year: 2010
CIA Name: Prof Karlheinz Peter
End Year: 2012
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $559,643
Title of research award:
Therapeutic targeting of CD40L-Mac-1 in inflammatory disease, in particular atherosclerosisTherapeutic
targeting of CD40L-Mac-1 in inflammatory disease, in particular atherosclerosis
Lay Description (from application):
Atherosclerosis is a major burden for human health resulting in myocardial infarction-stroke. We have
previously identified a novel interaction between two adhesion molecules, CD40L and Mac-1, which mediates
leukocyte adhesion to endothelial cells being a major determinant of atherosclerotic plaque development. We
are now developing blocking peptides and recombinant antibodies thereby exploring various antiinflammatory- anti-atherosclerotic strategies, targeting both Mac-1 and CD40L.
Research achievements (from final report):
Inflammatory disease such as rheumatoid arthritis and multiple sclerosis but also atherosclerosis with all its
complications such as potentially fatal myocardial infarctions and debilitating strokes are major health
problems. Therapeutic approaches are limited and associated with potentially severe side effects. We could
identify a new interaction between two leukocyte receptors (Mac-1 - CD40L), which contributes substantially
to inflammatory reactions. Furthermore, we could localise the interaction site and identified a small peptide
that is able to block this leukocyte interaction and thereby we could identify a novel potential therapeutic
approach. We could also show that this potential drug is very unique in its selective effect, not influencing
other receptor or leukocyte activities. This promises to reflect a drug effect that is not associated with typical
side effects of anti-inflammatory drugs. We could demonstrate that this therapeutic approach is capable of
inhibiting the development of atherosclerosis in mice. In addition, we could show that the anti-inflammatory
effect is powerful enough to reduce signs of rheumatoid arthritis in mice. Overall, we were able to establish a
promising new anti-inflammatory approach and to identify a template for the further development of a novel
small molecular weight drug class.
Expected future outcomes:
We are planing to extent the proof of concept of the anti-inflammatory potential of our novel therapeutic
approach to other inflammatory diseases beyond atherosclerosis and arthritis. In addition, we have developed
an additional therapeutic format, an antibody directed against the region that mediates the interaction between
leukocytes on the Mac-1 receptor. This antibody will be tested as well.
Name of contact:
Prof Karlheinz Peter
Email/Phone no. of contact:
karlheinz.peter@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 586660
Start Year: 2010
CIA Name: Dr Elisabeth Lambert
End Year: 2012
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $544,535
Title of research award:
Role of sympathetic nervous system in the development of early organ damage in obesity:an emerging target
for therapyRole of sympathetic nervous system in the development of early organ damage in obesity:an
emerging target for therapy
Lay Description (from application):
Young people with obesity often have no signs of cardiovascular disease but their organs, such as the heart, the
kidneys and the blood vessels present early evidence of damage that can, in time, progress to confer
cardiovascular risk. This study will look at the potential beneficial effect of a drug, by itself or in association
with a low calorie diet, in reversing the progression of organ damage in young obese subjects.
Research achievements (from final report):
Our hypothesis are (1) that young adults excess adiposity present with early signs of damages in their kidneys,
heart and vessels (2) that activation of the nervous system contributes substantially these damages (3)? that
strategies aiming at decreasing the activity of the nervous system may reverse the progression of the organ
damage.We examined cardiac, renal and vascular function and blood pressure regulation in non- hypertensive
young individuals with obesity and compared them with lean counterparts and measure the activity of the
nervous system. We recruited 18 lean and 25 overweight or obese healthy university students. We
comprehensively assessed organ damage, including renal function, heart structure and function and vascular
function. Nerve activity was assessed placing an electrode in a peripheral nerve. Our results indicated that
excess weight in young individuals is associated with alterations in renal and vascular function, as well as in
the structure of the heart, even in the absence of hypertension and that the nervous activity is closely associated
with cardiovascular and renal alterations observed in these subjects. In the second part of the project, subjects
are randomized to either a diet, diet with moxonidine (a drug that inhibits the nervous activity) or control for a
period of 6 months. We expect to complete the study by the end of 2013 and to publish the last results
thereafter.
Expected future outcomes:
Reducing the activity of the nervous system by drug therapy may prove to be a beneficial and novel way to
reduce the risk of cardiovascular disease in subjects with obesity. Adding such drug during a weight loss
program may further improve early organ damage and possibly improves metabolic profile.
Name of contact:
Elisabeth Lambert
Email/Phone no. of contact:
elisabeth.lambert@bakeridi.du.au
NHMRC Research Achievements - SUMMARY
Grant ID: 586667
Start Year: 2010
CIA Name: Prof Markus Schlaich
End Year: 2012
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $455,365
Title of research award:
Sympathetic nervous system inhibition for the treatment of diabetic nephropathySympathetic nervous system
inhibition for the treatment of diabetic nephropathy
Lay Description (from application):
One of the commonest consequences of diabetes is the development of renal impairment, in the worst case
scenario resulting in renal failure reuqiring renal replacement therapy. We aim to test a novel therapeutic
strategy based on inhibition of the sympathetic nervous system to halt progression of renal failure and to
improve outcomes in patients with this condition.
Research achievements (from final report):
Diabetic nephropathy is one of leading causes of end stage renal disease in Australia. Despite the successful
and effective introduction of lower blood pressure targets for patients with diabetes and the use of inhibitors of
the renin-angiotensin system, an immportant cardiovascular control system relevant in this context, current
treatment strategies only provide partial protection and a substantial proportion of these patients remain at
considerable residual risk for complications affecting both the kidnyes and the heart. There is an urgent need
for the development of novel strategies to curb this global burden of complications. Targeting the sympathetic
nervous system is an obvious but clearly neglected therapeutic strategy and its usefulness and effectiveness in
reducing albuminuria in diabetic nephropathy and related factors needs was the aim of this investigation. The
study is a randomized controlled trial in a cross over design and has not yet reached its final recruitment target,
hence final results are not yet available.
Expected future outcomes:
If our hypothesis is correct and inhibition of the sympatheic nervous system by means explored in this study
can reduce albuminuria, this could become a standard tretament for this conditon.
Name of contact:
Professor Markus Schlaich
Email/Phone no. of contact:
markus.schlaich@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 586676
Start Year: 2010
CIA Name: Prof Karin Jandeleit-Dahm
End Year: 2012
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Endocrinology
Total funding: $542,860
Title of research award:
Targeting the AGE-RAGE axis in diabetes associated atherosclerosisTargeting the AGE-RAGE axis in
diabetes associated atherosclerosis
Lay Description (from application):
Based on extensive preliminary data we porpose that the AGE intercation with RAGE plays an important role
in diabetes associated atherosclerosis. We will perform studies using a soluble form of the receptor RAGE
which will trap AGEs in the blood and tissues and thus prevent diabetes related blood vessel damage.
Furthermore, we will investigate if RAGE receptor on inflammatory cells such as macrophages plays a pivotal
role in blood vessel injury in diabetes.
Research achievements (from final report):
Based on the results generated by this grant we have made significant discoveries that inhibiton of the
AGE/RAGE pathway should include interventions at both sides, including inhibition of AGE formation as well
as inhibition of the interaction with RAGE. These findings have significant clinical implications. Furthermore,
we have identified that inhibition of early AGE intermediates such as methylglyoxal is the most promising
apporach to prevent diabetic complications.
Expected future outcomes:
This work will stimulate the development of novel agents to interfere with AGE and methyglyoxal formation
as well as blocking the interaction with receptors such as RAGE. Furthermore, it has stimulated the search for
potential activators of the glyoxylase system which detoxifies MGO.
Name of contact:
Karin Jandeleit-Dahm
Email/Phone no. of contact:
karin.jandeleit-dahm@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 586678
Start Year: 2010
CIA Name: A/Pr Terri Allen
End Year: 2012
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Endocrinology
Total funding: $405,594
Title of research award:
The Role of Urotensin II in Diabetes-Associated AtherosclerosisThe Role of Urotensin II in DiabetesAssociated Atherosclerosis
Lay Description (from application):
People with diabetes most commonly die from stroke or heart attack and we need to determine what makes
them more prone to these problems. The recently discovered UII system is increased in people with diabetes
and has been found in diseased parts of blood vessels. Thus, the aim of this project is to characterise the UII
system in the setting of diabetes using 2 unique genetically altered mice and a blocker a to study the effects of
high cholesterol, diabetes and a deletion of UII.
Research achievements (from final report):
N/A
Expected future outcomes:
N/A
Name of contact:
Assoc Prof Terri Allen
Email/Phone no. of contact:
N/A
NHMRC Research Achievements - SUMMARY
Grant ID: 586724
Start Year: 2010
CIA Name: Dr Yi Fu
End Year: 2011
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: International Exchange Early
Career Fellowships
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $149,321
Title of research award:
Inflammation in Hypertension: Mechanisms underlying increased blood pressure as a risk factor for
HypertensionInflammation in Hypertension: Mechanisms underlying increased blood pressure as a risk factor
for Hypertension
Lay Description (from application):
The proposed project aims to find a direct link by which high blood pressure contributes towards the
pathogenesis of atherosclerosis. We hypothesise that this may be through the induction of hypertension on
vascular inflammation, considered to be an early contributor to atherosclerosis. This project may indentify
novel therapeutic targets in the prevention of atherosclerosis in the hypertensive patient.
Research achievements (from final report):
We explored a new mechanism of vascular inflammation: the increased blood presure promotes the leukocyte
adhesion to blood vessel, indicating the vessel inflammation.Endothelial caveolae structure seems involved in
the process, working as a mechano-sensor., , Caveolin-1, the structure-maintain protein of caveolae, was found
to play a critical role in monocyte differentiation into macrophage, which is the key step of atherosclerosis.
This implys that intervention on monocytic caveolin-1 may have the potential effect to prevent atherosclerosis.
Expected future outcomes:
To keep blood pressure in normal range can modulate the blood vessel inflammation., To explore a novel
therapeutic target on white blood cells for blood vessel disease.
Name of contact:
Yi Fu
Email/Phone no. of contact:
yi.fu@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1000657
Start Year: 2010
CIA Name: Prof David Kaye
End Year: 2011
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Development Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $474,088
Title of research award:
Novel soluble guanylate cyclase activators for pulmonary artery hypertensionNovel soluble guanylate cyclase
activators for pulmonary artery hypertension
Lay Description (from application):
Pulmonary hypertension (elevated blood pressure in the lungs) is a life-threatening condition with few
treatment options. We have recently identified a new class of drug that may improve blood vessel function in
the lungs and thereby provide a new drug for the management of this group of patients.
Research achievements (from final report):
This series of studies was designed to develop a novel family of compounds which have the potential to
improve vascular function. Effects of the family of chemicals were examined in isolated cells and in the test
tube. The potency of lead compounds was determined and a further series of compex studies were performed to
synthesize a new set of chemicals in an attempt to increase potency beyond other clinically used drugs. In
parallel a model of pulmonary hypertension was established, which is being used to screen the effectiveness of
other candidate molecules.
Expected future outcomes:
This program of research lays the foundation for the identification of drugs that may help patients with vascular
disease and pulmonary hypertension.
Name of contact:
Prof David Kaye
Email/Phone no. of contact:
david.kaye@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1003106
Start Year: 2011
CIA Name: Prof Dmitri Sviridov
End Year: 2012
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $266,388
Title of research award:
Novel Apolipoprotein A-I Mimetic Peptides: a Research Tool and a Therapeutic Agent to Study and Treat
AtherosclerosisNovel Apolipoprotein A-I Mimetic Peptides: a Research Tool and a Therapeutic Agent to Study
and Treat Atherosclerosis
Lay Description (from application):
Drugs affecting lipid metabolism have revolutionized the treatment of heart diseases. There is, however, an
urgent need for further reduction of high remaining risk. A most promising direction is increasing levels of
“good cholesterol”. A new type of such therapy are simple compounds mimicking structure of good
cholesterol. We have synthesized new such compounds that are even more active than good cholesterol. Now
we will test these compounds in animals and in clinical trial.
Research achievements (from final report):
Drugs affecting lipid metabolism have revolutionized the treatment of heart diseases. There is, however, an
urgent need for further reduction of high remaining risk. A most promising direction is increasing levels of
"good cholesterol". Several attempts to implement such therapy have however failed because of insufficient
understanding how good cholesterol works. One therapy that worked very well was infusion of extra good
cholesterol isolated from donor plasma, but this is very expensive and impractical form of therapy. A
development of this approach is another type of such therapy consisting of simple compounds mimicking
structure of good cholesterol. We have synthesized new such compounds that are even more active than good
cholesterol. We tested these compounds these compounds in animals. Findings of this study were unexpected
showing that it is unlikely that these compounds directly act by themselves. Rather they initiate a complex
change in lipid metabolism and inflammatory response that eventually leads to reduction of atherosclerosis.
These findings on the one hand provided new explanation why some other forms of therapy were unsuccessful.
On the other hand they informed us how to design new forms of therapy that will hopefully be successful.
Specifically, we conducted new study with compounds selected on the basis of this knowledge and shown that
they reduce atherosclerosis in animal models.?????
Expected future outcomes:
We expect to finalize the study choosing a single compound (or a mixture) that have maximal effect in animal
models. This compound will then be tested in small clinical trial to ensure safety. As a result we may have a
compound ready for testing in an outcome based clinical trial.
Name of contact:
Prof. Dmitri Sviridov
Email/Phone no. of contact:
Dmitri.Sviridov@Bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1003234
Start Year: 2011
CIA Name: Prof Karlheinz Peter
End Year: 2013
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $586,965
Title of research award:
Preventing myocardial infarction: A mouse model of atherosclerotic plaque instability/rupture as unique tool
for establishing novel pharmacological strategies and targeted molecular imagingPreventing myocardial
infarction: A mouse model of atherosclerotic plaque instability/rupture as unique tool for establishing novel
pharmacological strategies and targeted molecular imaging
Lay Description (from application):
Myocardial infarction strikes without warning and thereby causes death or major disability. It is typically
caused by sudden rupture of atherosclerotic plaques and occlusion of coronary arteries. Research on this was
hampered by the lack of an animal model of plaque rupture. We have newly established a mouse model, which
we will now use to generate novel tools to image and identify plaques that are prone to rupture and to develop
novel therapies preventing plaque rupture and myocardial infarction.
Research achievements (from final report):
So far research aimed towards the understanding of plaque rupture was massively hampered since there was no
animal model available that truly reflects human pathology. Using flow characteristics seen to cause plaque
rupture in humans, we developed a surgicual 2 tandem stenosis model of the carotid artery of the mouse. Here
we could induce plaque instability and rupture and could show that all histological criteria normally used to
define human unstable atherosclerotic plaques could be found in the cartoid artery proximal to the proximal
stenosis. In addition we could define genes and in particular mircoRNA that are associated with plaque rupture.
Amongst these were in particular those that are know to be involved in inflammatory reactions. We are
currently investigating these with the aim to develop novel therapeutic approaches of plaque stabilisation and
thereby prevention of myocardial infarction., Finally, the model developed was the basis of a new in the
meantime patented fluorescence technology that allows the detection of unstable plaques, which is a highly
sought-after medical device development. We could also use the model to develop novel PET tracers that are
able to detect unstable, rupture-prone plaques.
Expected future outcomes:
The newly developed palque instability/rupture model will allow to test novel diagnostic and therapeutic
approaches with the aim to finally reduce the number of patients who suffer plaque ruptures.
Name of contact:
Karlheinz Peter
Email/Phone no. of contact:
karlheinz.peter@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1005329
Start Year: 2011
CIA Name: A/Pr Xiao-Jun Du
End Year: 2013
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $365,126
Title of research award:
beta-Adrenergic activation: a double-edged sword on cardiac angiogenesisbeta-Adrenergic activation: a
double-edged sword on cardiac angiogenesis
Lay Description (from application):
We will test our hypothesis that activation of beta-adrenergic receptors (b-AR) regulates significantly on
growth of blood vessels in the heart. While initialy promoting vessel growth, prolonged stimulation of b-AR, a
situation seen with diseased hearts, suppresses vessel growth thereby promoting disease progression. This
hypothesis is strongly supported by our recent experimental findings and would have important clinical
implication on the treatment of patients with heart disease.
Research achievements (from final report):
Diseased hearts exhibit many abnormalities, of them, two are of great therapeutic importance: first, dropout of
small blood vessels leading to reduced blood supply to the working muscle; and second, continous loss of
cardiac muscle cells. Boch changes are important in disease progression and heart failure development. This
project investigated the importance and mechanism by which ?-adrenergic receptor (?AR) regulates both
changes. Two key findings have been made. , 1) We discovered for the first time that activation of ?2-receptor
(?2AR) promotes small vessel growth in the heart. We documented step-by-step molecular link for this action
and its important for cardiac function. In a setting of disease simulating hypertensive heart disease, however,
this action becomes inactive. Our careful molecular assays identified two proteins (CaMKII, p53) that are
increased in their activities in diseaed heart and mediate the inhibitory signal to ?2AR-induced vessel growth.
This documentation is important because it indicates that a combined therapy using ?2AR activator and
inhibitors for CaMKII/p53 should be able to effectively support vessel growth in sick heart.(research paper
under journal review) , 2) As a down-side of ?AR functionality, we demonstated a new biochemical link
between ?AR and Bim, a protein important in cardaic muscle cell death. We confirmed the operation of this
mechanism under a few diseased conditions investigated. This finding points to a new therapeutic target (i.e.
?AR-Bim link) that allows for selective prevention of cardaic cell death, a common phenomenon in heart
disease, initiated by ?AR-Bim interaction. (this study has been published 2013, a new research grant submitted
2014 to continue this work)
Expected future outcomes:
Our studies showed that ?2AR stimulation promotes cardiac angiogenesis signalling. Although factors
associated with disease act as suppressor to this mechanism, our findings bear therapeutic potential, i.e.
activation of ?2AR signalling to stimualte cardiac angiogenesis with simultaneous inhibition of these unwanted
factors including CaMKII, p53 and Bim.
Name of contact:
Xiao-Jun Du, Secondxiao-Jun Du
Email/Phone no. of contact:
xiao-jun.du@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1005851
Start Year: 2011
CIA Name: Prof Karin Jandeleit-Dahm
End Year: 2013
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $441,512
Title of research award:
NOX isoforms in diabetes associated vascular injury: implications for therapeutic strategiesNOX isoforms in
diabetes associated vascular injury: implications for therapeutic strategies
Lay Description (from application):
These studies will investigate the role of oxidative stress and enzymes involved in oxidative stress production
in diabetes associated blood vessel injury and kidney damage, leading to heart attacks, stroke and kidney
failure. We will use unique knockout animal models and novel drug treatments. Ultimately, we aim to develop
novel treatments to better treat and prevent diabetes related complications.
Research achievements (from final report):
This grant has been very succesful. In our work we have identified Nox1 as the most important Nox isoform in
diabetes associated atherosclerosis (published in Circulation 2013) and Nox4 in diabetic nephropathy
(published in JASN in 2014). The work is ongoing with several other publications in progress. Furthermore,
this work has been widely presented as invited presentations at the major international and national diabetes,
heart and kidney conferences. We have submitted an ongoing project grant to continue this work. We have
established and expanded collaborations with the top groups in the world in this field and have an ongoing
collaboration with industry to investigate novel more specific Nox inhibitors initially preclinically and
ultimately in the clinical context.
Expected future outcomes:
Our work has shown that Nox4 in the vasculature may be beneficial. Ongoing and future research will
delineate the role of Nox4 and the human isoform Nox5 in the vasculature and in the kidney in diabetes. We
will identify novel targets and validate them in animal models as well as in investigator driven early phase
clinical trials.
Name of contact:
Karin Jandeleit-Dahm
Email/Phone no. of contact:
karin.jandeleit-dahm@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1007451
Start Year: 2011
CIA Name: Prof Geoffrey Head
End Year: 2013
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $609,424
Title of research award:
Importance of The Brain Renin-Angiotensin System For Regulating Blood Pressure and Cardiovascular
Autonomic Function.Importance of The Brain Renin-Angiotensin System For Regulating Blood Pressure and
Cardiovascular Autonomic Function.
Lay Description (from application):
The peptide angiotensin a major regulator of many brain areas controlling blood volume and blood pressure.
Brain angiotensin may well contribute to high blood pressure but how it acts in each of the different brain areas
is unknown. New gene transfer technology using viruses combined with genetically modified mice will enable
this project to inactivate or activate angiotensin in each brain nucleus and determine the role of individual areas
to setting of blood pressure leading to hypertension.
Research achievements (from final report):
AT1A receptor expression by C1 neurons in the rostral ventrolateral medulla is essential for the pressor
response to angiotensin II and this pathway plays an important role in the pressor response to aversive stress.
The expression of AT1A receptors in caudal ventrolateral medullary neurons including A1 neurons has little
influence on basal blood pressure but may play a tonic role in inhibiting cardiac vagal baroreflex sensitivity.
They strongly facilitate the forebrain response to aversive stress but reduce the pressor response presumably
through greater sympathoinhibition.Transfection of AT1A receptors on neurons in the nucleus tractus solitarius
elevates blood pressure independently of the sympathetic nervous system and pressor responses to aversive
stress are associated with greater Fos-expression in forebrain regions. This study suggests a novel mechanism
by which the NTS may modulate blood pressure in the long-term via AT1A receptors. Thus there are novel and
specific roles for angiotensin II in both the rostral and caudal ventrolateral medulla as well as the nucleus
tractus solitarius in autonomic regulation. In rabbits chronic treatment with low dose angiotensin increases the
responsiveness of specific central nervous system pathways regulating the sympathetic nervous system and
increases their dependence on superoxide production.
Expected future outcomes:
N/A
Name of contact:
Professor Geoffrey Head
Email/Phone no. of contact:
Geoff.head@baker.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1007712
Start Year: 2011
CIA Name: A/Pr Elizabeth Woodcock
End Year: 2013
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $548,908
Title of research award:
SHANK3 as a target to reduce hypertrophy and heart failureSHANK3 as a target to reduce hypertrophy and
heart failure
Lay Description (from application):
We have identified a large protein in heart that functions to facilitate the heart's response to disease. The
proposed studies will define how this protein mediates responses and whether we can successfully interfere
with the process to limit disease progression.
Research achievements (from final report):
We have achieved the goal of demonstrating that phospholipase Cbeta1b (PLCb1b) associates with SH3
domain and ankyrin repeat protein 3 (Shank3) via an interaction between the C-terminal proline-rich domain of
PLCb1b and the Src homology 3 (SH3) domain of Shank3. This was achieved using P/A mutations in the Cterminal sequence of PLCb1b and showing that they did not bind Shank3, did not increase PLC activity and did
not activate downstream responses. In addition we used domain deletion mutants of Shank3 to show that the Cterminal sequence of PLCb1b required the SH3 domain for binding. , We have identified other signalling
proteins that associate with Shank3 and are involved in downstream PLCb1b signalling. Homer1c was shown
to associate with Shank3 and to be required for PLCb1b-initiated responses. Homer1c associates with a
proline-rich sequence in the C-terminal region of Shank3. More recent studies have identified a splice variant
specific interaction of transient receptor potential canonical 4alpha (TrpC4a with Shank3. TrpC4a, but not
TrpC4b, associated with Shank3 and, in parallel, only TrpC4a was shown to be involved in responses
downstream of PLCb1b. The 2 splice variants of TrpC4 differ only in a sequence that binds PIP2, the substrate
of PLCb1b, with this sequence being present in TrpC4a but not TrpC4b.
Expected future outcomes:
We have performed studies with PLCb1b expressed in mouse hearts in vivo and are currently evaluating the
use of a mini-gene inhibitor, developed in our laboratory, to ameliorate phenotype following pressure overload
hypertrophy. Having identified the interface by which PLCb1b binds to Shank3 we have designed a screening
procedure to identify start compounds.
Name of contact:
Elizabeth Woodcock
Email/Phone no. of contact:
liz.woodcock@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1008682
Start Year: 2011
CIA Name: A/Pr Julie McMullen
End Year: 2013
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $553,634
Title of research award:
PI3K-regulated heat shock proteins and microRNAs as new treatment strategies for atrial fibrillationPI3Kregulated heat shock proteins and microRNAs as new treatment strategies for atrial fibrillation
Lay Description (from application):
Atrial fibrillation (AF) is the most common sustained arrhythmia presenting in cardiology departments
worldwide and is associated with increased mortality and morbidity. New treatment strategies are greatly
needed. We have discovered that lower levels of a gene with protective properties in the heart causes AF in
mice and is associated with AF in humans. This proposal will examine whether novel agents that target this
gene can reduce or prevent AF.
Research achievements (from final report):
Atrial fibrillation (AF) is the most common sustained arrhythmia presenting in cardiology departments
worldwide and is associated with substantially increased mortality and morbidity from heart failure and stroke.
With a growing aging population the incidence of AF is increasing, adding considerably to health care costs.
Current treatment strategies are not very effective. , In this project we have identified a novel drug (BGP-15)
which is able to reduce AF and improve heart function in 2 different mouse models which display AF.
Expected future outcomes:
Based on the promising results in mice we are planning to assess the impact of BGP-15 in a large animal model
(sheep). Since BGP-15 has an excellent safety profile (based on clinical trials for other diseases) we are hopeful
BGP-15 will enter a clinical trial for AF.
Name of contact:
A/Prof Julie McMullen
Email/Phone no. of contact:
julie.mcmullen@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1009025
Start Year: 2011
CIA Name: A/Pr Julie McMullen
End Year: 2013
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $532,921
Title of research award:
Manipulating cardiac-selective PI3K targets to reverse heart failure progressionManipulating cardiac-selective
PI3K targets to reverse heart failure progression
Lay Description (from application):
Heart failure is a major clinical problem which is becoming worse as our population ages. New therapeutic
strategies with the capability of improving function of the failing heart are greatly needed. We have identified
novel targets of a gene with protective properties in the heart. This proposal will examine whether these new
targets can reverse heart failure progression. Technologies that target these genes may lead to innovative
pharmacotherapies in the clinical management of heart failure.
Research achievements (from final report):
Most therapies for heart failure slow down disease progression but do not improve heart function and quality of
life. Exercise is known to improve heart function and quality of life in patients who can exercise. However, not
all patients can exercise and compliance can be poor. Therefore we undertook a strategy of identifying and
targeting "good" genes that are elevated in the heart with exercise as a new therapeutic approach. , In mouse
models of heart failure we have shown that a new gene therapy approach which increases "good genes" that are
increased in the heart with exericse, can improve heart function.
Expected future outcomes:
We hope to demonstrate that our gene therapy approach is also beneficial in a large animal model. This is
important for moving this approach into the clinic.
Name of contact:
A/Prof Julie R. McMullen
Email/Phone no. of contact:
julie.mcmullen@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1012100
Start Year: 2011
CIA Name: Prof Markus Schlaich
End Year: 2013
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $619,194
Title of research award:
Catheter based renal denervation to improve outcomes in congestive heart failureCatheter based renal
denervation to improve outcomes in congestive heart failure
Lay Description (from application):
In heart failure there is a large increase in sympathetic nerve activity that is detrimental to patient outcome, but
the factors causing this increased activity are not well defined. There is evidence that renal nerves play a
significant role. A novel catheter based technique allows silencing of these nerves. We will test whether this
novel technique has the potential to improve the outcomes for patients with heart failure.
Research achievements (from final report):
In heart failure there is a large increase in sympathetic nerve activity that is detrimental to patient outcome, but
the factors causing this increased activity are not well defined. Neural signalling from under-perfused organs is
a likely contributor to the elevated sympathetic drive indicating that renal nerves play a significant role. A
novel catheter based technique applying radiofrequency energy delivered by a catheter placed in the kidney
arteries (renal denervation) for the first time allows selective silencing of these renal nerves. In a
comprehensive and translational research approach combining studies in a large animal model (sheep) and in
patients with heart failure we investigated the effects of catheter-based renal denervation on relevant aspects
related to heart failure. We made several important observations including: 1. Renal and whole body
sympathetic nerve activity are significantly elevated in heart failure; 2. Catheter-based renal denervation results
in a significant reduction in renal and whole body nerve activity; 3. Renal denervation was associated with an
improved haemodynamic profile and had no adverse effects on kidney function 4. In sheep, there is evidence of
regrowth of sympathetic nerves at around 12 months after the procedure. While recent advances in
pharmacotherapy clearly improved outcomes in heart failure patients, their prognosis remains poor and there is
an urgent need for the development of novel strategies to curb the global burden of heart failure induced
cardio-renal complications and mortality. Our initial data indicate that renal denervation may be a useful
additional therapeutic approach for this patient cohort.
Expected future outcomes:
Our mechanistsic studies in sheep and preliminary studies in patients with heart failure combining state-of-the art technology to investigate the effects of renal denervation on sympathetic nerve activity and the
haemodynamic profile will be crucial to inform future clinical trials in this patient cohort.
Name of contact:
Professor Markus Schlaich
Email/Phone no. of contact:
markus.schlaich@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1012574
Start Year: 2011
CIA Name: Prof Murray Esler
End Year: 2013
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Cardiovascular medicine and Haematology nec
Total funding: $411,735
Title of research award:
Reducing the burden of orthostatic intolerance - Delineating mechanisms and improving therapyReducing the
burden of orthostatic intolerance - Delineating mechanisms and improving therapy
Lay Description (from application):
Orthostatic intolerance (OI) represents a heterogenous group of complex disorders which are poorly understood
and lack effective treatment. They are frequently disabling and may severely impact on quality of life. In the
proposed project, we will undertake a systematic investigation of “sympathetic nervous system” in OI patients
and assess the clinical effect of a drug “L-DOPS” in subjects suffering from OI.
Research achievements (from final report):
Orthostatic intolerance (OI), fainting brought on by standing, is quite common, poorly understood and not
effectively treated. We have made progress in understanding and treating one common subgroup of OI patients,
those whose blood pressure is low even when they are lying down (supine). Low supine blood pressure is often
discounted by doctors, but this is an important OI subgroup, of patients who can be very disabled by postural
blackouts. We find these patients have a defective autonomic (automatic) nervous system response to the
stimulus of postural gravity, in that their autonomic stimulant system, the sympathetic nervous system, does not
reflexly support their blood pressure while standing, through inadequate release of the neurotransmitter
(chemical messenger), noradrenaline. One aspect of this research project involved administration of a
noradrenaline pro-drug to these patients, which they converted to noradrenaline, therapeutically overcoming
the deficit, and producing marked improvement in symptoms.
Expected future outcomes:
Development of a successful targeted treatment for one group of patients with orthostatic intolerance (OI),
blackouts related to standing.
Name of contact:
Professor Murray Esler
Email/Phone no. of contact:
murray.esler@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1017670
Start Year: 2011
CIA Name: Prof Karlheinz Peter
End Year: 2013
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Development Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $606,524
Title of research award:
Development of Platelet-Targeted Nanoparticles for Magnetic Resonance Imaging towards the Detection of
Thrombi/Emboli and Vulnerable Atherosclerotic PlaquesDevelopment of Platelet-Targeted Nanoparticles for
Magnetic Resonance Imaging towards the Detection of Thrombi/Emboli and Vulnerable Atherosclerotic
Plaques
Lay Description (from application):
Heart attack, stroke and pulmonary embolism typically strike without warning and either kill patients or cause
devastating disabilities. Currently, we do not have diagnostic methods to identify patients and the blood vessels
at risk. We have developed a new innovative MRI nanoparticle directed against activated platelets for the
detection of “at risk” blood vessels. The current funding is requested to optimise the manufacture of this
targeted MRI nanoparticle and to undertake the animal studies required to enter early stage clinical trials.
Research achievements (from final report):
This project provided the basis for many follow-up projects. We compared several production methods for
single-chain antibodies (bacteria, insect cells, mammalian cells) and defined the one with the best
reproducibility and the highest yield. In addition with the company Starpharma we established the prodction of
dendrimers with up to 32 binding sites. However, the most important progress was achieved by the
development of various coupling methods that are mainly based around the sortase technoclogy. The latest
development in this regards was the combination of the biological coupling method based on sortase and the
chemical coupling method based on click chemistry. We then used this coupling method to develop mainly
targeted MRI contrast agents. However, we were able to extend this to molecular imaging using ultrasound,
fluorescence and finally PET imaging.
Expected future outcomes:
The technologies developed in this grant will allow to perform molecular imaging in various modalities
including MRI, ultrasound and PET. Clinical targes will be thrombosis, inflammation and atherosclerosis.
Name of contact:
Karlheinz Peter
Email/Phone no. of contact:
karlheinz.peter@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1017672
Start Year: 2011
CIA Name: Prof Geoffrey Head
End Year: 2013
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Development Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $511,037
Title of research award:
Development of Oral Natruiretic Peptides for Congestive Heart FailureDevelopment of Oral Natruiretic
Peptides for Congestive Heart Failure
Lay Description (from application):
Congestive heart failure is fatal disease and a major disease burden for the community affecting nearly half a
million Australians. Current therapies are inadequate. We seek to develop a new peptide therapy based on
snake venom version of the human B type natriuretic peptide which has to be given by injection. We will
produce an orally active, stable and effective treatment using a program of discovery involving testing in
animals and cells.
Research achievements (from final report):
Current treatments for Congestive Heart Failure (CHF) are inadequate, as they elicit many side-effects, often
treat only single symptoms and rarely address the progression of the disease. With very limited options for
heart transplants, there is a strong clinical need for new alternative therapies to treat this disease. While human
based natriuretic peptides (NP) have been launched for acute treatment of CHF they are limited by their
extremely short half-lives and intravenous formulation. We have identified chimeric orally active natriuretic
peptides with enhanced stability profiles that would make them ideal for further development. We have tested
in a rabbit a range of pegylated forms of the chimeric peptide and found that while we were not able to increase
oral bioavailability ufficienty, we have been able to effectively develop a subcutaneous formulation that proved
effective. The upscaled manufacture was achieved with gram quatities being proiduced in conjunction with
AusPep. We have now tested this compound in a large animal model of CHF (cardiac paceed sheep) and found
improved cardiac performance consistent with the known actions of NPs.
Expected future outcomes:
These studies provide the basis for a suitable candidate for phase 1 and II clinical studies for CHF. The
potential benefit and cost saving in reducing hospitalisation (now required for NP treatment) with an oral form
of NP is enormous.
Name of contact:
Professor Geoffrey A Head
Email/Phone no. of contact:
geoff.head@baker.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 376601
CIA Name: Prof Gregory Gass
Admin Inst: Bond University
Main RFCD: Primary Health Care
Total funding: $696,250
Start Year: 2007
End Year: 2008
Grant Type: NHMRC Project Grants
Title of research award:
Exercise: An examination of dose-response relationships for women aged 65-74 yr.Exercise: An examination
of dose-response relationships for women aged 65-74 yr.
Lay Description (from application):
The increasing number of older women in Australia presents a significant challenge to our health system.
Preventative and health promotion strategies must be developed for this important group of Australian's if
chronic disease and disability are to be contained and the decline in functional capacity attenuated. One
potential intervention strategy is regular exercise. However, if exercise is to have multi-systems benefits, the
dose of the exercise must be known. We do not know the exercise prescription that will maximize those health
benefits required for this group of Australian's. We propose to resolve this situation via two related experiments
involving women aged 65-74 yr. Experiment 1 will select moderate-intensity treadmill walking for 30 minsession with the weekly exercise frequency varied from 1 to 5 session-wk for 64 sessions. Experiment 2 will
also select moderate-intensity treadmill walking with the total exercise time per week (120 min-wk) and the
number of weeks of training (24 wk) fixed but varying the exercise duration per session (24 to 120 minsession) and the exercise frequency per week; 5 (x 24 min) to 1 (x 120 min) session-wk. Each subject will
undergo lung function tests, body fat test, fitness tests and blood tests at selected time intervals throughout each
experiment. A separate fitness test will be conducted on the subjects' leg muscle to help us understand what is
happening directly in the muscle. We will also conduct a tilt test to help us understand how regular exercise
might lessen the likelihood of 'falls' in older individuals. We expect to determine the optimum exercise
prescription to improve health and minimize injury and misadventure. It is essential that GP's who have the
main responsibility for prescribing exercise for their older patients, have access to knowledge on the optimum
exercise prescription to maximize the beneficial changes in health and functional capacity in females aged 6574 yr.
Research achievements (from final report):
The optimal prescription of exercise for older women to increase their physiological functional capacity and
manage chronic diseases has become clearer. Our results highlight that women aged 65-74 yrs can positively
adapt and without clinical misadventures to a sub-maximal exercise stimulus to produce significant gains in
their physiological functional capacity and their every day activities. Our results also challenge the utility of
using maximum exercise testing for prescribing a sub-maximal exercise programme. The project results have
identified a measure to select moderate intensity exercise for older women wishing to undertake a safe exercise
programme. General Medical Practitioners could use such a measure to select the exercise intensity in
conjunction with a consultation when prescribing an exercise programme.
Expected future outcomes:
The data from the project are being analysed for publication to inform health professionals about the
prescription of exercise for older women.
Name of contact:
Professor Gregory Gass
Email/Phone no. of contact:
g.gass@cqu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 511217
Start Year: 2008
CIA Name: Prof Jenny Doust
End Year: 2012
Admin Inst: Bond University
Grant Type: NHMRC Strategic Awards
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $499,199
Title of research award:
Implementation and cost-effectiveness of absolute risk for prevention of cardiovascular disease in
AustraliaImplementation and cost-effectiveness of absolute risk for prevention of cardiovascular disease in
Australia
Lay Description (from application):
Cardiovascular disease (CVD) causes more deaths and accounts for more hospital costs than any other disease
in Australia. Providing the best possible mix of treatments to prevent CVD in those at risk has the greatest
potential to reduce deaths, disability and costs associated with this disease. There is evidence that improving
the current mix of treatments that patients at risk of CVD receive would lead to significant improvements in
health in Australia. The project will determine the best mix of treatments that can be provided for patients at
risk of CVD whilst keeping spending on treatments to prevent the disease at current levels. We will also
examine how to increase the number of healthy years of life (and not just the number of people affected by
disease) by looking at how the mix of treatments can affect the timing of CVD. The project will develop a
decision support system for GPs to be able to a) establish the risk of CVD for an individual patient and b) a
treatment algorithm for patients at risk of CVD that can be used in general practice and that can take into
account other diseases that patients may also have. The treatment algorithm will then be tested in a randomised
controlled trial. The project differs from the Harris (510173) and Nelson (490042) projects in that it will assess
a mix of drug treatments and lifestyle interventions to determine the optimal balance. This project also
includes a formal cost-effectiveness component and has the support of the chair of the PBAC, Prof Lloyd
Samson.
Research achievements (from final report):
Better targeting of medications used for cardiovascular disease (CVD) prevention, such as blood pressure and
lipid lowering drugs, would improve the effectiveness and cost-effectiveness of these widely used drugs. We
conducted:, 1) a systematic review of CVD risk equations (Liew et al, 2011). We showed that recent analyses
are confounded by treatment effects, leading to potentially spurious associations (Liew et al, 2012). Treatment
effects explain the observed over-prediction of risk by the Framingham risk equation in recent populations, and
re-calibration of the equation is not necessary. , 2) an analysis of the AusDiab cohort, showing that the absolute
risk approach significantly changes who is treated with blood pressure and lipid lowering medications (Doust
et al, 2012). A further explanation of the clinical application of this analysis is outlined in a paper recently
accepted by the MJA (Nelson and Doust, 2013)., 3) a qualitative study of GPs and consumers and a vignette
study. These studies showed that a number of factors impact on GP prescribing other than the CVD risk level,
such as patient motivation for lifestyle interventions and attitudes to medication. There is also some ongoing
misundertanding of the clinical application of the absolute risk approach (2 publications ready for submission).
These factors need to be considered in improving the uptake of the absolute risk approach, and better targeting
of medication for CVD prevention.
Expected future outcomes:
We are currently analysing an economic evaluation of the absolute risk approach in Australia, based on the
distribution of risk factors from the AusDiab cohort. We are conducting the process evaluation of a NHMRC
funded trial of a decision aid for CVD risk prediction and the use of the heart age tool to better communicate
CVD risk to patients.
Name of contact:
Jenny Doust
Email/Phone no. of contact:
NHMRC Research Achievements - SUMMARY
jdoust@bond.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 396405
Start Year: 2006
CIA Name: Prof Ron Borland
End Year: 2009
Admin Inst: Cancer Council Victoria
Grant Type: NHMRC Project Grants
Main RFCD: Health, Clinical and Counselling Psychology
Total funding: $922,582
Title of research award:
Maximising the effectiveness of interactive automated programs for smoking cessationMaximising the
effectiveness of interactive automated programs for smoking cessation
Lay Description (from application):
This project is to design, implement and trial automated programs to help smokers quit. It makes use of the
powers of modern computing and telecommunications. It uses information the person provides to personally
tailor advice and assistance to smokers as they progress from beginning to think about quitting through to being
a stable, happy non-smoker. In particular, we are interested in the relative value of detailed advice as compared
with the capacity of modern messaging technology (SMS, voice, images) to provide a set of prompts and
reminders that help smokers manage a quit attempt and help prevent them relapsing back to smoking. Once
we have developed the interventions, we will subject them to a rigorous scientific trial to see how effective
they are and also how cost-effective they prove. Our hope is that these programs will provide a cheap,
accessible and effective way of helping smokers to quit and thus help reduce the huge toll of smoking-related
disease.
Research achievements (from final report):
We have refined an existing program of Internet-based automated tailored advice for smoking cessation
(QuitCoach), and developed a program delivering text messaging support via mobile phone (Quit onQ). These
programs have the capacity to be used as stand-alone interventions, or used together as an integrated package
of support. The programs were developed with extensive input from smokers to ensure their acceptability and
usability, and several field trials were conducted in which detailed feedback was obtained. Following this
development process, a randomised trial was carried out to determine the efficacy of the intervention
components, both in isolation and as an integrated package. The trial also examined different ways of offering
the forms of support, to provide information on how to maximise uptake of tailored automated interventions in
the population., The trial has provided one of the first investigations of the potential of text messaging as a way
to deliver smoking cessation advice. The findings demonstrate that such programs can be effective both as a
stand alone intervention and as a complement to a more intensive program of tailored advice. The onQ program
is now being used by QuitSA as a stand alone intervention., The trial suggests a need to improve how the tools
we have developed are marketed to recent quitters, and to improve the capacity of the interventions to stimulate
quit attempts, as much of the benefit seems to be in preventing relapse.
Expected future outcomes:
The text messaging program is now being used by Quit SA, while the original QuitCoach continues to be used
widely. Quit Victoria are currently building the infrastructure that will enable the trial version of QuitCoach to
be implemented, complemented by Quit onQ and enhanced via improved integration with the Quitline.
Name of contact:
Prof Ron Borland
Email/Phone no. of contact:
Ron.Borland@cancervic.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 520316
CIA Name: Dr Allison Hodge
Admin Inst: Cancer Council Victoria
Main RFCD: Epidemiology
Total funding: $304,002
Start Year: 2008
End Year: 2011
Grant Type: Early Career Fellowships (Australia)
Title of research award:
Dietary antioxidants and fatty acids and heart disease risk in Southern European migrants and Indigenous
AustraliansDietary antioxidants and fatty acids and heart disease risk in Southern European migrants and
Indigenous Australians
Lay Description (from application):
The aim in this research program is to learn more about how nutrition, particularly different types of dietary fat
and antioxidants from fruit and vegetables, can affect the risk of cardiovascular disease and diabetes. Data
from Indigenous Australians known to be at high risk for these conditions, as well as Greek and Italian
migrants to Australia, with low risk for cardiovascular disease, will be analyzed.
Research achievements (from final report):
Identification of important associations between healthy diet and a range of conditions including anxiety and
depression, impaired vision, osteoarthritis, cardiovascular risk factors, cancer and diabetes. Dietary patterns
including fruit and vegetables, limited amounts of red and processed meat and omega-3 fats or olive oil, lower
salt and moderate carbohydrate intake were associated with lower risks of these conditions, although we found
some evidence that consumption of red meat below the level recommended in the Australian dietary guidelines
was associated with mood and anxiety disorders., We developed a definition of healthy ageing based on the
absence of chronic disease, depression or anxiety and disability and found this was less common in people who
had diabetes 12 years earlier, was associated with consuming more calcium, important for bone health, and less
energy, and having an eating pattern reflecting that of southern European migrants to Australia, as well as
healthy weight, not smoking and being physically active in middle-age. Social interaction did not appear to be
associated with healthy ageing by our objective criteria, but may modify how people perceive the ageing
process (these papers are not yet published). Having a healthy weight in middle age was also associated
specifically with less disability after 70 years of age., On the basis of observations regarding diet and mental
health we are planning a study to see what happens when we provide food and advice on healthy diet to people
with clinical depression compared with others who get no dietary advice or food.
Expected future outcomes:
Results of above intervention study in depression if as hypothesised will add to options for treatment of
depression. Modelling dietary change over time to evaluate the benefits of a mediterranean style diet for
cardiovascular and total mortality will be important methodologically as it avoids the need to conduct
intervention studies.
Name of contact:
Allison Hodge
Email/Phone no. of contact:
allison.hodge@cancervic.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 475604
Start Year: 2008
CIA Name: Prof Jie Jin Wang
End Year: 2010
Admin Inst: Centre for Eye Research Australia Ltd Grant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $438,992
Title of research award:
Genetic Markers for Retinal Arteriolar Narrowing and Risk of Hypertension and Cardiovascular
DiseaseGenetic Markers for Retinal Arteriolar Narrowing and Risk of Hypertension and Cardiovascular
Disease
Lay Description (from application):
This submission proposes a study to identify the genes that determine retinal arteriolar narrowing - a marker of
hypertension, and to examine how these genes interact with environmental factors, and to investigate if these
genes do indeed predict persons at risk of heart disease.
Research achievements (from final report):
Genotyping on the highest and the lowest quartiles of central retinal arterial equivalent (CRAE) has been
completed, as has the GWAS data quality checking and imputation from HapMap in 2009. In addition, we have
genotyped the whole BMES sample and imputed SNPs from the 1000 genomes in 2010. Genetic association
analyses have been explored using both the case-control and the whole BMES GWAS data. To enhance
evidence quality, we have collaborated with the Cohorts for Heart and Aging Research in Genomic
Epidemiology (CHARGE) Consortium, which consists of five population-based cohorts, and other populationbased studies in the USA, UK and Singapore, to assess genetic associations with CRAE. Initial analyses of the
data by individual study and meta-analyses of findings from all studies have been completed. Two SNPs were
found to be associated with CRAE with p values at GWAS significance level. A manuscript is currently under
preparation and near completion. In addition, detailed analyses for genetic associations with CRAE using
BMES data are currently ongoing to carefully investigate effects of known cardiovascular disease risk factors
on CRAE genetic associations, including interaction or effect modifications. An abstract has been presented as
an oral presentation at the Annual Scientific Meeting of the High Blood Pressure Research Council of
Australia, December 2010, Melbourne.
Expected future outcomes:
Given that narrowing retinal arterioles is a marker indicating the risk of subsequent development of clinical
hypertension, knowledge of associations of retinal arteriolar calibre with genetic and cardiovascular risk factors
may provide insights into the mechanisms of a hypertension subtype that is primarily due to increase in
peripheral resistance.
Name of contact:
Sasha Helen Anagnostou
Email/Phone no. of contact:
sashaa@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 475605
Start Year: 2008
CIA Name: Prof Tien Wong
End Year: 2010
Admin Inst: Centre for Eye Research Australia Ltd Grant Type: NHMRC Project Grants
Main RFCD: Endocrinology
Total funding: $396,818
Title of research award:
Prediction of Microvascular Complications in Type 1 Diabetes Using Novel Retinal Vascular Imaging
TechniquesPrediction of Microvascular Complications in Type 1 Diabetes Using Novel Retinal Vascular
Imaging Techniques
Lay Description (from application):
Children with type 1 diabetes face the risk of developing severe complications later in life involving their eyes
(retinopathy), kidneys (nephropathy) and nerves (neuropathy). This study aims to determine if subtle, early
changes seen in the retinal blood vessels, as measured from new computer imaging techniques, predict the
subsequent development of these diabetes complications in children/adolescents with type 1 diabetes.
Research achievements (from final report):
The study commenced in 2008. To date, over 1200 baseline retinal images have been assessed and graded for
novel measures of retinal vascular architecture including retinal vascular caliber, tortuosity, branching angles
and fractal dimensions. We have demonstrated that retinal vascular geometry (branching angle, tortuosity,
optimality deviation) are altered following the advancement of adverse diabetes risk profiles (duration of
diabetes, HbA1c level, blood pressure, and cholesterol), and are associated with prevalent retinopathy and early
nephropathy. Furthermore we demonstrated that baseline arteriolar length to diameter ratio (LDR) and simple
tortuosity (ST) predicted incident retinopathy (manuscript under review - Diabetes Care). We are currently
studying the relationship between venular changes and early renal dysfunction. Longitudinal plantar fascia
study (adult follow up) had 152 patients with 278 visits graded for vessel calibre and fractal dimension, a total
of 555 eyes. Patients have been reassessed for follow-up examinations and undergone small artery elasticity,
blood pressure and plantar fascia thickness assessments as well as retinal photography. Grading of these images
was completed in December 2009. Abstracts were submitted for both Aims 1 and 2 and data presented at
several international meetings. The manuscript is currently being revised and will be submitted for publication
in March 2011. We completed recruitment of 310 patients and 125 controls for the cross-sectional plantar
fascia study in October 2010. Grading of vessel calibre and fractal dimension has been completed for 310
patients and the data is currently being analysed.
Expected future outcomes:
We expect to identify novel biomarkers for diabetic complications that are sensitive and specific, as well as
practical for clinical use.
Name of contact:
Prof. Tien Wong
Email/Phone no. of contact:
twong@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 475617
Start Year: 2008
CIA Name: Prof Jie Jin Wang
End Year: 2010
Admin Inst: Centre for Eye Research Australia Ltd Grant Type: NHMRC Development Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $254,714
Title of research award:
Development of a computer-based retinal imaging program for identification of people at risk of cardiovascular
disease.Development of a computer-based retinal imaging program for identification of people at risk of
cardiovascular disease.
Lay Description (from application):
Cardiovascular disease is the leading cause of death and imposes an enormous financial and healthcare burden
on the Australian community. This project will develop and deliver a novel clinical prediction tool,
incorporating retinal vascular imaging and assessment, to improve identification of asymptomatic people who
are at high risk of cardiovascular disease at an early stage, allowing implementation of preventative strategies
and medical interventions to effectively prevent CV disease.
Research achievements (from final report):
This project was funded under the Development Grant scheme of the NHMRC. Two key items of intellectual
property have been derived from this project and are at differing stages of prosecution. The first, "Feature
Detection and Mesurement In Retinal Images" is at PCT stagePCT/AU2010/001110 ; the second, "Disease
And Disease Predisposition" is an Australian provisional application. The latter invention is subject matter of a
licence agreement between the Centre For Eye Research Australia and Medalytix Ltd.
Expected future outcomes:
Integration of the invention from CERA into the Medalytix platform will have great potential for non-invasive
prediction of cardio-vascular disease using automated retinal grading.
Name of contact:
Dr Khay-Lin Teoh
Email/Phone no. of contact:
kteoh@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 590212
Start Year: 2010
CIA Name: Prof Tien Wong
End Year: 2012
Admin Inst: Centre for Eye Research Australia Ltd Grant Type: NHMRC Project Grants
Main RFCD: Epidemiology
Total funding: $754,255
Title of research award:
Novel Retinal Architectural Vascular Signs and Risk of Cardiovascular Disease: The AusDiab StudyNovel
Retinal Architectural Vascular Signs and Risk of Cardiovascular Disease: The AusDiab Study
Lay Description (from application):
Cardiovascular disease (CVD) and diabetes are major health problems. Identifying 'people at risk' is critical to
design preventative strategies. We have developed new computer software to measure detailed characteristics
of retinal vessels. By appling this system to predict CVD or diabetes in the AusDiab Study we aim to find 'the
best combination of risk factors' to predict CVD and diabetes. This will open up the possibility of new risk
assessment using a simple 'eye scan.'
Research achievements (from final report):
Cardiovascular disease (CVD), diabetes and its vascular complications are major causes of morbidity and
mortality in Australia. Early identification at asymptomatic stage is the key for successful prevention. We
aimed to examine whether retinal architectural parameters are sensitive measures to predict systemic vascular
diseases.We performed computer-based image analysis using retinal images and clinical data of the AusDiab
study participants at the Baseline (1999-2000) and 5-year follow up (2004-5). We refined the retinal imaging
technique to quantify retinal parameters of the fractal dimensions (FD), vessel tortuosities and calibres. We
also performed a validation study to evaluate how pulse cycle affects the measurements of retinal vessel
parameters; we confirmed that retinal vascular characteristics are stable against pulse cycle.We have collected
CVD outcome using questionnaires and medical records review from AusDiab study participants nationwide in
2010-12. Although we have completed a data collection, adjudication of clinical information is underway; we
could not fully utilize the information in the current analysis. Although we could not utilize CVD outcomes, we
have looked at cross-sectional associations of retinal architectural parameters to other systemic outcomes. We
found that persons with higher retinal FD were more than 50% more likely to have diabetes compared to the
persons with smaller FD. We also found Serum apolipoprotein are associated with microvascular endothelial
dysfunction. Higher retinal vascular tortuosities were also associated with diabetes and diabetic retinopathy.
These are in concordance with our hypothesis that retinal architectural parameters are associated with vascular
diseases.
Expected future outcomes:
Our proposed study will provide new insights into the inter-relationship between early microvascular changes
and subsequent risk of CVD, diabetes and its vascular complications. Furthermore, our research may
potentially allow the use of non-invasive retinal imaging as a tool to identify asymptomatic persons with higher
risk of CVD.
Name of contact:
Professor Tien Wong
Email/Phone no. of contact:
tien_yin_wong@nuhs.edu.sg
NHMRC Research Achievements - SUMMARY
Grant ID: 229030
Start Year: 2003
CIA Name: Dr Spencer PROCTOR
End Year: 2004
Admin Inst: Curtin University of Technology
Grant Type: Early Career Fellowships (Overseas)
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $174,288
Title of research award:
To characterise & attenuate cholesterol deposition in animal models of abesity, insulin resistance & diabetes
using noveTo characterise & attenuate cholesterol deposition in animal models of abesity, insulin resistance &
diabetes using nove
Lay Description (from application):
Not Available
Research achievements (from final report):
Cardiovascular disease (CVD) is the most common cause of death and morbidity in all prosperous societies,
leading to heart attacks, strokes and kidney disease. A major contributor to CVD is obesity non-insulin
dependent diabetes mellitus (NIDDM), or type-2 diabetes. CVD is caused by the accumulation of cholesterol
and lipid in blood vessels, which can lead to a complete blockage in the artery and stop blood flow. In diabetes,
the accumulation of cholesterol in arterial vessels is accelerated and CVD develops and progresses more
quickly, unfortunately it is still not clear how this happens. Strangely, the 'bad' types of cholesterol (called
LDL) that are thought to cause heart attacks, appear to be normal in people with early diabetes. We have
discovered recently that humans (and animals) with insulin-resistance (early type-2 diabetes) have raised levels
of dietary cholesterol (called chylomicrons), which are different from the traditional 'bad' cholesterol called
LDL.
Expected future outcomes:
We have developed an animal model that will allow us to explore how the intestine is modulated during
chronic disease and contrbutes to CVD risk
Name of contact:
Spencer Proctor
Email/Phone no. of contact:
spencer.proctor@ualberta.ca
NHMRC Research Achievements - SUMMARY
Grant ID: 353511
CIA Name: Prof James Semmens
Admin Inst: Curtin University of Technology
Main RFCD: Epidemiology
Total funding: $583,500
Start Year: 2005
End Year: 2007
Grant Type: NHMRC Project Grants
Title of research award:
The WA Safety and Quality of Surgical Care Project: Improving the Safety, Quality and Provision of Surgical
Care.The WA Safety and Quality of Surgical Care Project: Improving the Safety, Quality and Provision of
Surgical Care.
Lay Description (from application):
The basis of this application is a three-year project which aims to improve the safety, quality and the provision
of surgical care. This application constitutes the core of the WA Safety and Quality of Surgical Care Project
(SQSCP), which was established in 1996 to evaluate the clinical epidemiology, health care utilisation, patient
safety and health outcomes following admission to hospital for specific surgical and medical procedures in
Western Australia (WA). The study will use data from the WA Data Linkage System, which brings together 15
million records from hospital morbidity, death, cancer, midwives notification and mental health databases.
Surgical procedures have been selected for review based on national priorities and after consultation with the
WA Branch of the Royal Australasian College of Surgeons (RACS) and other clinical Colleges. This
application proposes to continue the core research activities of the SQSCP. A special focus will be on the use
of minimally invasive surgical techniques including laparoscopic, endoscopic and endoluminal procedures,
which have increased dramatically during the last decade. The study will also evaluate differences in the
outcomes of surgical care in rural and metropolitan settings. The findings of the SQSCP will be
comprehensively disseminated to surgeons, the RACS, hospital managers, health policy makers and
consumers.The rationale of this project is that by providing high quality data on the epidemiology, utilisation
and outcomes of surgical care, we will be able to increase the knowledge-base that will contribute to
improvements in the safety, quality and provision of surgical care in Australia and internationally. The aims of
the SQSCP are consistent with national health priorities and the recommendations of the Taskforce on Quality
of Australian Health Care Study, the Australian Council for Safety and Quality in Health Care and the National
Institute of Clinical Studies.
Research achievements (from final report):
The SQSCP used data from the WA Data Linkage System, supplemented by additional information from chart
review where appropriate, to evaluate the clinical epidemiology, utilisation and outcomes of a broad scope of
selected procedures. Each procedural involved surgeons as part of the evaluation team. The total research
output of the SQSCP since 1996 is 158 scientific papers, of which 37 papers and 3 book chapters were
published as a result of this grant. Of particular importance were open and endoluminal repair of abdominal
aortic aneurysm including the use of fenestrated grafts, wide bodied stent grafts to treat iliac disease; peripheral
artery disease; laparoscopic technology evaluation, hysterectomy, breast cancer management and treatment;
cataract surgery; the locational and social inequalities of procedural care, and the evaluation of laparoscopic
cholecystectomy and other endoscopic procedures. For these procedures we established benchmark standards
of performance, guidelines for treatment, assessed difference in outcomes between metropolitan and rural
patients, and assessed patient outcomes including the risk of adverse events. The outcomes were widely
disseminated to surgeons, the RACS, health care managers and policy makers, and consumers. We provided a
focus on translational research to change clinical practice and influence health policy. As a result of this work,
two of the CIs received national awards, CIA Semmens the RACS medal and CIC Lawrence-Brown an Order
of Australia. Continued funding was approved by the NHMRC for the SQSCP for 2008-2010 (#479205)
Expected future outcomes:
The future outcomes will include the provision of evidence based data to influence the guidelines and treatment
for patients requiring surgical care. The data will contribute to changes in safety and quality of surgical
practice, support health policy and influence the development of models of care.
NHMRC Research Achievements - SUMMARY
Name of contact:
Professor James Semmens
Email/Phone no. of contact:
James.Semmens@curtin.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 425505
CIA Name: Prof Robert Donovan
Admin Inst: Curtin University of Technology
Main RFCD: Preventive Medicine
Total funding: $592,838
Start Year: 2007
End Year: 2009
Grant Type: NHMRC Project Grants
Title of research award:
A longitudinal investigation of the efficacy of pharmacological smoking cessation aids in real-life settingsA
longitudinal investigation of the efficacy of pharmacological smoking cessation aids in real-life settings
Lay Description (from application):
Currently around 3 million Australians, or 17% of people aged 14 years and over, smoke tobacco daily. These
smokers are at major risk of developing coronary heart disease, stroke, peripheral vascular disease, and a
variety of cancers, including lung, laryngeal, oral, kidney, bladder, breast, pancreas and colon cancers. At any
one time almost half of Australian smokers intend to quit smoking or have already set a date to do so but few
(around 10%) succeed on each attempt. Clinical trials of quitting aids, such as nicotine patches, gum and
Zyban, suggest that smokers are around twice as likely to quit if using these. However clinical trials are
conducted in artificial environments and these quitting aids appear to have a far smaller impact on successful
quitting rates in the 'real world'. Pharmaceutical quitting aids are heavily advertised by drug companies and
widely used in Australia. Futhermore the Commonwealth Government has invested over $133 million dollars
subsidising such aids to Australian smokers in the past four years. However it is not known to what extent these
quitting aids have made a difference to Australian smoking rates. Sales volumes of pharmaceutical quitting aids
appear not to have translated into expected increases in numbers of smokers successfully quitting, suggesting
they are less effective than clinical trials suggest. The present study aims to investigate whether pharmaceutical
quitting aids actually are less effective in the 'real world', and if so, why.
Research achievements (from final report):
A sample of 1204 Western Austrlian smokers participated in one survey every three months over 9 consecutive
occasions to ask about any quit attempts and changes to their smoking habits. Half (49.8%) of the participants
made at least one quit attempt during the two year period and 24% successfully quit. We recorded their
incidental use of cessation pharmaceuticals and concluded that the efficacy of such in real-life situations is far
different than in randomised, placebo-controlled trials. We conclude that the efficacy of NRTs and Zyban may
be exagerated. For instance, nicotine replacement therapies conferred a 46% increased chance of remaining
abstinent at 6 months compared to no assistance but no difference was observed at 12 months. This contradicts
the established literature which suggests smokers are twice as likely to quit. Our results highlight the
limitations of relying upon double-blinded placebo trials to test cessation pharamceuticals trying to ween drug
addicts away from their drug of choice, and that comparison trials would be more appropriate.
Expected future outcomes:
A number of papers are currently being prepared for publication in peer-reviewed scientific journals covering
the areas of: the efficacy of cessation pharmaceuticals in real-life settings; the modern reasons smokers credit
for prompting quit attempts; and the relative adoption of cessation pharmaceuticals by SES.
Name of contact:
Professor Rob Donovan
Email/Phone no. of contact:
r.donovan@curtin.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 458552
Start Year: 2007
CIA Name: Prof James Semmens
End Year: 2007
Admin Inst: Curtin University of Technology
Grant Type: NHMRC Development Grants
Main RFCD: Biomedical Engineering not elsewhere classified
Total funding: $184,688
Title of research award:
Acoustic Blood Pressure Measurement on Implanted Biomedical SurfacesAcoustic Blood Pressure
Measurement on Implanted Biomedical Surfaces
Lay Description (from application):
Measurement of local blood pressure in is of great clinical importance. An application of particular interest is
the pressure measurement in and around endoluminal stents grafts, which are used for the treatment of
Abdominal Aortic Aneurysms (AAAs). These grafts are implanted by keyhole surgery and are used to reduce
the pressure on the aneurysm walls so that the artery can revert to its more anatomically correct shape on a
timescale of one to two years. If the seal between the graft and the artery wall is not blood tight, then the
aneurysm can become repressurised and may keep on expanding. Over time, an untreated, expanding AAA is
likely to rupture with severe consequences for the patient. Thus a convenient, non-invasive means of measuring
the pressure within the aneurysm and within the graft is highly desirable. In this proposal, we seek to produce
a device that can be incorporated into the walls of the endoluminal graft, which can measure absolute pressure
inside and outside the graft and where the pressure measurements can be obtained via standard acoustic or
medical ultrasound equipment. To do this, we would use specially designed ‘bubbles’ which can be
incorporated onto either side of the graft walls, where the resonant frequency of the bubbles provides a direct
measurement of the pressure around the bubbles. Trials at the CSIRO have found that pressures can be
measured to a resolution of better than 10 mmHg by using this technique on air bubbles in water. In this
proposal, we wish to develop flexible, but semi-permanent bubbles that can be incorporated onto a biomedical
implant surface. If such bubbles can be made, the researchers will use CSIRO-developed software and acoustic
equipment such that local blood pressure can be measured in real time.
Research achievements (from final report):
The existing methods of non-invasive blood pressure measurement, of which the inflatable cuff is the most
familiar example, give an averaged estimate for the whole body. It would be of great benefit if local blood
pressure in the vicinity of a particular organ or blood vessel could be measured non-invasively, since this could
indicate the health of particular tissues of concern. , Laboratory experiments were completed that assessed a
technique for measuring pressure using sound waves sent into the body. The underlying principles are that the
acoustic frequency at which a bubble resonates (or "rings") increases with pressure, and that measuring a
frequency rather than an amplitude gives greater accuracy and reliability. , The system works by sending
"chirps" of sound into the body and carefully processing the returning echoes to determine the resonant
frequency of a bubble or bubbles in the body., It was shown that pressures of physiological relevance could be
determined acoustically from the resonant frequency of a bubble, without any contact with the bubble or any
need for implanted wires or electronics. Moreover, it was shown that the pressure could be measured in a
system in which pressure was varying with time, as it does during the heartbeat. The accuracy is conservatively
estimated at 10 mm Hg, but data quality suggests 5 mm Hg is feasible. The range of pressures tested was 0 to
130 mm Hg (normal blood pressure varies from about 80 to 120 mm Hg during a heartbeat)., Recently
developed mathematical theory was shown to predict the measured relationship between pressure and
frequency, but experiments demonstrating the existence of a clear trend were sufficient to suggest that the
technique has promise for a practical device.
Expected future outcomes:
If developed into a practical device, a patient with certain pre-existing conditions could have the local blood
pressure relevant to their condition checked in the course of a simple examination lasting a few minutes, using
equipment that could be affordably deployed in most specialist or even GP rooms, connected to software
running on a PC.
NHMRC Research Achievements - SUMMARY
Name of contact:
Professor James Semmens
Email/Phone no. of contact:
James.Semmens@curtin.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 533500
CIA Name: Prof Peter Howat
Admin Inst: Curtin University of Technology
Main RFCD: Health Promotion
Total funding: $474,781
Start Year: 2009
End Year: 2011
Grant Type: NHMRC Project Grants
Title of research award:
An intervention to improve the nutrition and physical activity behaviours in mothers with young childrenAn
intervention to improve the nutrition and physical activity behaviours in mothers with young children
Lay Description (from application):
The aim of the project is to develop, implement and evaluate a six-month community based intervention that
will improve the nutrition and physical activity behaviours of mothers with young children. As mothers are a
major influence among the family, an intervention that successfully improves physical activity and nutrition
behaviours will also impact on behaviours of the whole family making it a 'whole family' approach.
Research achievements (from final report):
The major achievements of the research grant are: development, implementation and evaluation of a playgroup
based nutrition and physical activity program for mothers with young children. A significant improvement in
physical activity levels, and decrease in fat and sugar consumption and increase in fibre consumption was
achieved by the intervention group participants when compared to the control group participants., This physical
activity and nutrition program offers a unique approach compared to other such programs previously conducted
with mothers with young children in Australia, as the project was designed to evaluate the effects of combining
both physical activity and nutrition. The project provides guidelines for the development, implementation and
evaluation of a playgroup and home-based tailored physical activity and nutrition intervention program that can
be modified for ther ettings with this target group.
Expected future outcomes:
Building on the experience of this project , the research team is planning new projects for this target group.,
The team is also is in the process of disemminating the results and program information to relavant people who
may be able to utilise it in their health promotion programs. , , Publication and presentation of results.
Name of contact:
Professor Peter Howat
Sarojini Monteiro (Gin
Email/Phone no. of contact:
p.howat@curtin.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 533501
CIA Name: Prof Peter Howat
Admin Inst: Curtin University of Technology
Main RFCD: Health Promotion
Total funding: $477,957
Start Year: 2009
End Year: 2011
Grant Type: NHMRC Project Grants
Title of research award:
Physical activity and nutrition for seniors (PANS)Physical activity and nutrition for seniors (PANS)
Lay Description (from application):
Research has shown that participation in physical activity and the consumption of a healthy diet for older
people can produce significant health benefits. The aim of this study is to develop and evaluate a low cost,
accessible, sustainable and replicable, home based physical activity and nutrition program for older people
aged 55 to 70 that will ultimately reduce chronic disease (obesity, diabetes, cardiovascular disease), and
improve mental health.
Research achievements (from final report):
The positive results from the Physical activity and nutrition for seniors (PANS) program demonstrate that a
minimal contact, low-cost and home based physical activity program can positively influence changes to older
adults' physical activity and diet, and can be effective in improving participants' waist-to-hip ratio. Longer
studies should be implemented to obtain more data on the long term effectiveness of such interventions. , This
physical activity and nutrition program offers a unique approach compared to other such programs previously
conducted with older people in Australia, as the project was designed to evaluate the effects of combining both
physical activity and nutrition. The project provides guidelines for the development, implementation and
evaluation of a minimal, home-based tailored physical activity and nutrition intervention program that can be
modified for other settings.
Expected future outcomes:
Building on the experience of the PANS project the research team is now implementing a pilot physical
activity and nutrition project in retirement villages in WA., The research team is also is in the process of
disemminating the results and program information to relavant people who may be able to utilise it in their
health promotion programs.
Name of contact:
The Team Is Also Is In The Process Ofpeter Howa
Email/Phone no. of contact:
p.howat@curtin.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1067331
Start Year: 2014
CIA Name: Prof Lorna Rosenwax
End Year: 2016
Admin Inst: Curtin University of Technology
Grant Type: NHMRC Project Grants
Main RFCD: Public Health and Health Services not elsewhere classified
Total funding: $364,936
Title of research award:
Reducing demand on emergency departments in the last year of lifeReducing demand on emergency
departments in the last year of life
Lay Description (from application):
People in their last year of life who attend emergency departments (EDs) could often be better cared for
elsewhere. Our severely overcrowded EDs, and the staff who work in them, are poorly equipped to provide
appropriate end-of-life care. This research describes how people in their last year of life use EDs, the impact of
this use upon ED services and how the provision of adequate primary care and supportive care services in the
community care may be a more appropriate and economically viable option for people at the end-of-life.
Research achievements (from final report):
The significance of the Dementia Seeding Grant is the project now has progressed through the lengthy process
of acquiring the data from six different databases, data linkage has occurred, ethical approval has been
obtained, cleaning the data has progressed and analysis has commenced. The data was sourced from six
databases within the Data Linkage System in Western Australia.
Expected future outcomes:
Greater understanding of health service use in the last year of life for people with dementia.
Name of contact:
Professor Lorna Rosenwax
Email/Phone no. of contact:
l.rosenwax@curtin.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 274315
CIA Name: A/Pr Kylie Ball
Admin Inst: Deakin University
Main RFCD: Epidemiology
Total funding: $421,375
Start Year: 2004
End Year: 2008
Grant Type: Career Development Fellowships
Title of research award:
Contextual influences on nutrition, physical activity and obesityContextual influences on nutrition, physical
activity and obesity
Lay Description (from application):
Not Available
Research achievements (from final report):
Key findings to emerge from this study include: , o
Socioeconomic variations in healthy
eating are partly explained by lower levels of nutrition knowledge; less 'health consciousness' when making
food choices; and less social support for healthy eating from family and friends., o
Socioeconomic
variations in walking behaviours are partly mediated by personal factors (eg less enjoyment of walking) but
also by factors within the built environment (eg fewer walking tracks and poorer street connectivity in
socioeconomically disadvantaged neighbourhoods), o
Women of lower socioeconomic
position (SEP) more often report lower levels of 'social capital' (eg less trust in their neighbours) and this also
contributed to lower levels of walking and physical activity amongst these women. Crime levels do not appear
to predict lower levels of walking in disadvantaged neighbourhoods., o Physical inactivity and obesity are
key risk factors for depressive symptoms amongst women, and even low levels of physical activity can be
protective against risk for depressive symptoms.
Expected future outcomes:
This research will continue to inform the development of intervention strategies aimed at promoting physical
activity and healthy eating and reducing risk of obesity, particularly amongst persons experiencing
socioeconomic disadvantage.
Name of contact:
Kylie Ball
Email/Phone no. of contact:
kylie.ball@deakin.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 323519
CIA Name: Dr Sarah McNaughton
Admin Inst: Deakin University
Main RFCD: Nutrition and Dietetics
Total funding: $275,438
Start Year: 2005
End Year: 2009
Grant Type: Early Career Fellowships (Australia)
Title of research award:
Development and application of practical tools for the assessment of dietary patterns in the Australian
population.Development and application of practical tools for the assessment of dietary patterns in the
Australian population.
Lay Description (from application):
Not Available
Research achievements (from final report):
, The primary objective of this postdoctoral fellowship research program was the development and application
of methods for assessing dietary patterns, diet quality and the impact of specific dietary patterns on chronic
disease outcomes. While previous research has tended to focus on individual nutrients, there is increasing
interest in investigating aspects of total or overall diet and dietary patterns. This is an innovative approach in
nutritional epidemiology., A major contribution of my research was the development of a diet quality index.
This is the first comprehensive measure designed for use in Australia and I have shown that it is a valid
indicator of diet quality and has been shown to predict abdominal obesity, hypertension, and type 2 diabetes.
Importantly, this tool provides an integrated measure of eating patterns that can be used in population health
research. It is novel and practical way to characterise total diet and investigate the interactions between diet and
other health behaviours and the predictors of healthy eating. Requests for use of this index have been received
from the WA Department of Health, the Australian Longitudinal Study of Women's Health and researchers at
University of Sydney, Flinders University, Queensland Institute of Medical Research and Monash University.
Expected future outcomes:
This research has led to development of key methodological tools in assessing diet quality and dietary patterns
which underpin future research on diet across the life-course. An understanding of how dietary patterns and
their determinants vary across the life-course is critical to the development of preventative health strategies.
Name of contact:
Sarah Mcnaughton
Email/Phone no. of contact:
sarah.mcnaughton@deakin.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 374241
Start Year: 2007
CIA Name: Prof Kylie Ball
End Year: 2012
Admin Inst: Deakin University
Grant Type: NHMRC Strategic Awards
Main RFCD: Public Health and Health Services not elsewhere classified
Total funding: $2,072,674
Title of research award:
Preventing obesity among socioeconomically disadvantaged women and childrenPreventing obesity among
socioeconomically disadvantaged women and children
Lay Description (from application):
The research will investigate the causes of the increased risk of obesity among socioeconomically
disadvantaged women and children. It will also focus on women and children who appear ‘resilient’ to obesity
and will explore the possibility of applying the lessons learned to other women and children, in order to help
support them in adopting and maintaining obesity-protective behaviours. The research aims to provide
evidence to inform policies and programs that should be put into place to prevent obesity among
socioeconomically disadvantaged groups.
Research achievements (from final report):
The mechanisms by which social and economic disadvantage influence lifestyle choices that promote obesity
are poorly understood, and to date there has been insufficient evidence to inform primary prevention programs
and policies. This research yielded among the first multilevel data internationally on the mechanisms
underlying socioeconomic variations in obesity. It demonstrated that a number of socioeconomically
disadvantatged women and children mange to remain 'resilient' to obesity risk, despite their disadvantage, and
identified key characteristics associated with this resilience (e.g., behavioural skills; social support; positive
environmental perceptions) that serve as potential intervention levers in initiatives to promote healthy eating
and physical activity and reduce obesity. The research program also provided novel evidence from
experimental studies on the impact of modifications to perceptions and environments that resulted in improved
eating and physical activity attitudes and behaviours among socioeconomically disadvantaged individuals (e.g.
cognitive approaches to improving perceptions of healthy food affordability; refurbishments to a park in a
disadvantaged neighbourhood). The research has to date been published in 43 peer-reviewed journal papers and
at more than 50 scientific conferences and meetings. Findings have and continue to be translated in various
forums and to different key stakeholders (e.g. local govt/councils; Victorian Centre for Excellence in
Intervention and Preventive Science (CEIPS); Heart Foundation; Dept of Health) in order to inform best
practice in terms of future obesity prevention approaches.
Expected future outcomes:
Findings will lead to more evidence-based obesity prevention initiatives being rolled out by government and
NGOs, helping to address high rates of poor eating, inactivity and obesity in disadvantaged individuals and
communities.
Name of contact:
Professor Kylie Ball
Email/Phone no. of contact:
kylie.ball@deakin.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 546250
Start Year: 2009
CIA Name: A/Pr Andrea Driscoll
End Year: 2013
Admin Inst: Deakin University
Grant Type: Early Career Fellowships (Australia)
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $295,224
Title of research award:
Epidemiological modelling of heart failureEpidemiological modelling of heart failure
Lay Description (from application):
Heart rhythm devices have revolutionised the survival of patients with heart disease. However we still do not
know precisely what the outcomes are in patients attending our local hospitals. We will develop a registry for
these devices to monitor and benchmark their performance throughout the state. The development of a registry
enables us to assess the quality of health services at a local level. This project has the potential to improve the
health outcomes of 4 million people with heart disease
Research achievements (from final report):
This project involved the analysis of large population based studies. It comprised of three projects. 1 One
project involved collecting information from patients visiting their general practitioner. This project identified
groups of people at high risk of experiencing a heart attack. Women and people with a low socioeconomic
background were at the highest risk of experiencing a heart attack. These findings will be used for idenification
of high risk groups and groups to target health promotion programs. The Heart Foundation will be interested in
the outcomes of this project. The findings will be used to inform primary prevention programs. 2 Another
project involved an economic analysis of telemonitoring programs for patients with heart disease. These
programs were found to be cost-effective. However the benefits of less hospital admissions was greater in
programs where a nurse visited the patient at home. These findigs will inform the Department of Health about
future funding of health programs for heart disease particularly in rural and remote areas. 3 The number of
patients diagnosed with heart failure is on the rise particularly in people with stable heart disease. In a large
study of people diagnosed with stable heart disease we determined several risk factors that increased the risk of
developing heart failure. These findings provided evidence to guide clinicans management of heart disease to
reduce the risk of developing heart failure. It will also inform the development of clinical guidelines for heart
disease.
Expected future outcomes:
These findings will inform future directions and planning of health services for patients with heart disease. The
benefits of these services for people living in rural and remote Australia have been demonstrated. Health
promotion activites need to be targeted at women particularly in low socioeconomic areas and those people at
risk of developing heart failure.
Name of contact:
Andrea Driscoll
Email/Phone no. of contact:
andrea.driscoll@deakin.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 594767
CIA Name: Prof Kylie Ball
Admin Inst: Deakin University
Main RFCD: Public Nutrition Intervention
Total funding: $489,989
Start Year: 2010
End Year: 2013
Grant Type: NHMRC Project Grants
Title of research award:
Effectiveness of a skill-building and price reduction intervention for promoting healthy eatingEffectiveness of
a skill-building and price reduction intervention for promoting healthy eating
Lay Description (from application):
Many Australians consume diets that place them at risk of obesity and ill health. Research is required to
identify effective ways of helping people improve their diets. This study will investigate two approaches to
doing so: firstly, by providing people with increased skills in budgeting, selecting and preparing healthy foods;
and secondly, by reducing the prices of healthier foods.
Research achievements (from final report):
The SHELf randomised controlled trial achieved outstanding recruitment and retention success. More than 640
women were recruited within four weeks, with a waiting list accrued. By program completion, 9 months later,
95% of women remained engaged and completed final evaluation surveys. The program showed positive
outcomes on behaviours. The skills-based intervention strategies led to increased fruit consumption; the price
reductions increased fruit and vegetable purchasing; and participants receiving both strategies showed increases
in fruit purchasing and water consumption. Participants rated both approaches as appealing and helpful; many
reported ongoing use of program materials, and commented on the benefits for family members. The program
was recognized through being awarded the 2013 Victorian Health Promotion Foundation Award for Healthy
Eating, presented by the Victorian Premier the Hon. Dr Denis Napthine. The study also led to discussions and
the lead investigator's invited involvement in a Victorian Department of Health working group, focused on
improving the healthfulness of supermarket environments.
Expected future outcomes:
Wide dissemination of main outcomes is planned upon publication. Study materials have been sought by a
variety of community partners, including community health services. Future collaborative projects with study
partners Coles and the National Heart Foundation of Australia are being planned to build upon these successful
results.
Name of contact:
Prof Kylie Ball
Email/Phone no. of contact:
kylie.ball@deakin.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 534409
CIA Name: Prof Robert Newton
Admin Inst: Edith Cowan University
Main RFCD: Oncology and Carcinogenesis
Total funding: $519,331
Start Year: 2009
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
A Phase III clinical trial of exercise modalities on treatment side-effects in men receiving therapy for prostate
cancerA Phase III clinical trial of exercise modalities on treatment side-effects in men receiving therapy for
prostate cancer
Lay Description (from application):
Hormone therapy is very effective for treating prostate cancer however it produces a number of side effects
including muscle and bone loss, fat gain, and increased risk of death from heart disease and diabetes. In other
populations physical exercise has proven particulary effective for preventing such problems however no long
term studies with prostate cancer patients have ever confirmed this. Knowledge gained from this study has
potential to markedly reduce suffering and increase survival.
Research achievements (from final report):
This randomised controlled trial of different exercise modes is the longest and largest ever completed in men
with prostate cancer to our knowledge. With the primary outcome being bone mineral density it is also one of
the first to address bone loss as a devastating toxicity of androgen deprivation therapy. A particularly unique
feature of this project was the application of "impact" exercise as highly tailored and specific prescription to
slow or possibly prevent bone loss resulting from testosterone suppression. We observed for the first time that
exercise could totally prevent bone loss in men receiving androgen deprivation therapy while men receiving
usual care continued to exhibit declines in bone mineral density. Importantly in terms of current national and
international exercise recommendations a more standard exercise program consisting of aerobic and resistance
training did not appreciably slow bone loss in these patients. This was surprising given previous research
findings in men and women not receiving testosterone suppression received considerable benefit in terms of
bone health from such a standard program. In terms of muscle mass the combination of impact and resistance
training produced significantly greater gains in terms of muscle hypertrophy than the standard program and
usual care resulted in continuing muscle atrophy. This is also a novel finding as it appears that men with
prostate cancer undergoing testosterone deprivation appear much more susceptible to the interference effects of
aerobic exercise undertaken simultaneously with resistance exercise.
Expected future outcomes:
Exercise prescription for cancer patients appears to require much more specific attention to exercise mode and
dosage, in particular if treatment side-effects are to be prioritised for management. The principal future
outcome of this research should be the change to clinical practice with tailored exercise programs rather than
provision of current generic guidelines.
Name of contact:
Professor Rob Newton
Email/Phone no. of contact:
r.newton@ecu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 595312
CIA Name: Prof Ralph Martins
Admin Inst: Edith Cowan University
Main RFCD: Medical Biochemistry: Lipids
Total funding: $424,802
Start Year: 2010
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
The effect of human apoE isoforms and apoE receptors on the clearance of oligomeric A 42 by hepatocytes in
vitroThe effect of human apoE isoforms and apoE receptors on the clearance of oligomeric A 42 by
hepatocytes in vitro
Lay Description (from application):
Alzheimer's disease (AD) is a progressive memory disorder. Increased production of a short peptide called
amyloid- (A ) aggregates to form the sticky masses in the brains of AD patients. The amount of A in the brain
is a balance between production and clearance. Surprisingly, we recently demonstrated that the liver clears the
majority of A . These results connect AD and cardiovascular disease (CVD), enabling current CVD
therapeutics to target A clearance by the liver.
Research achievements (from final report):
This research project was designed to evaluate the role of the liver, apoE status and plasma lipid levels in
clearing a protein called amyloid beta, thought to be central to the pathogenesis of Alzheimer's disease (AD).
Dementia and AD account for a large proportion of the age-related chronic disease in Australia. Currently, over
266,000 Australians suffer from dementia with AD accounting for most of these cases. At the present rate, this
number will increase to 924,000 by the year 2050. The social and economic consequences of this disease
presents a significant challenge to society, and it is imperative that strategies to prevent or delay the onset of
AD are developed. The findings obtained from this project demonstrate that the liver is unique in that it is
responsible for the assembly and control of a variety of lipids and lipid receptors that play important roles in
maintaining lipid levels, and also in the clearance of the AD-related protein amyloid beta. Our findings also
demonstrate that this control over lipids can be affected by apoE status and high or low plasma lipid levels,
with apoE4 status and high plasma lipid levels decreasing the clearance of the AD-related protein amyloid beta.
These results will help further research elucidating the connection between AD and cardiovascular disease
(CVD) in elderly Australians, to help prevent the number of increased cases of dementia, specifically AD
which is expected to occur in Australia over the next several decades. The findings also support the notion that
controlling plasma lipid levels may contribute to decreasing the risk of developing AD later in life.
Expected future outcomes:
The results are expected to assist with furthering the connection between Alzheimer's disease (AD) and
cardiovascular disease (CVD). This will enable the development of therapeutic strategies targeting plasma lipid
levels to be used to increase factors that control the liver clearance of amyloid beta in AD pathology.
Name of contact:
Prof Ralph Martins
Email/Phone no. of contact:
r.martins@ecu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 219323
CIA Name: Prof Alexander Gallus
Admin Inst: Flinders Medical Centre
Main RFCD: Not Allocated
Total funding: $9,198
Start Year: 2002
End Year: 2004
Grant Type: International Collaborations
Title of research award:
European action of Anticoagulation (EAA)European action of Anticoagulation (EAA)
Lay Description (from application):
Not Available
Research achievements (from final report):
Oral anticoagulants (mainly warfarin) are now widely and increasingly used in community practice for the
long-term treatment of elderly patients with atrial fibrillation to prevent systemic embolism, and for medium to
long-term therapy after venous thromboembolism, and for other vascular conditions. Anticoagulant dose
monitoring and adjustment is time-consuming for patients and requires skill and experience for clinicians.
Computer-assisted dose adjustment based on algorithms relating warfarin effect (INR) to warfarin dose have
the promise of improving treatment outcomes and translating dose-adjustment to pharmacists, nurses and
patients. The purpose of this trial is to compare computer-assisted with traditional expert-based doseadjustment. This trial has now reached its half-way point world-wide and will continue world-wide and at FMC
for another 12 months.
Expected future outcomes:
The trial should assess by comparison with traditional dosing methods the effects of computer-assisted warfarin
dose adjustment on clinical outcomes (thrombosis and bleeding) and resource utilisation in clinical practice
(economic evaluation).
Name of contact:
Alexander Gallus
Email/Phone no. of contact:
alexander.gallus@flinders.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 102114
CIA Name: A/Pr Judith Morris
Admin Inst: Flinders University
Main RFCD: Autonomic Nervous System
Total funding: $809,935
Start Year: 2000
End Year: 2004
Grant Type: NHMRC Project Grants
Title of research award:
Neurotransmission in functionally distinct vasodilator pathwaysNeurotransmission in functionally distinct
vasodilator pathways
Lay Description (from application):
A surprising feature of our body is that there is not enough blood to fully supply all our organs at once. This is
why we sometimes faint when we are hot or get cramps when we are exercising. Consequently, the blood
vessels change their diameter so that blood can be directed to the organs with greatest demand at any particular
time. For example, if the vessel decreases in diameter, less blood flows through it, but if it increases in
diameter, more blood flows through it to reach the appropriate organ. An important function of the nervous
system is to control the flow of blood to different organs by changing the diameters of the blood vessels. One
set of nerves decreases the diameter of the arteries, and another set of nerves increases the diameter. The
nerves do this by releasing special combinations of chemicals when they get a message from the brain to do so.
In this project we are especially interested in the nerves which increase blood flow to organs in the head and
the pelvis. We will use a wide range of modern methods to find out how these nerves work. In some
experiments, we will use sophisticated electrical equipment to measure just how the nerve cells controlling the
diameter of the vessels respond to the instructions sent by the brain. In other experiments, we will find out
which chemicals the nerves use to make the blood vessels increase in diameter. We also will discover how the
various chemicals get released by the nerves at the right times, so that messages from the brain get to the blood
vessels as efficiently as possible. One of the special parts of our project is that we will be able to observe
directly the connections between the nerve cells and the blood vessels we are studying. Our results will be
important for designing new drugs that could help people whose nerves are not working properly, such as in
some patients with diabetes or vascular disease.
Research achievements (from final report):
Our novel findings about the nerve pathways between the spinal cord and the uterus have important
implications for understanding complex conditions involving abdominal and pelvic pain and how these affect
sexual and reproductive function in females. We have begun to examine which sensory nerves can interact in
the spinal cord with the nerves increasing pelvic blood flow, and whether these interactions during
inflammation can interfere with the sensory and psychological stimuli normally essential for sexual behaviour.
Expected future outcomes:
The results of these continuing studies may have direct clinical relevance for pelvic surgery in females or other
procedures that interfere with nerve pathways from the spinal cord to the reproductive organs. The results also
may aid in diagnosis or treatment of referred pain in the abdominal and pelvic region.
Name of contact:
A/Prof Judy Morris
Email/Phone no. of contact:
N/A
NHMRC Research Achievements - SUMMARY
Grant ID: 229907
Start Year: 2003
CIA Name: A/Pr Ida Llewellyn-Smith
End Year: 2005
Admin Inst: Flinders University
Grant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $470,500
Title of research award:
Neurotransmitters in synaptic inputs to medullary neurons subserving the baroreflexNeurotransmitters in
synaptic inputs to medullary neurons subserving the baroreflex
Lay Description (from application):
The baroreflex rapidly adjusts arterial blood pressure to meet changing physiological needs. The reflex alters
vascular resistance and changes the rate, volume and force at which blood is expelled from the heart, ensuring
that organs are adequately supplied with blood-borne nutrients and oxygen. Changes in baroreflex function
occur during exercise, correlate with increased mortality and morbidity from heart failure and myocardial
infarction and are responsible for postural hypotension in the elderly. Three areas in the brainstem are critical
for transmission of the arterial baroreflex. However, it is still not known exactly which chemicals
(neurotransmitters) are used to convey baroreflex information to and between neurons in these key sites. In this
project, we will use state-of-the-art anatomical techniques to examine nerve pathways that subserve the arterial
baroreflex. By changing blood pressure and specifically tagging nerve cells that respond, we can focus on
neurons activated by baroreflex stimuli. Concentrating on neurotransmitters known to affect blood pressure
control in the medulla, we will then label one or more of these in nerve fibers surrounding the "barosensitive"
neurons. Finally, we will determine by light and electron microscopy the relationships between the labelled
nerve fibers and the barosensitive neurons. These relationships will show which neurotransmitters could
influence barosensitive neurons directly, which indirectly and which not at all. This project will increase our
understanding of the baroreflex by clarifying which neurochemicals convey baroreflex information amongst
the key groups of brainstem neurons. These data will form the foundation for new studies on changes in nerve
pathways that underlie baroreflex dysfunction in such conditions as postural hypotension. Identifying
transmitters for the baroreflex may also point to, or rule out, new drug treatments for disturbances in baroreflex
function.
Research achievements (from final report):
- A region in the brainstem called the rostral ventrolateral medulla contains two groups of nerve cells
("neurons") that are essential for controlling blood pressure. We showed that both groups of neurons contain
the same small protein molecule. This molecule can now be used by researchers in the future as a common
marker to identify all cardiovascular nerve cells in this critical brain region., - The chemical serotonin affects
blood pressure when it is injected into hindbrain regions that are involved in controlling blood pressure. Nerve
cells that release serotonin occur in these same regions. We showed that the serotonin nerves rarely if ever
communicate directly with blood pressure controlling neurons. Our data suggests that another cell type ("glial
cells") may be involved in serotonin's effects on blood pressure. The glial cells may provide a target for future
therapies in conditions where brain control of blood pressure is altered as in heart failure., - We showed that
nerve cells which sense blood pressure changes do communicate directly with cardiovascular neurons in the
brainstem. Our anatomical data suggest that the pressure-sensing neurons could powerfully affect the activity
of the cardiovascular neurons. Future studies should investigate whether this connection has any therapeutic
potential for treating cardiovascular disease.
Expected future outcomes:
Information from this project will form the basis for future studies on changes in blood pressure control
pathways due to physiological challenges or dysfunction and will help in the development of treatments for
cardiovascular diseases such as hypertension and heart failure
Name of contact:
.A/Prof Ida Llewellyn-Smith
NHMRC Research Achievements - SUMMARY
Email/Phone no. of contact:
ida.llewellyn-smith@flinders.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 229921
CIA Name: A/Pr Ida Llewellyn-Smith
Admin Inst: Flinders University
Main RFCD: Not Allocated
Total funding: $894,250
Start Year: 2003
End Year: 2009
Grant Type: Established Career Fellowships
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
- Local spinal nerves are more important than brain nerves for controlling the urinary bladder whereas brain
nerves are more important for controlling blood pressure. It may therefore be easier to restore normal bladder
function after a spinal cord injury than normal control of blood pressure.
- Spinal nerves that control different automatic functions contain characteristic sets of chemicals that correlate
with their functions. Therapies that target the different functional types of autonomic nerves could be based on
these chemical signatures.
- One set of brainstem neurons involved in regulating blood pressure is not affected by fluctuating oxygen
levels so are unlikely to responsible for the increased blood pressure seen in sleep apnoea.
- Near term, the pregnant uterus has lost all of the nerves that are present before pregnancy. Failure of uterine
nerves to disappear completely by the end of pregnancy may contribute to pre-eclampsia, a disorder that is
characterized by maternal high blood and can have serious health consequences for mother and babies.
- The circuits of nerves that carry information about pain from the periphery to the brain are not organized as
originally believed. The new circuitry may provide additional avenues for treatment of central pain syndromes.
Expected future outcomes:
The new knowledge generated during this Fellowship will contribute to understanding how nerves within and
outside the brain and spinal cord control automatic bodily functions under normal circumstances and will
provide the basis for future studies on how these nerves cahnge in response to disease or injury.
Name of contact:
A/Prof Ida Llewellyn-Smith
Email/Phone no. of contact:
ida.llewellyn-smith@flinders.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 229961
CIA Name: A/Pr Xin-Fu Zhou
Admin Inst: Flinders University
Main RFCD: Central Nervous System
Total funding: $299,625
Start Year: 2003
End Year: 2005
Grant Type: NHMRC Project Grants
Title of research award:
Roles of brain-derived neurotrophic factor in the regulation of blood pressureRoles of brain-derived
neurotrophic factor in the regulation of blood pressure
Lay Description (from application):
Brain-derived neurotrophic factor (BDNF) is an extraordinary neurotrophin which acts not only as a classical
neurotrophic factor to promote neuronal survival and differentiation but also as a neuromodulator to modulate
nerve activity. Recently, we found that injection of exogenous BDNF into brain stem triggers a significant
increase in blood pressure. The present proposal is to test the hypothesis that BDNF is a physiological
neuromodulator regulating blood pressure. The aim of this study is to analyse physiological roles of BDNF in
the brains stem and spinal cord in the regulation of nerve activity and blood pressure. The successful execution
of the project will significantly enhance our understanding of how blood pressure is controlled by BDNF and
nerve activity. The knowledge from this study will form basis for designing new drugs to control high blood
pressure.
Research achievements (from final report):
Brain derived neurotrophic factor supports nerve and protect nerve from death. Our studies found that this
factor also plays a role in the neurotransmision. Injection of this factor into the brain can trigger increase in
blood pressure. We have investigated the underlying mechanism of BDNF in the regulation of blood pressure.
Expected future outcomes:
This study increases our knowledge of novel functions of BDNF and will result in further publications and
improve our understanding how blood pressure is controled by nerves in the brain.
Name of contact:
Xin-Fu Zhou
Email/Phone no. of contact:
xin-fu.zhou@flinders.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 275526
Start Year: 2004
CIA Name: Dr Anthea Magarey
End Year: 2006
Admin Inst: Flinders University
Grant Type: NHMRC Project Grants
Main RFCD: Public Health and Health Services not elsewhere classified
Total funding: $407,300
Title of research award:
Management of overweight pre-pubertal children - a randomised controlled trialManagement of overweight
pre-pubertal children - a randomised controlled trial
Lay Description (from application):
Obesity is an increasingly common problem in the Australian community, affecting both adults and children.
Up to 1 in 4 Australian children are overweight or obese, making it one of the most common chronic disorders
in this age-group. Obesity in childhood is associated with such complications as high blood pressure, risk of
diabetes, high cholesterol levels, hip, knee and ankle problems, and psychological distress. Given the impact
of overweight and obesity on the health of children, how can it be best treated? Surprisingly, there is little
information available to guide the management of this common problem. In this study we will test the
hypothesis that the addition of a parent skills training program will significantly increase the effectiveness of a
diet-activity program designed to reduce weight in overweight 6 to 9-year-olds. Children enrolled in the study
will receive one of two interventions (i) parenting + activity-diet or (ii) diet-activity. Parents in the parenting
intervention will participate in a parenting skills training program (Triple P) preceding the diet-activity
program. Triple P comprises four 2-hour weekly group sessions and four, 15 minute follow-up phone calls
which will focus on the skills and strategies required to supervise lifestyle changes. The diet-activity program
comprises 8 group sessions for parents over a 5 month period on specific dietary and activity changes and
simultaneous structured activity sessions for the children. "Success" will be judged in several ways. Over a
2 year period, we will monitor the child's weight, self-esteem, sense of well-being, blood pressure and
cholesterol levels. We will also monitor the family's functioning and the parents' parenting skills and sense of
efficacy. Results from the study should allow us to determine which treatment approach for management of
childhood obesity is the most appropriate to be established in community settings.
Research achievements (from final report):
This is the largest RCT evaluating treatment of overweight pre-pubertal children published to date. The
program (Parenting Eating and activity for child health (PEACH)evaluated the effectiveness of the addition of
parenting skills to a lifestyle education program for families with an overweight 5 to 9-year-old child. There
was a clinically relevant signficant weight loss of 8 to 13% at the end of the 6 month program in both arms of
the study (both BMI SD and waist SD). The addition of parenting skills training resulted in a significantly
lower BMI SD at the end of the 6-month intervention (12% versus 8%) but did not confer any significant
improvement in relative weight reduction at subsequent follow-up compared with the lifestyle only group.
There was no group effect on waist SD. However an additional important finding was that with no further
contact (other than 6-monthly measurement) the loss in waist SD was maintained for a further 18 months ie to
24 months from baseline and there was a further 2.5% reduction in BMI SD (p=0.02). In addition, at the end of
the 6 month program there were signficant improvements in parent reported child quality of life as well as
lifestyle factors (diet and activity) and these changes were maintained longer-term. The program was well
accepted by participants. This program offers an effective intervention for management of overwight and obese
pre-pubertal children.
Expected future outcomes:
Demonstration of the effectiveness of PEACH when delivered in the wider community by health professionals
after undertaking facilitator training. This trial will begin in 2008. Dissemination of the program in the wider
community will provide an effective weight management program to which families with an overweight or
obese child may be referred
Name of contact:
Dr Anthea Magarey
NHMRC Research Achievements - SUMMARY
Email/Phone no. of contact:
anthea.magarey@flinders.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 275530
CIA Name: Prof Simon Brookes
Admin Inst: Flinders University
Main RFCD: Gastroenterology
Total funding: $353,250
Start Year: 2004
End Year: 2006
Grant Type: NHMRC Project Grants
Title of research award:
How spinal afferent nerves cause vasodilation of mesenteric arteriesHow spinal afferent nerves cause
vasodilation of mesenteric arteries
Lay Description (from application):
Healthy function of the gastrointestinal tract requires an adequate blood supply during periods of varying
demand. Inadequate blood supply to the gut contributes to disorders ranging in severity from mild through to
lethal. Reduced blood supply to the gut is a trigger for multiple organ failure syndrome; a leading cause of
death in critically ill patients following major surgery, trauma or haemorrhage. It is believed that damage to
the lining of the gut, during periods of reduced flow, trigger inflammatory mechanisms throughout the body.
Mesenteric ischaemia is a disorder which occurs as a chronic, non-occlusive form, or as acute episodes, which
are often lethal, . Temporary increases in blood supply are also known to play a vital role in protecting the gut
from acid, toxins and attack by pathogens. The major mechanism underlying increases in bloody supply is
dilation of arterial vessels. This occurs focally, at the site of damage, via local mechanisms, but this is
supplemented by a more widespread dilation of arteries upstream, mediated by branches of sensory neurones
that innervate blood vessels directly. Currently, there is no information about how these sensory neurones are
activated. This is crucial to understand how they work. We hypothesise that these sensory neurones are
activated by chemical and mechanical stimuli in the gut wall, which make them release vasodilator chemicals
onto the arteries upstream and thus amplify the local increases in blood flow. We will test this by recording
from sensory nerves, identifying the ones which project to blood vessels and determine which chemicals and
mechanical stimuli they are excited by. We will then fill them with dye, using a method that we have recently
developed, to visualise their branching patterns both inside and outside the gut wall. In this way, we will
understand how this powerful protective mechanism is activated at times of need, and how it may fail under
some circumstances.
Research achievements (from final report):
The human body does not contain enough blood to be able to supply all organ systems with a maximal supply
at the same time. Optimising blood flow to ensure that it is sufficient for local needs, on a moment-to-moment
basis, is a major physiological challenge. One important control mechanism is the presence of sensory nerve
fibres on blood vessels: these are known to cause blood vessels to dilate and thereby increase flow. However,
their functional role in controlling blood flow to the gut was poorly understood; in particular what causes them
to become active. , , This project showed that sensory nerve fibres on blood vessels both running to the gut, and
within the gut wall itself are activated by a variety of stimuli known to cause pain. Thus, excessive distension
activates a population of sensory nerve fibres within the gut wall which have endings on intestinal arteries. The
project also showed that these same neurons often also had endings on the blood vessels leading to the gut.
Thus we identified a major pain pathway from the gut and shown that it comprises an important mechanism
that normally controls blood vessel diameter. The project has also started to explain the mechanisms by which
these fibres are activated, which may be important for the future development of drugs to treat gut pain in
disorders such as irritable bowel syndrome
Expected future outcomes:
Sensory nerves are found on blood vessels throughout the body: not just on gut arteries. This project identified
a major pain pathway to many organs which likely plays an important role in tissue defence. These findings
will lead to better understanding and hopefully treatment of many painful disorders.
Name of contact:
Professor Simon Brookes
NHMRC Research Achievements - SUMMARY
Email/Phone no. of contact:
simon.brookes@flinders.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 324736
Start Year: 2005
CIA Name: Dr Eugene Nalivaiko
End Year: 2007
Admin Inst: Flinders University
Grant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $425,250
Title of research award:
Cardiac arrhythmias and cardiac contractility during stress: regulation by brainstem medullary raph
neuronsCardiac arrhythmias and cardiac contractility during stress: regulation by brainstem medullary raph
neurons
Lay Description (from application):
Life is stressful, and in subjects with predisposed hearts stressful events may provoke sudden life-threatening
or fatal disturbances of the heart rhythm (arrhythmias). Activity in nerves that control the heart is the main
trigger of arrhythmias. This activity is initiated in the brain, when, for example, we have a sudden emotional
shock. At present, the neurochemistry and connections of the brain neurons responsible for arrhythmias, have
not been identified. Our project is designed to find answers to these questions.
Our hypothesis is that the
responsible neurons are located in the midline portion of the medulla oblongata (the lower part of the brain);
that activation of these neurons will increase cardiac function in a manner that may provoke arrhythmias; and,
conversely, that their inhibition will protect the heart during stressful events by suppressing potentially
arrhythmogenic neural signals. We hypothesise that cardiac-controlling neurons possess receptors for serotonin
(one of the brain neurotransmitters), and that the neurons can be inhibited by drugs that selectively activate a
specific subtype of these receptors.
Our results will increase our understanding of the causes of cardiac
arrhythmias by elucidating the link between emotional/psychological events in the brain and stress-induced
cardiac events. Our findings could contribute to the identification of new drugs that will protect the heart
during stress.
Research achievements (from final report):
We found that drugs similar to serotonin (one of natural neurochemicals present in the brain) reduce activity of
some brain neurons that control the heart. This results in preventing the rise in heart rate and other cardiac
disturbances induced by psychological stresses and by fever. Importantly, the drugs did not affect neural
control of the heart in normal conditions.
Expected future outcomes:
Currently, drugs for protecting the heart from the excessive neural influences act at the level of the heart. Our
findings provide the experimental basis for an alternative therapeutic strategy, namely suppressing this
excessive activity at its origin - in the brain.
Name of contact:
Eugene Nalivaiko
Email/Phone no. of contact:
eugene.nalivaiko@flinders.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 375100
CIA Name: A/Pr Judith Morris
Admin Inst: Flinders University
Main RFCD: Autonomic Nervous System
Total funding: $472,771
Start Year: 2006
End Year: 2008
Grant Type: NHMRC Project Grants
Title of research award:
Neural circuits producing pelvic vasodilation in femalesNeural circuits producing pelvic vasodilation in
females
Lay Description (from application):
The reproductive organs and genitalia in males and females experience a large increase in blood flow during
sexual and reproductive activity. This increased blood flow (vasodilation) is a key component of penile and
clitoral erection, and enhances secretion from the lining of the internal reproductive organs. Vasodilation
during sexual activity is produced by a special sets of nerves receiving signals from the genitalia and the brain.
In fact, Viagra works by enhancing and prolonging the actions of these nerves. An important part of this neural
pathway is a group of nerve cells in the spinal cord that connects the central nervous system with peripheral
nerves in the reproductive organs - these are called preganglionic neurons. Recently we discovered that a major
pathway from the spinal cord to the pelvic blood vessels in females leaves the spinal cord at a different level
(lumbar) from that thought previously (sacral level). Currently there is no information on how these lumbar
preganglionic nerves in females are connected to other nerve pathways that are active during sexual activity,
and how they integrate signals from both the internal organs and the brain. We will use an array of modern
cellular techniques together with direct observation of dilation in isolated uterine arteries to discover how these
nerve cells are wired up in circuits in the spinal cord. This information is vital for us to understand the factors
producing increased blood flow in normal sexual activity, and how these might be altered in inflammation or in
conditions where there could be selective damage to one nerve pathway and not the other, such as after pelvic
surgery, spinal cord damage at different levels, or stimulation of the spinal cord for treatment of chronic pain.
Our study also will help understand referred pain and sensations of discomfort in abdominal and pelvic organs.
Research achievements (from final report):
We studied the nerve pathways that are important for increasing blood flow to the female reproductive organs
during sexual activity and the early stages of pregnancy. Using newly developed animal models we showed
that a previously under-recognised nerve pathway leaving the lumbar spinal cord and descending to the
reproductive organs can be activated by artificial stimulation of nerves from the genital region. However, we
found that this new pathway is normally inhibited by other nerves within the spinal cord during genital
stimulation. It is unclear at the moment how much this new pathway contributes to increased blood flow during
normal sexual activity when other nerve pathways at sacral spinal levels are also activated. However, our
results indicate that the lumbar nerve pathway is likely to be very important under conditions where the sacral
nerves are damaged after essential surgery or low level spinal cord injury. This pathway is also likely to be
involved in some sorts of pelvic pain, and may help to explain sexual and reproductive dysfunction during
chronic inflammatory conditions. As the lumbar pathway has not been widely recognised in previous medical
research and clinical practice, our results present a shift in thinking about neural regulation of the reproductive
organs in health and disease.
Expected future outcomes:
This study should stimulate new research directions and promote use of our animal models to complement data
from current research. Once the significance of our findings have been clarified in animal studies it is likely
that they will impact on surgical and medical practice addressing a range of women's health issues.
Name of contact:
Prof Ian Gibbins
Email/Phone no. of contact:
Ian.Gibbins@flinders.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 375129
Start Year: 2006
CIA Name: Prof Andrew Bersten
End Year: 2008
Admin Inst: Flinders University
Grant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $312,022
Title of research award:
Breathing in Chronic Heart Failure: Is there novel pulmonary compensation?Breathing in Chronic Heart
Failure: Is there novel pulmonary compensation?
Lay Description (from application):
Chronic heart failure (CHF) is a growing modern epidemic and therefore a costly health burden in Australia.
Not only is it associated with a high mortality rate, symptoms of CHF are a major cause of patient suffering.
Shortness of breath and exercise intolerance are both indicators of a link between CHF and lung function.
There are a number of different ways in which CHF may be impacting on breathing and in this project we will
be utilising an animal model to examine some of them. Firstly, the lung secretes a substance called surfactant
which assists in normal breathing by decreasing surface tension in the lung. Previous studies in our laboratory
have suggested an increase in surfactant production during CHF. In this project we will further examine this
process to see if increased surfactant can aid breathing by decreasing surface tension during CHF. Secondly,
we will examine the contribution made by the chest wall, increased heart size, lung volume and blood pressure
during CHF on breathing. Thirdly, one of the problems thought to inhibit breathing in CHF patients is an
increase in fluid in the lungs. The final stage of this project will examine the trasport of fluid into and out of the
lung during CHF. This project will not only increase our understanding of the processes affecting breathing in
response to CHF, but will also provide information for the development of potential therapeutic targets.
Research achievements (from final report):
Our last three years of research have revealed new insights into the CHF lung. They have generated a number
of presentations at the American Thoracic Society and the Cardiac Society of Australia and New Zealand
Scientific Sessions and have been reported as a major integrated manuscript in the pre-eminent Respiratory and
Critical Care journal the American Journal of Respiratory and Critical Care Medicine. In summary, we have
found that despite measurable changes indicative of the syndrome of CHF in our model including an increase
in lung tissue, these animals are able to maintain normal breathing. However, when the lung protective
substance, surfactant, is removed, lung function in the CHF animals deteriorates compared to that of healthy
animals. We found that in our model of CHF there is both an increase in the cells that produce surfactant and in
the total amount which compensates for lung tissue changes due to CHF. This may indicate the presence of
'better than normal' surfactant in these animals. In parellel studies, we examined why the CHF lung is 'dry' ie
has no increase in fluid despite an increase in lung vascular pressure. Surprisingly we found that with
increasing severity of CHF, lung fluid clearance decreased. Analysis of various regulators of fluid clearance in
these lungs has not yeilded an explaination thus far therefore investigation in this area is on going. Finally, we
examined lung function following further increases in lung vascular pressure. Previous studies have indicated
that strengthening of the lung tissues during CHF may help prevent fluid flow into the lung during these
pressure spikes. However, we found that in our CHF model these sharp rises in pressure result in immediate
and severe deterioration in lung function and accumulation of lung fluid. Bringing a lung focus to CHF
research provides excellent opportunities for cross-disciplinary progress in the development of therapies for
reducing CHF morbidity in the foreseeable future.
Expected future outcomes:
Investigation into post-transcriptional control of AFC is on-going. Final studies assessing the effect of
increasing left atrial pressure (Pla) on the CHF lung are completed and under analysis. Submission of the AFC
manuscript to the Am J Resp Cell Mol Biol and the increased Pla manuscript to AJP is imminent.
Name of contact:
Dr Dani-Louise Dixon
NHMRC Research Achievements - SUMMARY
Email/Phone no. of contact:
dani.dixon@flinders.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 480414
Start Year: 2008
CIA Name: A/Pr Ida Llewellyn-Smith
End Year: 2010
Admin Inst: Flinders University
Grant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $382,539
Title of research award:
Does pregnancy cause morphological changes in central as well as peripheral nerve pathways that control
blood pressure?Does pregnancy cause morphological changes in central as well as peripheral nerve pathways
that control blood pressure?
Lay Description (from application):
Pregnancy changes blood pressure but the mechanism is unknown. We will use state-of-the-art anatomical
methods to define how pregnancy alters nerves controlling blood pressure. We will identify changes in the
information the nerve cells receive, in their shape and in the way they communicate with other blood pressurecontrolling nerve cells. This information will help to develop new ways to prevent and treat pre-eclampsia, a
major cause of death and disability for mothers and their newborns.
Research achievements (from final report):
This project has provided important new information about pregnancy-related changes in nerves that control
blood pressure and the uterus. We showed that by the end of pregnancy all of the uterine nerves that are
normally present in the non-pregnant uterus have disappeared. Nerve pathways in the spinal cord that control
blood pressure are not as effective at restricting blood flow in pregnant females as they are in non-pregnant
females and there are changes in nerve cells in an important blood pressure control region in the brainstem.
These nerve changes probably ensure an adequate supply of oxygen and nutrients to the developing foetus and
a normal birth sequence. if these normal changes in nerves fail to occur, this failure may contribute to the
development of disorders of pregnancy, such as pre-eclampsia, that have adverse consequences for mothers and
babies.
Expected future outcomes:
The new knowledge generated by the project will be important for understanding hypertensive disorders of
pregnancy, such as pre-eclampsia, and could point to new avenues for the development of treatment strategies
for these conditions.
Name of contact:
A/Prof Ida Llewellyn-Smith
Email/Phone no. of contact:
ida.llewellyn-smith@flinders.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 480459
CIA Name: Prof David Currow
Admin Inst: Flinders University
Main RFCD: Respiratory Diseases
Total funding: $414,535
Start Year: 2008
End Year: 2010
Grant Type: NHMRC Project Grants
Title of research award:
Systematic expansion of the clinical evidence base in opioid prescribing for refractory dyspnoea at the end of
lifeSystematic expansion of the clinical evidence base in opioid prescribing for refractory dyspnoea at the end
of life
Lay Description (from application):
Morphine can relieve breathlessness in the palliative setting. But many important questions remain. What is the
best dose, should the dose change over time, do different medications provide the same relief, and how
common is dyspnoea in the general population? This three part project will extend our knowledge to answer
these questions. Population data will provide critical background to plan best care for future palliative patients
distressed by breathlessness.
Research achievements (from final report):
Breathlessness has been demonstrated in this study to be highly prevelant across the community with one in
300 people unable to leave their house because their breathlessness is so severe. These are the first data to
publish the levels of and severity of breathlessness. A study that explored the safety of regular low dose oral
morphine was conducted across one site in Australia. It demonstrated that the medicaiton was efficacious and
safe when used in this way. No person was hospitalised as a complication of taking regular low dose morphine
(which the body already makes in response to breathlessnes). , , The final study in this funded program
continues. It was been expanded to answer a number of key questions around the use of opioids including for
different causes of breathlessness. To do this, additonal funding has been sourced beyond the National Health
and Medical Research Council and it is expected that this study will finish in 2013.,
Expected future outcomes:
These data challenge widely held beliefs that opioids should not be used in people with respiratory
compromise. Such beliefs are not based on data from people on regular low dose opioids, and, in fact, none of
the study participants had an episode of respiratory compromise. The data also challenges concerns about the
withdrawal of opioids when they are no longer effective or not wanted.
Name of contact:
David Currow
Email/Phone no. of contact:
david.currow@health.sa.gov.au
NHMRC Research Achievements - SUMMARY
Grant ID: 535081
CIA Name: Prof Ian Gibbins
Admin Inst: Flinders University
Main RFCD: Autonomic Nervous System
Total funding: $498,465
Start Year: 2009
End Year: 2011
Grant Type: NHMRC Project Grants
Title of research award:
Convergent regulation of sympathetic neuronal excitability by peptide hormones and transmittersConvergent
regulation of sympathetic neuronal excitability by peptide hormones and transmitters
Lay Description (from application):
This project will examine how hormones involved in regulating blood pressure interact with the nerves that
control blood flow to the gut. We will combine electrical recordings of the activity of single nerve cells with an
innovative new method of optically tracking the movements of single molecules, including hormons and
neuronal messengers, that send signals to the nerve cells. Our results will reveal how blood pressure is
normally maintained at healthy levels, even if we are ill.
Research achievements (from final report):
The overall aim of this project is examine how circulating peptide hormones and neuropeptides interact to
increase the excitability of peripheral sympathetic neurons controlling gastrointestinal blood flow and motility.
This involved several new technical developments including fully calibrating the scan timing circuits of our
Leica SP5 confocal microscope, by-passing the Leica image acquisition system to take the raw read-out of the
our ultra-sensitive detectors directly to a photon-counting imaging system and developing real-time live cell
imaging using the ultra-sensitive detectors. Thus, we can image peptide binding to native sympathetic and or
sensory neurons in close to real time (20-25 256x256 pixel frames/second). To further study receptor-peptide
interactions, we have established new transfected cell lines co-expressing NK1 and AT1 receptors with
different fluorescent tags. From these data, we have derived classical pharmacological kinetic data from images
with high spatial resolution. We also developed a realistic mathematical model of peptide diffusion in the
neuropil surrounding sympathetic neurons. These approaches and the dat awe have collected with them offer a
radical new way to investigate agonist-receptor interactions in a wide range of applications.,
Expected future outcomes:
Our data allow new interpretations of classical pharmacological models that will allow more realistic
understanding of hormone, neurotransmitter and drug action.
Name of contact:
Ian Gibbins
Email/Phone no. of contact:
ian.gibbins@flinders.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1024008
Start Year: 2012
CIA Name: Prof Derek Chew
End Year: 2013
Admin Inst: Flinders University
Grant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $508,567
Title of research award:
A randomized comparison evaluating the value of high-sensitivity troponin in the efficient management of
chest pain patients across the spectrum of risk for an acute coronary syndromeA randomized comparison
evaluating the value of high-sensitivity troponin in the efficient management of chest pain patients across the
spectrum of risk for an acute coronary syndrome
Lay Description (from application):
Chest pain patients are a large burden of emergency department demand. Their effective care requires timely
risk assessment. High-sensitivity assays for cardiac muscle damage (troponin) increases the ability to detect
patients with heart attacks, but may also lead to more abnormal results from other causes and more admissions.
This randomized trial of current troponin versus a new troponin assays with robust initial evaluation of patient
risk will provide a rationale for their use in modern care.
Research achievements (from final report):
High sensitivity troponin assays have been proported to provide improved sensitivity for detecting myocardial
infarction, yet reduced specificity and positive predictive value raises the health service risk of increased
hospital admissions, excessive investigation of patients, and consequently increased costs and reduced patient
outcomes.The randomized clincial trial has demonstrated little impact of high-sensitivity troponin reporting on
clinical care and short term outcomes when compared with standard troponin reporting methods in short term
measures of care and outcome. High-sensitivity troponin reporting did not precipitate a large increase in patient
admissions, and nor did it faciliatte discharge of chest pain patients with low results. No increase in the use of
invasive angiography and coronary revascularization was observed. The avaliability of high-sensitivity
troponin testing did not improve patient outcomes, such as a reduction in the rate of missed myocardial
infarction. Nevetheless, the high -sensitivity troponin result has greater risk discriminatory capacity than
standard clincial assessment. A clear gradient of risk for future events was observed with small increases in
troponin levels below the level avaliable within standard reporting. This study has demonstrated that pragmatic
clinical trials to emerging diagnostic and therapeutic innovations can be conducted within the routine clinical
care, though fully capitalizing on these innovations will require more formal redesign of clinical decisionmaking and clinical practice taking advantage of the new information provided. Passive release of such
information without formally redesigning care at best, represets a missed opportunity to the health system.
Expected future outcomes:
Effective integration of high-sensitivity troponin testing into routine clinical practice to enable more efficient
care will require robustly implemented standardized protocols to inform clinical decision making. Evaluation
of this formal integration have been designed and clinical engagement has been achieved. Funding support to
enable this clinical research has been sought.
Name of contact:
Derek Chew
Email/Phone no. of contact:
derek.chew@flinders.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 276430
Start Year: 2004
CIA Name: Prof Edward Kraegen
End Year: 2006
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Project Grants
Main RFCD: Endocrinology
Total funding: $481,500
Title of research award:
Role of impaired insulin signalling in fatty acid-induced muscle insulin resistance in vivoRole of impaired
insulin signalling in fatty acid-induced muscle insulin resistance in vivo
Lay Description (from application):
Type 2 diabetes represents an escalating global health problem. In Australia 7.5% of the population has
diabetes and another 16% insulin resistance (impaired action of insulin in tissues). As well as diabetes, insulin
resistance is closely associated with obesity, dyslipidaemia, hypertension and cardiovascular diseases
(Syndrome X). While genetic factors play a role, a high caloric intake (particularly with a high fat content) and
a sedentary lifestyle are extremely important environmental contributors to Syndrome X and diabetes. From
evidence that we and others have obtained over the last few years it is now evident that an important mediator
of insulin resistance is the quantity of fat molecules which accumulate in muscle and liver. This project
examines mechanisms whereby this fat accumulation can disrupt the signalling mechanism normally causing
increased glucose metabolism in response to insulin. While basic experiments in cell systems have identified
some candidates, a need exists to demonstrate whether they actually cause the insulin resistance in the whole
animal or human, or are merely associated with it. We will combine metabolic/physiological studies with a
novel technique we have recently established in our laboratory for introducing DNA into skeletal muscle of
laboratory animal models. We now aim to exploit this approach to obtain more definitive data about the
importance of insulin signalling changes to insulin resistance. Two major steps in insulin signalling will be
investigated, involving the insulin receptor substrate proteins and the kinase Akt/PKB, both strongly implicated
in lipid-induced insulin resistance. This knowledge will be invaluable in improving strategies to lessen or
prevent lipid-associated insulin resistance, a major contributor to the metabolic derangement in Type 2 diabetes
and Syndrome X.
Research achievements (from final report):
Our overall aim was to determine the in vivo mechanisms whereby accumulation of fatty acids and/or their
metabolites cause insulin resistance in muscle. We first established a new technique (in vivo electrotransfer
IVE) to alter local gene expression in skeletal muscle of rodents as a means of investigating the role of
signalling proteins in vivo. Extensive validation work was performed based on mechanisms which enhance
glucose transport in muscle and were published in Diabetes. We demonstrated that IVE combined with
appropriate methodology could be used to both enhance and diminish local muscle gene expression, thus
making it a powerful tool to establish important targets for insulin action in muscle in vivo. Our results
highlight the utility of IVE for the acute manipulation of muscle gene expression in the study of glucose
metabolism, led on to the signaling studies in this project as follows. We targetted a particular protein in insulin
signalling, namely Akt ; this has two isoforms whose respective roles in muscle were not clear. We overexpressed active forms of both isoforms (Akt1 and Akt2) in rat muscle using IVE and 1-2 weeks later assessed
responses. Both isoforms led to muscle hypertrophy but Akt-2 had a greater influence on glucose transport.
However insulin-stimulated glucose uptake was not altered by over-expression of either isoform despite
approximate 30% reductions in the upstream signalling protein IRS-1 These data indicate distinct roles for Akt1 and Akt-2 in muscle glucose metabolism and that moderate reductions in IRS-1 expression do not result in
the development of insulin resistance in skeletal muscle in vivo. Rather the results point to the likely
importance of steps in insulin signalling downstream of Akt in generating insulin resistance.
Expected future outcomes:
Novel techniques (in vivo electrotransfer) developed for manipulating muscle gene expression to study
metabolism have proved of considerable use to many groups. The new data on insulin signalling in skeletal
muscle in intact animals obtained using these novel techniques have implications for designing
pharmaceuticals targeting insulin signaling as a treatment of insulin resistance.
NHMRC Research Achievements - SUMMARY
Name of contact:
Prof Edward Kraegen
Email/Phone no. of contact:
e.kraegen@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 276431
Start Year: 2004
CIA Name: Prof Donald Chisholm
End Year: 2006
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Project Grants
Main RFCD: Endocrinology
Total funding: $335,800
Title of research award:
An examination of the contribution of visceral adiposity to insulin resistance in humans.An examination of the
contribution of visceral adiposity to insulin resistance in humans.
Lay Description (from application):
The worldwide epidemic of Type 2 diabetes is related to major nutritional and activity changes interacting with
a genetic predisposition. The two key defects in Type 2 diabetes are a reduced response to insulin (insulin
resistance) and relative failure of insulin production. Insulin resistance is the earliest defect and is closely
associated with cardiovascular risk. Obesity generates insulin resistance, but intraabdominal (visceral) fat has
particular importance. Visceral fat cells are different to other fat cells; they are very metabolically active and
'spill out' fatty acids indiscriminately contributing to insulin resistance in liver and muscle; they also produce
hormones which may modify the action of insulin. We will study people undergoing abdominal surgery.
Participants will be (1) normal weight and sensitive to insulin, (2) abdominally overweight and insulin
resistant, (3) insulin resistant with Type 2 diabetes. We will document abdominal fat, circulating lipid and
hormone levels and insulin action. At surgery fat biopsies will be obtained from (a) inside the abdominal
cavity, (b) the fat layer under the abdominal skin and (c) fat in the buttock. The activity of a large number of
genes in the fat tissue will be assessed in 8 subjects using DNA array (4 each from Groups 1 and 2). Then a
small number of genes will be selected on the basis of different activity in visceral fat from buttock fat, and
between insulin sensitive and insulin resistant people. The activity of these genes will be determined in all
subjects in the 3 groups. We anticipate identifying a few (perhaps 3) genes whose activity is closely associated
with insulin resistance and will examine their capability to block insulin action in a series of animal and
cellular studies. These studies should identify specific mechanisms by which visceral fat creates insulin
resistance. This would be an important step towards prevention and improved medication for Type 2 diabetes.
Research achievements (from final report):
The amount of visceral fat [fat inside the abdomen] is strongly associated with risk of Diabetes and
Cardiovascular disease.This research has examined the activity of a large number of genes in visceral and
peripheral [subcutaneous] fat and has demonstrated major differences in genes promoting inflammation and
regulating fat mobilisation [lipolysis] ,cortisol metabolism [11 B hydroxysteroid dehydrogenase] and metabolic
activity [Leptin].Major differences in genes controlling tissue development have also been found,indicating
that visceral fat is a different type of tissue to peripheral fat.Of most interest,it has been found for the first time
that an important developmental gene,Islet-1,is active in visceral but not peripheral fat -- this gene was
previously not thought to be active in any fat tissue.The expression [activity] of Islet-1 in visceral fat was
shown to be reduced with increasing obesity in both humans and rodents [mice fed a high fat diet or mice with
obesity due to deficiency of the Leptin gene] ;conversely expression was increased in mice with a genetic
manipulation [c-Cybl knockout] causing leanness and increased insulin sensitivity.Islet-1 was predominantly in
preadipocytes [the cells which develop into fat cells] suggesting it may play an important role in the
development and differentiation of visceral fat - which would be consistent with a role already established in
the pancreas,heart and nerve cells.This suggests Islet-1 could be a future target for drugs to reduce
accumulation of visceral fat and reduce risk of Diabetes and Cardiovascular disease.
Expected future outcomes:
This research has clarified major differences between abdominal fat and fat elsewhere in the body and has
identified a developmental gene,Islet-1,uniquely expressed in abdominal fat.This could lead the way to
modifying the adverse effects of abdominal fat,which include increased inflammation and increased release of
fats into the blood stream
Name of contact:
NHMRC Research Achievements - SUMMARY
Prof.Donald Chisholm
Email/Phone no. of contact:
d.chisholm@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 325624
Start Year: 2005
CIA Name: Prof David James
End Year: 2007
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Project Grants
Main RFCD: Protein Targeting and Signal Transduction
Total funding: $454,500
Title of research award:
Mechanistic studies of c-Cbl - a modulator of energy homeostasis.Mechanistic studies of c-Cbl - a modulator
of energy homeostasis.
Lay Description (from application):
Obesity has become one of the most serious health care problems in the world. It is a problem not just because
more people are getting fatter. It is a problem because obesity is a major risk factor for many other diseases
including Type 2 diabetes and heart disease. While many consider the solution to be straight forward, ie eat
less, this is obviously not an effective solution because the problem is accelerating at lightning speed around
the world. At the Garvan Institute we have recently identified a new mouse model bearing a disruption in one
single gene. This mouse eats 30% more food than its siblings but has half the body fat. This exciting discovery
constitutes the foundation for the present proposal.
Research achievements (from final report):
1. Tissue specificity. Conditional c-Cbl-/- mice have now gone germ line and mice are planned to be shipped to
the Garvan within the next month. 2. The role of c-Cbl in the fat cell. We have studied insulin signalling
pathways in adipocytes from c-Cbl-/- mice and have found no significant difference compared to wild type
animals. We are currently developing fat cell transplantation techniques to examine the effects of c-Cbl fat
when transplanted into a wild type recipient. 3. Energy expenditure. The activity of a series of oxidative
enzymes has been measured and we have found no significant difference in the oxidative capacity of muscle of
c-Cbl-/- mice compared to wild type controls. Furthermore, in high fat fed animals there was an equivalent
increase in oxidative capacity in muscle from knock out and wild type animals (Molero et al Casitas b-Lineage
Lymphoma-Deficient Mice Are Protected Against High-Fat Diet-Induced Obesity and Insulin Resistance.
Diabetes 55:708-15, 2006)4. Domains in c-Cbl. Considerable progress has been made on this aim. We have
shown that knock in animals in which the Ubiquitin ligase domain in Cbl has been disarmed have a phenotype
resembling the knock out animals. This provides compelling evidence that the phenotype we have observed
relies to a great extent on the ubiquitinylation function of this protein. In combination with the tissue specific
knock out experiments (Aim 1) this should provide important information for target identification. This work
has now been published.
Expected future outcomes:
Once conditional mice have been received we will be in a strong position to map the tissue specificity for the cCbl metabolic phenotype by creating adipose tissue, muscle, liver and brain specific c-Cbl knock out mice.
Name of contact:
David James
Email/Phone no. of contact:
d.james@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 325625
Start Year: 2005
CIA Name: Prof Edward Kraegen
End Year: 2007
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Project Grants
Main RFCD: Endocrinology
Total funding: $454,500
Title of research award:
Mechanisms of the insulin-sensitising effects of AMPK activation in liver and muscle.Mechanisms of the
insulin-sensitising effects of AMPK activation in liver and muscle.
Lay Description (from application):
Type 2 diabetes represents an escalating global health problem. In Australia 7.5% of the population has
diabetes and another 16% insulin resistance (impaired action of insulin). Insulin resistance is closely associated
with obesity, dyslipidemia, hypertension and cardiovascular diseases (Syndrome X) as well as diabetes. A high
caloric intake (particularly with a high fat content) and a sedentary lifestyle are extremely important
environmental contributors to Syndrome X and diabetes. One of the most exciting developments in the past
few years has been the discovery that an enzyme, AMP kinase (AMPK), normally activated by exercise, may
be involved in its beneficial effects. We have contributed to this exciting field by showing in an animal model
that one dose of AICAR, a chemical agent which can activate AMPK, ameliorates the effects of insulin
resistance in muscle and liver. Further very recent work has linked AMPK with various drugs (particularly
glitazones and metformin) and hormones which can enhance insulin sensitivity. The goal of the experiments in
this project is to determine the overall mechanism by which AMPK has ameliorating effects on counteracting
insulin resistance. We hypothesize that the mechanism for this involves an effect of AMPK to reduce fat
molecules accumulating within muscle and liver cells, and our studies will examine this hypothesis. Our
studies should lead to a better understanding of how exercise and pharmacological activators of AMPK help in
management of diabetes and insulin resistant states. In addition because AMPK activation enhances glucose
metabolism by a separate pathway to insulin, it offers promise of developing compounds able to bypass
metabolic steps impaired by insulin resistance. Our studies should help in the design of new therapeutic agents
which can counteract insulin resistance.
Research achievements (from final report):
There is a need to better understand factors that lead to reduced insulin potency in Type 2 diabetes and similar
metabolic states. The AMP-activated protein kinase K pathway may be involved in a bidirectional regulatory
system which influences the potency of insulin action, although the components of this system, the
mechanisms involved and the in vivo relevance are poorly defined. Our aim was investigate firstly the
mechanisms by which AMPK activation leads to enhanced insulin action, and secondly whether AMPK
activation is a major contributor to the beneficial effects of insulin sensitisers (thiazolidinediones TZDs). We
identified that the TZD rosiglitazone can potentiate AMPK activation and increase muscle glucose uptake. As
this pathway is normally activated by exercise our finding suggests that some of the beneficial effects of the
TZDs may be related to a potentiation of AMPK during exercise. Adiponectin is an endogenous AMPK
activator. We also overexpressed (in vivo by electroporation) muscle adiponectin receptors, plus APPL1, an
adiponectin interacting protein, to clarify their importance in influencing insulin action, and found that
increasing APPL1 can rescue the muscle from deleterious actions of excessive dietary lipids and oppose insulin
resistance. Conversely we have established that there is significant downregulation of adiponectin receptors in
skeletal muscle accompanying the onset of insulin resistance, suppression of AMPK activity and accumulation
of cytosolic lipid. Preventing the accumulation of cytosolic lipids (by enhancing mitochondrial transfer of
lipid) can increase insulin sensitivity in muscle. These findings have important therapeutic implications for
counteracting muscle insulin resistance.
Expected future outcomes:
The work has continued under a new NHMRC project (ID#481303) funded 2008-2010 to focus on adiponectin.
The new work is focussing on the precise steps in the insulin signalling pathway that are influenced by AMPK,
adiponectin and its signalling proteins such as Appl1. This has already led to a publication in 2009 (jointly with
collaborator Prof Aimin Xu) in Cell Metabolism.
NHMRC Research Achievements - SUMMARY
Name of contact:
Edward Kraegen
Email/Phone no. of contact:
e.kraegen@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 427611
Start Year: 2007
CIA Name: A/Pr Gregory Cooney
End Year: 2008
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Project Grants
Main RFCD: Nutrition and Dietetics
Total funding: $349,264
Title of research award:
The role of circadian rhythm genes in the regulation of energy balance and substrate metabolism in muscle and
liverThe role of circadian rhythm genes in the regulation of energy balance and substrate metabolism in muscle
and liver
Lay Description (from application):
Obesity is increasing at an alarming rate worldwide and as the standard of living increases in developing
countries such as India and China, the incidence of obesity and its related diseases of diabetes, cardiovascular
disease and cancer will become the major health problem of the 21st century. The epidemic of obesity appears
to be due to a complex interaction between genetic background and changes in the environment such as
reduced physical activity and increased availability and consumption of high energy food. The accumulation
of excess body fat in most individuals is not a precipitous event that occurs over a few days or weeks. Obesity
actually occurs insidiously over a period years and is essentially the cumulative result of small differences in
daily energy balance. In humans and animals energy balance is subject to diurnal or day/night variations in
body temperature, feeding behaviour and physical activity (sleep/wake cycles). Recent research has
determined that all tissues in the body have the same genes that regulate circadian (daily) rhythms in the brain.
It has also become clear that the expression of these gene cycles over 24 hours in muscle liver and fat tissue the
same way that they do in the brain. What is not understood is the extent to which these circadian genes control
energy metabolism pathways such as glucose and fat utilisation and storage in liver and muscle. The aim of
this grant is to test the effects of changing diet, feeding times and circulating hormones on metabolism and
gene expression in muscle and liver to determine the extent to which circadian rhythm genes regulate the
normal diurnal metabolism of glucose and fat and whether dysregulation of these systems contributes to
metabolic disease.
Research achievements (from final report):
Most organisms including humans have patterns of behaviour and metabolism that are linked to the daily
light/dark cycle. These cycles of waking/sleeping, feeding/fasting are regulated by daily variations in gene
exprerssion in the brain and in most other tissues. This project has examined whether making animals eat at
different times of the day can upset the normal rhythms of metabolism in different tissues leading to
abnormalities in energy metabolism. The results so far show that forcing animals to eat during the day (when
they normally sleep) can change liver and muscle metabolism and also alter total body energy metabolism in a
way that can impact negatively on glucose metabolism in the muscle and also reduce daily energy expenditure.
These results have important implications for understanding how best to lead a healthy lifestyle avoid practices
(like midnight snacking) which could predispose to metabolic disease.
Expected future outcomes:
We expect to provide evidence that altered feeding patterns can impact on energy metaoblism in a detrimental
way which could predispose to metabolic diseases like insulin resistance and obesity.
Name of contact:
Gregory Cooney
Email/Phone no. of contact:
g.cooney@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 427644
Start Year: 2007
CIA Name: Dr Mark Cleasby
End Year: 2008
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Project Grants
Main RFCD: Endocrinology
Total funding: $340,400
Title of research award:
Role of Akt in insulin resistanceRole of Akt in insulin resistance
Lay Description (from application):
Type 2 diabetes represents an escalating global health problem. In Australia 7.2% of the population has
diabetes but an additional 16% have difficulty handling glucose, a problem which frequently precedes the
development of diabetes. Resistance of tissues to the action of insulin is an essential pre-requisite for type 2
diabetes but is also closely associated with the syndrome of obesity, dyslipidaemia, hypertension and
cardiovascular diseases (Syndrome X). Genetic factors combined with a high caloric intake and a sedentary
lifestyle are together responsible for the development of insulin resistance. From evidence that we and others
have obtained in recent years it is evident that an important mediator of insulin resistance is the amount of fat
which accumulates in muscle and liver. One way in which this abnormality seems to cause insulin resistance is
through interference with the normal signalling mechanism which causes increased glucose metabolism in
response to insulin. While experiments in cell systems have identified some candidate molecules that may be
involved, a need exists to demonstrate whether their dysregulation actually causes the insulin resistance in the
whole animal or human, or are merely associated with it. We will use novel techniques to manipulate the levels
of one of these candidate genes, protein kinase B/Akt, and its regulators in the muscle of rodents. We will then
examine the effects of these manipulations on insulin resistance using a combination of metabolic and
molecular tests. Building upon earlier work we will also determine how important different subtypes of this
molecule are for both normal and abnormal insulin-glucose metabolism, and whether these molecules or others
in the pathway are more important in insulin resistance. This knowledge will be invaluable in tailoring specific
novel treatment strategies or drugs for prevention or treatment of insulin resistance, and thus reducing the
burden of type 2 diabetes and Syndrome X.
Research achievements (from final report):
This NHMRC Project grant was terminated prematurely at the end of 2008 and was replaced by Program Grant
support (Grant 535921, "Pathways to Diabetes Prevention - Alleviating the type 2 diabetes burden in Australia"
James, D.E., Martin, J.L., Kraegen, E.W., Chisholm, D.J., Cooney, G.J., Ye, J.M, commencing in 2009).
Documentation regarding Research Achievments etc will be included in reporting for the Program Grant.
Expected future outcomes:
This Project Grant Support was a contributing factor to subsequent NHMRC Program Grant support from 2009
on., Documentation regarding Future Outcomes etc will be included in reporting for the Program Grant.
Name of contact:
Prof Edward Kraegen
Email/Phone no. of contact:
e.kraegen@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 145310
Start Year: 2001
CIA Name: Prof John Headrick
End Year: 2003
Admin Inst: Griffith University
Grant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $265,699
Title of research award:
Adenosine A1 and A3 Receptor Mediated Cardioprotection in Ischaemic MyocardiumAdenosine A1 and A3
Receptor Mediated Cardioprotection in Ischaemic Myocardium
Lay Description (from application):
Damage to the heart from coronary vascular disease causes significant morbidity and mortality in Australia.
Indeed, ischaemic injury represents the single greatest cause of premature death. Moreover, due to the
increasing age of our population the problem is growing - coronary artery disease affects 50% of those older
than 65, contributing to an increased incidence of angina pectoris, myocardial infarction, arrhythmia,
congestive heart failure, and sudden death. Protective strategies have been, and continue to be, developed to
reduce the extent of tissue damage and minimise prolonged reductions in heart function. The success of these
interventions has been mixed. This research project takes the novel approach of identifying the true roles of
two receptors present in the heart (the adenosine A1 and A3 receptors) which may play a crucial role in
enhancing tolerance of the heart to disease and injury. We currently do not fully understand the roles of these
receptors, although preliminary findings suggest they can exert powerful protective effects during disease
conditions. From a fundamental viewpoint, identifying the roles of these two receptors will significantly
advance our understanding of the mechanisms of injury and protection in the heart. From a therapeutic
viewpoint, this study will take us closer to the potential use of adenosine receptor-based therapy in protecting
the heart from ischaemic injury.
Research achievements (from final report):
This research has identified novel pathways by which the heart protects itself from damage during heart attack
(when coronary blood flow is reduced so that heart cells die). Our findings reveal ways of protecting both
cardiac muscle and vascular cells during heart attack. In future work we will more thoroughly examine how
these proteins control cell death, and attempt to devise strategies to harness these responses in order to improve
outcome from ischaemic heart disease.
Expected future outcomes:
N/A
Name of contact:
N/A
Email/Phone no. of contact:
N/A
NHMRC Research Achievements - SUMMARY
Grant ID: 231419
Start Year: 2003
CIA Name: Prof John Headrick
End Year: 2005
Admin Inst: Griffith University
Grant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $470,250
Title of research award:
Reduced Ischaemic Tolerance in the Aged Myocardium: The Role of Adenosine and Adenosine
ReceptorsReduced Ischaemic Tolerance in the Aged Myocardium: The Role of Adenosine and Adenosine
Receptors
Lay Description (from application):
Despite a decline in deaths rates due to heart disease over the last decade, cardiovascular disease remains the
single greatest cause of premature death in individuals over 65 years of age. It accounts for a major and
increasing portion of health care costs. Coronary artery disease affects 50% of those older than 65, and with the
ageing of our population it is estimated that the elderly population will nearly double from 13-14% to 25% over
the next 30 years. Unfortunately, it appears that the aged heart is less resistant to disease and injury,
contributing to the increase in mortality with ageing. The reasons are not known. This research project will
attempt to identify molecular changes which occur in the heart during ageing which may lead to a decline in
ability to withstand disease and injury. The research will specifically examine the possibility that a key
protective response, known as the adenosine receptor system, is somehow impaired or abnormal in the cells of
the aged heart. If it is found that this process is impaired, the research will attempt to rectify this abnormality
using new genetic therapy techniques to switch on the heart's own intrinsic defense mechanisms. This may
ultimately open up new avenues for specific therapeutic approaches to treatment of ischaemic heart disease in
the elderly.
Research achievements (from final report):
N/A
Expected future outcomes:
Based on this research our group is investigating the changes in signaling proteins that underly changes in
cardiac resistance to damage with age. This ongoing research, when completed, may allow for specific design
of pharmacological approaches to reducing the impact of heart attack and cardiac surgery in the elderly
population.
Name of contact:
John Headrick
Email/Phone no. of contact:
j.headrick@griffith.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 326222
Start Year: 2005
CIA Name: Prof John Headrick
End Year: 2007
Admin Inst: Griffith University
Grant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $339,375
Title of research award:
Adenosinergic Control of Cell Death in Ischaemic-Reperfused MyocardiumAdenosinergic Control of Cell
Death in Ischaemic-Reperfused Myocardium
Lay Description (from application):
Despite a decline in death rates due to heart disease over the last decade, cardiovascular disease remains a
major cause of premature death and disability in our population. During a heart attack the single most
important factor determining outcome is the extent of cell death. Thus, the most valuable thing we can do is
reduce the numbers of cardiac cells which die during and following heart attack. In recent years we have
learned that cell death during a heart attack occurs via an active process termed "apoptosis" (or programmed
cell death). Novel therapeutic strategies for limiting cardiac apoptosis are highly desirable. This research
project will examine the possibility that a locally generated chemical (termed adenosine) can very effectively
reduce this form of death via multiple pathways. By understanding how one of the heart's own intrinsic defense
mechanisms functions (the adenosine system), it may be possible to design new therapeutic approaches for
treatment and management of ischaemic heart disease.
Research achievements (from final report):
Death and disability from heart attack remains a major problem. This study showed the ways in which
damaging oxidants are generated within the cells mitochondria to produce damage and cell death in the heart.
The research project additionally showed that one of the hearts intrinsic defence mechanisms - the adenosine
receptor system - does inhibit this injury process. Thus, it may be possible to selectively target this source of
damage during heart attack. The importance of these adenosine receptors was further confirmed by engineering
mice lacking a receptor for adenosine, and which were found to be more sensitive to heart attack. Similarly,
when mice lack an enzyme that breaks down adenosine, hearts become more resistant to heart attack. Overall,
the study shows the importance of the adenosine system in determining the ability of hearts to withstand
damage during heart attack or infarction, and revealed the ways in which the adenosine system may reduce the
damaging effects of free radicals to improve recovery.
Expected future outcomes:
This increased understanding of how one of the heart's defense mechanisms functions (the adenosine system)
may facilitate design of new approaches for treatment of ischaemic heart disease. Our findings point to novel
ways of limiting damaging effects of infarction, and in targeting specific aspects of the cell death process.
Name of contact:
John Headrick
Email/Phone no. of contact:
j.headrick@griffith.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 326238
Start Year: 2005
CIA Name: Dr Jason Peart
End Year: 2007
Admin Inst: Griffith University
Grant Type: Early Career Fellowships (Australia)
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $180,290
Title of research award:
Acute and chronic G-protein coupled receptor mediated cardioprotectionAcute and chronic G-protein coupled
receptor mediated cardioprotection
Lay Description (from application):
Not Available
Research achievements (from final report):
The Howard Florey fellowshio allowed my return to Australia and the subsequet establishment of my own
laboratory within the Heart Foundation Research Centre at Griffith University. My reasearch has continued to
follow the original aims, that is, further examination of adenosine and opioid receptor cross-talk, the sustained
preconditioning phenotype, and the effects of age upon the response to ischemia and reperfusion., Regarding
outcomes in relation to aims, we have detailed receptor cross-talk at a transcriptional level, we have further
characterised the phenotype associated with sustained ligand preconditioning in great detail and, importantly,
reported a failure in essentail kinase signaling which may be reponisble for the age related reduction in
ischemic tolerance.
Expected future outcomes:
Expected future outcomes in relation to the Howard Florey fellowship will hopefully extend to contiuned
NHMRC fellowship support.
Name of contact:
Jason N. Peart
Email/Phone no. of contact:
j.peart@griffith.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 376608
CIA Name: Prof Lyn Griffiths
Admin Inst: Griffith University
Main RFCD: Genome Structure
Total funding: $978,500
Start Year: 2006
End Year: 2008
Grant Type: NHMRC Strategic Awards
Title of research award:
Use of the Norfolk Island Genetic Isolate for Disease Gene MappingUse of the Norfolk Island Genetic Isolate
for Disease Gene Mapping
Lay Description (from application):
This gene mapping study will use a unique founder effect population to investigate two major public health
disorders. We aim to identify genes that play a role in migraine and in cardiovascular disease, using a
population from Norfolk Island. The Norfolk Island community is a population of ~1200 permanent residents,
the majority of whom are direct descendents of 18th century English Bounty mutineers and Polynesian women.
We will undertake a full genome scan to identify migraine gene loci and QTL that influence cardiovascular
disease using samples from this population isolate.
Research achievements (from final report):
This research utilised a unique founder effect population to investigate two major public health disorders. The
study was aimed at identifying genes that play a role in migraine and in cardiovascular disease, using a
population from Norfolk Island. The Norfolk Island community is a population of ~1200 permanent residents,
the majority of whom are direct descendents of 18th century English Bounty mutineers and Polynesian women
who relocated to Norfolk Island from Pitcairn Island in the 1850s. The majority part of this population can
trace their genetic heritage back to a small number of families derived from the original Bounty
mutineers/Polynesians. As a genomic study population, Norfolk is of interest because there are strong family
groupings and well-documented family histories;
the population initially grew in
isolation from other communities and as a result produced a relatively homogeneous genetic pool; and
isolated founder effect communities
provide powerful resources for studies of genetically inherited conditions, as statistically, their pedigree
structure and size provide high information content and power.Using samples collected from this population
isolate, we undertook a full genome scan to identify regions within our genome that influence migraine and
cardiovascular disease. This linkage scan identified a number of implicated genomic regions including 6
regions relating to CVD risk traits and a novel migraine gene locus. In order to more clearly define implicated
disease loci, we have been undertaking a variety of forms of analysis of this genome scan data, including
phenotypic class and admixture analysis methods, and also undertaken fine mapping of implicated genomic
regions investigating variants and candidate genes within these regions. These studies have resulted in a
number of publications outlining the demographics, heritability, ancestry effect and genetics of these disorders
in the Norfolk population.
Expected future outcomes:
CVD is a major public health disorder, accounting for ~50% of Western deaths. Migraine is very debilitating
and also extremely common, affecting ~12% Australians. The Norfolk Island population provides a unique tool
to investigate and identify the genetic components involved in CVD and migraine-ultimately this could have
significant diagnostic and therapeutic benefits to these common disorders
Name of contact:
Prof Lyn Griffiths
Email/Phone no. of contact:
l.griffiths@griffith.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 428251
Start Year: 2008
CIA Name: Dr Jason Peart
End Year: 2011
Admin Inst: Griffith University
Grant Type: Career Development Fellowships
Main RFCD: Clinical Sciences not elsewhere classified
Total funding: $367,567
Title of research award:
Acute and chronic GPCR Medicated Cardioprotection: Roles of receptor Cross-Talk, Cellular signaling, and
effects of AgeAcute and chronic GPCR Medicated Cardioprotection: Roles of receptor Cross-Talk, Cellular
signaling, and effects of Age
Lay Description (from application):
Not Available
Research achievements (from final report):
i) Chronic Opioid-Mediated Cardioprotection: Now termed "Sustained-Ligand Activated Preconditioning"
(SLAP). We find that Opioid-triggered SLAP is specifically δ-OR mediated; SLAP may be induced in as little
as 48 hrs; protection persists for at least 7 days; and SLAP is additive with other stimuli. Preliminary findings
also support protective efficacy of post-ischaemic SLAP (ie. a Postcon-like effect). Finally, in terms of possible
mechanisms of SLAP protection, exciting data indicates SLAP increases caveolar density, and reverses the
negative impact of aging on caveolar formation. We report that the induction of SLAP involves profound
changes in levels of total and phosphorylated Akt, PKA, GSK3beta and PDK1, all members of important
protective signalling pathways. Most recent data shows amazing efficacy in the diabetic heart., ii)
Adenosinergic-Opioid Cross-Talk: Myocardial survival kinase activation (Erk1/2, Akt) by A1AR agonism is
similarly MMP/HB-EGF/EGFR dependent. Thus MMP-mediated EGFR activation appears essential to cardiac
protection and signaling via A1ARs and preconditioning., iii) Alterations In Protective Signalling With
Ageing: Our data indicate that aging-related loss of delta-opioid-mediated cardioprotection involves failure to
activate p38 MAPK and HSP27. Direct targeting of this pathway elicits comparable protection in both age
groups. A follow-up study found that moderate age worsens cardiac ischemic tolerance; associated with
reduced expression of autophagy regulators, dysregulation of p70S6K and GSK3β, and postischemic p38MAPK activation. Caloric restriction counters age effects; associated with reversal of age effects on p70S6K,
augmentation of Akt and Bcl2 levels, and preischemic p38-MAPK activation.
Expected future outcomes:
The research has the potential to improve outcomes from ischemic injury through pharmacological means.
Name of contact:
Jason Peart
Email/Phone no. of contact:
j.peart@griffith.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 481922
Start Year: 2008
CIA Name: Prof John Headrick
End Year: 2010
Admin Inst: Griffith University
Grant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $496,303
Title of research award:
The Importance of p38 MAPK Signalling in Aging-Related Ischaemic Intolerance and Failed
CardioprotectionThe Importance of p38 MAPK Signalling in Aging-Related Ischaemic Intolerance and Failed
Cardioprotection
Lay Description (from application):
Ischaemic heart disease is the leading cause of death in Australia, and will rise in coming years with the aging
of our population. Our research shows aged hearts become less resistant to damage during ischaemia/heart
attack, and insensitive to normally beneficial therapies. This project will identify molecular changes
responsible for these changes. By understanding how age impairs the hearts defences, it may be possible to
improve therapy of ischaemic heart disease in older patients.
Research achievements (from final report):
Our aim was to test our hypothesis that age-related reductions in the ability of the heart to withstand damage
with hearty attack stemmed from shifts in internal signalling networks that trigger a 'survival' response in heart
cells. The research showed that several signalling pathways were negatively influenced by aging, which may
explain both why aged hearts do not respond well to heart attack and also to therapies being trialled to protect
the heart. A series of molecular changes were reported that may negate the hearts own intrinsic protective
responses. However, it was also established that diet (specifically calorie restriction) was able to limit these
negative effects of age and restore the older hearts ability to withstand the damaging effects of infarction or
heart attack. Similar effects were also apparent with increases in volutnary activity (exercise). Overall the
research provides insight into why aged hearts are less tolerant of disease/infarction, and ways of potentially
countering these effects (eg. informing development of new cardioprotective interventions with efficacy in
aged hearts).
Expected future outcomes:
This work provides rational molecular targets for the manipulation of ischaemic tolerance in aged hearts, and
for manipulation of the negative effects of aging itself. Understanding which signal networks are dysfunctional
permits not only strategic targeting of efficacious targets, but also modulation of the processes that contribute
to cardiac aging.
Name of contact:
John Headrick
Email/Phone no. of contact:
j.headrick@griffith.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 536518
CIA Name: Prof Lyn Griffiths
Admin Inst: Griffith University
Main RFCD: Gene Expression
Total funding: $697,409
Start Year: 2009
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
Use of expression profiling to identify genes influencing cardiovascular risk in the Norfolk Island population
isolateUse of expression profiling to identify genes influencing cardiovascular risk in the Norfolk Island
population isolate
Lay Description (from application):
This study will use a unique population isolate from Norfolk Island. We aim to identify genes that play a role
in cardiovascular disease risk. Norfolk has a population of ~1200 permanent residents, most of whom are direct
descendents of 18th century English Bounty mutineers and Polynesian women. We will undertake gene
expression mapping to identify genomic loci that influence cardiovascular disease using samples from this
population isolate.
Research achievements (from final report):
The Norfolk Island population has been studied to determine genetic contributors to cardiovascular disease risk
traits. This population was used as it comprises a large multigenerational family therefore facilitating the study
of the heritability and identity of these traits in a large population. One of the major findings of the study was
the identification of a region of the genome on chromosome 1 that contributes significant influence on several
risk traits associated with cardiovascular disease such as body fat, blood pressure and kidney function. In
addition the study identified a locus on chromosome 12 that appears to influence the expression of multiple
different genes on other chromosomes. The outcomes of this study therefore include novel genomic
susceptibility regions and transcriptional biomarkers for CVD risk factor traits. These outcomes provide novel
avenues for investigating the genetic architecture behind cardiovascular disease and the complex interplay of
risk traits that contribute to the overall disease state. Understanding the genetic variation that contributes to
these risk traits, as well as developing knowledge of how heritable these traits are and how they interact, will
assist in the development of targeted therapeutics and/or preventative lifestyle measures that address specific
mechanisms that contribute to the risk of cardiovascular disease. There are currently two publications from this
work but two additional major papers are currently under review.
Expected future outcomes:
The results of this study will guide ongoing research that will target these identified regions of the genome with
the aim of elucidating the genes and mechanisms through which these regions are influencing the heritability of
cardioascular risk traits.These genes may then be targeted for diagnostic testing and therapeutic development.
Name of contact:
Prof Lyn Griffiths
Email/Phone no. of contact:
l.griffiths@griffith.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 151630
Start Year: 2001
CIA Name: Prof Michael Davies
End Year: 2003
Admin Inst: Heart Research Institute
Grant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $196,018
Title of research award:
Role of transition metal ions and redox activity in the development of atherosclerotic plaquesRole of transition
metal ions and redox activity in the development of atherosclerotic plaques
Lay Description (from application):
Metal ions such as iron and copper have been reproted to be present in the lesions present in diseased human
arteries and it has been suggested that these metal ions contribute to the development of atherosclerosis
(hardening of the arteries) via their ability to catalyse the formation of highly reactive molecualr fragments
called free radicals. Though metal ions are known to catalyse such reactions in test-tube experiments, both the
presence of metal ions in diseased arteries and their ability to generate free radicals is controversial. This study
will employ a novel, minimally-invasive, technique to assess the nature and quantity of metal ions present in
well-defined human and animal lesions at different stages of lesion development. The ability of these metal
ions to catalyse free radical formation from components present in the artery wall will also be assessed. The
release of these metal ions from the artery wall to added organic molecules will be assessed as this might
minimise their potential to cause damage, and provide a possible therapeutic strategy. These studies will
therefore provide valuable information as to the significance and role of reactive metal ions in the development
of human artery disease and the possible prevention, or minimisation, of such processes.
Research achievements (from final report):
The hypothesis behind this study was that elevated levels of transition metals are present in elevated
concentrations in atherosclerotic plaques compared to healthy tissue, that these species catalyse radical
reactions that result in protein and lipid oxidation and antioxidant depletion, and hence these processes are
linked to lesion development. In this study we quantified iron and copper levels in tissue samples using EPR
spectroscopy, and inductively-coupled plasma mass spectroscopy. , EPR studies on healthy human artery
samples showed only low levels of Fe. In contrast, with human lesions signals were detected characteristic of
non-heme Fe(III) complexes. Statistically elevated levels of iron and copper were detected in the intima of
lesions compared with healthy controls. The iron levels did not correlate with the gender or age of the donor, or
tissue protein or calcium levels, but cholesterol levels correlated positively. Organic radicals were also detected
in artery samples, with the concentration increased in lesions. These metal ions have been shown to catalyse
the generation of protein oxidation products, similar to those detected in advanced human atherosclerotic
lesions, from extracellular matrix., We also examined the accumulation of Fe and Cu in apoE-knockout mice
fed a high fat diet versus controls. Elevated levels of Fe were present in the most advanced lesions when
compared to age-matched controls and an age-dependent increase in Fe accumulation with time on the high fat
diet was detected. ,
The effect of novel and specific
chelators on the levels of iron present in advanced human lesions was examined. Some of these ligands reduced
the iron levels present in lesions, wit the extent removal dependent on the concentration of the chelator
employed, the structure of these materials, and the incubation time. These exciting findings suggest that it may
be possible to remove, or prevent the continued accumulation of, such metals from human lesions.
Expected future outcomes:
Further studies are currently underway, funded by the National Heart Foundation, to examine the correlation
between metal ions levels and the extent of oxidation within human lesions. Preliminary data suggest that the
levels of iron correlate well with the observed extent of protein oxidation, suggesing that iron is a causative
factor in these reactions. Studies with chelators are also ongoing.
Name of contact:
Dr Michael Davies
NHMRC Research Achievements - SUMMARY
Email/Phone no. of contact:
m.davies@hri.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 189800
Start Year: 2002
CIA Name: Prof Roger Dean
End Year: 2004
Admin Inst: Heart Research Institute
Grant Type: NHMRC Project Grants
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $406,320
Title of research award:
Mechanisms of proteolysis of proteins containing oxidised amino acidsMechanisms of proteolysis of proteins
containing oxidised amino acids
Lay Description (from application):
There is evidence that during ageing, and age-related diseases, proteins which have been chemically modified
by oxidation accumulate in the body, and may have deleterious effects. Oxidation of proteins is a process akin
to that by which fats go rancid. It has been demonstrated by the applicants to be an important process in
formation of cataracts, and in development of the blood vessel disease, atherosclerosis, which is responsible for
most heart attacks and stroke. Other important age-related diseases, such as Alzheimer s disease and other
neurological disorders, are also claimed to be associated with deranged protein oxidation, and accumulation of
oxidised products. There is clear evidence that certain defensive mechanisms, such as those acting to remove
invading organisms and clear wounds, are also associated with an enhanced production of oxidised proteins.
Perhaps the most important component of defense against oxidised proteins is their removal by complete
breakdown to constituent components, and excretion. Normally, the machinery for breakdown of proteins is in
vast excess over the required rate of degradation. However, clearly in these conditions of accumulation of
oxidised proteins, this is no longer the case, or no longer suffices. Mechanisms by which oxidised proteins are
degraded are poorly understood, and quite controversial. Therefore, the present studies bring to bear a new
approach to studying this issue, which has been developed by the applicants. The aim is to reveal mechanisms
involved in the breakdown of proteins containing oxidised amino acids, both in cellular systems, and in vivo.
Such an understanding may allow us to envisage how to remove oxidised proteins by therapeutic means and
therefore interfere with the development of age-related diseases such as Alzheimer s disease and cataract
formation and the diseases of the blood vessels associated with attack and stroke.
Research achievements (from final report):
Proteins which have been damaged by oxidation (oxidised proteins) can accumulate in cells and tissues and are
implicated in the pathology of a number of diseases associated with ageing such as the blood vessel disease,
atherosclerosis, which is responsible for most heart attacks and strokes as well as neurological disorders such
as Alzheimer's disease. , , Using a novel approach we developed we were able to identify some of the key
mechanisms used by cells to remove oxidised and damaged proteins. This allowed us to discover where this
process may fail and why these toxic proteins accumulate in certain diseases. We identified the importance of
the heat shock proteins in preventing oxidised proteins from interacting with each other and forming
aggregates. Increasing the levels of heat shock proteins in cells may provide a new approach to treat age-related
disorders., , We also discovered that oxidised proteins can increase the production of a family of enzymes
called cathepsins. Cathepsins can break down tissues and have been implicated in a range of diseases including
tumour invasion and heart disease. This important finding linking the accumulation of oxidised proteins to
levels of these enzymes could have implications in many of the diseases of ageing. , , We demonstrated that the
oxidised amino acid 3,4 dihydroxyphenylalanine (dopa) can be mistaken for the natural amino acid tyrosine
and used by cells to make proteins. The dopa-containing proteins however have the capacity to accumulate in
the cell. This has important implications for Parkinson's disease where dopa is the most commonly used and
effective therapeautic agent.
Expected future outcomes:
These studies highlighted the critical role of the heat shock proteins in protecting the cell from damaged
proteins. Studies are underway to determine if increasing the levels of these proteins in cells can protect the cell
from some of the damaging effects of oxidation and slow the ageing process.
Name of contact:
NHMRC Research Achievements - SUMMARY
Dr Ken Rodgers
Email/Phone no. of contact:
k.rodgers@hri.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 277600
Start Year: 2004
CIA Name: Prof Michael Davies
End Year: 2006
Admin Inst: Heart Research Institute
Grant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $384,750
Title of research award:
Myeloperoxidase-catalysed damage to arterial extracellular matrix and its consequencesMyeloperoxidasecatalysed damage to arterial extracellular matrix and its consequences
Lay Description (from application):
A heme enzyme (myeloperoxidase) has been shown to be present in the lesions present in diseased human
arteries, and it has been reported that this enzyme contributes to the development of arterial disease via its
ability to catalyse the formation of highly reactive oxidants. Recent studies have shown that the level of this
enzyme correlate strongly with the presence of coronary artery disease, and that this enzyme may play a role in
plaque rupture, a leading cause of sudden coronary death. It has also been reported that elevated levels of
metal ions are present in advanced human atherosclerotic lesions. In recent experiments we have shown that
products generated by myeloperoxidase can interact with metal ions and superoxide radicals, and that this
process results in an exacerbation of damage. This synergism between the oxidants generated by
myeloperoxidase and metal ions may explain, at least in part, the complex mixture of products detected in
human lesions and be responsible for the weakening of lesion structure and contribute to an enhanced
likelihood of plaque rupture. This study will examine the potential effects and mechanisms of damage to
extracellular matrix materials from normal arteries and cultured cells We will examine under what
circumstances interactions occur and whether these reactions may play a key role in plaque rupture. We will
also examine how materials arising from damage to the extracellular matrix may affect the cells whic grow
upon this scaffolding, and whether this may be partly responsible for altered behaviour of cells within
dveloping atherosclerotic lesions. A detailed knowledge of which processes are important in plaque rupture is
an essential pre-requisite to the development of new therapeutic strategies.
Research achievements (from final report):
This project has resulted in a major body of work concerned with the mechanisms, rates and consequences of
the generation of oxidants by the heme enzyme myeloperoxidase. During the period covered by this project a
considerable body of work has been published that has established that this enzyme may playa key role in the
development and progression of atherosclerosis and understanding how the species generated by this enzyme
cause damage is a major goal of current research, as understanding the nature and sites of damage will
underpin the development of agents that may inhibit or modulate damage. We have obtained detailed evidence
on the sites of damage induced by HOCl, one of the major species generated by myeloperoxidase and have
shown that this agent damages a limited number of specific protein side-chains in preference to most other
biological molecules. We have also shown that certain sites on sugar molecules - particularly unsubstituted
amino sugars - are also key sites of damage, and that this results in the fragmentation of glycosaminoglycan
chains. Such fragmentation, which may be enahnced by the binding of the enzyme to such structures, is
believed to have significant effects on cellular behaviour and also to modulate the action of a number of
enzymes, co-factors and growth factors.
Expected future outcomes:
We believe that understanding the fundamental biochemistry of myeloperoxidase will underpin future
developments of novel agents that may modify the activity, and hence extent of damage, induced by this
enzyme.
Name of contact:
Michael Davies
Email/Phone no. of contact:
daviesm@hri.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 482800
Start Year: 2008
CIA Name: Prof Philip Barter
End Year: 2012
Admin Inst: Heart Research Institute
Grant Type: Programs
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $10,461,682
Title of research award:
Atherosclerosis: Lipoproteins, cell biology and vascular physiologyAtherosclerosis: Lipoproteins, cell biology
and vascular physiology
Lay Description (from application):
The world is confronting a major new epidemic of premature heart disease that is being driven by a global
increase in obesity. There are several factors that contribute to the increased risk of heart disease in overweight
and obese people. One is a low blood level of the “good” HDL cholesterol that normally protects against heart
disease. Another relates to a decreased ability to remove cholesterol from the walls of arteries where it builds
up to cause heart disease. A third is the fact that obesity is associated with a state of chronic inflammation of
the blood vessels. This inflammation not only accelerates the development of heart disease but also makes
people who have cholesterol accumulated in their arteries more likely to actually have a heart attack. And a
fourth is the fact that the lining of blood vessels does not function normally in overweight and obese people.
This loss of normal function is a very early sign of future heart disease. These factors are closely inter-related,
with the “good” HDL playing a central role in removing cholesterol from arteries, inhibiting arterial
inflammation and promoting normal function and repair of the lining of blood vessels. HDL is complex,
consisting of a mixture of several subpopulations of particles that vary in shape, size and composition.
Furthermore, these HDL subpopulations are continually remodelled as they circulate in blood in reactions
promoted by a number of blood factors that change their size and composition. A major component of the
research to be conducted in this program relates to understanding how the HDL subpopulations in human blood
are regulated and how they protect against heart disease. The applicants have already made major contributions
to understanding the functions of the “good” HDLs, how they take cholesterol out of cells in the artery wall,
how they inhibit inflammation of the arteries and how they improve the function of the artery lining. We
propose to extend these studies to establish how these protective functions can be enhanced, to find out which
of the HDL subpopulations are most protective, and to identify how to increase the most protective HDLs in
people at risk of heart disease.
Research achievements (from final report):
We have identified several mechanisms by which high density lipoproteins (HDLs) protect against heart
disease.We have shown that HDLs increase the synthesis and secretion of insulin by the pancreas and
identified the mechanism responsible for this effect.We have shown that HDLs improve diabetic control in
humans.We have identified the mechanism by which HDLs inhibit inflammation in blood vessels We have
shown that HDLs promote the repair of damaged arteries. We have defined the mechanism by which
cholesterol is taken out of cells in the artery wallWe have identified novel roles for several proteins involved in
the development of heart disease.We have demonstrated that abnormal function of arteries in obesity involves
both the endothelial cells that line the blood vessels and also the smooth muscle cells in the artery wall.We
have found a strong relationship between maternal cigarette smoking and low HDL levels in lean children.We
have found that lower HDL-cholesterol levels are significantly associated with greater arterial wall thickness in
early childhood.We have found a relationship between maternal cigarette smoking and low HDL levels in lean
children.We have identified the factors responsible for remodelling of HDLs and the implications of this
remodelling on the ability of HDLs to protect against heart disease.
Expected future outcomes:
Our understanding of the factors responsible for regulating HDLs and our discovery of the mechanisms by
which HDLs protect against heart disease have provided new insights that are leading to novel strategies
designed to prevent and treat heart disease.
Name of contact:
NHMRC Research Achievements - SUMMARY
Philip Barter
Email/Phone no. of contact:
p.barter@unsw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 310300
CIA Name: Prof Robert Pierce
Admin Inst: Institute for Breathing and Sleep
Main RFCD: Respiratory Diseases
Total funding: $361,030
Start Year: 2004
End Year: 2007
Grant Type: NHMRC Project Grants
Title of research award:
The Interactions between Sleep Disordered Breathing, Metabolic Syndrome and Vascular Risk.The
Interactions between Sleep Disordered Breathing, Metabolic Syndrome and Vascular Risk.
Lay Description (from application):
We will look at two common diseases in the Australian community, the metabolic syndrome and obstructive
sleep apnoea (OSA), and explore the common links they have to the risk of disease of the heart and blood
vessels. We will then take a group of patients who have both diseases, treat the OSA, and assess the impact of
this treatment on their cardiovascular health. Metabolic syndrome is a term given to patients who have high
blood sugar, obesity, high lipid levels and raised blood pressure. The Australian Bureau of Statistics estimates
that half the Australian population is overweight, and US studies suggest that nearly of the adult population
has metabolic syndrome. This is strongly linked to diseases of the heart and blood vessels, eg heart attacks and
stroke.Patients with OSA stop breathing during the night when their throat closes over. The blood oxygen falls,
which causes the patient to wake momentarily, then start breathing again. This cycle repeats itself throughout
the night. The usual treatment is an air pump (CPAP) connected to a nose mask, which blows air into the throat
and prevents closure. This disease is strongly linked to high blood pressure, raised blood sugar levels and heart
and blood vessel disease. Patients with the metabolic syndrome will have an overnight sleep study to diagnose
OSA, giving the likelihood of having OSA in this group of patients. They will then have extensive
investigations of the health of their heart and blood vessels. From these, we will determine which aspects of
OSA are more likely to result in cardiovascular disease. Those patients diagnosed with OSA will be treated
with CPAP for 3 months. Half the patients will receive normal CPAP; the other half will receive ineffective
CPAP. They will then be re-tested and we will compare the results before and after treatment.Thus we will
measure likelihood of OSA in this large group of patients, and the health benefits they may gain from treatment
of their OSA.
Research achievements (from final report):
Obstructive sleep apnoea (OSA) is a common disease that affects approximately 5% adult Australians. It is
more common in those who are overweight, thus is a growing problem for the Australian healthcare system.
Both obesity and OSA are associated with an increased risk of cardiovascular disease; those who are at the
greatest risk of poor cardiovascular outcomes are those who have other medical problems, particularly diabetes,
elevated blood pressure and high blood lipid levels. These diseases, together with obesity, are termed the
Metabolic Syndrome (MetSyn)., This study has shown that the prevalance of OSA in those with MetSyn is
68.9% and symptomatic OSA is seen in 43.9% our group, both of which are much higher than in the general
population. Those with OSA had worse hypertension, particularly during the night., Diabetes was associated
predominantly with low oxygen levels during sleep rather than with sleep disruption. Treatment uptake was
poor, but in those who used the CPAP pump there was some improvement in intermediate measures of
cardiovascular risk.
Expected future outcomes:
Analysis of intermediate markers of endothelial function is ongoing. The relationship between these outcomes,
sleep-disordered breathing and metabolic syndrome will be investigated.
Name of contact:
Maree Barnes
Email/Phone no. of contact:
maree.barnes@austin.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 603810
CIA Name: Prof David Power
Admin Inst: Institute for Breathing and Sleep
Main RFCD: Nephrology and Urology
Total funding: $582,295
Start Year: 2010
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
The role of fatty acid metabolism in renin secretionThe role of fatty acid metabolism in renin secretion
Lay Description (from application):
People who are overweight often have high blood pressure. This project aims to find out why. By showing that
the kidneys, which control blood pressure, use fat as an important controller of their function, we may be able
to work out ways to modify the relationship between obesity and high blood pressure. The project wil be
performed in genetically modified mice, but we expect that the findings will be applicable to humans.
Research achievements (from final report):
One-third of adults around the world have raised blood pressure, a condition that is accountable for around 13
per cent of all global deaths. The World Health Organization also attributes half of the deaths from heart
disease and strokes to high blood pressure. The research in this grant asked how control of metabolism,
especially of fats, affects the ability of the kidney to regulate blood pressure. An enzyme called AMPK is
known to contribute to a large number of other biological functions, especially control of the rate of
metabolism. The research attempted to determine whether changes in the activity of AMPK and, therefore, the
rate of fat metabolism inmfluence kidney behaviour and blood pressure control. To do this, we studied renin, a
protein that is made, secreted and collected in the kidney. The actions of renin secretion within the human body
increase blood pressure, because it results in actions that contract the small arteries and induces the kidney to
store salt. The studies found that mice with a genetic change in AMPK, or a mutation in one of the fat
metabolism proteins that AMPK controls, have a very greatly increased renin response. This indicates that
changes in the rate of fat metabolism have an effect on the regulation of blood pressure. It is the first evidence
that fat metabolism and blood pressure control are linked.
Expected future outcomes:
This work should open new avenues in control of blood pressure, especially for those with metabolic diseases
that disturb metabolism, such as obesity and diabetes.
Name of contact:
David Power
Email/Phone no. of contact:
david.power@austin.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1006517
CIA Name: Prof David Power
Admin Inst: Institute for Breathing and Sleep
Main RFCD: Nephrology and Urology
Total funding: $524,820
Start Year: 2011
End Year: 2013
Grant Type: NHMRC Project Grants
Title of research award:
Regulation of SPAK by AMPK links salt reabsorption to energy metabolismRegulation of SPAK by AMPK
links salt reabsorption to energy metabolism
Lay Description (from application):
Excessive salt and energy intake have emerged as major features of the unhealthy fast-food culture. Salt
promotes high blood pressure, whereas high energy intakes increase obesity and diabetes. In this study, we aim
to determine how energy availability and salt handling are linked in the kidney. This research will lead to new
ways to treat high blood pressure by limiting salt reabsorption in the kidney.
Research achievements (from final report):
High blood pressure, or hypertension, remains a significant health problems throughout the world. High salt
uptake by the kidney is one of the most important factors leading to high blood pressure. This uptake is done
through a series of salt transporters in the kidney. We have demonstrated that obesity leads to a change in the
activity of a kidney salt transporter called NKCC2, so increasing its ability to retain salt. The protein that
increases the activity of the salt transporter is known as a protein kinase. This new interaction between a
protein kinase and NKCC2 in the kidney leads to high blood pressure in obesity. We hope that further study of
this pathway will lead to new treatment approaches in people with high blood pressure, especially when it is
caused by obesity. Obesity can be viewed as a disorder of excess energy supply so, in another part of this
study, we have examined the effect of levels of energy on salt uptake by the kidney. We found that proteins
which sense energy levels in cells of the kidney also influence NKCC2, so providing a route for levels of
energy within the kidney to control salt uptake. These studies are helping to redefine the way that we view the
effect of energy metabolism and diseases of energy excess, especially obesity, on salt uptake and high blood
pressure.
Expected future outcomes:
These studies demosntrate that there are likely to be multiple pathways to high blood pressure. Identifying
these in the individual patient may lead to the use of specific therapy for each person who has high blood
pressure, rather than the trial and error approach that currently exists.
Name of contact:
David Power
Email/Phone no. of contact:
david.power@austin.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 232905
Start Year: 2003
CIA Name: Dr Stuart Pitson
End Year: 2005
Admin Inst: Institute of Medical and Veterinary Science
Grant Type: NHMRC Project Grants
Main RFCD: Enzymes
Total funding: $442,500
Title of research award:
The molecular mechanism of sphingosine kinase activationThe molecular mechanism of sphingosine kinase
activation
Lay Description (from application):
Many cell processes like growth, death and differentiation are controlled by hormones and other molecules that
interact with receptors on the outside of the cell. When this type of molecule binds to a receptor, it often
triggers the production of signaling molecules inside the cell that initiate a change in the cells behaviour. The
lipid molecule, sphingosine phosphate has been identified as such a signaling molecule that appears to be
involved in the regulation of a diverse array of important mammalian cellular processes. Recent studies have
found that sphingosine phosphate is involved in the inflammation of cells, and if its production can be blocked,
inflammation is not seen. Therefore, this provides a potential target for therapeutic intervention in the
inflammation process. However, the manner by which cells regulate sphingosine phosphate levels is not well
known. It is known that sphingosine phosphate is produced by the enzyme sphingosine kinase, and strong
evidence suggests that changes in this enzyme's activity in the cell regulate sphingosine phosphate levels.
However, how the cell changes the levels of sphingosine kinase activity is completely unknown. This study
will investigate this problem with the view that understanding this process will allow the development of new
drugs to block increases in sphingosine kinase activity, preventing increases in sphingosine phosphate levels,
and it turn, preventing cellular inflammation.
Research achievements (from final report):
Sphingosine kinase is an enzyme that produces the lipid signalling molecule, sphingosine phosphate that is
involved in the regulation of a diverse array of important mammalian cell functions like growth, death and
differentiation. Sphingosine kinase is involved in tumorigenesis, and if its activity can be blocked, tumor size
can be reduced. Therefore, this provides a potential target for therapeutic intervention in cancer. However, the
manner by which cells regulate sphingosine kinase is not well known. In this study we have established that
phosphorylation of sphingosine kinase increases the activity of this enzyme, and also causes a shift in its
localisation within the cell. Importantly, we have also found that both of these processes are essential for the
tumorigenic effects of sphingosine kinase. Thus, this study has identifed potential therapeutic targets that can
be exploited for the development of new drugs to block the tumorigenic effects of sphingosine kinase.
Expected future outcomes:
The findings of this study are likely to provide the basis for the search for new anti-cancer therapies targeting
the regulation of sphingosine kinase.
Name of contact:
Stuart Pitson
Email/Phone no. of contact:
stuart.pitson@imvs.sa.gov.au
NHMRC Research Achievements - SUMMARY
Grant ID: 278802
Start Year: 2004
CIA Name: Dr Yeesim Khew-Goodall
End Year: 2006
Admin Inst: Institute of Medical and Veterinary Science
Grant Type: NHMRC Project Grants
Main RFCD: Cellular Interactions (incl. Adhesion, Matrix, Cell Wall)
Total funding: $496,500
Title of research award:
A tyrosine phosphatase that regulates adherens junctions, cell migration and the epithelial-mesenchymal
transitionA tyrosine phosphatase that regulates adherens junctions, cell migration and the epithelialmesenchymal transition
Lay Description (from application):
Cell-cell adhesion which physically glues cells together to form tissues and organs, also controls processes in
development, wound healing and cancer progression. I have identified a novel regulator of cell-cell adhesion
that regulates cell migration and cell morphology. Since these events are crucial during metastasis (the spread
of cancer) and during wound healing, understanding the function of this novel regulator may provide the basis
for new approaches to developing therapeutics. Specifically, in this proposal I aim to further our understanding
of the function of this novel regulator in normal physiology and to elucidate how its functions are regulated.
Research achievements (from final report):
In this study, we (i) demonstrated that the protein tyrosine phosphatase Pez is a regulator of epithelialmesenchymal transition (EMT), (ii) that its role in regulating EMT is crucial for the proper development of
some organs using a zebrafish model to study organ development and (iii) that it is a regulator of the growth
factor TGF-beta production leading to the EMT. In addition to its role in organ development, EMT is also a
process required for the initial stages of metastasis of solid tumours as well as a source of additional fibroblasts
in fibrotic diseases that lead to organ failure. Although TGF-beta level is well-known to be elevated in both
cancers and fibrotic diseases and play a role in the progression of both these diseases, little is known about the
mechanisms that lead to elevated TGF-beta levels in these diseases. Our findings implicate Pez as a potential
protagonist of both cancer metastasis and organ fibrosis and hence a potential therapuetic target for novel drugs
to inhibit or retard these processes. The findings from this study and reagents generated as a result led to a
collaboration with a colleague in which we identified a family microRNAs that could regulate EMT with
implications for their use in preventing or retarding metastasis.
Expected future outcomes:
We expect that in future we will establish a role for Pez in metastasis and fibrotic diseases and head towards
determining whether it is a worthy therapeutic target for controlling cancer progression and/or fibrotic diseases.
We will also establish the mechanism by which Pez upregulates active TGF-beta and this would impact on our
undestanding of developmental processes, homeostasis and diseases.
Name of contact:
Yeesim Khew-Goodall
Email/Phone no. of contact:
yeesim.khew-goodall@imvs.sa.gov.au
NHMRC Research Achievements - SUMMARY
Grant ID: 233200
CIA Name: Prof Paul Zimmet AO
Admin Inst: International Diabetes Institute Inc
Main RFCD: Epidemiology
Total funding: $2,677,855
Start Year: 2003
End Year: 2007
Grant Type: NHMRC Project Grants
Title of research award:
A five year follow-up of people with Type 2 diabetes & other states of glucose intolerance and associated risk
factorsA five year follow-up of people with Type 2 diabetes & other states of glucose intolerance and
associated risk factors
Lay Description (from application):
The Australian Prospective Diabetes Study (APDS) is a 5 year follow-up study established to examine the
natural history of diabetes and its complications, as well as heart disease and kidney disease. It is a follow-up
to the recently completed AusDiab study and addresses some of the important gaps that exist nationally and
internationally in the understanding of the burden of Type 2 diabetes and related problems. AusDiab found
that 1 in 4 Australians aged 25 years and over has either diabetes or a condition of impaired glucose
metabolism (this condition is associated with substantially increased immediate risk of heart disease as well as
increased risk of diabetes in the future). This new study-APDS, will be the first Australian and indeed
international study of its type.We intend to invite 7000 out of the original 11,247 AusDiab sample to
participate. Participants who agree to take part in the follow-up study will be involved in 2 ways: 1. A 6-12
monthly contact with participants by telephone or mail to allow reporting of changes in health and utilisation of
health services.2. A 5 year biomedical follow-up survey. This will involve a survey team travelling around
Australia to test the participants for diabetes, heart and kidney disease and cardiovascular risk factors (e.g.
blood pressure and cholesterol). It will accurately define how many Australians are likely to develop diabetes
(as well as kidney and heart disease) in the future, and who is at highest risk. It is expected that outcomes from
this study will provide crucial information for both planning and testing public health policy and for the
appropriate allocation of resources including specific treatments of individuals and specific groups with or at
risk of Type 2 diabetes and its complications within the Australian population.
Research achievements (from final report):
This project (AusDiab) has had a major impact on our understanding of the burden of diabetes, obesity and
cardiovascular and kidney disease, as experienced across the population of Australia. In particular, it has
produced the first national estimates of the incidence of diabetes, obesity, chronic kidney disease and
hypertension. These figures have not only been described for the first time in Australia, but this study is one of
only a handful around the world to produce such figures for a national population. AusDiab has identified risk
factors for the development of diabetes, and described the pattern of weight change in the population over five
years. Furthermore, AusDiab has produced the first ever accurate figures relating pre-diabetes and diabetes to
the total burden of deaths due to cardiovascular disease, showing that two thirds of such deaths occur in people
whio had either diabetes or pre-diabetes within the previous five years. AusDiab has also allowed us to
estimate the risk of developing diabetes over a lifetime, and to examine how this might be affected in coming
decades by changes in the population's risk factor profile. Using the findings from AusDiab we have now
developed a screening tool (a 'tick test') that can be used by the general public and by health care professionals
to estimate an individual's risk of developing diabetes. This will allow people at risk of diabetes to be directed
into lifestyle programs aimed at preventing diabetes.
Expected future outcomes:
Further work will continue to be undertaken, examining the risk factors for diabetes, cardiovascular disease and
kidney disease, and looking at the impact that each of these conditions has on individuals and on society.
Name of contact:
Associate Professor Jonathan Shaw
Email/Phone no. of contact:
NHMRC Research Achievements - SUMMARY
jonathan.shaw@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 279408
CIA Name: Prof Jonathan Golledge
Admin Inst: James Cook University
Main RFCD: Surgery
Total funding: $299,250
Start Year: 2004
End Year: 2006
Grant Type: NHMRC Project Grants
Title of research award:
Role of osteoprotegerin in protecting the diabetic aorta from aneurysm formationRole of osteoprotegerin in
protecting the diabetic aorta from aneurysm formation
Lay Description (from application):
Between 5% and 10% of men over the age of 60 years develop weakening of their main abdominal artery
(aorta) leading to slow dilation of the vessel. If this process continues long term the artery can burst resulting in
sudden death. At present the only treatment available for this problem is surgery, either open or minimally
invasive. Both these forms of treatment are associated with significant complications and unsuitable for some
patients. Thus the development of a drug treatment which can slow or halt the weakening and dilation of the
aorta would have great patient benefits'. Surprisingly patients with sugar diabetes are less likely to develop this
form of artery weakening. This important negative association may form the basis of discovering a new
medication to protect arteries from rupture. In this study we investigate the role of a recently discovered
protein in protecting the main abdominal artery from weakening in diabetics. This protein is of particular
interest for the following reasons: 1. It comes from a group of proteins believed to be important in artery
calcium build-up. 2. Artery calcium is common in patients with diabetes who are relatively protected from
aortic weakening. 3. It is being used for the treatment of bone weakening, appears to be safe in patients and
therefore is a potential therapeutic agent. We believe this work is an important step towards the development
of a successful medical treatment for artery weakening.
Research achievements (from final report):
Abdominal aortic aneurysm affects approximately 5% of the middle aged and elderly population and can result
in sudden death due to rupture of the main abdominal artery. In this project we have investigated the role of a
bone protein in artery weakening. By examining human biopsies, serum samples and experimental models we
have demonstrated a significant association of this bone protein in the presence, growth and functional changes
seen in artery weakening. The project thereby suggests a potential target for medical therapy for this condition.
Expected future outcomes:
Therapies aimed at bone proteins may have a role in the medical therapy of abdominal aortic aneurysm. Future
studies involving treatments which interfere with the presence of bone proteins need to be examined in models
of aortic aneurysm.
Name of contact:
Professor Jonathan Golledge
Email/Phone no. of contact:
jonathan.golledge@jcu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 379600
CIA Name: Prof Jonathan Golledge
Admin Inst: James Cook University
Main RFCD: Surgery
Total funding: $427,398
Start Year: 2006
End Year: 2008
Grant Type: NHMRC Project Grants
Title of research award:
Interaction of Angiotensin II and PPARg in aortic aneurysm formationInteraction of Angiotensin II and PPARg
in aortic aneurysm formation
Lay Description (from application):
Between 5% to 10% of men and 1% of women over the age of 60 years develop weakening of their main
abdominal artery leading to slow dilation of the vessel. If this process continues long term the artery can burst
resulting in sudden death. At present the only treatment available for this problem is surgery, either open or
minimally invasive. Both these forms of treatment are associated with significant complications and unsuitable
for some patients. Thus the development of a drug treatment which can slow or halt the weakening and dilation
of the aorta would have great patient benefits. We have identified an important role for a newly discovered
protein in weakening of the abdominal aorta. In this study we investigate the role of a pathway which appears
to be fundamental in generating this protein. In particular we will assess the role of drug treatment in blocking
this pathway as a basis for medical treatment for artery weakening.
Research achievements (from final report):
In this study we assessed and supported the potential value of a therapeutic pathway for abdominal aortic
aneurysm based on experimental and in vivo work. The work has led to a number of publications and further
successful grant applications.
Expected future outcomes:
We found a negative association between HDL and human abdominal aortic aneurysm (AAA). We also linked
obesity with AAA. These studies may be very important for identifying novel treatments and medications for
AAA based on the lipid lowering drugs used widely in cardiovascular medicine.
Name of contact:
Jonathan Golledge
Email/Phone no. of contact:
Jonathan.Golledge@jcu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 431503
CIA Name: Prof Jonathan Golledge
Admin Inst: James Cook University
Main RFCD: Surgery
Total funding: $300,387
Start Year: 2007
End Year: 2011
Grant Type: Established Career Fellowships
Title of research award:
Practitioner FellowshipPractitioner Fellowship
Lay Description (from application):
I am a vascular surgeon. My research is centred on the following problems relevant to my patients: 1. The
management of aortic aneurysm. 2. The management of occlusive atheroma, particularly unstable atheroma,
aortic calcification, intermittent claudicati
Research achievements (from final report):
The work of this fellowship has been focused on improving understanding of artery weakening. The fellow,
working with a team of researchers, has undertaken work using a range of novel methods and tools to identify
pathways, circulating markers, genes and potential treatment targets relevant to improving the clinical
management of artery weakening. The work has highlighted the potential of a number of medications in
limiting artery weakening, some of which are now being investigated in clinical trials.
Expected future outcomes:
The work undertaken in this fellowship is expected to form a platform for future work which leads to
improvements in the understanding of aortic aneurysm thereby fostering new prognostic models, diagnostics
and treatments for patients with aortic aneurysm.
Name of contact:
Jonathan Golledge
Email/Phone no. of contact:
Jonathan.Golledge@jcu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 540403
CIA Name: Prof Jonathan Golledge
Admin Inst: James Cook University
Main RFCD: Surgery
Total funding: $457,779
Start Year: 2009
End Year: 2011
Grant Type: NHMRC Project Grants
Title of research award:
Role of the tissue kallikrein-kinin system in abdominal aortic aneurysm formation and progressionRole of the
tissue kallikrein-kinin system in abdominal aortic aneurysm formation and progression
Lay Description (from application):
Up to 5% of people over 60 years develop weakening of their aorta leading to slow dilation of the vessel,
which may burst resulting in sudden death. The only treatment is surgery, which has complications and is
unsuitable for some patients. Drugs which slow the disease would be invaluable. We have identified a role for
kinins in aneurysms. We will investigate how these molecules contribute to aortic disease and if blocking them
can be used as a basis for medical treatment of artery weakening.
Research achievements (from final report):
The purpose of this work was to determine the role of certain receptor types in promoting the aortic dilatation
in abdominal aortic aneurysm (AAA). The work has identified a causative link between receptor stimulation or
antagonism and the corresponding progression or inhibition of aortic dilatation. We have also investigated the
effects and relative importance of a range of inflammatory pathways leading to AAA within a mouse model.
These findings suggest the model used has good comparability to human AAA. In addition, we have completed
genotyping of genetic polymorphisms and found an association between one specific polymorphism and large
AAA presence. A manuscript regarding this work has recently been published in the journal Atherosclerosis.
We have also recently had published a manuscript describing the association of one biomarker with AAA.
Expected future outcomes:
Work is still on-going as part of a PhD and at this stage it is too early to tell.
Name of contact:
Jonathan Golledge
Email/Phone no. of contact:
jonathan.golledge@jcu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 540404
CIA Name: Prof Jonathan Golledge
Admin Inst: James Cook University
Main RFCD: Surgery
Total funding: $514,777
Start Year: 2009
End Year: 2013
Grant Type: NHMRC Project Grants
Title of research award:
Association between obesity, TGFb, thrombospondin and small abdominal aortic aneurysm
progression.Association between obesity, TGFb, thrombospondin and small abdominal aortic aneurysm
progression.
Lay Description (from application):
Abdominal aortic aneurysm (AAA) is an important cause of mortality in middle aged and elderly Australians.
The incidence of AAA continues to increase despite improvements in the medical management of
atherosclerosis. We postulate that obesity is important in the progression of AAA. In a community screening
study we found that waist-hip ratio was independently associated with AAA. In this project we investigate the
mechanisms underlying this association between obesity and AAA.
Research achievements (from final report):
This project focussed on the role of obesity and transforming growth factor beta in the development and
progression of artery weakening. This project has identified a number of important findings relevant to artery
weakening. A number of genes related to the transforming growth factor pathway have been associated with
aneurysm development including thrombospondin-1, transforming growth factor receptor 2, low density
lipoprotein-related protein-1, a variant on chromosome 9 and latent transforming growth factor-4. We have
associated circulating homocysteine with artery weakening. We studied the association of visceral obesity with
aneurysm presence and progression through designing a novel method of thresholding aorto-iliac computed
tomography angiograms. Importantly obesity does not appear to be an important risk factor for artery
weakening, as oppossed to artery disease in general, suggesting this is not a good target for therapies designed
to limit aneurysm development and progression. We also have identified that statins do not appear to be an
effective therapy to limit aneurysm progression through the development of a collaborative cohort of patients
with small aortic aneurysms. The development of new techniques, new models and a patient cohort with artery
weakening will facilitate future studies of aneurysm pathogenesis and studies designed to exam new drug
therapies for aortic aneurysm. This cohort has also enabled the identification of a number of important and
novel risk factors for mortality and cardiovascular events in patients with peripheral vascualr disease such as
serum thrombospondin-2 and chronic kidney disease. We have also identified new methods, such as aortic
volume, for sensitively monitoring aneurysm growth.
Expected future outcomes:
Through studies performed as part of this project we have identified a cohort of patients with small aortic
aneurysms suitable for future investigation of medical therapies designed to limit aneurysm progression. We
have also established rodent models for further investigation of novel drug targets to limit aneurysm
develpment. We have established methods to analyse fat volumes on CTs.
Name of contact:
Jonathan Golledge
Email/Phone no. of contact:
jonathan.golledge@jcu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 540405
Start Year: 2009
CIA Name: Prof Jonathan Golledge
End Year: 2011
Admin Inst: James Cook University
Grant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $332,162
Title of research award:
Angiopoietin-2, aortic inflammation and cardiovascular eventsAngiopoietin-2, aortic inflammation and
cardiovascular events
Lay Description (from application):
Based on detailed preliminary data, we plan to investigate the importance of a novel protein (the cytokine
angiopoietin-2) in cardiovascular disease. The results of this study will clarify the role of this cytokine in
vascular pathology and may provide an important target for novel therapy and/or diagnostic markers for
cardiovascular disease progression.
Research achievements (from final report):
The aim of the work was to assess the effects of a specific protein on the progression of atherosclerosis.
Contrary to our original hypothesis, we have found that the protein of interest inhibits the progression of
atherosclerosis and anuerysm formation. We have also assessed human biopsies taken from patients with
abdominal aortic aneurysm (AAA) and demonstrated a novel association between a specific cytokine and
AAA. In addition, our related studies have emphasised the likely importance of calcification involving the
abdominal aorta in predicting cardiovascular events.
Expected future outcomes:
Work is still on-going as part of a PhD and at this stage it is too early to tell.
Name of contact:
Jonathan Golledge
Email/Phone no. of contact:
jonathan.golledge@jcu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 540409
Start Year: 2009
CIA Name: Prof Geoffrey Dobson
End Year: 2013
Admin Inst: James Cook University
Grant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $489,635
Title of research award:
Towards a new normokalemic arrest paradigm for orthotopic heart transplantationTowards a new
normokalemic arrest paradigm for orthotopic heart transplantation
Lay Description (from application):
Innovations from Nature to Heart Transplantation:a Real Heart Stopper Heart preservation is limited to 4-6
hours of cold-ischaemic storage (0 to 4 C). The risk of post-transplant death doubles if the donor heart is stored
from 1 to 5 hours, and triples with 7 hrs storage times. We have developed a new preservation solution
borrowing from natural hibernators that will permit organs to be safely stored for up to 15 hours, and offering
new opportunities to organ donors and recipients worldwide.
Research achievements (from final report):
The current safe cold storage times for the human heart for transplantation is 4 to 5 hours. Our work has the
potential to extend these safe times to 8 hours and possibly 16 and 24 hours and thus permit increase the
availability of donor hearts from greater distances and the use of marginal hearts. We further developed new
ways to reduce ischemia-reperfusion injury during reanimation after cold or warm storage of hearts. This
period is the most vulnerable to injury and can lead to post-transplant rejection. Our technology has global
significance to arrest, protect and preserve the donor heart, and possibly other cells, tissues and organs for
human donor-recipient transplantation, including stem cells. A research team in Canada recently examined our
polarized concept of heart reanimation in the pig and showed that after cardiocirculatory death ex-vivo
perfusion with our solution minimized myocardial injury and improved short-term post-transplant function.
The CIA has presented this work in a number of keynote addresses in the USA at the American Academy of
Cardiovascular Perfusionists and Grand Rounds.
Expected future outcomes:
Future work includes clinical translation of the heart preservation solution into human use, as has been
successfully carried out for the world's first polarizing cardioplegia. This work includes kidney and lung
preservation with surgeons at Univ. of Arizona, USA and Verona, Italy. Preservation of stem cells is also being
investigated to enhance their therapeutic potential and improved viability.
Name of contact:
Geoffrey Dobson
Email/Phone no. of contact:
geoffrey.dobson@jcu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 540419
CIA Name: Prof Natkunam Ketheesan
Admin Inst: James Cook University
Main RFCD: Infectious Diseases
Total funding: $374,817
Start Year: 2009
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
Determination of Disease Specific Epitopes in Rheumatic Heart Disease in AustraliaDetermination of Disease
Specific Epitopes in Rheumatic Heart Disease in Australia
Lay Description (from application):
Rheumatic Fever and Rheumatic Heart Disease (RF-RHD) remain a significant cause of illness in Aboriginal
communities in Australia. RF-RHD is a complication which follows infection with a specific bacterium. The
purpose of this study is to compare the body's response and find out the patterns of antibody and immune cell
reactivity to the bacterium and body proteins in RF-RHD patients and controls. It will also enable us to study
the mechanisms that initiate the disease process.
Research achievements (from final report):
Rheumatic Fever and Rheumatic Heart Disease (RF/RHD) are chronic diseases. It is a serious problem in the
developing world among children and young adults and also affects Indigenous communities of tropical
Australia. The highest prevalence rates of RHD in the world have been observed among the Indigenous people.
RF/RHD is initiated by an infection caused by bacteria known as streptococci. In RF/RHD the heart is
damaged irreversibly. This is due to the fact that our body's own immune response against the infection also
starts attacking the heart tissue due to the similarities between the structure of the bacteria and the proteins
known as cardiac myosin in the heart. We have shown that one of the body's immune system components
known as antibodies that are formed during the infection against the bacteria also reacts with a specific part of
the cardiac myosin protein. This reaction could be used as a marker for disease reactivity. We also found that
these antibodies can interact with the cells of the blood vessel and heart valves and trigger the changes in the
heart. Indigenous capacity building was an integral part of the project and we have trained a James Cook
University Indigenous Medical Student under the National Indigenous Cadetship Programme (NICP). The
cadet successfully concluded her programme and is in the final year of the medical studies.
Expected future outcomes:
We have linked with the Queensland wide RHD Register Programme team which has given us the opportunity
to continue with the project in Australia. To further validate the project a study has been initiated in India. We
are also investigating the effect of various streptococci in triggering RF/RHD using a laboratory model
supported by a grant from the NHMRC.
Name of contact:
Natkunam Ketheesan
Email/Phone no. of contact:
n.ketheesan@jcu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1016349
Start Year: 2011
CIA Name: Dr Sai Wang Seto
End Year: 2012
Admin Inst: James Cook University
Grant Type: International Exchange Early Career
Fellowships
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $189,401
Title of research award:
An investigation of the involvement of clotting factors in abdominal aortic aneurysm (AAA) progression
within a mouse modelAn investigation of the involvement of clotting factors in abdominal aortic aneurysm
(AAA) progression within a mouse model
Lay Description (from application):
Early stage weakening of the main abdominal artery is present in ~100,000 Australians and currently has no
accepted therapy. Development of drug therapies which limit progression of the weakening process is urgently
needed. In this study involvement of the clotting cascade in artery weakening will be investigated. The study
have been planned in order to identify new strategies which can be developed as treatments for artery
weakening in patients.
Research achievements (from final report):
Weakening of the main abdominal artery (abdominal aortic anenrysm (AAA)), is an age-related lethal disease
which affect ~5% of men and ~1% of woman, leading to ~1,000 deaths and ~2,500 operations per year in
Australia. Currently surgical therapies are the only available treatments for AAAs which have been shown to
be inappropriate for majority of AAAs and ~50% of cases expand progressively to a size at which aortic
reputure is a concern. One of the characteristic of AAA is the present of thrombus . This study provided
detailed study on the roles of the major clotting factors which present in the thrombus on AAA development
using a mouse model. Our results identified that clotting factor (FXa), but not FIIa, contributes significantly in
AAA development. Moreover, we demonstrated that fondaparniux (a specfic FXa inhibitor) suppressed AAA
progression in the mouse model. Fondaparniux significantly reduced expression of vairous inflammatory
markes in AAA. Putting these together, our reults identified a novel pathway/mechanism for AAA progression.
Given the fact that there is not effective drug is available for AAA currently, our reuslt also suggesting that
fondaparniux could be a pontential drug therapy to limit AAA and other arterial diseses in patients.
Expected future outcomes:
Our current data has provided novel findings to advance current management deficiencies for AAA by
identifying a potential therapy for this disease. Futher work using additional strains of knockout mouse and
human explant culture are being conducted to consolidate our findings and translating this potential therapy to
clincial setting.
Name of contact:
Sai-Wang Seto
Email/Phone no. of contact:
saiwang.seto@jcu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 217011
CIA Name: A/Pr Richard Weisinger
Admin Inst: La Trobe University
Main RFCD: Basic Pharmacology
Total funding: $558,000
Start Year: 2002
End Year: 2006
Grant Type: Established Career Fellowships
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
Each year, cardiovascular disease kills around 40,000 Australians, accounting for about 40% of all mortality.
Hypertension is the single most important risk factor for cardiovascular disease. In work published Nature
Medicine(2001), I showed that rats maintained on an omega-3 PUFA deficient diet in the perinatal period
(conception to 9 weeks of age) had raised blood pressure. Increased blood pressure occurred even when the rats
were subsequently (9 to 33 weeks of age) fed a diet containing omega-3 fatty acids, whereby levels of omega-3
PUFA in the brain were restored. The results suggested that the provision of omega-3 PUFA early in life is
necessary for normal development and function of the systems that regulate body fluid and cardiovascular
homeostasis. The results also suggested that fatty acid levels in the brain were determined by the contemporary
diet. My hypothesis is that failure to obtain an adequate supply of omega-3 fatty acids, during a critical period
early in life, results in abnormal central control of blood pressure., With funding from the NHMRC (NHMRC
Project Grant 350313), I have:, identified diet-related changes in brain composition, and its effects on
development and disease. In light of the problems that hypertension and heart disease pose to our society, the
results of this work have the potential to bring about changes in nutritional advice, dietary supplementation,
infant formula composition and counselling, particularly for those with a family history of hypertension and
cerebrovascular or cardiovascular disease.
Expected future outcomes:
My work has identified the gene and brain composition changes by which supply of omega-3 fatty acids during
the perinatal period impacts on the health of offspring. I have also shown that providing adequate dietary
omega-3 fatty acids to the elderly assists in ameliorating life threatening disturbances in body fluid
homeostasis. I plan in the future to identify the mechanisms whereby these occur.
Name of contact:
Dr. Richard S. Weisinger
Email/Phone no. of contact:
r.weisinger@latrobe.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 234420
CIA Name: Prof Graham Lamb
Admin Inst: La Trobe University
Main RFCD: Cell Physiology
Total funding: $315,375
Start Year: 2003
End Year: 2005
Grant Type: NHMRC Project Grants
Title of research award:
Aberrant behaviour of cardiac calcium release channels induced by ryanodine receptor peptide probesAberrant
behaviour of cardiac calcium release channels induced by ryanodine receptor peptide probes
Lay Description (from application):
Contraction of heart muscle is regulated by the release of calcium ions from an intracellular store known as the
sarcoplasmic reticulum. Calcium is released from this store to trigger contraction and then taken up again to
let the heart muscle relax. Calcium flows out from the store through a specialised type of ion channel protein
known as the ryanodine receptor. Recently, genetic studies have indicted that some forms of sudden cardiac
death are due to mutations in the ryanodine receptor in the heart of susceptible individuals. However, nothing
is currently known about how such mutations affect the function of the ryanodine receptor or how this can
cause the abnormal heart beating that leads to sudden cardiac death. This project will investigate the normal
functioning of the ryanodine receptor and what aberrations occur with the different mutations. This could lead
to better treatment of individuals susceptible to this type of sudden cardiac death. The effectiveness of one
type of drug in preventing aberrant channel behaviour will also be examined.
Research achievements (from final report):
This project investigated the molecular basis of the dysfunction that can occur in important ion channels inside
heart cells. These ion channels, so-called calcium release channels, regulate the release of calcium ions from
internal stores within the heart cells, which in turn triggers heart contraction and pumping of blood. In some
susceptible individuals, these ion channels malfunction, which leads to calcium leaking from the stores into the
heart cell during the normal resting phase of a heart beat. Such calcium leak can trigger abnormal electrical
activity in the heart cells and disrupt the normal heart rhythm, leading to sudden cardiac death. The present
project showed that addition of synthetic proteins mimicking particular segments of the normal ion channel
disrupted the normal function of the channel and made it leaky. This demonstrated that the ion channel is
normally stabilised in the closed position by binding interactions between particular sub-regions within the
channel protein, and that individuals with ion channel mutations in these regions have channels that lack the
normal stabilising interactions and hence are abnormally leaky and prone to trigger abnormal electrical activity
in the heart. With this understanding it may be possible to develop specific drugs to rectify this channel
leakiness and thereby help reduce the chance of sudden cardiac death in the susceptible individuals.
Expected future outcomes:
The findings should lead to an improved understanding of how the calcium release channels in heart normally
function at the molecular level, what can go wrong in susceptible individuals and in heart disease, and help
direct future therapeutic strategies for treating this.
Name of contact:
Professor Graham Lamb
Email/Phone no. of contact:
g.lamb@latrobe.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 280623
CIA Name: Prof Graham Lamb
Admin Inst: La Trobe University
Main RFCD: Cell Physiology
Total funding: $687,750
Start Year: 2004
End Year: 2008
Grant Type: NHMRC Project Grants
Title of research award:
Mechanisms regulating excitation-contraction coupling in skeletal muscleMechanisms regulating excitationcontraction coupling in skeletal muscle
Lay Description (from application):
Muscle contraction occurs when an electrical impulse from a nerve travels over the surface of a skeletal muscle
fibre and triggers the release of calcium ions from special stores inside the fibre. However, little is known
about the regulatory mechanisms involved in turning on and turning off the calcium release. This project
investigates the properties of the calcium release and what processes are involved in regulating it. Information
about this is vital for understanding how normal muscle works and why muscles show reduced performance
with exercise (muscle fatigue), with aging, and in certain diseases.
Research achievements (from final report):
This study was aimed at identifying and characterising the mechanisms causing muscle fatigue and weakness
in skeletal muscle, both after exercise and in certain muscle diseases. One major finding was that, contrary to
common perceptions, increased intracellular acidity actually counters rather than causes muscle fatigue,
because it reduces chloride leakiness of the muscle cell membrane, thereby helping the muscle fibre stay
electrically excitable despite intensive use. The study also identified how of reduction of energy stores, and
accumulation of particular metabolic byproducts such as inorganic phosphate, lead to muscle fatigue with
intense or prolonged exercise. The study also showed how long term muscle fatigue or weakness can arise due
to damage of structures and criticial signalling mechanisms within muscle fibres following periods of excessive
exercise, such as with downhill walking. The deficit likely arises due to activation of specific proteases that
break down other proteins inside the muscle fibres. The proteases become active owing to excessive release of
calcium ions from intracellular stores or excessive entry of calcium ions into the cells, particularly in some
types of muscular dystrophy. Muscle dysfunction was also shown to be caused by the action of excessive levels
of 'oxygen radicals'. A separate finding was how acute creatine intake affects muscle performance, which was
relevant to the widespread practice by body-builders and some sports people of taking creatine supplements.
Expected future outcomes:
The findings should lead to better understanding of muscle fatigue and weakness, and possibly help identify
treatments that could be beneficial.
Name of contact:
Professor Graham Lamb
Email/Phone no. of contact:
g.lamb@latrobe.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 350313
CIA Name: A/Pr Richard Weisinger
Admin Inst: La Trobe University
Main RFCD: Systems Physiology
Total funding: $280,650
Start Year: 2005
End Year: 2007
Grant Type: NHMRC Project Grants
Title of research award:
Mechanisms responsible for hypertension caused by perinatal omega-3 fatty acid deficiencyMechanisms
responsible for hypertension caused by perinatal omega-3 fatty acid deficiency
Lay Description (from application):
Does the nourishment we receive as babies, or even before birth, affect our adult health? The recent findings
from Barker, Meaney, Langley-Evans and their co-workers, has established that intra-uterine and early postnatal factors, particularly nutrition, influence adult neural development and cardiovascular function. It appears
that the dietary intake of omega-3 fatty acids in early life may be a critical factor in the development of
hypertension. We reported (Nature Medicine 2001, 7: 258-259) for the first time that the essential omega-3
fatty acid, alpha-linolenic acid (ALA), supplied in the early developmental period, affects blood pressure later
in life. The work showed that moderate omega-3 fatty acid deficiency in the perinatal period resulted in
hypertension, despite reversal of the deficiency at a time months before the assessment of blood pressure.
These findings are suggestive of a critical period, during which time the development of normal blood pressure
control mechanisms appears, at least partially, dependent upon the supply of omega-3 fatty acids. These
findings suggest that omega-3 deficiency early in life may affect fatty acid metabolism, transport or uptake
systems, such that re-feeding of the nutrients is functionally ineffective. Alternatively, deficiency of omega-3
fatty acids early in life may arrest development of one or more of the key signalling pathways in the control of
blood pressure, such as the Brain Angiotensin System. The influence of dietary omega-3 fatty acid supply,
relative to the critical period, on expression of genes involved in the control of blood pressure as well as in
fatty acid metabolism, will be defined. Also, the role of the brain angiotensin system in omega-3 fatty acid
deficiency-induced hypertension will be determined. We expect that the results of this study will profoundly
affect hypertension research, as well as nutrition, particularly that for infants.
Research achievements (from final report):
We have found that there is a significant up-regulation of genes in the brain related to hypertension following
implementation of an omega-3 polyunsaturated fatty acid deficient dietary regime at an early age, prior to any
observable hypertension. When hypertension did develop, later in life, there were changes observed in different
neurotransmitter systems in the brain. This indicates that prenatal omega-3 PUFA deficiency has profound
effects on both brain neurotransmission and its control of the cardiovascular system.
, We also
analysed brain phospholipid fatty acid composition of animals fed diets either prenatally sufficient or deficient
in omega-3 polyunsaturated fatty acids. Our results confirmed previous reports of significantly lower levels of
long chain omega-3 polyunsaturated fatty acids, particularly DHA, in the brain tissue of prenatally deficient
animals compared to the animals on sufficient diets. Also, animals maintained on the deficient diet have higher
levels of long chain omega-6 polyunsaturated fatty acids suggesting a shift in membrane composition. We
identified that when supply of omega-3 polyunsaturated fatty acids was provided later in life this
predominantly restored brain omega-3 fatty acid levels. However, some changes in membrane composition
remained, as did the hypertension., Finally we found that antagonism of the renin-angiotensin system reduces
the hypertension that occurs with insufficient supply of omega-3 PUFA. Specifically, we found that an
angiotensin converting enzyme inhibitor could reverse the hypertension effects of lifelong omega-3
polyunsaturated fatty acid deficiency. This work has implication for future trends in nutritional advice, and the
treatment and prevention of hypertension and cardiovascular disease.
Expected future outcomes:
The results of this project have the uncovered potential mechanisms responsible for hypertension in omega-3
fatty acid deficiency which may bring about changes in nutritional advice, dietary supplementation, infant
formula composition and counselling, particularly for those with a family history of hypertension and
cerebrovascular or cardiovascular disease.
NHMRC Research Achievements - SUMMARY
Name of contact:
Richard Weisinger
Email/Phone no. of contact:
R.Weisinger@latrobe.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 487311
Start Year: 2008
CIA Name: Dr Hamsa Puthalakath
End Year: 2011
Admin Inst: La Trobe University
Grant Type: NHMRC Project Grants
Main RFCD: Cell Development (incl. Cell Division and Apoptosis)
Total funding: $558,189
Title of research award:
DETERMINING THE ROLE OF ER STRESS INDUCED APOPTOSIS IN THYMIC NEGATIVE
SELECTIONDETERMINING THE ROLE OF ER STRESS INDUCED APOPTOSIS IN THYMIC
NEGATIVE SELECTION
Lay Description (from application):
Apoptosis is an evolutionarily conserved mechanism for killing unwanted cells that are no longer needed,
damaged, infected with pathogens or dangerous. Defects in apoptosis can cause a number of diseases. For
example, abnormal survival of cells can cause cancer or autoimmune disease. Bim is a protein that induces
apoptosis and act as a barrier against cancer and autoimmune diseases. This work is aimed at understanding
how Bim acts as a barrier against the development of autoimmunity.
Research achievements (from final report):
This project was aimed at understanding the role of ER stress in thymic negative selection. Understanding the
molecular mechanism of this process would have profound implications for the wider understanding of how
auto-immunity develops. However, soon after the project started, our results clearly showed that ER stress did
not have any role in determining the outcome of thymic selection. Instead, we found that it was the
transcription factor c-Myc that regulated the cell death process during thymic selection. Subsequently, our
effort was focused towards understanding the molecular mechanism of c-Myc induced apoptosis. Our results
clearly demonstrate that c-Myc together with the co-factor CBP regulates the apoptosis process by inducing
epigenetic modifications at the bim locus which, in turn, regulates the apoptosis mechanism. To better
understand this in an in vivo system, we generated a knock-in mouse model where c-Myc biding sites on the
bim promoter are mutated. Analysis of the cells from these mouse showed that bim expression was muted in
these cells and they don't respond to stress hormones such as beta-adrenergic catecholamines. These findings
have implications for understanding the molecular basis of the stress-induced diseases in humans i.e.
cardiomyopathy and immune deficiency. Furthermore, we are in the process of designing a high throughput
screening strategy for developing drugs that can counter the apoptosis process.
Expected future outcomes:
Through this project, though we did not achieve the initial objective, we have been able to understand the
molecular basis of two major human diseases i.e. cardiomyopathy and immune deficiency. We are in the
process of validating our findings in in vivo models and developing therapeutic drugs against these.
Name of contact:
Hamsa Puthalakath
Email/Phone no. of contact:
h.puthalakath@latrobe.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 280903
Start Year: 2004
CIA Name: A/Pr Marc Achen
End Year: 2008
Admin Inst: Ludwig Institute for Cancer Research Grant Type: Established Career Fellowships
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $602,500
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
The lymphatic vasculature is a network of vessels throughout the body that is critical for tissue fluid balance,
immune function and absorption of dietary fat. Despite these essential functions, and the central role of the
lymphatics in lymphoedema and the metastatic spread of cancer, little is known about the molecular control of
the lymphatic vessels. During the course of my NHMRC Fellowship, my team established the biological
function of a protein, called VEGF-D, that regulates the growth of lymphatic vessels (lymphangiogenesis). We
showed that VEGF-D modulates the abundance and function of lymphatic vessels in different tissues in adults.
Further, we identified enzymes that activate VEGF-D and are key regulators of lymphangiogenesis. In
collaborative studies, we characterized key signalling pathways that drive the growth of the lymphatic
vasculature during embryogenesis, and we validated viral-based strategies for delivery of lymphangiogenic
molecules in disease settings. These studies have identified numerous cell surface and secreted molecules
which could be useful targets for novel therapeutics designed to block the metastatic spread of cancer via the
lymphatics. In addition, these studies have defined novel approaches for therapeutically driving angiogenesis
and lymphangiogenesis for treatment of cardiovascular diseases and lymphoedema. Finally, it was pleasing that
some of our discoveries have progressed in clinical development, most notably an adenoviral vector encoding
VEGF-D that is currently in a phase III clinical trial in the USA to test its ability to enhance the patency of
vascular access grafts that facilitate dialysis for end-stage renal patients.
Expected future outcomes:
Expected future outcomes from this work are:, i) enhanced understanding of lymphatic function in health and
disease, ii) novel treatments for metastatic cancer and agents to prevent metastasis, iii) novel therapeutic
approaches for lymphoedema and cardiovascular diseases , iv) a novel molecular-based approach to enhance
the patency of vascular access grafts
Name of contact:
Associate Professor Marc Achen
Email/Phone no. of contact:
Marc.achen@ludwig.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 266800
Start Year: 2004
CIA Name: A/Pr Denise Jackson
End Year: 2008
Admin Inst: Macfarlane Burnet Institute for Medical Research and Public Health
Established Career Fellowships
Main RFCD: Pathology
Total funding: $549,750
Grant Type:
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
Research Achievements include: Immunoreceptors 1). Identified that PECAM-1-regulated signalling
thresholds control peripheral tolerance in B-cells; 2). Defined that a deficiency of PECAM-1 is sufficient to
alter in vitro and in vivo T cell function including negative selection of double positive thymocytes; 3).
Identified that CEACAM1 serves as a negative regulator of platelet-collagen interactions and thrombus growth
in vitro and in vivo; 4). Identified that PECAM-1 regulates Salmonella typhimurium infection in vivo; 5).
Defined that PECAM-1 regulates the 'outside-in' signalling properties of integrin alphaIIbbeta3 in murine
platelets; 6). Defined that palmitoylation of PECAM-1 at Cys595 is essential for PECAM-1 localisation into
membrane microdomains and for efficient PECAM-1-mediated cytoprotection; and 7). Defined that
CEACAM1 regulates the 'outside-in' signalling properties of integrin alphaIIbbeta3 in murine platelets., Other
research achievements include: Tetraspanins: 1). Defining that the haematopoietic specific tetraspanin, TSSC6
regulate the 'outside-in' signalling properties of integrin alphaIIbbeta3 in murine platelets and thrombus
stabilisation in vivo; 2). Defined that CD151 plays an essential role in platelet thrombus stabilisation and
embolisation in vivo; and 3). Identified a relationship between CD151 and P2Y12 signalling pathway that
involves Erk-1/2 and released ADP/thromboxane generation.
Expected future outcomes:
This research defines the importance of contact-dependent regulation of thrombogenesis mediated by
immunoreceptors including PECAM-1 and CEACAM1., This research defines the importance of plateletplatelet interactions mediated by tetraspanins, CD151 and TSSC6 in regulating platelet thrombus formation and
stability., It highlights the importance of immunoreceptors in infection and immunity.
Name of contact:
A/Prof. Denise Jackson
Email/Phone no. of contact:
djackson@burnet.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 315403
Start Year: 2005
CIA Name: A/Pr Denise Jackson
End Year: 2007
Admin Inst: Macfarlane Burnet Institute for Medical Research and Public Health
NHMRC Project Grants
Main RFCD: Haematology
Total funding: $469,500
Grant Type:
Title of research award:
Understanding how tetraspanin superfamily members modulate platelet functionUnderstanding how tetraspanin
superfamily members modulate platelet function
Lay Description (from application):
Platelets are small cells in the blood stream that play an important role in preventing excessive blood loss at
sites of tissue injury by sticking together and forming a haemostatic plug. Excessive platelet clumping in
diseased blood vessels can lead to blockages and cause thrombotic diseases such as heart attack and stroke, two
of the biggest killers of humans in the western world. In this proposal, we will seek to understand how
tetraspanin superfamily members expressed on the surface of platelets modulate the function of the major
platelet integrin, integrin alphaIIbbeta3 and the low-affinity IgG receptor, FcgammaRIIa. This aims of this
work will define the roles of these receptors in platelet clumping both in cell-based assays and in mouse models
of thrombosis. This work could lead to new strategies for therapeutic management of thrombotic disorders.
Research achievements (from final report):
We have identified a novel signaling pathway involving tetraspanin CD151 linked to signaling molecule Erk1/2 in platelets., We have shown the first genetic evidence that CD151 and TSSC6 regulates the 'outside-in
signaling properties of integrin alphaIIbbeta3 in platelets. , We have demonstrated that CD151 and TSSC6
regulate thrombus stability with CD151 affects the primary stability of arterial thrombi in vivo upon vascular
injury, while TSSC6 affects the secondary stability of arterial thrombi in vivo upon vascular injury.
Expected future outcomes:
Our studies provide a new insight into the functional role of tetraspanins in platelet function which was
previously undefined. Our work provides the first evidence that tetraspanins serve an essential role to regulate
the major platelet integrin alphaIIbbeta3 to regulate clot stability in vivo.
Name of contact:
A/Prof. Denise Jackson
Email/Phone no. of contact:
djackson@burnet.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 365200
Start Year: 2006
CIA Name: A/Pr Denise Jackson
End Year: 2008
Admin Inst: Macfarlane Burnet Institute for Medical Research and Public Health
NHMRC Project Grants
Main RFCD: Haematology
Total funding: $522,773
Grant Type:
Title of research award:
The anti-thrombotic potential of immunoreceptors in platelet thrombus formationThe anti-thrombotic potential
of immunoreceptors in platelet thrombus formation
Lay Description (from application):
Platelets are small cells in the blood stream that play an important role in preventing excessive blood loss at
sites of tissue injury by sticking together and forming a haemostatic plug. Excessive platelet clumping in
diseased blood vessels can lead to blockages and cause thrombotic diseases such as heart attack and stroke, two
of the biggest killers of humans in the western world. In this proposal, we will seek to understand how
immunoreceptors expressed on the surface of platelets modulate the function of platelet collagen interactions
involving collagen GPVI receptor, the low affinity IgG receptor, FcgammaRIIa and the major platelet integrin,
integrin alphaIIbbeta3. The aims of this work will define the role of these receptors in platelet aggregation
both in cell-based assays and in mouse models of thrombosis. This work could lead to new strategies for
therapeutic management of thrombotic disorders.
Research achievements (from final report):
Major Achievements: 1.
Defined that palmitoylation of
cysteine 595 in PECAM-1 is required for constitutive association to membrane microdomains and PECAM-1mediated cytoprotection, where it may act as a crucial regulator of signalling and apoptosis events., 2.
Defined that CEACAM1 may act as a
negative regulator of platelet-collagen interactions and thrombus growth in vitro and in vivo., 3.
Identified
impaired 'outside-in' integrin alphaIIbbeta3 signaling in platelets of CEACAM1-deficient mice., 4.
Demonstrated that PZR negatively
regulates FcgammaRIIa-mediated signalling in human platelets.4.
Demonstrated that PZR negatively
regulates FcgammaRIIa-mediated signalling in human platelets.
Expected future outcomes:
This research defines the importance of contact-dependent regulation of thrombogenesis mediated by
immunoreceptors including PECAM-1 and CEACAM1.
Name of contact:
A/Prof. Denise Jackson
Email/Phone no. of contact:
djackson@burnet.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 434109
Start Year: 2007
CIA Name: Prof David Power
End Year: 2009
Admin Inst: Macfarlane Burnet Institute for Medical Research and Public Health
NHMRC Project Grants
Main RFCD: Nephrology and Urology
Total funding: $531,697
Grant Type:
Title of research award:
Protein kinases regulate salt reabsorption in the kidneyProtein kinases regulate salt reabsorption in the kidney
Lay Description (from application):
This proposal is designed to determine how the kidney senses the level of salt in the body and monitors blood
pressure. This is critical for diseases such as hypertension, kidney and heart failure, where salt is retained
inappropriately. We propose that the kidney uses proteins called kinases that are activated by salt in the kidney.
When it is too low, they detect this and cause the kidney to absorb more salt to correct the deficiency. The way
that they are able to do this has profound implications for human heart and kidney disease, and biology in
general.
Research achievements (from final report):
We have discovered that there is a relationship between the ability of the kidney to control its energy supply
(ie. the "foods" it eats) and the way it handles blood pressure. Retaining salt in the body is a big job for the
kidney, and it uses a lot of energy to do so. When it can't adjust its "diet" to suit the available foods, then it
cannot retain salt as usual. This work shows that food intake and blood pressure are likely to be related at a
very basic level, and could help to explain why some people with so-called metabolic diseases (eg. obesity,
diabetes) cannot control their blood pressure.
Expected future outcomes:
This research will lead to greater interest in the way that the kidney controls blood pressure and regulates its
energy supply. It might lead to useful new approaches to blood pressure management.
Name of contact:
David Power
Email/Phone no. of contact:
david.power@austin.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 434220
CIA Name: Dr Louise Brown
Admin Inst: Macquarie University
Main RFCD: Biophysics
Total funding: $369,003
Start Year: 2007
End Year: 2009
Grant Type: NHMRC Project Grants
Title of research award:
The Structural Basis for the Control of Cardiac and Skeletal Muscle by the Troponin ComplexThe Structural
Basis for the Control of Cardiac and Skeletal Muscle by the Troponin Complex
Lay Description (from application):
Many key physiological processes are controlled by large, multi-protein complexes. These molecular
machines ensure that signals transmitted in the body are correctly interpreted and amplified so as to control key
body functions. The Troponin protein complex is one such large multi-protein complex which is the switch
used to control both heart and skeletal muscle contraction in the body. The Troponin complex responds to
increasing cellular calcium levels, switching the muscle on at high calcium. When calcium returns to its
normal basal level, the Troponin complex switches the muscle off. Naturally occurring genetic errors can lead
to the malfunction of the Troponin complex. This, in turn, can lead to severe and possibly fatal diseases of the
heart and muscle systems. To gain an understanding of these molecular diseases, it is important to understand
the structure, dynamics and function of the Troponin complex. This project will use a newly-developed
magnetic resonance method to monitor changes in the Troponin structure as a function of calcium level. Each
component of the Troponin complex will be labeled with magnetic tags, allowing the determination of both
structure and dynamics of Troponin, both in solution and in active muscle fibres. The study will result in a
molecular understanding of how the Troponin switch works. This will give great insight in how mutations
result in cardiac and muscular diseases.
Research achievements (from final report):
Many key physiological processes in the body are controlled by large, multi-protein complexes. The Troponin
protein complex is one such large multi-protein complex which is the switch used to control both heart and
skeletal muscle contraction in the body. The Troponin complex responds to increasing cellular calcium levels,
switching muscle contraction on at high calcium and off again once calcium levels returns to their normal basal
level. Naturally occurring genetic errors can lead to the malfunction of the Troponin complex and this includes
severe and sometimes fatal diseases of the heart. The Troponin complex is notoriously difficult to study at a
molecular level due to its large size and its dynamic nature, necessary for its function in the cell. This project
has used newly-developed magnetic resonance methods to gain an understanding of the structure, dynamics
and function of the Troponin complex as it functions to control muscle contraction. We have revealed for the
first time how several key regions of this complex move in response to calcium levels and have also
determined the structure of a the second major regulatory region of Troponin called the 'Mobile Domain'. We
have performed our measurements in as close to physiological conditions as possible by using applying our
novel structural tools in whole muscle filaments. Throughout this project, we have also probed the structure of
Troponin when mutations linked to the heart disease cardiomyopathy are present which has allowed us to
suggest mechanisms as to why the heart muscle becomes damaged in the presence of genetic mutations.
Expected future outcomes:
Our results have not only provided an insight into the structure and workings of the Troponin complex in
muscle filaments during the regulation of muscle contraction but can also be used to understand why genetic
mutations result in disease states, including the heart disease cardiomyopathy.
Name of contact:
Louise Brown
Email/Phone no. of contact:
Louise.Brown@mq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 244214
Start Year: 2003
CIA Name: Prof Prashanthan Sanders
End Year: 2005
Admin Inst: Melbourne Health
Grant Type: Early Career Fellowships (Overseas)
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $196,219
Title of research award:
Importance of pulmonary venous electrophysiology in the development of atrial fibrillationImportance of
pulmonary venous electrophysiology in the development of atrial fibrillation
Lay Description (from application):
(ii) Transplant rejection can be inhibited by expression in the graft of CTLA4-Fc a reagent that blocks T cell
co-stimulation enhancing allo-graft acceptance (Transplantation 2000 69:1806). High-level expression for over
100 days is expected to correlate with optimal graft acceptance. Our ability to use Kunjin to express beta
galactosidase for several months in vivo without inflammation illustrates the potential for this approach (CIB
ref 15). Initially we intend to use P815 cells injected i.p. into C57BL-6, where they are usually rejected within
a few days. In contrast, P815 cells with Kunjin replicon-mediated CTLA4-Fc expression should survive for an
extended period. Graft survival is easily monitored using FACS and anti-H-2d antibodies.
Research achievements (from final report):
The duration of this NHMRC-NHF Neil Hamilton Fairley Fellowship was spent at the Hopital Cardiologique
du Haut Leveque with the team of Professor Haissaguerre. Several studies were undertaken that identified the
mechanisms of different forms of atril fibrillation. Atrial fibrillation is the most common sustained heart
rhythm disorder and affects approximately 2% of the unselected adult population. It can result in blackouts,
heart failure, stroke and an increased mortality. The studies performed while on this fellowship have led to a
better understanding of the mechanisms of this arrhythmia and shift in our clinical approach to cure patients
with this rhythm disorder. In particular, we have identified that localized sources of activity could maintain
atrial fibrillation and identifying and eliminating these sources can result in cure of atrial fibrillation.
Expected future outcomes:
Several publications and international invited talks have resulted from this time. This work is expected to
change the clinical approach to the ablation of atrial fibrillation.
Name of contact:
Prof Prash Sanders
Email/Phone no. of contact:
prash.sanders@adelaide.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 244311
Start Year: 2003
CIA Name: Prof Jonathan Kalman
End Year: 2005
Admin Inst: Melbourne Health
Grant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $428,250
Title of research award:
Atrial electrical remodeling due to chronic stretch: Defining the substrate for atrial fibrillationAtrial electrical
remodeling due to chronic stretch: Defining the substrate for atrial fibrillation
Lay Description (from application):
Background: Cardiac failure is a common heart disorder in which the pumping function of the heart is
significantly weakened. Mitral regurgitation is a common condition where there is a leakage of blood from the
left ventricle (lower heart chamber) back into the left atrium (upper heart chamber) during normal cardiac
contraction. This puts a strain on the heart and may cause heart failure. Atrial septal defect is a common form
of congenital heart disease which may not be diagnosed until adulthood. There are several forms but the basic
problem is leakage of blood from the left atrium into the right atrium .This also puts a strain on the heart and
can cause heart failure. All 3 conditions are associated with a significantly increased risk of atrial fibrillation
(AF). This abnormal fast irregular cardiac rhythm makes the pumping of the heart inefficient. People with AF
may feel short of breath, tired, or develop palpitations. AF is an important cause of stroke and premature death
and is the most common heart rhythm disturbance occurring in upto 10% of the over 70 age group. Even after
repair of the leaky valve or atrial septal defect there is still a high risk of developing this rhythm. Purpose of
the study: This study will try to understand why patients with these conditions are at risk of developing atrial
fibrillation, and why this risk might persist after surgical correction when this is possible (mitral regurgitation
and atrial septal defect). The study will utilise sophisticated new mapping techniques to gain original insights
into the mechanism of this very common and as yet poorly understood heart rhythm disturbance. The study has
the potential to determine the cause of atrial fibrillation in these patient groups and as such represent a quantum
advance in our understanding of he mechanism of atrial fibrillation. It would be expected to form a foundation
on which development of curative and preventative approaches may be based.
Research achievements (from final report):
We have successfully characterised the electrophysiologic and electroanatomic consequences in the atrium that
create the substrate for atrial fibrillation under conditions of chronic atrial stretch in patients with (i) advanced
cardiac failure, (ii) chronic severe mitral insufficiency and (iii) patients with an atrial septal defect., Patients
with CHF and mitral regurgitation demonstrated an increase in atrial ERP, an increase of atrial conduction
time, prolongation of the corrected sinus node recovery times, and conduction delay along the crista terminalis.
Electroanatomic mapping demonstrated regional conduction slowing with a greater number of electrograms
with fractionation or double potentials, associated with areas of low voltage and electrical silence (scar).
Patients with CHF demonstrated an increased propensity for AF., In patients with and atrial septal defect, atrial
ERP, P-wave duration, sinus node recovery time, and extent of conduction delay across the crista terminalis
were significantly longer than in controls. At follow-up studies after ASD closure, there was persistence of
regional conduction delay. , In these studies we also evaluated the effects of aging on atrial electrophysiology.
Aging is associated with regional conduction slowing, anatomically determined conduction delay at the crista
terminalis, and structural changes that include areas of low voltage. In addition, impairment of sinus node
function and an increase in atrial ERP occurred with aging., Thus conditions of chronic stretch and aging have
many common electrophysiological and electroanatomical consequences, These studies have provided
important insights into the mechanism of atrial fibrillation and have helped tailor treatment and ablation
strategies for cure of this condition.
Expected future outcomes:
It is expected that a better understanding of the mechanism of atrial fibrillation in these conditions will
facilitate development of improved curative procedures. Atrial fibrillation has significant impact on health
resources as it causes a marked increase in annual risk of stroke and a doubling of mortality.
NHMRC Research Achievements - SUMMARY
Name of contact:
Jonathan Kalman
Email/Phone no. of contact:
jon.kalman@mh.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 282406
CIA Name: A/Pr Kate Leslie
Admin Inst: Melbourne Health
Main RFCD: Surgery
Total funding: $189,625
Start Year: 2004
End Year: 2004
Grant Type: NHMRC Project Grants
Title of research award:
Perioperative beta-blockade to prevent cardiac morbidity in high-risk patients undergoing surgery (The POISE
Study)Perioperative beta-blockade to prevent cardiac morbidity in high-risk patients undergoing surgery (The
POISE Study)
Lay Description (from application):
Non-cardiac surgery is associated with significant risk of complications and death, particularly in elderly
patients who are known to have heart disease, or who have risk factors for it (ie smoking, high blood pressure).
About 11% of the Australian population are currently taking medications for heart disease or high blood
pressure and about 80% have at least one risk factor for heart disease. As more than 2 million Australians have
general anaesthesia for non-cardiac surgery every year, a substantial group of patients are therefore at risk of an
adverse outcome following surgery. Despite the magnitude of this problem, however, few studies have
established treatments to decrease the risk of complications and death following surgery. Beta-blockers are a
group of drugs which have been used for decades in the treatment of heart disease and high blood pressure.
Beta-blockers are known to improve the way the heart copes with the stress of surgery. They decrease the heart
rate, make the heart more efficient at using energy and reduce the likelihood of imbalance between oxygen
supply and demand. Some previous studies showed that beta-blockers may reduce the risk of heart attack and
death for up to 2 years after surgery. However, other studies have shown no effect of beta-blockers on
outcome. These previous studies have involved small numbers of patients who may not represent the broader
population having surgery. We therefore propose to undertake a large trial to definitively answer the question
about whether beta-blockers improve the outcome after non-cardiac surgery in patients with, or at risk of, heart
disease. Even if the effect of beta-blockers is relatively modest, because such large numbers of patients with
heart disease have surgery, the overall effect on the rate of complications and death in the population could be
very significant. The results of this study could have major implications for the success of, and cost of, surgery
worldwide.
Research achievements (from final report):
Heart attack and death following major non-cardiac surgery are devastating and costly events. Beta-blockers
may prevent heart attack and death in patients at high-risk but their value is currently unproven. In addition, the
side-effects and feasability of large-scale perioperative beta-blockade are unproven. The POISE study is a large
(10,000 patient) international trial that seeks to determine the effectiveness, side-effects and feasibility of
perioperative beta-blocade in high-risk patients having non-cardiac surgery. This grant supported the
recruitment of 393 patients in 2004. This trial is ongoing and is now funded by an NHMRC Program Grant
(344008). Recruitment is expected to be completed in 2006.
Expected future outcomes:
N/A
Name of contact:
Kate Leslie
Email/Phone no. of contact:
kate.leslie@mh.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 332502
CIA Name: Dr David Curtis
Admin Inst: Melbourne Health
Main RFCD: Haematology
Total funding: $422,600
Start Year: 2005
End Year: 2007
Grant Type: NHMRC Project Grants
Title of research award:
Regulation of red blood cell and platelet formation by bHLH proteinsRegulation of red blood cell and platelet
formation by bHLH proteins
Lay Description (from application):
Continuous production of normal blood cells by the bone marrow is a process critical to human life. Disruption
of this process leads to diseases such as leukemia, aplastic anemia and myelodysplasia which have devastating
consequences for affected patients. Pivotal to understanding these diseases is a knowledge of the regulation
of normal blood production. Our laboratory works on a gene known as SCL that is critical for blood formation.
We have recently shown that loss of SCL in adult bone marrow leads to abnormalities in two types of blood
cells, the red blood cells and the platelets. This grant will extend this important observation to understand how
the production of these cells is altered and what is its consequence. Our studies will help clarify the basis of
blood cell formation and may impact on how we diagnose and treat a wide variety of blood disorders.
Research achievements (from final report):
This research award has generated a genetically modified mouse strain that has allowed us to study the role of a
gene called SCL in the blood system of the adult. We have shown that while SCL is essential for the
development of stem cells of the blood, it is not required for the maintence of these stem cells during adult life.
In adult stem cells it is important for determining the type of cells that blood stem cells can generate.
Specifically, SCL is required for the production of platelets, especially during times of stress such as after
chemotherapy, and is required to prevent the formation of mast cells, a cell type that mediates allergic
conditions such as asthma, food and drug allergies. These findings suggest that tagetting this gene could be
useful for controlling the production of platelets or mast cells.
Expected future outcomes:
This work will lead to a better understanding of how the body regulates blood cell production from stem cells.
Name of contact:
David Curtis
Email/Phone no. of contact:
dcurtis@wehi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 332503
Start Year: 2005
CIA Name: Dr David Curtis
End Year: 2007
Admin Inst: Melbourne Health
Grant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $334,375
Title of research award:
Hematopoietic cytokines for the repair of myocardial infarctionHematopoietic cytokines for the repair of
myocardial infarction
Lay Description (from application):
Heart attacks remain one of the most common causes of heart failure. Unlike many other tissues such as the
skin or bone marrow, the heart is unable to repair itself following a heart attack. Recently it has been
recognised that bone marrow cells can to a small degree repair the heart. How this is done is not known but it
may be due to the formation of new blood vessels and perhaps new heart muscle. Unfortunately, the repair by
bone marrow cells is not very efficient. One way of improving the efficiency of heart repair by bone marrow
cells is to give people bone marrow growth factors that increase the number of bone marrow cells in the blood
and thus, increase the number at the site of heart injury. Our preliminary research shows that this is the case
although the efficiency of repair is still not enough as a useful therapy. This project will examine how bone
marrow growth factors improve heart repair following heart attacks and explore ways of improving the
efficiency of repair to permit trials in humans.
Research achievements (from final report):
This research award has demonstrated that a administration of a drug called G-CSF improves heart function
and repair in mice after myocardial infarction (heart attack). Previous groups have suggested that G-CSF works
by encouraging blood stem cells to move to the area of damage where the stem cells form new heart muscle
and blood vessels. Our research has shown that this is not the case. Instead,G-CSF improves heart repair by
modifying the inflammatory response to damage, and in particular encourages increased numbers of a special
type of white cell called a type II macrophage. This research will lead to new and improved methods of
repairing the heart muscle after a heart attack.
Expected future outcomes:
This work will lead to novel therpaies for trial in humans.
Name of contact:
David Curtis
Email/Phone no. of contact:
dcurtis@wehi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 435108
CIA Name: A/Pr Kate Leslie
Admin Inst: Melbourne Health
Main RFCD: Anaesthesiology
Total funding: $385,928
Start Year: 2007
End Year: 2008
Grant Type: NHMRC Project Grants
Title of research award:
The Perioperative Ischaemic Evaluation StudyThe Perioperative Ischaemic Evaluation Study
Lay Description (from application):
Non-cardiac surgery is associated with significant risk of complications and death, particularly in elderly
patients who are known to have heart disease, or who have risk factors for it (ie smoking, high blood pressure).
About 11% of the Australian population are currently taking medications for heart disease or high blood
pressure and about 80% have at least one risk factor for heart disease. As more than 2 million Australians have
general anaesthesia for non-cardiac surgery every year, a substantial group of patients are therefore at risk of an
adverse outcome following surgery. Despite the magnitude of this problem, however, few studies have
established treatments to decrease the risk of complications and death following surgery. Beta-blockers are a
group of drugs which have been used for decades in the treatment of heart disease and high blood pressure.
Beta-blockers are known to improve the way the heart copes with the stress of surgery. They decrease the heart
rate, make the heart more efficient at using energy and reduce the likelihood of imbalance between oxygen
supply and demand. Some previous studies showed that beta-blockers may reduce the risk of heart attack and
death for up to 2 years after surgery. However, other studies have shown no effect of beta-blockers on
outcome. These previous studies have involved small numbers of patients who may not represent the broader
population having surgery. We therefore are undertaking a large trial to definitively answer the question about
whether beta-blockers improve the outcome after non-cardiac surgery in patients with, or at risk of, heart
disease. Even if the effect of beta-blockers is relatively modest, because such large numbers of patients with
heart disease have surgery, the overall effect on the rate of complications and death in the population could be
very significant. The results of this study could have major implications for the success of, and cost of, surgery
worldwide.
Research achievements (from final report):
Heart attack and death following major non-cardiac surgery are devastating and costly events. Previous
research suggested that beta-blockers may prevent heart attack and death in patients at high-risk, but the
evidence was not conclusive. In addition, the side-effects and feasability of large-scale perioperative betablockade were unproven. The POISE study was a large (8,351 patient) international trial that sought to
determine the effectiveness, side-effects and feasibility of perioperative beta-blocade in high-risk patients
having non-cardiac surgery. Patients at risk of perioperative heart attack were randomised to 30 days of
metoprolol or placebo, commenced just before surgery. The results showed that beta-blockers were effective at
preventing heart attacks after surgery. However, this came at the cost of increased rates of stroke and noncardiac death. Routine beta-blockade of patients having non-cardiac surgery is now no longer recommended.
Our results highlight the risk in assuming a benefit without substantial harm, and the importance and need for
large randomised trials in the perioperative setting.
Expected future outcomes:
The POISE study showed that perioperative heart attack is common, but that beta-blockade is not a suitable
preventative strategy. Other treatments therefore will be sought. In addition, the POISE study revealed the need
for intensive post-operative care of these patients, as low blood pressure was common and heart attacks were
most often silent.
Name of contact:
A/Prof Kate Leslie
Email/Phone no. of contact:
kate.leslie@mh.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 489417
Start Year: 2008
CIA Name: Dr Kurt Roberts-Thomson
End Year: 2010
Admin Inst: Melbourne Health
Grant Type: Early Career Fellowships (Overseas)
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $272,872
Title of research award:
Electrophysiologic Properties of the Ventricular Myocardium Promoting ReentryElectrophysiologic Properties
of the Ventricular Myocardium Promoting Reentry
Lay Description (from application):
Ventricular tachycardia is a dangerous heart rhythm that usually occurs in people with prior heart attacks.
These people often have scarring on their heart and the tachycardia occurs due to electrical activity forming a
circuit around the scar. This study will examine the factors that cause ventricular tachycardia to begin by
looking at the characteristics of the scarring.
Research achievements (from final report):
This fellowship allowed further training to occur overseas. This enabled significant research and clinical
experience in the management of ventricular arrhythmias at one of the world's leading centres.
Expected future outcomes:
This experience has allowed myself to return to Australia as a leader in the management of ventricular
arrhythmias and to set up a research program in ventricular arrhythmias.
Name of contact:
Kurt Roberts-Thomson
Email/Phone no. of contact:
kurt.roberts-thomson@adelaide.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 435712
CIA Name: Dr Seana Paul
Admin Inst: Menzies Research Institute
Main RFCD: Epidemiology
Total funding: $282,008
Start Year: 2007
End Year: 2010
Grant Type: Early Career Fellowships (Australia)
Title of research award:
Cardiovascular disease risk behaviours: understanding childhood origins.Cardiovascular disease risk
behaviours: understanding childhood origins.
Lay Description (from application):
Not Available
Research achievements (from final report):
Using data from the Childhood Determinants of Adult Health study my research achievements have included
demonstrating the clear association between childhood behaviour and environment with adult health. The
potential benefit of this research is that interventions that alter unfavourable environments or behaviours in
childhood may reduce the prevalence of CVD among adults. A further achievement was the demonstration of
the importance of education on health behaviours in young adults. Unlike findings from Europe and the USA,
we found that the education level that a person achieved, not the education level of their parents, determined
how healthy their lifestyles were. The potential benefits of this research is that interventions that improve
school retention and outcomes should have benefits for the health of the Australian population.
Expected future outcomes:
Future studies will further explore education and health found in this cohort. We will examine how school
factors, i.e. enjoyment or performance, contribute to adult health. Our goal is to develop an index to identify 'at
risk' children who may benefit from tailored educational and health interventions.
Name of contact:
Seana Gall
Email/Phone no. of contact:
Seana.Gall@utas.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 457603
CIA Name: Prof Michael Clark
Admin Inst: Menzies Research Institute
Main RFCD: Endocrinology
Total funding: $433,973
Start Year: 2007
End Year: 2009
Grant Type: NHMRC Project Grants
Title of research award:
Central and peripheral actions of insulin for the control of muscle capillary recruitmentCentral and peripheral
actions of insulin for the control of muscle capillary recruitment
Lay Description (from application):
Type 2 diabetes is on the increase world wide and reflects the ever-increasing incidence of obesity. Whereas
the likely cause of type 2 diabetes includes low physical activity and high fat diet, the primary metabolic
abnormality is likely to be muscle insulin resistance. The cause of this resistance is controversial, but may stem
from microvascular dysfunction where muscle becomes poorly perfused and unresponsive to the action of
insulin to recruit capillary flow. In this project we will further extend our seminal discoveries that insulin
mediates capillary recruitment under normal circumstances and that in various models of insulin resistance
insulin's ability to increase the perfusion of muscle is markedly impaired. We will explore the hypothesis, that
insulin controls microvascular perfusion of muscle by a central neural mechanism ending at terminal arterioles
on the vasculature and endeavour to identify the details of this control. We will use in-house novel techniques
for examining both the role of central control mechanisms involving the brain as well as peripheral
mechanisms by local infusion of various agents likely to either enhance or block insulin's microvascular action.
A positive outcome will enhance our understanding of insulin action and the insulin resistance that precedes
type 2 diabetes. There is also the possible outcome that important clues will be obtained leading to new
therapeutic agents that could be used to treat type 2 diabetes.
Research achievements (from final report):
Type 2 diabetes is increasing worldwide in epidemic proportions and its associated morbidity and mortality not
only adversely affects the health and quality of life of the sufferer, but places a major burden on the health care
system. Insulin resistance is closely associated with the development of type 2 diabetes and may arise because
of altered blood flow within skeletal muscle. This project discovered that the recruitment of microvascular
blood flow in muscle in response to insulin was not due to a direct action of insulin in the brain. However
processes in the brain that depend upon nitric oxide signalling can impair the normal insulin-mediated
recruitment of blood flow in muscle and lead to insulin resistance. These outcomes may be relevant to the
underlying causes of stress related diabetes., The project also discovered that the local action of insulin to
recruit microvascular blood flow in skeletal muscle was dependent on nitric oxide production. Insulin action
also involved alterations in the rhythmical patterns of blood flow normally seen in muscle.
Expected future outcomes:
The discovery that insulin alters the rythmical variation of blood flow in muscle may provide new diagnostic
tests for insulin resistance and new avenues for therapeutic intervention to halt the progression of insulin
resistance to diabetes.
Name of contact:
Prof Steve Rattigan
Email/Phone no. of contact:
S.Rattigan@utas.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 490042
Start Year: 2008
CIA Name: Prof Mark Nelson
End Year: 2009
Admin Inst: Menzies Research Institute
Grant Type: NHMRC Strategic Awards
Main RFCD: Public Health and Health Services not elsewhere classified
Total funding: $197,992
Title of research award:
Absolute risk prediction of subsequent cardivascular events in a large cohort of elderly Australians with
hypertention.Absolute risk prediction of subsequent cardivascular events in a large cohort of elderly
Australians with hypertention.
Lay Description (from application):
Media Summary not available
Research achievements (from final report):
Estimating absolute risk for heart attack and stroke rather than measurement of blood pressure alone is
considered the best way to identify those who would most likely benefit from medication. Risk calculators used
to estimate risk in those without previous cardiovascular disease (CVD) events are based on the Framingham
Heart Study, which had no person 74 years of age at baseline. Age is the most important determinant of risk.
We estimated the predictive value of 3 risk equations for CVD end points in the Second Australian National
Blood Pressure study cohort (mean age: 71.9 years at baseline). Our model had modest discrimination of the
algorithms for prediction of the outcomes for coronary heart disease and CVD morbidity and mortality,
myocardial infarction, or stroke (Framingham); cardiac death (Pocock); and CVD events (Dubbo).
Recalibration analyses showed that it would be inappropriate to apply the risk equations to the Second
Australian National Blood Pressure study population. New risk equations for CVD events in the hypertensive
aged are needed. Our second paper tried to address this shortfall. Our model performed similarly to existing
models so rather than replacing them we recommended that existing algorithms be extended into older age
groups.
Expected future outcomes:
As above we have developed a score for predicting cardiovascular events in this population. We are to
extending this work by developing a risk score to predict 10-year cardiovascular and all-cause mortality in the
hypertensive aged and examine its internal validity. It is to be published shortly.
Name of contact:
Mark Nelson
Email/Phone no. of contact:
Mark.Nelson@utas.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 544923
CIA Name: Prof Alison Venn
Admin Inst: Menzies Research Institute
Main RFCD: Epidemiology
Total funding: $360,326
Start Year: 2009
End Year: 2011
Grant Type: NHMRC Project Grants
Title of research award:
Inter-relationships between life-stage transitions, depression and cardio-metabolic health in young adultsInterrelationships between life-stage transitions, depression and cardio-metabolic health in young adults
Lay Description (from application):
This study will investigate how social transitions and depression in young Australian adults affect the
development of obesity and the adoption or persistence of behaviours that are associated with the risk of heart
disease and diabetes. These behaviours include smoking, poor diet, physical inactivity and alcohol
consumption. A better understanding of how psychosocial factors influence risk factors for heart disease and
diabetes is needed to improve prevention strategies.
Research achievements (from final report):
The Childhood Determinants of Adult Health (CDAH) study is a cohort study with follow-up of 8,498 chidlren
who participated in the 1985 Australian Schools Health and Fitness Survey (ASHFS) when aged 7 to 15 years.
This funding was used to conduct a second wave of follow-up, five years after the first follow-up. The study
aims were to investigate associations between life-stage transitions, depression and cardio-metabolic disease
risk in adults under 40 years of age., Overall, 58% of the 5,174 participants who provided some data in the first
wave of follow-up participated in the second wave. Of the 2,410 participants who completed the study clinics
in Wave 1, 78% completed the Wave 2 follow-up., Data cleaning is currently underway and the analyses will
be conducted in 2012-13.
Expected future outcomes:
This study will provide a better understanding of how social transitions and depression in young Australian
adults affect the development of obesity and the adoption or persistence of behaviours that are assoicated with
the risk of heart disease and diabetes. These behaviours include smoking, poor diet, physical inactivity and
alcohol consumption. This research will inform prevention strategies.
Name of contact:
Alison Venn
Email/Phone no. of contact:
Alison.Venn@utas.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 124319
Start Year: 2001
CIA Name: Prof Kerin O'Dea
End Year: 2004
Admin Inst: Menzies School of Health Research Grant Type: NHMRC Project Grants
Main RFCD: Indigenous Health
Total funding: $1,699,292
Title of research award:
Community-Based Interventions to Reduce the Risk of Diabetes and Cardiovascular Disease in Indigenous
AustraliansCommunity-Based Interventions to Reduce the Risk of Diabetes and Cardiovascular Disease in
Indigenous Australians
Lay Description (from application):
Poor nutrition is one of the main factors causing high rates of diabetes and heart disease in Aboriginal and
Torres Strait Islander people. Obesity is one of the main risk factors for diabetes and cardiovascular diseases
and it is associated with poor diet, lack of exercise and many social factors. Access to fresh vegetables and
fruit is often difficult for indigenous people , especially in remote areas. The aim of this project is to work with
indigenous communities in rural and remote areas to plan and run programs to lower the risk of diabetes and
heart disease. The programs will be designed by community members and involve health education, diet,
exercise and improving availability of healthy food choices in community stores. The programs will target
diabetic people and their families or, in most cases, the whole community. It is very difficult for overweight
adults to lose weight permanently, so school-based programs will be run to provide health education and
"healthy canteen" policies put in place to try and prevent excess weight gain in younger people. To see
whether these programs are effective, we will measure changes over time in risk factors for diabetes and heart
disease, nutrition and community support and involvement in the program. Where a community achieves even
modest improvements in diet and exercise, this is likely to lead to a much lower risk of diabetes and heart
disease. We will identify what factors make a program effective and sustainable over the long term. This
study will help us to set up a system for introducing and monitoring similar programs in other indigenous
communities. (1358 characters)
Research achievements (from final report):
Given the very high rates of premature type 2 diabetes and related conditions and risk factors (obesity,
cardiovascular disease, and renal failure) among Indigenous peoples, the major goals of this research program
were to work with Indigenous communities in rural and remote areas to plan, implement and evaluate
interventions to reduce the risk and/or severity of these conditions, and to develop a better understanding of the
barriers to, and enablers of, health promoting behaviour change at the community level - a PhD thesis due for
submission in 2006. We worked primarily with three communities: Galiwinku and Marthakal Homelands in
northeast Arnhem Land, NT; and Rumbalara community in Victoria (The Heart Health Project). The health
screenings in 2001-2 in the NT indicated the strong relation between biochemical markers of poor diet quality
and markers of inflammation and oxidation linked to vascular disease risk. Furthermore, relatively modest
increases in body weight greatly increased the risk of diabetes. These results provided the rationale for
community-driven interventions to improve the quality of the food supply. Included in the initiatives
undertaken was the establishment of home gardens (fruit trees and vegetables), and the establishment of a
partnership between a community organization and the major providers of food in the community (store, takeaways, school canteen, child care centre, meals-on-wheels) to develop a coordinated approach to improving the
quality of the food supply. Changes in the food supply have been monitored since 2001 using the store turnover
method.
Expected future outcomes:
We would like to report on the sustainability of the community-based interventions over the long term,
focussing onthe structural factors in the community (and outside) that support or hinder the sustainability of
improvements in diet and lifestyle at the community level. This follow up could be done as part of our Program
Grant.
Name of contact:
NHMRC Research Achievements - SUMMARY
Kerin O'dea
Email/Phone no. of contact:
kod@medstv.unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 283300
Start Year: 2004
CIA Name: Dr Shelley WALTON
End Year: 2006
Admin Inst: Menzies School of Health Research Grant Type: NHMRC Project Grants
Main RFCD: Infectious Diseases
Total funding: $465,750
Title of research award:
Characterisation of immune responses to Sarcoptes scabiei cysteine proteases, group 1 allergen homologues, in
scabiesCharacterisation of immune responses to Sarcoptes scabiei cysteine proteases, group 1 allergen
homologues, in scabies
Lay Description (from application):
Scabies, a parasitic skin infestation by the 'itch' mite Sarcoptes scabiei, causes significant health problems for
children and adults in many remote Aboriginal communities in Australia. Scabies is often the underlying cause
of streptococcal skin infections which can cause serious complications such as kidney and heart disease.
Although diagnosed scabies cases can be successfully treated, individuals have often already transmitted the
disease to others prior to receiving therapy. A particularly dreadful form of scabies, known as crusted scabies,
can develop in a minority of people, in which mites multiply in their millions and the affected person develops
severe crusting of the skin. This has resulted in death within 5 years for up to 50% of people with this form of
scabies. Scabies mites are scientifically very similar to house dust mites, and they produce cross reactive
proteins. Molecular studies in our laboratory have enabled the identification and cloning of a number of scabies
molecules with considerable similarity to known house dust mite proteins that cause allergic disease. In this
study we propose to focus on a group of scabies proteins with significant identity to the extensively studied
Group 1 house dust mite allergens, reported to cause an immune response in 90% of mite allergic people. We
propose to use these scabies mite molecules to characterise the immune response in ordinary scabies and
compare it to the more severe and debilitating crusted form of the disease. Characterisation of the immune
response in scabies will ultimately aid in the development of new treatment for crusted scabies based on
immunotherapy. Studies will also investigate for any cross reactivity with the house dust mite group 1
molecules and enable the design of specific immunodiagnositics to distinguish house dust mite allergy from
scabies infestation and thus facilitate early diagnosis of scabies carriers and better control of the infestation in
endemic communities.
Research achievements (from final report):
This project carried out the first investigations of specific immunity in scabies. Scabies, a parasitic skin
infestation by the 'itch' mite Sarcoptes scabiei, causes significant health problems for children and adults in
many remote Aboriginal communities in Australia. A particularly dreadful form of scabies, known as crusted
scabies can develop in a minority of people, in which mites multiply in their millions and the affected person
develops severe crusting of the skin. Scabies mites produce proteins with considerable similarity to known
house dust mite proteins that cause allergic disease. In this study we focused on a group of scabies proteins
with identity to the extensively studied Group 1 house dust mite allergens, reported to cause an immune
response in 90% of mite allergic people. We expressed these scabies mite molecules as recombinant proteins
and used them to characterise the immune response in ordinary scabies and compare it to the more severe and
debilitating crusted form of the disease. Studies also investigated for any cross reactivity with the house dust
mite group 1 molecules for future design of specific immunodiagnositics for scabies infestation. In summary
ordinary scabies and crusted scabies patients have a specific 'allergic' IgE response to S. scabiei cysteine
proteases and clinical severity is associated with differences in the type and magnitude of the antibody and
cellular responses to these molecules.
Expected future outcomes:
These studies will facilitate the development of tools for the early diagnosis of scabies carriers and better
control of the infestation in endemic communities. Characterisation of the immune response in scabies will
ultimately aid in the development of new treatment for crusted scabies based on immunotherapy.
Name of contact:
NHMRC Research Achievements - SUMMARY
Dr Shelley Walton
Email/Phone no. of contact:
shelley.walton@menzies.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 283301
Start Year: 2004
CIA Name: Dr Shelley WALTON
End Year: 2006
Admin Inst: Menzies School of Health Research Grant Type: NHMRC Project Grants
Main RFCD: Infectious Diseases
Total funding: $516,000
Title of research award:
Investigating the molecular basis of emerging drug resistance in scabies mitesInvestigating the molecular basis
of emerging drug resistance in scabies mites
Lay Description (from application):
Scabies is a disease of the skin caused by the burrowing of the 'itch' mite Sarcoptes scabiei. In remote
Aboriginal communities in northern and central Australia up to 60% of children can be infected. Scabies
causes intense itching of the skin, resulting in skin damage through scratching, and serious secondary bacterial
infections leading to kidney and heart disease. Some remote communities in the NT are documented to have
the highest rates of kidney and heart disease in the world. The location of the Menzies School of Health
Research in this region where scabies is endemic has enabled us to undertake a number of studies on the
disease. Our world first molecular study using microsatellite markers demonstrated that scabies mites on
people were genetically distinct from those on dogs. This had important implications in control programs in
the communities. Additional work has focused on laboratory studies to monitor the sensitivity of mites to
current treatments used in community control programs and for the treatment of crusted scabies, a very severe
and debilitating form of the disease. We have reported evidence of increasing resistance of scabies mites to
topical 5%permethrin and documented both in vitro and clinical evidence of resistance to oral ivermectin. We
now seek support to extend this work to identify at the molecular level the mechanisms of resistance and use
this knowledge to design a diagnostic test. This work has both local and global implications. Scabies is a
significant disease of children primarily in many indigenous and third world communities, as well as associated
with nursing homes and HIV infection. The tools developed in this project will enable the assessment of drug
treatment failures and assist in the development of more sensitive methods for monitoring resistance in the
community, including the potential for reversing it. This will avoid the current global problems of resistance
observed in other organisms such as headlice.
Research achievements (from final report):
Scabies is a disease of the skin caused by the burrowing of the 'itch mite' Sarcoptes scabiei. It is a significant
disease of humans with over 300 million people affected worldwide. In some remote Aboriginal communities
in northern and central Australia up to 60% of children can be infected with scabies underlying serious
secondary bacterial infections, potentially leading to kidney and heart disease. Scabies is also a significant
veterinary disease., This project carried out the first investigations into the genetic basis for drug resistance in
these mites. We focused on mechanisms of resistance to permethrin and ivermectin, the main drugs used for
treatment of scabies in northern Australia. Resistance to both of these drugs has been documented in a wide
variety of organisms which makes our recent clinical and in vitro observations of increasing permethrin
tolerance and of ivermectin resistance particularly alarming. Knowledge of the mechanisms mediating drug
resistance has enabled us to begin to develop tools which will enable the assessment of treatment failures and
assist in the development of sensitive methods for monitoring for drug resistance in scabies mites in the
community, and potentially the ability for reversing it., Our research is a major step towards ensuring that the
global problem of drug resistance seen in related organisms such as head lice, does not occur in scabies mites.
As the development of treatments is unlikely in the near future, prolonging the life of our limited group of
drugs is essential.
Expected future outcomes:
Understanding the mechanisms of drug resistance will enable the development of surveillance tools to detect
emerging resistance in scabies mites. These tools will differentiate resistance from other forms of treatment
failure and help avoid the development of widespread resistance as seen in other organisms such as head lice.
Name of contact:
NHMRC Research Achievements - SUMMARY
Dr. Shelley Walton
Email/Phone no. of contact:
shelley.walton@menzies.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 333420
Start Year: 2006
CIA Name: Dr Danielle Esler
End Year: 2007
Admin Inst: Menzies School of Health Research Grant Type: NHMRC Strategic Awards
Main RFCD: Indigenous Health
Total funding: $29,650
Title of research award:
Sadness and Heart DiseaseSadness and Heart Disease
Lay Description (from application):
This project will examine the acceptability and validity of a depression screening tool for use with Aboriginal
and Torres Strait Islander patient with ischaemic heart disease, and concurrently determine depression
prevalence in the sample population attending an urban Aboriginal community controlled health service.
Research achievements (from final report):
N/A
Expected future outcomes:
N/A
Name of contact:
N/A
Email/Phone no. of contact:
N/A
NHMRC Research Achievements - SUMMARY
Grant ID: 361617
Start Year: 2005
CIA Name: Prof Kerin O'Dea
End Year: 2005
Admin Inst: Menzies School of Health Research Grant Type: International Collaborations
Main RFCD: Indigenous Health
Total funding: $8,318
Title of research award:
Community and individual resilience for positive health in Indigenous populations at risk for diabetes and
cardiovasculaCommunity and individual resilience for positive health in Indigenous populations at risk for
diabetes and cardiovascula
Lay Description (from application):
Not Applicable
Research achievements (from final report):
We undertook activities involved in preparing the full application. These activities included visiting remote
Indigenous community partners for consultations on the proposal (flights accommodation, workshops),
teleconferences between chief investigators and co-principal investigators, and employment of a research
assistant (short term contract) to pull together all the necessary background information.
Expected future outcomes:
There were no outcomes as the proposal was not funded.
Name of contact:
Kerin O'dea
Email/Phone no. of contact:
kod@medstv.unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 383500
Start Year: 2006
CIA Name: Dr Wendy Gunthorpe
End Year: 2008
Admin Inst: Menzies School of Health Research Grant Type: NHMRC Project Grants
Main RFCD: Indigenous Health
Total funding: $192,841
Title of research award:
Strong Souls StudyStrong Souls Study
Lay Description (from application):
Cardiovascular Disease (CVD) is major problem among indigenous Australians, and imposes a significant
financial burden on the Australian health care system. CVD cannot be sufficiently explained by the increased
prevalence of conventional cardiovascular risk factors such as diabetes, smoking and overweight. Predicted
CVD rates among young Indigenous adults using conventional risk factors are about 30 times lower than the
observed rate. Increased recognition has been given to the role of psychosocial factors in CVD, particularly, the
poor psychosocial circumstances of Indigenous Australians. However, psychological phenomena resulting
from adverse day-to-day experiences and their relationships to CVD, are poorly understood. This study aims
to examine relationships between culturally valid measures of social, emotional and spiritual wellbeing, and
traditional and novel cardiovascular risk factors. Findings from this study will help determine if the adverse
psychosocial environment of many Aboriginal Australians contributes to the current excess morbidity and
mortality from CVD. This study is embedded in a longitudinal study so that early life experiences can be taken
into account. Sadly this population is especially suitable for a life course study, because the premature adult
mortality and early onset of non-communicable diseases means the time intervals for development of morbidity
and mortality events is relatively short.
Research achievements (from final report):
This research recognised that there were no culturally appropriate tools to assess social and emotional
wellbeing (SEWB) for Indigenous Australians in the NT. We therefore developed, pilot tested and validated an
assessment tool (Strong Souls) that could be used with Indigenous youth in the NT that were to be assessed as
part of the Aboriginal Birth Cohort Study. The final Strong Souls instrument consisted of 25 questions that
related to the four SEWB constructs of depression, anxiety, suicide risk and resilience. This tool was
successfully used to identify the relationships between each of these factors and SEWB generally, and
substance use, cognition, cardiovascular disease, diabetis and other chronic diseases. These data continue to be
analysed from the Aboriginal Birth Cohort of over 400 participants. The Strong Souls instrument has also been
adopted by many researchers and clinicians across Australia, as well as some in Canada, to assess SEWB
among Indigenous people. It has also been validated for use with Indigenous adults from a study conducted at
the Darwin prison and these data have been accepted for publication.
Expected future outcomes:
The Strong Souls instrument is likely to be adopted for more widespread use across Australia for adults and
adolescents, in research, clinical and treatment services. There are very few relevant tools in this area.
Name of contact:
Dr Sheree Cairney
Email/Phone no. of contact:
Sheree.Cairney@menzies.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 436009
Start Year: 2007
CIA Name: Dr Allen Cheng
End Year: 2008
Admin Inst: Menzies School of Health Research Grant Type: NHMRC Project Grants
Main RFCD: Medical Bacteriology
Total funding: $421,746
Title of research award:
Mathematical modelling of bacterial carriage in childrenMathematical modelling of bacterial carriage in
children
Lay Description (from application):
Children exposed to larger numbers of other children are at risk of persistent bacterial infections. Such
circumstances explain the high rates of ear and chest infections, and skin sores seen in children in historical
times. Changing social circumstances (smaller families, better housing, nutrition and hygiene), as well as the
introduction of antibiotics, explain the decline of such infections in affluent communities since the early 20th
century. However, even today, in affluent countries, children attending group child care are at high risk of ear
infections. As many bacteria are resistant, antibiotics are now much less effective than when they were first
introduced. Furthermore, there is a continuing load of infection for children in Aboriginal communities, in
PNG and other developing countries, causing hearing loss, chronic respiratory problems, and heart disease and
renal disease in later life. Using data previously collected from other studies in Indigenous communities and
children in child care, mathematical models allow us to ask "what if?", and answer important public health
questions: 1. What environmental and public health measures can reduce the cycle of cross-infection in childcare and high-risk populations? 2. What coverage rates with pneumococcal vaccine will eliminate the vaccinespecific bacteria from child care centres, from the wider community, and from high risk populations? 3. Will
infections with bacteria not covered by vaccine then increase? 4. Will the resistant bacteria tend to disappear if
antibiotic use is restricted? 5. Under what circumstances will antibiotics help to control infection? The
modelling will promote understanding of the social and health costs of bacterial infection in Aboriginal
communities and child care and use educational scenarios to promote uptake of the most cost-effective and
socially acceptable interventions.
Research achievements (from final report):
Work to combine multiple existing data sets containing information on bacterial carriage and otitis media was
completed and led to a NHMRC funded case-control study (VIABLE; 490317). Collaborative links have been
established with the Finnish Public Health Institute and the Gates Foundation funded PneumoCarr Consortium
who have been adopting a similar approach to analysis using other detailed data sets. A Markov chain Monte
Carlo model structure has been developed for otitis media, and has demonstrated that the incidence of otitis
media is high (~2%/day) and the duration of this otitis media is longer than has been observed in other
communities and settings. Using these parameters, we have established that the serotype-specific clearance is
relatively homogeneous for most commonly-observed pneumococcal serotypes. We have determined the high
sensitivity of nasal carriage for pathogens identified in severe otitis media. Further molecular typing of
serotype 6A isolates has demonstrated that the recently described 6C serotype is a significant replacement
carriage serotype. Group A streptococcal molecular typing has demonstrated an extraordinary diversity of GAS
emm sequence types in two remote Indigenous communities over 16 years suggesting that the proposed 23valent GAS vaccine would not be useful in this setting. A review of epidemiology of acute post-streptococcal
glomerulonephritis documented a high rate in remote communities (correlated to indices of socio-economic
disadvantage). We have found that outbreaks have tended to occur in the dry-season and appear to be Territorywide, with significant implications for control programs.
Expected future outcomes:
Work from this grant contributed to a successful NHMRC project grant that found adenovirus to be a major
cause of severe otitis media in Indigenous communities. This has implications for control measures for otitis
media in these communities.
Name of contact:
NHMRC Research Achievements - SUMMARY
Allen Cheng
Email/Phone no. of contact:
allen.cheng@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 436011
Start Year: 2007
CIA Name: Dr Gurmeet Singh
End Year: 2009
Admin Inst: Menzies School of Health Research Grant Type: NHMRC Project Grants
Main RFCD: Indigenous Health
Total funding: $505,213
Title of research award:
Aboriginal Birth Cohort Study: from childhood to adulthood.Aboriginal Birth Cohort Study: from childhood to
adulthood.
Lay Description (from application):
Aboriginal peoples have poor health at both ends of their life span. There are more low birth weight babies at
the beginning and more kidney, heart disease and diabetes at the end of the life spectrum. The Aboriginal Birth
Cohort study aims to examine the effect of early life events (such as low birth weight) on the risk of developing
chronic disease in later life with a view to early intervention. The "babies" of the study were last seen at 11
years and are now being seen again near their 18th birthday. Data available are weight, length and gestational
age of these babies at birth, the health and lifestyle of their mothers during pregnancy and the children's growth
and health. By 11 years of age, the low birth babies still remained shorter and thinner than their peers who were
normal size at birth, but importantly, markers of chronic disease were not higher in these children. The current
round of investigation, in addition to the tests done before, now includes non-invasive markers of heart disease,
such as heart rate variability, measures of arterial stiffness and the thickness of carotid intima media (lining)
and a dental examination looking at both teeth and gums. For the first time, the study will look beyond the
physical to examine the psychological wellbeing of these young adults using a specially designed questionnaire
(Strong souls). Little is known about this age group because they are relatively healthy and do not present to
clinics for treatment. The continuing life course study of this cohort, forming the oldest and largest birth cohort
of any indigenous population in the world, will help us understand the relationships between early life and the
sequential events that lead to chronic adult disease. This will help determine the most effective time for
intervention programmes, and will influence public health planning and policy directed towards the
improvement of the health of Aboriginal peoples.
Research achievements (from final report):
The study provides important information on the health of young adults which is often not available. At this
age, the participants were healthy with normal blood and urine tests. At 18 years the cohort participants
continue to have low body mass indices (BMI) and had low levels of abnormal markers of diabetes, heart and
kidney disease. , One major finding is that the low birth weight (LBW) babies weighed less and were shorter at
11 years and continued to be lighter and shorter even at 18 years. This is important as overweight and obesity
are the major predictors of adult chronic diseases such as diabetes, heart and kidney disease. This suggests that
there is still a window of opportunity to reinforce healthy lifestyle habits and emphasise the importance of
maintaining a healthy body weight., Gum and tooth disease were very common; 73 per cent had decayed teeth.
A mental health questionnaire revealed a self report of anxiety or depression in as many of 50 per cent of the
girls and only a slightly lower percentage of boys. , Iodine is an essential component of the thyroid hormones.
Low iodine affects many functions, particularly brain activity, temperature regulation and metabolic rates.
Levels of iodine in urine samples were found to be low in our participants. As these levels were collected
before the mandatory fortification of bread with iodine, we will be able to assess how effective this measure is
in improving the iodine status of our participants.
Expected future outcomes:
Analyses of various aspects are ongoing. Future plans include analysis of inflammatory markers and in-depth
analysis of wellbeing. Also planned are comparisons of anthropometry and chronic disease markers with agematched non-Aboriginal males and females living in Darwin.
Name of contact:
Gurmeet Singh
NHMRC Research Achievements - SUMMARY
Email/Phone no. of contact:
gurmeet.singh@menzies.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 436034
Start Year: 2007
CIA Name: Dr Rebecca Towers
End Year: 2011
Admin Inst: Menzies School of Health Research Grant Type: Early Career Fellowships (Australia)
Main RFCD: Infectious Diseases
Total funding: $283,024
Title of research award:
Investigation of cardiac autoantigens identified by screening a cDNA library with acute rheumatic
feverInvestigation of cardiac autoantigens identified by screening a cDNA library with acute rheumatic fever
Lay Description (from application):
Not Available
Research achievements (from final report):
Elucidation of the population genetic structure of group A streptococcal isolates circulating in remote
Indigenous communities shows that the extraordinary level of diversity seen is the result of introduction of new
strains from overseas and elsewhere rather than generation of new strains within the region. This would seem
to indicate that the high level of diversity is linked to environmental factors specifically those associated with
high rates of skin infection and transmission in remote Indigenous communities such as overcrowding, poor
hygeine and limited access to medical facilities. This further highlights the need to address the issue of
streptococca skin infection in remote Indigenous communities., A similar study examining streptococcal
species infecting dogs in Indigenous communities shows that strains infecting dogs are genetically distinct
from those infecting humans and very rarely cause clinically significant infections (less than 1 per 100,000).
Dogs therefore do not pose a significant health risk with respect to streptococcal infections.
Expected future outcomes:
This research will support future policy decisions regarding the control and treatment of streptococcal
infections in remote Indigenous communities. This will include housing and infrastructure policy as well as the
development and implementation of future streptococcal vaccines.
Name of contact:
Dr Rebecca Towers
Email/Phone no. of contact:
rebecca.fagan@nt.gov.au
NHMRC Research Achievements - SUMMARY
Grant ID: 490302
Start Year: 2008
CIA Name: Prof Ross Bailie
End Year: 2011
Admin Inst: Menzies School of Health Research Grant Type: NHMRC Project Grants
Main RFCD: Health Promotion
Total funding: $666,593
Title of research award:
A structured systems approach for improving health promotion practice for chronic diseases in Indigenous
communitiesA structured systems approach for improving health promotion practice for chronic diseases in
Indigenous communities
Lay Description (from application):
This project will trial a model for continuous improvement, with the aim of assisting health services and
community based organisations to improve the services they deliver to promote health and prevent chronic
disease in Indigenous communities.
Research achievements (from final report):
The extent to which evidence is used in practice together with the state of health centre system development
and functioning have contributed to the variable success of many primary health care and health promotion
programs in Indigenous communities. This study, undertaken in collaboration with four Indigenous Primary
Health Care health services in the Top End of the Northern Territory, explored the development and use of a
structured systems approach for improving health promotion. Together, we developed data collection tools
(health promotion Continuous Quality Improvement (CQI) tools) that systematically describe the scope and
quality of health promotion and the systems that support effective practice. Their ongoing use in a structured
quality improvement framework, based on the ABCD CQI approach, has enabled staff of participating health
centres to collect and use their data to set, and in many cases achieve, goals for health promotion quality
improvement.
Expected future outcomes:
The health promotion CQI tools are available and supported through One21Seventy, the National Centre for
Quality Improvement in Indigenous Primary Health Care. The tools are therefore now widely available to
support development, refinement and evaluation of health promotion programs, including Closing the Gap in
Indigenous health outcomes.
Name of contact:
Ms Nikki Percival
Email/Phone no. of contact:
nikki.percival@menzies.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 605831
Start Year: 2010
CIA Name: Dr Tsin Yeo
End Year: 2013
Admin Inst: Menzies School of Health Research Grant Type: Early Career Fellowships (Australia)
Main RFCD: Infectious Diseases
Total funding: $251,592
Title of research award:
Consequences of decreased vascular nitric oxide bioavailability in the pathogenesis of severe
malariaConsequences of decreased vascular nitric oxide bioavailability in the pathogenesis of severe malaria
Lay Description (from application):
Media Summary not available
Research achievements (from final report):
Based on results of clinical research studies conducted during my fellowship I have 1 In falciparum malaria Delineated novel pathogenic mechanismsm of severe falciparum malaria and evaluated L-arginine as an
adjunctive agent in adults and children in Indonesia. This was done with funding from a NHMRC project grant
605807 from 2010-2014. I have also collaborated on similar studies in African children in Tanzania. These
studies have led to the publication of 18 papers in peer-reviewed journals and 4 in conferences which have
increased the understanding of novel pathogenic mechanisms of severe falciaprum malaria and identified new
potential targets for adjunctive therapy for this disease which has a 10-20% mortality rate. 2 In human knowlesi
malaria - Conducted studies detailing the epidemiology diagnosis clinical features and management of this
emerging zoonotic malaria Plasmodium knowlesi in Malaysian Borneo. This is currently being done with
funding from a NHMRC project grant 1045156 funded from 2013 to 2015. Results from our study have shown
that the rates of knowlesi malaria are increasing and that it is as virulent and dangerous as falciparum malaria
currently the human malaria with the highest mortality rate. Our studies also showed that use of Artemisinin
Combination Therapies ACT instead of chloroquine the standard therapy was associated with a faster rate of
parasite clearance in both severe and uncomplicated knowlesi malaria. These findings have since being used by
the Malaysian Ministry of Health 2013 Guidelines on the Management of Malaria as well as the World Health
Organization in their 2013 Guidelines on management of severe malaria. This project has up to the time of the
report published 11 papers in peer-reviewed journals and 4 conference presentations.
Expected future outcomes:
We are currently continuing clinical studies to further delineate the pathogenic mechanisms of severe
falciparum malaria and also continuing studies of adjunctive agents. I am also continuing both hospital and
community based studies to further determine the factors resulting in the increased incidence of knowlesi
malaria and studies to determine the best treatment for knowlesi malaria
Name of contact:
Tsin Wen Yeo
Email/Phone no. of contact:
Tsin.Yeo@menzies.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 143541
Start Year: 2001
CIA Name: Prof Christina Mitchell
End Year: 2003
Admin Inst: Monash University
Grant Type: NHMRC Project Grants
Main RFCD: Cellular Interactions (incl. Adhesion, Matrix, Cell Wall)
Total funding: $423,564
Title of research award:
Characterization of a novel family of LIM-only proteins; role in skeletal muscle
differentiation.Characterization of a novel family of LIM-only proteins; role in skeletal muscle differentiation.
Lay Description (from application):
This project aims to study the role of a new family of related proteins in skeletal muscle. One of these proteins
has been shown to be deficient in muscle cancers. These proteins are important for the development and normal
functioning of muscle. Related proteins have been shown to be linked with heart failure in animals. These
proteins also potentially interact with proteins causing muscular dystrophy. We have identified a new family
of proteins in skeletal muscle. These proteins contain so-called LIM domains, which mediate binding to other
proteins. This study proposes to determine how these proteins influence skeletal muscle development and the
consequences of abnormal levels of these proteins. This may lead to insights into the mechanism of cardiac
failure, muscle cancers and muscular dystrophy.
Research achievements (from final report):
This grant has examined the role of a family of muscle proteins called FHL proteins and how they regulate
both heart and peripheral skeletal muscle function. Inherited muscle disorders of the heart and peripheral
muscle include cardiomyopathies and muscular dystrophies that cause significant muscle weakness and in
some cases early death, due to respiratory failure or muscle weakness. We have identified a new family of
proteins - the FHL proteins that may play a major role in both inherited and acquired muscle diseases. We have
shown that the FHL proteins if overexpressed disrupt muscle function and lead to a form of muscle
hypertrophy. This is of significance given others have identified that a family member FHL1 is highly
expressed in some conditions associated with cardiac hypertrophy. We have identified a potential mechanism
by which FHL-1 may cause such muscle enlargement, which despite an increase in muscle size the muscle is
actually weakened. We have shown the FHL1 protein forms a complex with a structural protein called myosin
binding protein C, which itself binds myosin, a protein critical to muscle function. We have demonstrated
FHL1 expression regulates myosin binding protein C activity. This is of significance given myosin binding
protein C is mutated in a significant number of inherited diseases associated with cardiac abnormalities leading
to cardiac death, in particular in young adults.
Expected future outcomes:
These studies should lead to further understanding of the molecular mechanisms leading to inherited and
acquired heart disease which may lead to novel therapies.
Name of contact:
Christina Mitchell
Email/Phone no. of contact:
christina.mitchell@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 143548
Start Year: 2001
CIA Name: Prof Henry Krum
End Year: 2003
Admin Inst: Monash University
Grant Type: NHMRC Project Grants
Main RFCD: Clinical Pharmacology and Therapeutics
Total funding: $196,018
Title of research award:
Role of urotensin II, a novel vasoconstrictor factor, in cardiovascular diseaseRole of urotensin II, a novel
vasoconstrictor factor, in cardiovascular disease
Lay Description (from application):
Urotensin II (UII) is a newly discovered peptide that may play an important role in human health and disease.
It has been found to be a potent constrictor (narrower) of blood vessels and therefore may be involved in
diseases such as hypertension (high blood pressure) and heart failure (weak heart muscle disease).
Furthermore, many other factors that constrict blood vessels have also been found to have effects on key
organs, such as the heart. Our preliminary data suggests that this is also true of urotensin II. The proposal
studies seek to determine the role of urotensin II in the : (i) periphery, by assessing contraction of forearm
vessels to low doses of UII in normal volunteer subjects and patients with hypertension & heart failure; (ii)
heart, by measuring expression of UII and its receptor in normal and failing human heart tissue; the UII
response to experimental heart attack in the rat and in cell culture of important heart cells; (iii) general
circulation, by measuring plasma levels in health and disease. The significance of this project is that if it is
found that UII plays an important role in these diseases, then agents that block this system may represent a
major therapeutic advance in the management of these diseases.
Research achievements (from final report):
We conducted a very comprehensive series of evaluations of the role of urotensin II within the myocardium
itself. Up until then the thought was that urotensin II was primarily acting on the cardiovascular system via
effects on vascular tone., We were the first to demonstrate that urotensin II exerts pro-fibrotic effects within the
myocardium and also has hypertrophic effects in the setting of urotensin II receptor up-regulation. We also
characterised the pathway by which urotensin II exerts its effect, the g-alpha Q/ras pathway. Finally this series
of experiments comprehensively explored the UII system in the post-MI setting, observing for the first time the
up-regulation of both the ligand and its receptor (UII-R) in post-MI compared to sham operated animals. These
data were recognised by the international medical community as being of significant importance by virtue of
numerous presentations at major meetings, AHA, ESC and ACC. Furthermore these data resulted in a major
primary publication in Circulation Research with a number of further invited publications., We also sought to
characterise the role of urotensin II in human disease by evaluation of effects of urotensin II on vascular tone
using iontophoresis with laser Doppler velocimetry. We compared responses to urotensin II in skin microcirculation of chronic heart failure patients to normal subjects. This was the first administration ever of
urotensin II exogenously to patients with disease. There was a dose-dependent vasodilation to urotensin II in
normal subjects but dose dependent vasoconstriction in CHF patients. This data was published rapidly as a
Brief Rapid Communication in Circulation., In summary, the grant has permitted us to make a number of novel
and we believe, highly relevant, observations that will guide the direction of future urotensin II research and
approaches to therapeutic intervention in this system.
Expected future outcomes:
We expect the totality of the data to guide future clinical research in the area of UII and cardiovascular disease.
We plan to go onto examine the role of UII in diabetes with and without heart failure in collaboration with
Professor Richard Gilbert in our Program Grant to start in 2005. We will also study UII receptor antagonists in
animal models and man.
Name of contact:
Henry Krum
Email/Phone no. of contact:
NHMRC Research Achievements - SUMMARY
henry.krum@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 143564
CIA Name: A/Pr Robert Widdop
Admin Inst: Monash University
Main RFCD: Basic Pharmacology
Total funding: $692,040
Start Year: 2001
End Year: 2005
Grant Type: NHMRC Project Grants
Title of research award:
Angiotensin AT2 receptor: a novel target for cardiovascular modulationAngiotensin AT2 receptor: a novel
target for cardiovascular modulation
Lay Description (from application):
The hormone, angiotensin II, circulates in the blood and increases blood pressure and thickens the heart and
blood vessels, all of which contributes to high blood pressure (hypertension). Angiotensin II causes these
excitatory effects by acting at particular target sites called AT1 receptors. Drugs called AT1 receptor
antagonists are known to block these excitatory actions of angiotensin II at AT1 receptors. Consequently,
these compounds lower blood pressure in humans because they block the ongoing stimulatory action of
angiotensin II. However, it is now thought that angiotensin II may also be able to act at another target site
(AT2 receptor) to cause opposite effects, i.e. decrease blood pressure and inhibit growth effects. Therefore,
this project will examine if direct stimulation of AT2 sites can alter blood flows measured in different body
regions in hypertensive rats as part of their mechanism to lower blood pressure. In addition, the effects of
continuous stimulation of the AT2 site will be examined in hypertensive rats which will be implanted with a
radiotransmitter to measure blood pressure without interference, and afterwards, structural measurements of the
heart and blood vessels will be made. Additionally, this project will investigate whether stimulation of the
AT2 site also contributes to the blood pressure-lowering effect of drugs already mentioned (AT1 receptor
antagonists). The rationale for this is that the hormone angiotensin II is still 'free' to act at the AT2 site, even
with AT1 receptors being blocked, and lower blood pressure. These studies will determine if stimulation of
AT2 sites contributes to the beneficial effects (i.e. decreased blood pressure and decreased cardiovascular
growth) of AT1 receptor antagonists in the treatment of high blood pressure. More importantly, these findings
may also identify a new therapeutic target site (AT2 receptor) for drug development in the treatment of
cardiovascular disease.
Research achievements (from final report):
This project examined the functional cardiovascular effects when a naturally occurring hormone, called
angiotensin II, binds to a particular binding site in the body, known as the angiotensin II subtype 2 receptor
(AT2R)., , These studies provided proof-of-concept for the hypothesis that the AT2R can mediate the
relaxation of blood vessels leading to a decrease in blood pressure, when it is stimulated by angiotensin II or by
other synthetic compounds. In addition, it was shown that this mechanism of action also contributes the clinical
effect of 'sartan'-type compounds which are available for the treatment of high blood pressure. There are also
other break-down products of angiotensin II that are circulating in the body. We have also shown that some of
these shorter fragments of angiotensin II are able to activate the AT2R site and cause relaxation of blood
vessels., , Thus, these studies have identified the importance of the AT2R as playing a role in the regulation of
blood pressure, and have illustrated the complex interplay between different hormonal angiotensin fragments in
the circulation. The potential benefits arising from these studies are that we have confirmed that the AT2R may
be a therapeutic target that could be pharmacologically exploited.
Expected future outcomes:
This project has identified the AT2R as a novel therapeutic target. Future studies will examine whether or not
new synthetic compounds have biological effects to decrease blood pressure and associated cardiovascular
parameters, which would indicate that such compounds represent a new therapeutic class of drugs.
Name of contact:
Robert Widdop
Email/Phone no. of contact:
NHMRC Research Achievements - SUMMARY
robert.widdop@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 143569
CIA Name: Prof Hatem Salem
Admin Inst: Monash University
Main RFCD: Haematology
Total funding: $406,528
Start Year: 2001
End Year: 2003
Grant Type: NHMRC Project Grants
Title of research award:
Cytoskeletal regulation of platelet adhesion and thrombus formationCytoskeletal regulation of platelet adhesion
and thrombus formation
Lay Description (from application):
Platelets are small specialised blood cells that are essential for normal blood clotting and repair of damaged
blood vessels following injury. When platelets stick to sites of blood vessel injury they undergo dramatic
changes in their shape and internal structure that are necessary for these cells to spread over the damaged
surface and facilitate the formation of a stable blood clot. We are studying these changes in the intracellular
structure (cytoskeleton) of platelets and how these events might regulate the reactivity of platelets and their
ability to adhere to blood vessels. An understanding of these processes will add significantly to our knowledge
of how blood clots. This information is relevant to many human diseases such as heart attack and stroke.
Research achievements (from final report):
Our research during the period of the award focussed on the identification and characterisation of novel
mechanisms involved in the regulation of platelet adhesive function and thrombus formation. A better
understanding of the mechanisms by which platelet function is regulated will add significantly to our
knowledge of how potentially life threatening blood clot formation is controlled in cardiovascular diseases
including heart attack and stroke. We have identified that the platelet actin cytoskeleton plays an important role
in regulating platelet adhesion and thrombus formation on a von Willebrand factor (vWf) surface under
physiological and pathological blood flow conditions. We demonstrated that thrombus formation, specifically
regulation through changes to the actin cytoskeleton was dependent on the prevailing shear conditions; on a
vWf matrix under low shear conditions, thrombus formation was significantly increased when actin
polymerisation was inhibited, whereas under high shear conditions, inhibiting actin polymerisation resulted in
the formation of larger than normal thrombi which were highly unstable and prone to embolise from the vWf
surface. These results suggest the potential importance of the platelet cytoskeleton in preventing abnormal
thrombus formation in the circulation. We also investigated the mechanisms by which the cytoskeleton
regulates the adhesive function of the platelet GPIb/V/IX receptor, which is critical for mediating platelet
adhesion to vWf. We demonstrated that although inhibiting actin polymerisation results in enhanced
GPIb/V/IX-dependent platelet aggregation processes, this upregulation does not involve affinity modulation of
the receptor, unlike the regulation of integrin function. In contrast, regulation of GPIb/V/IX appears to involve
vWf dependent actin polymerisation and potential changes in receptor clustering and/or avidity, based on vWf
binding studies and the adhesion of GPIb/V/IX transfected cells to vWf.
Expected future outcomes:
N/A
Name of contact:
Prof Hatem H Salem
Email/Phone no. of contact:
hatem.salem@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 143603
CIA Name: A/Pr Roger Evans
Admin Inst: Monash University
Main RFCD: Systems Physiology
Total funding: $410,617
Start Year: 2001
End Year: 2005
Grant Type: NHMRC Project Grants
Title of research award:
Renal medullary blood flow: regulation by paracrine, endocrine and neural factorsRenal medullary blood flow:
regulation by paracrine, endocrine and neural factors
Lay Description (from application):
High blood pressure is a condition afflicting more than 10% of our community, and is the leading risk factor
for stroke and heart disease. The kidneys play a critical role in control of blood pressure under normal
conditions, and probably also in the initiation and maintenance of high blood pressure. This influence is
exerted both through the excretion of salt and water, and by the release of substances into the circulation that
affect blood pressure (hormones). Recent experiments performed by us and others have indicated that the inner
part of the kidney (the medulla) is critical in these functions, which appear to be regulated by the level of blood
flow in the medulla of the kidney. Our recent experiments also show that hormones and nerves have diverse
effects on blood flow in the different regions of the kidney, showing that these factors can differentially affect
blood pressure depending on their effects on medullary blood flow. Importantly, these hormones and nerves do
not act in isolation, but act in concert, and in association with so called 'second messenger' systems that act
locally to directly affect the contraction of muscle in blood vessels, and so blood vessel size. The experiments
described in this application are aimed at determining how circulating and locally acting hormones, and the
nerves in the kidney, interact together to control blood flow in the different regions of the kidney. This will
help us understand how blood flow to the medulla of the kidney is regulated normally, so that we can begin to
understand how malfunction of these systems can contribute to the development of high blood pressure.
Research achievements (from final report):
The blood circulation of the kidney is really two circulations in one. All blood flows through the outer part of
the kidney (cortex), but only ~10% flows through the inner part (medulla). We have studied how blood flow in
the kidney medulla is regulated, because this has important effects on the functions of this part of the kidney.
These functions include control of blood pressure and conservation of the body's water. We found that various
hormones, and activation of the nerves in the kidney, have diverse effects on blood flow in the kidney medulla
compared with the cortex. We have identified many of the mechanisms responsible for this. Firstly, the
structure of the kidney circulation protects the medulla from many of the factors that reduce blood flow in the
cortex. Secondly, locally acting hormones are released within the kidney to protect the medulla from reduced
blood flow. These include the gas nitric oxide, and a group of hormones called prostaglandins. There are also
some hormonal factors that reduce blood flow in the medulla more than in the cortex. This seems to be due to
the release of specific locally acting hormones within the cortex, that protect it from reduced blood flow. In
other experiments, we have shown how hormonal systems modify the influence of the kidney's nerves on blood
flow in the cortex and medulla.
Expected future outcomes:
Our ongoing and future studies will show: (i) how control of blood flow to the cortex and medulla is altered in
chronic high blood pressure, (ii) how the delivery of oxygen to kidney tissue is regulated, and (iii) how blood
flow within the medulla is regulated. Our results will provide the basis for new ways to treat, or even cure or
prevent, high blood pressure and kidney disease.
Name of contact:
Roger Evans
Email/Phone no. of contact:
roger.evans@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 143615
CIA Name: A/Pr Robert Medcalf
Admin Inst: Monash University
Main RFCD: Gene Expression
Total funding: $241,528
Start Year: 2001
End Year: 2003
Grant Type: NHMRC Project Grants
Title of research award:
Post transcriptional regulation of the plasminogen activator inhibitor type 2 genePost transcriptional regulation
of the plasminogen activator inhibitor type 2 gene
Lay Description (from application):
The process of wound healing, removal of blood clots, cell migration and the metastatic spread of cancers
requires the recruitment of specialised proteases. These proteases act primarily to degrade other proteins,
mainly in the extracellular space, which in turn allow cells to move around, wounds to close, and blood clots to
disappear. The plasminogen activating system is one of the most important enzyme systems involved in these
events. One of the proteases that cleaves plasminogen to its active form, plasmin, is urokinase (u-PA).
Plasminogen activator inhibitor type 2 (PAI-2) is a serine protease inhibitor that inhibits u-PA activity. The
degree of u-PA activity therefore depends on the relative levels of u-PA and PAI-2. In addition to controlling
u-PA activity, PAI-2 also influences intracellular events including cell proliferation, differentiation and
apoptosis. PAI-2 protein and mRNA levels are substantially modulated by many cytokines and growth factors.
This project addresses the molecular mechanisms underlying the regulation of PAI-2 gene expression. We have
recently shown that a significant degree of PAI-2 regulation occurs at the level of PAI-2 mRNA stability, and
we have identified two regions within the PAI-2 mRNA that play a role in this process. Both regions provide
binding sites for cellular proteins. We have identified one of these binding proteins to be HuR, a protein that
has recently been shown to control the stability of other mRNAs. The specific aims of this project are firstly, to
determine the role of HuR in the control of PAI-2 mRNA stability, and secondly, to clone a characterise the
other PAI-2 mRNA binding proteins we have identifed. An understanding of how cells modulate levels of
PAI-2 mRNA will significantly add to the broader field of gene regulation and may also provide new clues to
influence PAI-2 levels in the body.
Research achievements (from final report):
The plasminogen activator inhibitor type 2 (PAI-2) gene encodes for an inhibitor of a protease called
urokinase. Urokinase is involved in the spread of cancer and the presence of PAI-2 limits the activity of
urokinase. PAI-2 is therefore able to limit cancer spreading via inhibiting urokinase. The basic aim of the
project was to determine how this protease inhibitor is regulated in cells. PAI-2 is subject to posttranscriptional regulation and we have shown that the longevity of the PAI-2 transcript is strongly influenced
by sequences located within the 3'-untranslated region (3'-UTR). We had previously identified HuR as a
protein that binds to the mRNA instability element in the 3'-UTR. One of the aims of this project was to
identify and characterise additional proteins that associate with this instability element in the 3'-UTR. This was
successful as we identified by genetic means, a cytoplasmic protein called tristetraprolin (TTP) as an important
protein that binds to the instability element in the 3'-UTR and results in PAI-2 mRNA turnover. We are
currently seeing how HuR and TTP interact in the regulation of PAI-2 mRNA turnover. We also identified and
characterised an instability element within exon 4 of the PAI-2 coding region and demonstrated that this region
provides a binding site for proteins with a molecular weight of 52-54 kD. , Although PAI-2 inhibits urokinase
which is an extracellular protease, PAI-2 exists predominantly intracellularly. During the course of this project,
we also assessed the functional role of PAI-2 in monocytes. Using THP-1 cells that cannot express PAI-2, we
stably expressed either wild-type or mutant variants of PAI-2 into these cells. We demonstrated that PAI-2
caused in a significant decrease in the proliferation rate of the THP-1 cells and also altered the ability of these
cells to differentiate in response to phorbol ester. Hence, a novel role for PAI-2 has been identified.
Expected future outcomes:
It is expected that we will be able to better understand the role of TTP in the regulation of PAI-2 mRNA
turnover, and how it is involved with HuR and other factors that influence PAI-2 mRNA instability. We also
expect to reveal novel intracellular targets for PAI-2 that are involved in cell proliferation.
NHMRC Research Achievements - SUMMARY
Name of contact:
Robert Medcalf
Email/Phone no. of contact:
robert.medcalf@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 143619
CIA Name: Dr Richard Lang
Admin Inst: Monash University
Main RFCD: Cell Physiology
Total funding: $411,623
Start Year: 2001
End Year: 2003
Grant Type: NHMRC Project Grants
Title of research award:
Molecular mechanisms of nitric oxide modulation of calcium-activated potassium channels in smooth
muscleMolecular mechanisms of nitric oxide modulation of calcium-activated potassium channels in smooth
muscle
Lay Description (from application):
The inappropriate production of nitric oxide (NO) is increasingly being linked to the pathogenesis of numerous
disease states such as septic shock, hypoxic-ischaemic brain damage, anti-microbial defense and inflammation.
In mammalian visceral smooth muscle organs, the release of NO plays an essential role in the processes that
underlie the endothelial-dependent relaxation of vascular smooth muscle, as well as the relaxation of many
smooth muscles evoked upon stimulation of intrinsic non-adrenergic non-cholinergic (NANC) inhibitory motor
nerves. It is becoming clear that the inappropriate release of NO may also contribute to a number of disorders
of visceral organs. In fact, NO donors and NO synthesis blockers are presently being tested in >15 NIH
sponsored clinical trials of treatments of such disparate diseases as acute myocardial infarction, endothelial
dysfunction during atherosclerosis or coronary heart disease, aspiration syndrome or persistent pulmonary
hypertension in infants, and hormone therapy in postmenopausal women. This project represents a unique
international collaboration of Drs Lang (Monash Uni.) and Neylon (Baker Inst.) with Dr Reinhart (Duke
Uni.)(Neylon et al 1999). We intend to establish the precise site and mechanisms of action of NO on both
naturally occurring and artificially reconstructed K channels obtained from intestinal and vascular smooth
muscle.
These experiments will for the first time establish the molecular site of NO action on the K channels
that set the membrane potential and excitability of smooth muscle. This specific knowledge may well lead to a
rational development of drugs that specifically restore smooth muscle function in a number of disorders such as
slow gastric emptying and slow transit constipation.
Research achievements (from final report):
This project has funded two avenues of our research for the last 3 years: , (i) the post-junctional non guanylate
cyclase dependent actions of the nitric oxide. We have examined the effects of NO* donors on the activity of
large conductance Ca-activated K (BKCa) channels in excised membrane patches of guinea-pig intestine. NO*
donors increase BKCa channel activity in the presence of the specific guanylyl cyclase blocker ODQ (10
microM), excluding the involvement of either cytosolic or membrane-bound guanylyl cyclases. NEM (1 mM)
prevented the excitatory action of NOCys suggesting that the cysteine thiols must be S-nitrosylated by NOCys.
We have also examined whether alkanethiolation of cysteine residues by charged methanethiosulfonate (MTS)
reagents can prevent the actions of NOCys. Previously exposing excised patches to negatively-charged MTSES
(2.5 mM for 2-5 min) prevented any further activation of BKCa channels by NOCys (10 microM). It was
concluded that MTSES would be selectively binding to cysteine residues within basic regions of the channel
protein. , (ii) the origin of pacemaker activity in two pelvic smooth muscle organs, the ureter and prostate.
Recently we have demonstrated in the muscle wall (stroma) of the guinea pig prostate that spontaneous
contractions and are little affected by blockers of neuronal propagation or spontaneous neurotransmission from
cholinergic, adrenergic and sensory nerves. We have also demonstrated the presence of cKit immuno-reactive
interstitial cells of Cajal, which may well act as the pacemaker in this organ, as well as integrate the many
neural inputs present.
Expected future outcomes:
This discovery has caused some excitement in the prostate literature as it raises the possibility that slow wave
activity is responsible for the spontaneous tone in the prostate and therefore an avenue of intervention in
patients with prostatic disease
Name of contact:
NHMRC Research Achievements - SUMMARY
R Lang
Email/Phone no. of contact:
rick.lang@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 143678
CIA Name: Prof Shaun Jackson
Admin Inst: Monash University
Main RFCD: Haematology
Total funding: $196,528
Start Year: 2001
End Year: 2003
Grant Type: NHMRC Project Grants
Title of research award:
Investigation of shear-sensitive signalling pathways in human plateletsInvestigation of shear-sensitive
signalling pathways in human platelets
Lay Description (from application):
Platelets are extremely important cells that control bleeding by sticking to injured blood vessels to form a blood
clot. Excessive clotting can lead to fatal vascular events such as heart attacks and strokes. On the other hand,
defects in blood clotting can result in life threatening bleeding problems. Platelets stick to the wall of a blood
vessel when receptors on the surface of these cells interact with materials (ligands) that are exposed when the
vessel wall is injured. The "stickiness" or adhesive behaviour of platelets is controlled by many proteins
(enzymes) which are contained inside these cells. These enzymes transmit messages from platelet receptors on
the surface into the cell interior, thereby controlling platelet behaviour. We are in the process of identifying
several types of enzymes which are responsible for controlling platelet "stickiness". Our research will provide a
better understanding of the complicated pathways regulating platelet stickiness and clot formation. The
knowledge gained from these studies may ultimately asssist in the design of specific drugs for the prevention
and/or treatment of heart attacks and strokes.
Research achievements (from final report):
We have made important progress in the understanding of the signalling mechanisms operating downstream of
the platelet adhesion receptors Glycoprotein (GP) Ib/V/IX and alpha(IIb) beta(3). This is a highly topical area
of research and as yet no consensus model has been developed to explain shear-activation of platelets. These
studies identified that GPIb/V/IX can induce intracellular calcium mobilisation critical for platelet activation.
Furthermore we showed using pharmacological inhibitors and knock-out mice that this signalling pathway is
mediated by activation of the tyrosine kinase Src and Src-induced activation of the the enzyme phospholipase
C gamma 2. In addition to these findings we also showed using these knock out mice that signalling
downstream of another important platelet receptor integrin alpha(IIb) beta(3) also utilises this signalling
pathway. Integrin alpha(IIb) beta(3) outside-in signalling plays an imporant role in sustaining firm platelet
adhesion and platelet-platelet aggregation at sites of thrombosis. We demonstrated in our findings that Src
kinase and PLCgamma2 play an indispensable role in maintaining firm platelet adhesion and activation under
flow. Given the important role for GPIb/V/IX and integrin alpha(IIb) beta(3) in mediating platelet adhesion and
activation at sights of arterial stenosis these findings may be important for the development of various
thrombotic diroders in cardiovascular disease.
Expected future outcomes:
Future studies will focus on defining the key signaling processes utilised by GPIb/V/IX and integrin alpha(IIb)
beta(3) to induce platelet activation and arterial thrombus formation under pathological blood flow conditions.
This work has the potential to identify new therapeutic targets for the prevention of cardiovascular disease.
Name of contact:
Shaun Jackson
Email/Phone no. of contact:
shaun.jackson@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 143872
CIA Name: Dr Simone Schoenwaelder
Admin Inst: Monash University
Main RFCD: Haematology
Total funding: $312,981
Start Year: 2001
End Year: 2004
Grant Type: Career Development Fellowships
Title of research award:
Investigate the role of the small RHoA in platelet functionInvestigate the role of the small RHoA in platelet
function
Lay Description (from application):
Not Available
Research achievements (from final report):
In the event of blood vessel injury, platelets elicit a series of responses that must be tightly regulated on a
number of levels. They must ensure the formation a thrombus that is of sufficient size to seal off the damaged
area, preventing blood loss, whilst not disrupting blood flow to vital organs by causing vessel occlusion.
Unfortunately, the consequences of disrupted platelet regulation are seen all too frequently in the clinical
setting, with the incidence of cardiovascular related diseases such as DVT, heart attack and stroke, remaining
some of the major causes of morbidity and mortality in the western world today. Therefore, it is pertinent to
gain a comprehensive understanding of the platelet-facilitated mechanisms regulating vessel wall maintenance.
Studies durign this funding period have focussed on examination of the major platelet receptor Integrin aIIbb3,
as it is critical in the physiological process of haemostasis and is also implicated in pathological thrombosis.
The adhesive properties of this integrin must be tightly regulated so as to prevent inappropriate platelet
interactions in the absence of vessel injury, but at the same time allow rapid up regulation of integrin affinity
upon vessel injury, in order to allow thrombus growth and prevent blood loss. Our studies suggesting distinct
yet cooperative roles for a family of enzymes, the Ras family members Rap1b and RhoA, in regulating integrin
aIIbb3 adhesive function. Ultimately, characterisation of the role of these small GTPases, and their relevant
regulatory molecules, including PI3 -kinase, may provide important insight into the key regulators of platelet
integrin function, and may offer novel insight into potential therapeutic targets with which to manipulate
platelet function.
Expected future outcomes:
By identifying the key enzymes and signalling pathways regulating aspects of platelet function, we hope to
utilise this knowledge to provide better strategies for drug design to combat thrombosis.
Name of contact:
Simone Schoenwaelder
Email/Phone no. of contact:
Simone.Schoenwaelder@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 166902
CIA Name: A/Pr Michael Hickey
Admin Inst: Monash University
Main RFCD: Rheumatology and Arthritis
Total funding: $377,037
Start Year: 2001
End Year: 2003
Grant Type: NHMRC Project Grants
Title of research award:
Role of Adhesion Molecules in Autoimmune VasculitisRole of Adhesion Molecules in Autoimmune Vasculitis
Lay Description (from application):
Lupus is a disease which causes inflammation and pain throughout the body. The inflammation is caused by
white blood cells attacking the lining of blood vessels in tissues. The aim of this project is to understand the
reasons why these white blood cells attack the blood vessel lining. This process is impossible to study in
humans. However, there is a strain of mouse which is affected by a disease which is very similar to human
lupus. This disease occurs spontaneously in these mice. Using a microscope, it is possible to study the tiny
blood vessels which are affected by this disease in these mice . Under the microscope, it is possible to see the
white blood cells as they undergo the process of attacking the blood vessel lining. Visualizing this attack then
allows us to study it and determine which molecules are important in causing this damaging inflammatory
response. Specifically I will examine diseased blood vessels in the skin and brain of these mice, two of the
tissues most dramatically affected by this disease. This information should help us gain an increased
understanding of lupus as it affects humans.
Research achievements (from final report):
The results of these studies indicate that white blood cells are attracted to the blood vessel lining of various
tissues in the human disease, systemic lupus erythematosus (SLE) where they can act to injure the blood vessel
and tissue. We were also able to work out which molecules on the blood vessel lining were responsible for this
attraction. This knowledge allows us in future experiments to test ways of stopping these molecules from
working or preventing from being made by the blood vessel lining. These types of interventions have the
potential to reduce the damaging inflammation which occurs in the tissues of SLE patients.
Expected future outcomes:
N/A
Name of contact:
N/A
Email/Phone no. of contact:
N/A
NHMRC Research Achievements - SUMMARY
Grant ID: 182814
Start Year: 2002
CIA Name: Prof Alexander Smith
End Year: 2005
Admin Inst: Monash University
Grant Type: Established Career Fellowships
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $527,750
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
Over the period of this research fellowship I have relocated from the Baker Medical Research Institute where I
was an Associate Director to Monash University. I took with me a talented team of investigators with a broad
depth of experience and expertise in physiology, biochemistry and proteomics. Research from this group has
generated over 50 publications in top ranked international journals despite the obvious disruption of the move
to Monash . Over the last 5 years I have been invited to edit special issues of J Neuroscience Research and
Cellular and Molecular Life Sciences and have authored 4 book chapters, 4 chapters for conference
proceedings and 2 invited reviews. In addition, over this period, I have received invitations to speak at 10
international meetings (including 6 plenary lectures), and 9 national meetings and have chaired 14
symposium/plenary sessions at national and international scientific meetings. Also within the Fellowship
period, I have been invited to become a handling editor for Journal of Neurochemistry and join the editorial
board of Molecular and Cellular Proteomics as well as being a foundation editorial board member for two new
journals, Protein & Peptide Letters and International Journal of Peptide Research and Therapeutics. I have been
involved in many societies and have been on the organising committees for many meetings. I was Associate
Director at the Baker Medical Research until August 2004. At Monash University, I am foundation director for
Biomedical Proteomics and a member of the Monash University Faculty of Medicine Research Committee. For
the last four years I have served on the NH&MRC Biochemistry grant review panel, the last two as chairman. I
am a co-founder of the proteomics-based biotechnology company, Cryptome Research Pty Ltd., and I am a
non-executive director of Auspep Pty Ltd. My research laboratory is currently funded by four (2 as CIA)
NH&MRC and one ARC project grants
Expected future outcomes:
The move to the Department of Biochemistry and Molecular Biology at Monash University allows increased
access to grants and students, a major impediment at the Baker Medical Research Institute, which was off
campus. Taking all the above into account, I would be confident of an increase in research profile and
productivity over the next five years.
Name of contact:
Alexander Ian Smith
Email/Phone no. of contact:
Ian.smith@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 194210
CIA Name: Prof Shaun Jackson
Admin Inst: Monash University
Main RFCD: Haematology
Total funding: $221,210
Start Year: 2002
End Year: 2004
Grant Type: NHMRC Project Grants
Title of research award:
Investigation of novel mechanisms regulating platelet reactivity during haemostasis and
thrombosisInvestigation of novel mechanisms regulating platelet reactivity during haemostasis and thrombosis
Lay Description (from application):
Platelets are small specialised blood cells that are critical for normal blood clotting and blood vessel repair
following injury. We are studying the processes that enable platelets to stick to the site of vessel injury and to
each other to form a stable blood clot. These very processes, when unchecked, are responsible for the formation
of harmful blood clots in the bloodstream that may block blood vessels in the heart or brain and result in a heart
attack or stroke. Many factors control how big and how rapidly a blood clot grows and whether it becomes
harmful enough to lead to a heart attack or stroke. One of these factors is the level of platelet 'reactivity' or
'stickiness' . We are working towards a better understanding of how platelet reactivity is regulated and how this
dictates the potential of a blood clot to become harmful. This knowledge will not only increase our knowledge
of blood clot formation in health and disease, but also help in the development of new therapies for the
prevention of heart attack and stroke.
Research achievements (from final report):
Many factors control how big anfd how rapidly blood clots grow, and whether they become harmful enough to
lead to heart attack and stroke. One of these factors is the level of platelet 'reactivity' or 'stickiness'. We have
examined how platelet reactivity is regulated and how this dictates the potential of a blood clot to become
harmful. Our findings have demonstrated that platelets possess a feedback mechansim to limit excessive
stickiness, in order to keep blood clots at a size that is not harmful to cause vessel blockade., These findings
will not only increase our knowledge of blood clot formation in health and disease, but may also help in the
development of new therapies for the prevention of heart attack and stroke.
Expected future outcomes:
In further studies, we have evidence identifying a factor responsible for regulating platelet reactivity. We will
investigate the way in which this factor regulates platelet stickiness, and whether it may provide useful
information to help identify individuals at risk of heart attack/stroke.
Name of contact:
Shaun Jackson
Email/Phone no. of contact:
Shaun.Jackson@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 194214
Start Year: 2002
CIA Name: Dr Daniel Grant
End Year: 2004
Admin Inst: Monash University
Grant Type: NHMRC Project Grants
Main RFCD: Foetal Development and Medicine
Total funding: $421,980
Title of research award:
Heart-lung interactions determine right ventricular function in the perinatal period.Heart-lung interactions
determine right ventricular function in the perinatal period.
Lay Description (from application):
Birth, and the ensuing stress of newborn life, requires the heart to dramatically increase its level of functioning.
Understanding how this process occurs remains a key problem as the heart lacks any ability to increase its level
of functioning immediately before birth. Failure to effect this increase in heart function promptly at birth has
serious implications for the well being of the newborn and represents a major problem in newborn medicine.
Of the 250,000 babies born each year in Australia, as many as 5,000 require intensive care primarily for
cardiorespiratory complications. Accurate diagnosis and effective treatment of these infants demands
knowledge of the normal heart adaptations that accompany birth, adaptations that are critically linked to the
way in which the heart and the lungs interact. This project investigates how interactions between the heart and
the lungs determines heart function throughout life. By understanding this process we will provide essential
information that will aid the diagnosis and treatment of sick neonates undergoing intensive care.
Research achievements (from final report):
Failure to effect the major cardiovascular transformations that are essential to increment cardiac output and
oxygen delivery promptly at birth has serious implications for the well being of the newborn and represents a
major problem in perinatal medicine. Of the 250,000 babies born each year in Australia, 5,000 require intensive
care primarily for cardiorespiratory complications, amounting to $150 million per annum. Although precise
figures are not available in the literature, the observation that 20-30% of the babies in Neonatal Intensive Care
Unit (NICU) at Monash Medical Centre receive volume and inotropic support indicates that cardiac
dysfunction represents a life threatening complication in critically ill infants. By compromising the perfusion of
vital organs, cardiac dysfunction also contributes to secondary complications such as cerebral ischemia,
intracranial haemorrhage, necrotizing enterocolitis, and renal impairment, each of which contribute
significantly to neonatal mortality and morbidity. Clinical management of these babies conventionally treats
the lung and the heart as separate entities, a view that fails to appreciate the potential for adverse interactions
between these two systems. Our studies addressed how the normal cardiorespiratory transformations that
accompany birth are critically linked to how the heart and the lungs interact.
Expected future outcomes:
Understanding the mechanisms that interact to determine heart function before and after bith will provide the
basis upon which improved clinical treatments for cardiac dysfucntion in the newborn can be developed.
Name of contact:
Adrian Walker
Email/Phone no. of contact:
Adrian.Walker@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 194246
CIA Name: Prof Barry McGrath
Admin Inst: Monash University
Main RFCD: Nephrology and Urology
Total funding: $326,980
Start Year: 2002
End Year: 2004
Grant Type: NHMRC Project Grants
Title of research award:
A Randomised controlled trial of high dose folic acid to slow the progression of atheroma in renal failure
(194246)A Randomised controlled trial of high dose folic acid to slow the progression of atheroma in renal
failure (194246)
Lay Description (from application):
The Atherosclerosis and Folic Acid Supplementation Trial (ASFAST) is examining the effect of high dose
folic acid supplementation on the development of desease of the heart and blood vessels in people with kidney
failure. Subjects in the study take 15mg folic acid daily or a dummy tablet for 3 to 5 years. Folic acid is known
to reduce the levels of a substance called homocysteine which is elevated in people with kidney disease.
Homocysteine has been associated with disease of the heart and blood vessels and these diseases occur very
commonly in people who also have kidney failure. I t is hoped that by using folic acid to reduce the levels of
homocysteine, we can reduced the amounbt of heart and blood vessel disease in people with kidney failure.
Research achievements (from final report):
Hyperhomocysteinaemia is a potential contributor to the high rates of cardiovascular morbidity and mortality in
patients with chronic renal failure (CRF). The Atherosclerosis and Folic Acid Supplementation Trial
(ASFAST) was an Australian/New Zealand randomised, double blind, placebo controlled trial that aimed to
establish whether high dose folic acid would slow the progression of atherosclerosis and reduce cardiovascular
events in patients with CRF. 315 subjects, mean age 57 years received folic acid 15mg daily or an identical
placebo tablet and followed for a median of 3.6 years. After treatment folate levels were increased 3-fold in the
folic acid group and resulted in a 19% reduction in total homocysteine levels. There was however no
significant effect of this on atheroma progression, rate of cardiovascular events or any other measure of artery
health. We conclude that high dose folic acid does not slow atheroma progression or improve cardiovascular
morbidity or mortality in patients with CRF.
Expected future outcomes:
Our study may have missed a small effect (<30%) but a much larger study would be required to determine this.
The study has confirmed the utility of arterial function measures, particularly central arterial compliance, in
predicting cardiovascular outcome in this high risk group. , The study is the largest prospective study of CRF in
Aust. and identifies areas for improvement in CVD management.
Name of contact:
Prof Barry P Mcgrath
Email/Phone no. of contact:
barry.mcgrath@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 194255
Start Year: 2002
CIA Name: Dr Melanie Pritchard
End Year: 2004
Admin Inst: Monash University
Grant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $431,310
Title of research award:
The role of the calcineurin negative regulator, DSCR1, in heart development and hypertrophy.The role of the
calcineurin negative regulator, DSCR1, in heart development and hypertrophy.
Lay Description (from application):
Congenital heart defects in the young and heart disease later in life place a heavy burden on our society in
terms of illness, disability and death and are very costly in terms of the health care budget. Failure of heart
valve development and holes in the heart, are very common abnormalities occurring in nearly 1 % of all live
births. This type of anomaly is also observed in about 44 % of individuals with Down syndrome, which results
when individuals carry an extra copy of chromosome 21. Thus, it is likely that a gene located on human
chromosome 21 contributes to this pathology and indeed our work on the identification of genes with the
potential to cause the heart defect observed in Down syndrome, has led to the discovery of a gene called
DSCR1. DSCR1 is a negative regulator of a biological pathway which when disturbed in the heart can lead to
developmental heart malformations, similar to the type seen in Down syndrome, and when over stimulated can
result in the abnormal growth of the heart seen in humans with hypertension and heart disease. If we are to
make rational decisions about the design of potential treatments for heart defects and disease, we firstly need to
understand how these biological pathways work and how molecules such as DSCR1 regulate them. We aim to
investigate how DSCR1 functions by generating mice that lack the gene, to see what happens when it is
missing and mice over expressing the gene to investigate the consequences of elevated levels of DSCR1
analogous to the situation in Down syndrome.
Research achievements (from final report):
Our research to identify genes responsible for the characteristic heart defect associated with Down syndrome
had previously identified DSCR1. DSCR1 is a negative regulator of a biological pathway which when
disturbed in the heart can lead to developmental heart malformations, similar to the type seen in Down
syndrome, and when over stimulated can result in the abnormal growth of the heart seen in humans with
hypertension and heart disease. The major objective of this proposal was to employ cell- and animal-based
approaches to elucidate the role of DSCR1 in cardiac development and growth. We established mice in which
DSCR1 was over-expressed, then examined the hearts from these mice during normal growth and during
exposure to a chemically induced growth stimulus to mimic a human heart disease condition. Since DSCR1 is a
natural suppressor of a pathway that becomes over active in heart disease, we considered that if we caused an
elevation of DSCR1 levels in the heart that we could further suppress this pathway and either prevent or
reverse the enlargement of the heart associated with heart failure. Our expectation was that elevated levels of
DSCR1 would cause heart cells to be smaller in size resulting in a reduction of heart weight. We also expected
that an increased amount of DSCR1 would attenuate the growth in size of the heart that occurs when normal
mouse hearts are exposed to the chemical. We observed no difference between DSCR1 over-expressing and
control hearts for any parameter tested.
Expected future outcomes:
Our research is of value to the field of heart disease since therapies designed to elevate DSCR1 expression may
not be clinically effective. On the positive side, we show that there is no overt detrimental effect of increased
amounts of DSCR1 in the body.
Name of contact:
Melanie Pritchard
Email/Phone no. of contact:
melanie.pritchard@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 194274
Start Year: 2002
CIA Name: Dr David Phillips
End Year: 2008
Admin Inst: Monash University
Grant Type: Established Career Fellowships
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $781,750
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
This NHMRC Fellowship underpinned research into a relatively undescribed role of the growth factor, activin
and of its high affinity binding protein, follistatin, in inflammatory processes. Activin and follistatin were
originally characterised as reproductive hormone-like molecules, but my work first begun in 1996 on my return
from overseas post-doc position has established activin and follistatin as factors that are involved in the innate
immune response of all biological organisms. Specifically in terms of potential benefit, I have defined the
response of activin and follistatin in a variety of clinical inflammatory syndromes and begun to evaluate the use
of follistatin in blocking the effects of activin during acute inflammation. This has suggested that activin is
promising as a diagnostic marker of the severity of inflammation and may be prognostic of oucome, and that
follistatin used in therapeutic modes might be effective in improving outcome in inflammatory syndromes.
Expected future outcomes:
With appropriate commercial backing and phase 1 trials, it would be hoped that activin might prove a
diagnostic marker of the severity of clinical inflammatory processes and follistatin is showing strong promise
as a therapeutic option in inflammatory and other related processes such as fibrosis
Name of contact:
Dr David Phillips
Email/Phone no. of contact:
david.phillips@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 194331
CIA Name: Dr James Whisstock
Admin Inst: Monash University
Main RFCD: Enzymes
Total funding: $504,500
Start Year: 2002
End Year: 2006
Grant Type: Established Career Fellowships
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
James Whisstock is a structural biologist and a bioinformatician. His work primarily focuses on a family of
enzymes called proteases, as well as the molecules (inhibitors) that control them. Outcomes of this fellowship
include understanding the role of proteases and inhibitors in the nucleus, and the link between proteolysis and
the packaging of DNA. James Whisstock leads the NHMRC Program grant on protease systems biology, and in
2006 he was awarded the Science Ministers Prize for Life Scientist of the year.
Expected future outcomes:
Whisstock has established a major program on protease biology. Future outcomes will be anticipated to include
discoveries in the diverse areas of medicine such as cancer, heart disease and neurological disorders.
Name of contact:
James Whisstock
Email/Phone no. of contact:
James.Whisstock@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 194454
CIA Name: Dr Joanne Favaloro
Admin Inst: Monash University
Main RFCD: Basic Pharmacology
Total funding: $252,813
Start Year: 2002
End Year: 2006
Grant Type: Early Career Fellowships (Australia)
Title of research award:
The Vasoative effects of the nitroxyl anion (NO) in vitro and in vivoThe Vasoative effects of the nitroxyl anion
(NO) in vitro and in vivo
Lay Description (from application):
Not Available
Research achievements (from final report):
This project investigated the vascular effects of nitroxyl (HNO), a variant of the well known signalling
molecule nitric oxide (NO). These two molecules are chemically closely related, only differing by a single
electron. , We examined the pharmacology of HNO and compared it to NO. We discovered that HNO acts in a
subtle, but significantly different way to NO, despite their chemical similarities. We were the first to elucidate
the molecular mechanism used by HNO to cause relaxation of large and small blood vessels, including
coronary vessels. In addition to showing that HNO is a useful blood vessel relaxant, we have also shown that
HNO donors do not display tolerance, which is a clinical problem with currently used NO donors. Thus, new
HNO donor drugs may have a significant therapeutic advantage over the currently available NO donor drugs.
Expected future outcomes:
Further research into HNO donor compounds may result in better therpeutic agents for cardiovascular disease.
Name of contact:
Dr Joanne Favaloro
Email/Phone no. of contact:
joanne.favaloro@rmit.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 194472
CIA Name: A/Pr Michael Hickey
Admin Inst: Monash University
Main RFCD: Not Allocated
Total funding: $425,000
Start Year: 2002
End Year: 2006
Grant Type: Career Development Fellowships
Title of research award:
Role of adhesion molecules in autoimmune vasculitisRole of adhesion molecules in autoimmune vasculitis
Lay Description (from application):
Not Available
Research achievements (from final report):
The aim of this scheme is the support of early career biomedical researchers aiming to establish themselves as
independent investigators. Therefore the achievements which have resulted from this support can be gauged by
the assessment of my career development. I entered the scheme as a junior investigator, supervising three
researchers. I now supervise a laboratory of 8-9 people. Over this period I have supervised four students to the
completion of their PhD, as well as several young researchers who have recently graduated from their PhDs,
and four Honours students. I have been able to gain substantial support for my research both within Australia,
and from international sources. And importantly I have performed and published a large number of significant
research studies. The research performed in my laboratory has revealed new information about the nature of the
inflammatory response in the autoimmune disease, SLE (or lupus), and how it affects the blood vessels in the
brain. It has also generated new information on the reasons underlying the accumulation of white blood cells in
glomeruli in the kidney, a process which underlies the disease glomerulonephritis. It has also revealed new
information on the function of the protein known as MIF, in inflammatory responses. This fellowship has
allowed me to work in diverse areas and collaborate widely with talented scientists. In combination, these
benefits have allowed me to become established as an independent scientist.
Expected future outcomes:
This fellowship has allowed me to establish myself as an independent investigator in Australia, with an
international reputation in the field of inflammation. The future outcome of this support will be that my lab
continues to produce high quality internationally competitive research.
Name of contact:
Dr. Michael Hickey
Email/Phone no. of contact:
michael.hickey@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 219101
CIA Name: Prof Henry Krum
Admin Inst: Monash University
Main RFCD: Not Allocated
Total funding: $347,750
Start Year: 2002
End Year: 2004
Grant Type: SRDC - Research
Title of research award:
A ramdomised trial of telephone support for chronic heart failure patients at high rish of re-hospitalA
ramdomised trial of telephone support for chronic heart failure patients at high rish of re-hospital
Lay Description (from application):
Not Available
Research achievements (from final report):
As an Australia-wide, randomised controlled trial, the CHAT study has adapted the TeleWatchTM
telemedicine program for Australian patients into a system-of-care accessible to patients chronic heart failure
patients residing in rural or remote regions. Over 300 General Practitioners have participated, with more than
400 eligible patients recruited. Those in the intervention arm of the trial have been provided specialist cardiac
nurse support in addition to usual care. Interim results and other insights gained from the CHAT study have
been accepted by publishers such as the Medical Journal of Australia and Australian Family Physician.
Additional contributions include input to various telehealth forums and research conferences.
Expected future outcomes:
Final evaluation and publication of the study results will inform policy-makers as to the effectiveness of
telephone-based support for patients with limited access to specialist chronic health services. If successful in
improving patient outcomes, the CHAT system-of-care could also applied to a range of other chronic
conditions and language groups.
Name of contact:
Henry Krum
Email/Phone no. of contact:
henry.krum@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 232324
CIA Name: Dr Stavros Selemidis
Admin Inst: Monash University
Main RFCD: Basic Pharmacology
Total funding: $289,000
Start Year: 2003
End Year: 2007
Grant Type: Early Career Fellowships (Australia)
Title of research award:
Roles of NADPH oxidase and caveolae in oxidative stress in vascular diseaseRoles of NADPH oxidase and
caveolae in oxidative stress in vascular disease
Lay Description (from application):
Not Available
Research achievements (from final report):
Heart disease continues to pose as a major health problem in Australia and other developed countries. It often
involves a loss of function of the arteries, which normally carry blood, oxygen and essential nutrients to the
heart muscle itself. We believe that an enzyme called NADPH oxidase produces excessive amounts of oxygen
free radicals in diseased arteries, which are thought to be responsible for the reduction in blood flow observed
in heart disease patients. We have recently discovered that a class of nitrovasodilator drugs, which have been
used for over a century in patients with heart disease to relieve angina, also block oxygen free radical
production in cells from humans and in appropriate animal models. Our results provide us with new
information into how these drugs improve blood flow through arteries, leading to alternative, more appropriate
and safer therapies for the treatment of heart disease.
Expected future outcomes:
Our studies have enhanced our understanding of how nitrovasodilators exert vasoprotection and are likely to
strengthen the argument for the prophylactic use of newer classes of such compounds for the causes and not
just the symptoms of cardiovascular disease.
Name of contact:
Stavros Selemidis
Email/Phone no. of contact:
stavros.selemidis@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 236821
CIA Name: A/Pr Kate Denton
Admin Inst: Monash University
Main RFCD: Systems Physiology
Total funding: $286,250
Start Year: 2003
End Year: 2005
Grant Type: NHMRC Project Grants
Title of research award:
Neural control of renal function: Functionally specific populations of sympathetic nervesNeural control of
renal function: Functionally specific populations of sympathetic nerves
Lay Description (from application):
The kidneys are supplied with a dense network of nerves. Working properly, these nerves help maintain normal
filtering of the blood by the kidneys. Over-activity of the nerves going to the kidney is associated with
congestive heart failure, liver cirrhosis, chronic renal failure and hypertension. We have recently made
several major discoveries about these nerves. Our studies suggest, based on structural and functional evidence,
that stimulation of subgroups of nerve fibers going to the kidney will causes different effects with in the kidney
. We therefore suggest that salt excretion , the control of blood flow to the kidney and the release of hormones
by the kidney can be seperately regulated by the nerves. Using techinques only practise in a handful of
laboratories around the world, we aim to determine to how the nerves control kidney function normally. These
studies will suggest new directions in which the renal nerves may be implicated in disease.
Research achievements (from final report):
Kidney function is under the influence of nerves. Our studies demonstrate that there are more than one
population of nerves innervating the kidney. This means that the nerves innervating the kindey are not all the
same and that the central nervous system may be able to selectively activate one or other population at a time.
We have evdience that demonstrates that is is possible to selectivley influence different renal functions by
differential activation of the nerves. We have also demonstrated that in a model of hypertension the relative
number of nerves in the kidney can change.
Expected future outcomes:
Our studies suggest that the relative innervation density of different populations of renal nerves can be altered
under pathological conditions. The mechanism causinng alterations in innervation desnity will be examined in
furture studies, this may leaad to new targets for the treatment of hyperrtension and renal disease.
Name of contact:
Dr Kate Denton
Email/Phone no. of contact:
kate.denton@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 236851
Start Year: 2003
CIA Name: Dr Miodrag Dodic
End Year: 2005
Admin Inst: Monash University
Grant Type: NHMRC Project Grants
Main RFCD: Foetal Development and Medicine
Total funding: $497,500
Title of research award:
Hypertension induced by prenatal glucocorticoid exposure: roles of cerebral and renal renin-angiotensin
systemsHypertension induced by prenatal glucocorticoid exposure: roles of cerebral and renal reninangiotensin systems
Lay Description (from application):
High blood pressure is a major public health problem in Australia and other developed countries as it is a
common risk factor for stroke, heart failure and kidney damage. At present, there is a great interest in the
possibility that high blood pressure in adults can result from stresses experienced by the fetus before birth.
However, it is not known how prenatal compromise could lead to high blood pressure. We have recently
established an animal model (using sheep) in which brief exposure to glucocorticoids - known as "stress
hormones" - administered to the mother during early gestation results in high blood pressure in the offspring in
adulthood. Increased levels of these hormones could occur in women at times when many may be unaware of
their pregnancy (ie. smoking marijuana, chronic insomnia, accidents, loss of loved one, physical or mental
stress or abuse). In addition, high doses of synthetic glucocorticoids might be given to pregnant patients for the
treatment of asthma and acute migraine. The early origins of hypertension are of considerable importance to a
large section of the community, namely the 25% who develop hypertension at the age 45 or over. If even a
small proportion of hypertension can be prevented by reducing fetal exposure to excess glucocorticoids the
impact on cardiovascular illness may be large. This research proposal has the potential to explain the basis for
at least some of the 'essential' hypertension for which a mechanism has not been discovered after decades of
research. This project will examine the separate roles of the kidney and brain, and in particular will determine
whether permanent changes can be induced by exposure to stress hormones during early fetal life. Knowledge
gained from this project could be used in devising strategies aimed at preventing or treating high blood
pressure in adults.
Research achievements (from final report):
These studies provided proof that exposure to natural stress hormones, such as cortisol, or synthetic
glucocorticoid hormones, such as dexamethasone, during early pregnancy can have serious deleterious
consequences for the fetus after birth. These consequences include a predisposition to develop high blood
pressure (hypertension) and altered metabolism (high blood glucose), as well as a significant defect in normal
kidney development Of interstg was the finding that the neural control of blood pressure was altered by
exposure to the synthetic steroid, but not by the natural stress hormone. Thus whilst some outcomes were
similar with both treatments (hypertension, impaired kidney development) the mechanisms were different..
Expected future outcomes:
It is expected that more subtle abnormalities of kidney function will be seen when all data has been analysed.
Name of contact:
Professor E.M.wintour-Coghlan
Email/Phone no. of contact:
mwc@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 236860
CIA Name: A/Pr Robert Medcalf
Admin Inst: Monash University
Main RFCD: Not Allocated
Total funding: $614,750
Start Year: 2003
End Year: 2007
Grant Type: Established Career Fellowships
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
The plasminogen activating (fibrinolytic) system is known for its role in blood clot removal. However, some of
the components of this system (namely tissue-type plasminogen activator; t-PA) play important role in normal
brain function, but can be deleterious under pathological conditions. My laboratory investigated the means by
which the genes encoding t-PA and other members of this system are regulated and the means by which t-PA
activates and damages neurons. We also compared the neurotoxic effects of t-PA with a related plasminogen
activators derived from the vampire bat saliva (desmoteplase). We showed that in contrast to t-PA,
desmoteplase displays no neurotoxicity and this has important implications for the treatment of patients with
ischaemic stroke. We also discovered a series a functional elements and domains in the t-PA promoter region
which has enhanced our understanding as to how the t-PA gene is regulated. We also identified a powerful
neuroprotective effect of a cytokine called oncostatin M and of soluble thrombomodulin (that blocks the action
of thrombin) which provides a justified platform to explore the therapeutic benefit of these molecules in models
of brain injury, including stroke. Our studies on the post-transcriptional regulation of plasminogen activator
inhibitor 2 (PAI-2) led to the discovery of the importance of the mRNA binding proteins tristetraprolin, HuR
and NFAR1 in the control of PAI-2 mRNA stability while our study on the post-transcriptional regulation of
prothrombin revealed the functional importance of upstream sequences in prothrombin 3'-UTR in prothrombin
mRNA processing.
Expected future outcomes:
Desmoteplase may become a new treatment for patients with ischaemic stroke. Further understanding on how
t-PA activates neurons will lead to novel approaches to inhibit this stimulatory activity, while preserving its
fibrinolytic function. The identification of posttranscriptional regulators of PAI-2 may led to approaches to
influence PAI-2 expression in vivo
Name of contact:
Robert Medcalf
Email/Phone no. of contact:
robert.medcalf@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 236862
CIA Name: A/Pr Robert Medcalf
Admin Inst: Monash University
Main RFCD: Gene Expression
Total funding: $490,500
Start Year: 2003
End Year: 2005
Grant Type: NHMRC Project Grants
Title of research award:
Molecular mechanisms for the cell-type specific regulation of the tissue-type plasminogen activator
geneMolecular mechanisms for the cell-type specific regulation of the tissue-type plasminogen activator gene
Lay Description (from application):
Tissue-type plasminogen activator (t-PA) is an important enzyme that is widely known for its ability to remove
blood clots. More recently, t-PA has been shown to influence memory development and under pathological
conditions can promote neuronal cell death. t-PA is produced by many cells including the endothelial cells that
line the blood vessels, fibroblasts, as well as cells within the central nervous system. The t-PA gene is regulated
very differently in these cell types and this project will address the mechanisms underlying the cell-type
specific regulation of the t-PA gene. Endothelial cells, fibroblasts and neuronal cell cultures will be used to
study the regulation of t-PA expression. Information gained will not only add to the understanding of the
broader field of gene regulation, but may also provide clues to manipulate the expression of the t-PA gene in
different cells.
Research achievements (from final report):
Tissue-type plasminogen activator (t-PA) is a naturally occurring enzyme that is well appreciated for its role as
a fibrinolytic (blood clot dissolving) enzyme. More recent findings have establised a role for t-PA within the
central nervous system where it participates in memory development and plasticity. Under pathological
conditions (stroke, excitotoxicity, traumatic brain injury), the presence of t-PA is detrimental to the host. It is
therefore important to determine how the t-PA gene is regulated and how it influences cell function. The
expression pattern of the t-PA gene is also influenced by polymorphisms within the t-PA gene promoter and
also by many agonists. The primary aim of this project was to determine how the t-PA gene is regulated in cells
at the level of gene transcription. A number of key milestones were met. Firstly, we were able to show the
functional significance of a clinically relevant C/T polymorphism located at position -7351. Also we identified
a functionally important NF-kB site in the t-PA promoter that is utilised in neuronal cells and we also identifed
a novel region within the t-PA promoter that was responsible for transcriptional regulation by a neurotrophic
agent known as brain-derived neurotrophic factor (BDNF). In addition to this, we also initiated a research
program to study the means by which t-PA can modulate neuronal function. This resulted in the identification
of a critically important cell surface receptor that t-PA needs to bind in order to modulate neuronal function. By
understanding how t-PA activates neurons has implications in the treatment of patients with ischaemic stroke
Expected future outcomes:
The delineation of the BDNF-responsive element in the t-PA promoter and to determine whether this element
mediates transcriptional induction by other agonists. Elucidating the mechanisms by which t-PA activates
neurons and which signaling pathways are activated may also provide for novel approaches for the treatment of
patients with stroke.
Name of contact:
Robert Medcalf
Email/Phone no. of contact:
robert.medcalf@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 236872
CIA Name: Dr Sharyn Fitzgerald
Admin Inst: Monash University
Main RFCD: Systems Physiology
Total funding: $225,500
Start Year: 2003
End Year: 2005
Grant Type: NHMRC Project Grants
Title of research award:
Role of endothelial vasodilator mechanisms in cardiovascular control during diabetesRole of endothelial
vasodilator mechanisms in cardiovascular control during diabetes
Lay Description (from application):
Cardiovascular diseases such as stroke and heart attack are the greatest killers in developed societies such as
Australia. We now know that a number of metabolic disorders, and genetic and lifestyle factors, can increase
the likelihood of individuals developing cardiovascular disease later in life, such as obesity, diabetes, and
smoking. In many cases, individuals with these risk factors also have high blood pressure, which is a known
cause of stroke and heart attack. This seems to be a particular problem in patients with diabetes, a condition
that currently affects around 150 million people worldwide. Indeed, almost 70% of patients that develop
diabetes in later life, also develop high blood pressure. The aim of the studies outlined in this application is to
increase our understanding of the way diabetes affects blood pressure. High blood pressure often accompanies
established diabetes, but we have recent evidence that suggests that a gas (nitric oxide) made by the cells that
line blood vessels (endothelial cells) and in nerve cells, protects the cardiovascular system from hypertension
during the onset of diabetes. Our experiments will show whether the 'protective' nitric oxide comes from nerves
or the endothelial cells, and how it affects various blood pressure control mechanisms in diabetes. Our
experiments will also show whether this protective action of nitric oxide is eventually lost as the organ damage
that occurs in diabetes proceeds. This information should help in the design of new drug treatments and other
therapies aimed at reducing the occurrence of high blood pressure, and hence cardiovascular disease, in
diabetes.
Research achievements (from final report):
A facility to measure blood pressure and heart rate in 16 mice simultaneously has now been established, only a
few laboratories in Australia are currently capable of undertaking these types of studies. Hence, we can now
investigate the influence of a range of factors including disease state, genetic manipulation and drug treatment
on blood pressure and heart rate in mice, measured continuously 24 hrs/day. With the use of these techniques
we have now studied the influence of nitric oxide (an endogenous vasodilator) on blood pressure regulation in
normal and diabetic mice. Under both normal and diabetic conditions , nitric oxide does not appear to play a
major role in short- to medium-term control of blood pressure of mice. However, there does appear to be an
important role for nitric oxide in long-term blood pressure control in both normal and diabetic mice. A colony
of endothelial nitric oxide synthase (eNOS) knockout mice (with reduced nitric oxide activity) has now been
established at Monash University - one of only two colonies in Australia. These mice are now being used to
study the effect of diabetes on the cardiovascular system in the absence of a functional nitric oxide system and
also the relative roles of nitric oxide and other vasodilators on blood vessel tone.
Expected future outcomes:
Identifying the extent of involvement of nitric oxide and other endothelium-derived vasodilators in blood
pressure regulation during diabetes may lead to more appropriate therapies for blood pressure control in
diabetes. These studies may also greatly contribute to our understanding of the mechanisms responsible for the
organ damage observed in diabetes.
Name of contact:
Sharyn Fitzgerald
Email/Phone no. of contact:
sharyn.fitzgerald@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 236879
Start Year: 2003
CIA Name: A/Pr Stephen Bernard
End Year: 2006
Admin Inst: Monash University
Grant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $309,000
Title of research award:
A randomised trial of core cooling versus surface cooling in comatose survivors of prehospital cardiac arrestA
randomised trial of core cooling versus surface cooling in comatose survivors of prehospital cardiac arrest
Lay Description (from application):
Pre-hospital sudden cardiac arrest (SCA) is a major public health problem that is estimated to cause around one
death per thousand adults per year. The aetiology of SCA is usually ischaemic heart disease causing
ventricular fibrillation (VF). The current medical response to this condition involves a "Chain of Survival",
including early call to 000, bystander CPR, early defibrillation and early advanced cardiac life support.
Following successful cardiac resuscitation, patients are transported to hospital for further care. Despite this
approach and recent improvements such as decreased ambulance response times, outcome remains poor and
there are very few survivors who make a good recovery. This proposal is for funding to conduct a
randomised, controlled trial, which compares two different techniques of induction of hypothermia in patients
who are resuscitated from pre-hospital sudden cardiac arrest. Recently available data suggests that the outcome
from SCA is significantly improved if moderate hypothermia is used as a treatment of neurological injury.
However, the technique of induction of hypothermia requires further research. This study compares corecooling using large-volume ice-cold intravenous fluid with the current technique of using ice packs for surface
cooling, initiated in the field by ambulance paramedics and continued in hospital for a total of 12 hours. This
study has the potential to demonstrate a significant improvement in outcome in a common clinical condition,
which currently carries a very high mortality rate. This will be the first trial internationally which assess core
versus surface cooling initiated pre-hospital, in SCA patients. It is highly likely that with the successful results
from this trial that induced hypothermia in SCA patients will become standard care. The use of induced
hypothermia could lead to over 500 lives saved per year accross Australia.
Research achievements (from final report):
This clinical trial enrolled 396 patients. It was found that paramedics are able to safely and effectively induce
mild hypothermia after cardiac arrest resuscitation using a rapid infusion of 2000mL of ice-cold intravenous
fluid. The analysis of outcomes demonstrated that there was no benefit at hospital discharge from paramedic
cooling after cardiac arrest compared with cooling commenced in the Emergency Department. It is
hypothesised that the relatively small delay between paramedic cooling and hospital arrival does not adversely
impact on neurological outcomes.
Expected future outcomes:
It is proposed that mild hypothermia might be induced during CPR to improve neurological outcomes after
cardiac arrest and resuscitation
Name of contact:
A/Prof Stephen Bernard
Email/Phone no. of contact:
stephen.bernard@alfred.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 236884
CIA Name: Prof Roger Summers
Admin Inst: Monash University
Main RFCD: Basic Pharmacology
Total funding: $801,500
Start Year: 2003
End Year: 2007
Grant Type: NHMRC Project Grants
Title of research award:
Novel functional domains on adrenoceptors for drug interaction and cell signallingNovel functional domains
on adrenoceptors for drug interaction and cell signalling
Lay Description (from application):
Our work involves studying cell-surface proteins (receptors) that respond to hormones such as adrenaline or
substances that transmit signals in the nervous system (neurotransmitters). These receptors play a vital role in
orchestrating responses to stimuli such as stress, pain, changes in blood pressure, body temperature, fluid and
energy status, and exercise. They allow communication between different organs or different parts of the
nervous system. G-protein coupled receptors (GPCRs) are the major group of cell surface receptors that
interact with hormones and neurotransmitters. Treatment of many diseases and conditions relies on the use of
drugs that selectively activate or block a single type of GPCR. In fact, about 2/3 of existing therapies are based
on these drugs. In designing new drugs it is important to understand as much as possible about the properties of
the target receptors. There is emerging evidence concerning interactions between drugs, receptors and proteins
inside cells that translate signals into responses (signalling proteins). For example, receptors have additional
sites of drug action that can modulate their activity, and can also couple to multiple signalling pathways. We
are studying adrenoceptors that respond to adrenaline and to the neurotransmitter noradrenaline. Our studies
will use adrenoceptors as model systems to identify novel potential sites for drug interaction, to gain new
insights into signalling mechanisms utilized by these receptors and to examine how a variety of
phosphorylation mechanisms affect the ability of receptors to couple to particular signalling pathways.
Research achievements (from final report):
β-Adrenoceptors are cell-surface receptors that mediate responses to the circulating hormone adrenaline and to
the neurotransmitter noradrenaline that is released from sympathetic nerves. Drugs (agonists) that selectively
activate the β2-adrenoceptor have widespread clinical use in the treatment of asthma, chronic obstructive
pulmonary disease and pre-term labour, while a second class of drugs (antagonists) that block the activity of
β1- and β2-adrenoceptors are routinely used to treat heart failure. The discovery that a drug acting at a single
receptor subtype may change the activity of multiple signalling pathways, both in a positive and negative
direction, has called into question the strict definition of agonist versus antagonist. We have examined
activation of the β3-adrenoceptor, and have found that drugs acting as antagonists for cAMP generation can act
as powerful agonists for activation of MAP kinases, a class of proteins that modulate cell stress responses
culminating in cell survival or cell death. These MAP kinases are present in all cell types, and are considered to
be important in determining the response of the heart to acute loss of oxygen and nutrients, as well as long-term
overload. We are therefore interested in expanding our study to look at the effects of antagonists on signalling
by all three β-adrenoceptors. We have also discovered that the signalling properties of the β3-adrenoceptor are
influenced by its localisation within microdomains of the cell membrane called lipid rafts. This work
contributes to overall knowledge about how cellular responses are regulated.
Expected future outcomes:
Many drugs on the market are antagonists thought to act purely by preventing access of natural
neurotransmitters or hormones to receptors. We now know that antagonists may block one signalling pathway
but activate other pathways. We seek to understand this process and to develop assays that will aid in testing
new drugs.
Name of contact:
Prof Roger Summers
Email/Phone no. of contact:
NHMRC Research Achievements - SUMMARY
roger.summers@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 236905
Start Year: 2003
CIA Name: Dr Karen Anderson
End Year: 2005
Admin Inst: Monash University
Grant Type: NHMRC Project Grants
Main RFCD: Protein Targeting and Signal Transduction
Total funding: $457,500
Title of research award:
Identification and characterization of novel PI3-kinase signal transducing elements in plateletsIdentification
and characterization of novel PI3-kinase signal transducing elements in platelets
Lay Description (from application):
Platelets play an important role in blood clotting and blood vessel repair. Upon vessel injury, platelets rapidly
adhere to the site of damage where they undergo dramatic shape change to spread over the site of injury.
Activation and regulation of these processes relies on a complex network of signal transduction processes,
involving the integration of multiple receptors and pathways. One pathway demonstrated to play a role in
regulating platelet responses is the enzyme phosphatidylinositol 3-kinase (PI3-kinase) and its lipid products
PtdIns(3,4,5)P3 and PtdIns(3,4)P2. However, very little is known about exactly how PI3-kinase and its
products regulate the platelet responses. Our research studies aim to gain a deeper understanding into the
molecular mechanisms of PI3-kinase signal transduction in platelets, through the identification and
characterization of novel platelet proteins that bind to PI3-kinase lipid products, and to define what role these
proteins play in platelet PI3-kinase dependent responses.
Research achievements (from final report):
Platelets are important blood cells which are critical for the formation of healthy blood clots. These cells act
through their ability to stick to materials exposed at sites of blood vessel injury, ultimately sealing the injured
area and preventing blood loss. This 'stickiness' is mediated through adhesion receptors expressed on the
surface of the platelet which recognise and bind to the exposed materials within the injured vessel wall. Platelet
adhesion receptors must be tightly regulated, as abnormal stickiness plays a major role in cardiovascular related
diseases such as heart attack and stroke. An important signalling pathway involved in the activation and
regulation of platelet stickiness is the enzyme phosphatidylinositol 3-kinase (PI3K) and its lipid products.
Platelets contain several Types (I-III) and isoforms of PI3K. , Our studies have made considerable progress in
defining how PI3K regulates platelet stickiness, and identified some of the partners that act alongside PI3K to
regulate platelet stickiness.
Expected future outcomes:
By gaining a better understanding of the exact role PI3K plays in platelet activation and function, these studies
will provide us with important insights into the regulation of haemostasis and thrombosis, and may provide
novel insight into potential targets for drug design of novel anti-thrombotics.
Name of contact:
Hatem Salem
Email/Phone no. of contact:
Hatem.Salem@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 236910
Start Year: 2003
CIA Name: A/Pr Michael Hickey
End Year: 2004
Admin Inst: Monash University
Grant Type: NHMRC Project Grants
Main RFCD: Cellular Interactions (incl. Adhesion, Matrix, Cell Wall)
Total funding: $146,500
Title of research award:
Mechanisms of immune complex-mediated inflammation in the cerebral microvasculatureMechanisms of
immune complex-mediated inflammation in the cerebral microvasculature
Lay Description (from application):
Immune complexes are formed when an antibody binds to the molecules it is directed against. Normally, this
is important for fighting infection. However in some autoimmune diseases, inappropriate formation of immune
complexes can be damaging to our own tissues. This damage occurs because immune complexes attract white
blood cells to the areas where they form. Many tissues can be affected by this process. However, we know
very little about the effects of immune complexes specifically in the brain. This is important because immune
complexes are found in the brain in diseases such as lupus. Therefore the aim of this proposal is to determine
how immune complexes induce damaging inflammation in the brain.
Research achievements (from final report):
Immune complexes are molecules which induce inflammatory responses in various tissues such as skin, blood
vessels and joints, particularly in diseases such as systemic lupus erythematosus (SLE) and rheumatoid
arthritis. SLE patients are affected by inflammation in various organs including the brain. However it is not
known if the brain responds to immune complexes the same way as other tissues such as the skin do. This is
important because the reasons why the brain is affected in SLE patients remains unclear. Therefore the aim of
this project was to examine the ability of immune complexes to induce an inflammatory response in the brain
and to compare this with immune complex-induced responses in other organs. These experiments showed for
the first time that the brain is sensitive to inflammation induced by the presence of immune complexes. Also
the molecules and cells involved in this response are quite similar to those involved in other organs such as
muscle. This suggests that one pathway whereby brains are damaged in cerebral SLE patients is via the
proinflammatory effects of immune complexes. This raises the possibility that therapies targeting immune
complexes may be useful in cerebral SLE patients.
Expected future outcomes:
This increases our understanding of the mechanisms of inflammation in cerebral SLE, and with further research
raises the possibility that therapies against immune complexes are worth investigating in cerebal SLE patients.
Name of contact:
Dr. Michael Hickey
Email/Phone no. of contact:
michael.hickey@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 236982
CIA Name: Prof Helena Teede
Admin Inst: Monash University
Main RFCD: Not Allocated
Total funding: $217,750
Start Year: 2003
End Year: 2007
Grant Type: Career Development Fellowships
Title of research award:
Hormones and the cardiovascular systemHormones and the cardiovascular system
Lay Description (from application):
Media Summary not available
Research achievements (from final report):
As a?clinician & researching Endocrinologist, I combined clinical practice/management (0.5 EFT hospital
position) with research (0.5 EFT) over my CDA fellowship and developed a reputation in
hormonal/metabolic/cardiovascular interaction culminating in a Chair in Women's Health at Monash
University. I have attracted 20 international and national awards and fellowships. I have a leading National role
in research and strong active International?collaborations with 82 refereed publications (majority first/last
author and many in international high impact journals): 7 book chapters, editor *5, reviewer for international
journals and grants, NH&MRC fellowship and grant panels.Competitive grants - International Diabetes
Federation grant, 3 NHF grants, NH&MRC grant, 4 DART grants, 2 Anti-cancer Council grants, multiple
philanthropic grants, investigator initiated industry grants, funded pharma studies and a 2007 research budget
of ~$1,600,000. I supervised 3 PhD and 1 MD students to completion and now lead a multidisciplinary
research team of 7 postdoctoral, 9 PhD or Masters students and others, including doctors, psychologists,
dieticians, nurses and scientists. I am a clinician practising in the area of my research; inclusive of 3 national
health priority areas. Through the resources of JHF and the School of Public Health, I have a significant role in
research translation. I completed training in leadership and management (2001-2) & a 2008 Leadership
Victoria Fellowship. Research efforts also focus on leadership & teams in collaborative ARC research project
improving collaborative efforts across the clinical/basic science research divide.?
Expected future outcomes:
Having established a strong multidisciplinary research team with a focus on prevention of diseases, future
outcomes will include improved health and prevention of complications in lifestyle related metabolic diseases
including diabetes, obesity, PCOS and cardiovascular disease.????
Name of contact:
Helena Teede
Email/Phone no. of contact:
helena.teede@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 237010
CIA Name: Prof Shaun Jackson
Admin Inst: Monash University
Main RFCD: Haematology
Total funding: $267,750
Start Year: 2003
End Year: 2005
Grant Type: NHMRC Project Grants
Title of research award:
Investigation of the role of the GPIb/V/IX-filamin-1 interaction in regulating platelet function in
vivoInvestigation of the role of the GPIb/V/IX-filamin-1 interaction in regulating platelet function in vivo
Lay Description (from application):
Platelets play an essential role in blood clotting and blod vessel repair. Upon injury to a blood vessel, platelets
rapidly adhere to the area of damage where they undergo dramatic changes in their shape and internal structure
that facilitates spreading over the area of injury and subsequent formation of a stable blood clot. Our research
studies are aimed at understanding more closely the factors that regulate the adhesiveness of platelets, since
this is an important determinant not only in normal blood clot formation but also in the development of harmful
blood clots (thrombosis) associated with the development of diseases such as heart attack and stroke. Our
particular focus is on the interaction between adhesion receptors on the surface of the platelet and components
of the intracellular platelet structure referred to as the cytoskeleton and how this interaction might regulate the
reactivity of platelets and their ability to adhere to blood vessels. We believe this may be an important
mechanism that regulates platelet adhesion and notmal blood clotting.
Research achievements (from final report):
The formation of blood clots is important in preventing excessive blood loss but is also responsible for the
occurence of life threatening heart attacks and stroke. The adhesive function of blood platelets is critical to the
formation of a stable clot to prevent significant blood loss. If not regulated correctly, this process can result in
inappropriate blood clot formation, causing vessel obstruction thereby preventing the flow of blood to vital
organs. We have identified that the GPIb/V/IX adhesion receptor induces changes in platelet morphology and
the platelet actin cytoskeleton, both of which regulate platelet adhesion particularly under high shear stress
conditions. In particular, the role of the interaction between GPIb/V/IX and filamin appears to be critical in
allowing platelets to maintain their adhesive function under these high shear conditions. These findings have
increased our knowledge of how blood clot formation is regulated and may also aid in the development of new
therapies for the prevention of heart attack and stroke.
Expected future outcomes:
Our current evidence suggests that the GPIb/V/IX-filamin interaction plays a fundamentally important role in
the regulation of platelet function. In future studies we will develop mouse models which have defects in the
GPIb/V/IX filamin interaction. Combined with in vivo models of thrombosis, these GPIb/V/IX mutant mice
will enable us to determine how platelet thrombus formation is regulated in vivo
Name of contact:
.Shaun Jackson
Email/Phone no. of contact:
shaun.jackson@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 237011
CIA Name: Prof Shaun Jackson
Admin Inst: Monash University
Main RFCD: Haematology
Total funding: $267,750
Start Year: 2003
End Year: 2005
Grant Type: NHMRC Project Grants
Title of research award:
Investigation of Activating signals Transmitted during Platelet AggregationInvestigation of Activating signals
Transmitted during Platelet Aggregation
Lay Description (from application):
The blood platelet is a specialized adhesive cell that plays a critical role in the normal blood clotting process
through its ability to rapidly adhere to sites of vascular damage. Upon injury to a blood vessel, platelets
undergo a number of internal signalling process and strucural changes that allow them to rapidly adhere to the
area of damage. Following this initial adhesion process, platelet-platelet interactions occur leading to the
development of a stable blood clot. Our research studies are aimed at understanding more closely the factors
that regulate platelet-platelet interactions during the course of blood clot formation, since this is an important
determinant not only of normal clot formation, but also in the development of harmful blood clots (thrombi)
associated with the onset of diseases such as heart attack and stroke. Our particular focus is on the way in
which platelets communicate to one another during the course of platelet thrombus development. Particulary,
we are interested in the role of calcium as a signal mediating platelet-platelet communication. We believe that
the transmission of these calcium signals may be the key signaling mediator of blood clot formation and
normal haemostasis.
Research achievements (from final report):
Platelets are small blood cells critical to stop bleeding. Platelets perform this function by sticking to areas of
blood vessels injury, as well as each other, eventualy forming a blood clot or thrombus. It is critical that platelet
reactivity be finely balanced in order to allow for normal blood clot formation, as insufficient blood clotting
can result in life threatening bleeding problems, while excessive clotting can lead to acute myocardial
infarction (heart attack) and ischaemic stroke, which remain leading causes of death and disability in western
society. , The repertoire of proteins (receptors) that platelets possess so they can stick to injured vessel walls to
form a blood clot have been defined, however the signals that regulate the stickiness of these receptors, and
therefore control the level of clotting are less well defined. , This grant application aimed to define the
important signal pathways in platelets used to regulate the stickiness of platelet receptors. By further defining
these important signals that regulate platelet stickiness, we can devise better strategies for dampening platelet
stickiness in disease situations.
Expected future outcomes:
We have defined calcium as a critical signal regulating platelet stickiness, and in doing so, defined a new
model for clot fromation. These findings will help define differences between haemostasis and thrombosis, and
ultimately contribute to development of better anti-thrombotics to treat thrombosis whilst reducing bleeding
side-effects associated with current anti-platelet drugs.
Name of contact:
Prof. Shaun Jackson
Email/Phone no. of contact:
Shaun.Jackson@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 237019
CIA Name: Dr Sharyn Fitzgerald
Admin Inst: Monash University
Main RFCD: Systems Physiology
Total funding: $166,421
Start Year: 2003
End Year: 2004
Grant Type: Early Career Fellowships (Australia)
Title of research award:
Cardiovascular control during diabetes: Role of endothelial vasodilator mechanismsCardiovascular control
during diabetes: Role of endothelial vasodilator mechanisms
Lay Description (from application):
Not Available
Research achievements (from final report):
A facility to measure blood pressure and heart rate in 16 mice simultaneously has now been established. With
the use of the this system we are able to investigate the influence of a range of factors including disease state,
genetic manipulation and drug treatment on blood pressure and heart rate in mice, measured continuously 24
hrs/day for up to two weeks. This is a very technically demanding model, involving an initial surgery to allow
implantation of the equipment needed to measure blood pressure and only a few laboratories in Australia are
currently capable of undertaking these types of studies. With the use of these techniques we have now studied
the influence of nitric oxide (an endogenous vasodilator) on blood pressure regulation in the normal and
diabetic mice. Under both normal and diabetic conditions , nitric oxide does not appear to play a major role in
short- to medium-term control of blood pressure of mice. However, there does appear to be an important role
for NO in long-term blood pressure control in both normal and diabetic mice. , A colony of endothelial nitric
oxide synthase (eNOS) knockout mice (with reduced nitric oxide activity) has now been established at Monash
University - one of only two colonies in Australia. These mice are now being used to study the effect of
diabetes on the cardiovascular system in the absence of a functional nitric oxide system and also the relative
roles of nitric oxide and other vasodilators on blood vessel tone.,
Expected future outcomes:
In these studies discovering the extent of involvement of nitric oxide and other endothelium-derived
vasodilators in blood pressure regulation during diabetes may lead to more appropriate therapies for blood
pressure control in diabetes. These studies may also greatly contribute to our understanding of the mechanisms
responsible for the organ damage observed in diabetes.
Name of contact:
Dr Sharyn Fitzgerald
Email/Phone no. of contact:
sharyn.fitzgerald@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 237037
CIA Name: Dr Emma Ashton
Admin Inst: Monash University
Main RFCD: Nutrition and Dietetics
Total funding: $181,125
Start Year: 2003
End Year: 2008
Grant Type: Early Career Fellowships (Australia)
Title of research award:
Epidemiological research into nutrition and cardiovascular diseaseEpidemiological research into nutrition and
cardiovascular disease
Lay Description (from application):
Not Available
Research achievements (from final report):
The Universe study was completed and results showed no improvement in cardiac remodelling with statin
therapy in heart failure patients. These results can be combined with other data to affect drug therapy given to
heart failure patients.
Expected future outcomes:
Research is continuing in the area of heart failure and modifiable risk factors to identify if ifestyle changes can
be made to slow the progression of heart failure.
Name of contact:
Emma Ashton
Email/Phone no. of contact:
emma.ashton@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 237097
Start Year: 2003
CIA Name: Dr Pierre Mangin
End Year: 2004
Admin Inst: Monash University
Grant Type: International Exchange Early Career
Fellowships
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $68,438
Title of research award:
Investigation of inter-cellular calcium communication (ICC) during platelet aggregation and thrombus
formationInvestigation of inter-cellular calcium communication (ICC) during platelet aggregation and
thrombus formation
Lay Description (from application):
Not Available
Research achievements (from final report):
Blood clot formation is a complex process that can ultimately lead to heart attck and stroke. Blood platelets
play a central role in this process due to their ability to stick to the exposed collagen present in the
subendothelial layer of the vessel wall. We have studied the importance of one of the collagen receptor
expressed on the platelet surface: Glycoprotein (GP) VI. GPVI has been proposed to be a major regulator of
blood clot formation and an interesting target for anti-thrombotic drugs. Our results suggest that this receptor is
probably not a suitable target alone, however, use of anticoagulant in combination could act as an ideal antithrombotic target to prevent thrombosis.
Expected future outcomes:
In further studies, we would like to study the effect of the combination of anticoagulants with GPVI blockers
administrated to animals on tail bleeding times, in order to determine the effect of these drugs on haemostasis
Name of contact:
A/Prof. Shaun Jackson
Email/Phone no. of contact:
Shaun.jackson@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 268913
Start Year: 2004
CIA Name: Prof Alexander Smith
End Year: 2006
Admin Inst: Monash University
Grant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $399,750
Title of research award:
Regulation of Endothelin Converting Enzyme Subcellular Distribution and Vascular Endothelin
Production.Regulation of Endothelin Converting Enzyme Subcellular Distribution and Vascular Endothelin
Production.
Lay Description (from application):
Endothelin is a hormone produced by the endothelial cells that line blood vessels. The role of this hormone is
cause blood vessels to constrict (vasoconstriction), thus causing a rise in blood pressure. The synthesis of this
hormone is crucially dependant on an enzyme that has to be located on the surface of the endothelial cell. The
aim of this grant is to understqand the mechanisdms by which the location of this enzyme within the cell is
regulated. The knowledge gained from this study will not only help us better understand the mechanism of
endothelin production but it may also offer an insight into future therapeutic startegies to prevent the formation
of endothelin, thus preventing vasoconstriction.
Research achievements (from final report):
The potent vasoconstrictor endothelin-1, is a 21 amino acid peptide whose principal, physiological function is
to regulate vascular tone. The generation of this peptide is crucially dependent on the local presence and
activity of endothelin converting enzyme-1 (ECE-1) on the surface of vascular endothelial cells. In this study
we show for the first time that in both endothelial cells and CHO cells transfected with the major endothelial
isoform of ECE, ECE-1c, the enzyme is phosphorylated, and that phosphorylation is increased by phorbol ester
stimulation of protein kinase C (PKC). Furthermore, following PKC activation and phosphorylation, the
enzyme migrates to the cell surface where it is positioned to catalyse the generation of active endothelin. This
novel finding, which we believe is unprecedented for a peptide processing enzyme, has significant implications
in the regulation of endothelin generation and thus vascular tone
Expected future outcomes:
We will continue these studies to further chracteise the mechanisms involved in this novel pathway thus
opening the door to the identification of novel potential therapeutic targets
Name of contact:
Ian Smith
Email/Phone no. of contact:
Ian.smith@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 268914
Start Year: 2004
CIA Name: Prof Alexander Smith
End Year: 2006
Admin Inst: Monash University
Grant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $492,625
Title of research award:
ACE2, a New Regulator of the Renin Angiotensin SystemACE2, a New Regulator of the Renin Angiotensin
System
Lay Description (from application):
Angiotensin converting enzyme (ACE) is a key enzyme in the renin-angiotensin system (RAS), converting
Angiotensin I to the potent vasoconstrictor Angiotensin II (Ang II). ACE inhibitors have been highly successful
in the management of hypertension, are standard therapy following myocardial infarction to delay the
development of heart failure, and also reduce the rate of progression of renal disease. Recently, a novel
enzyme called ACE2 has been discovered in the heart and kidneys. Unlike ACE, ACE2 causes the formation
of the vasodilator, Ang 1-7. We have data in the heart and the kidney that supports the concept that ACE2
acts in a counter-regulatory manner to ACE. We suggest that ACE2 may play an important role to modulate
the balance between vasoconstrictors and vasodilators in the heart and kidney. The studies detailed in this
proposal are designed to specifically examine the role and regulation of ACE2 in the healthy heart and kidney
as well as in cardiovascular and renal disease. The project brings together two groups with complementary
skills and techniques, both of whom have collaborations with the discoverers of ACE2, and who have been
exploring the role of ACE2 as evidenced from our recent publication (Tikellis et al, Hypertension in press,
2003).
Research achievements (from final report):
Angiotensin converting enzyme-2 (ACE2) is thought to act in an opposing manner to its homologue,
angiotensin converting enzyme (ACE), by inactivating the vasoconstrictor peptide angiotensin II and
generating the vasodilatory fragment, angiotensin 1-7. Both ACE and ACE2 are membrane-bound
ectoenzymes and may circulate in plasma as a consequence of a proteolytic shedding event. In this project, we
show that ACE2 circulates in human plasma, but its activity is suppressed by the presence of an endogenous
inhibitor. We have shown that expression of ACE2 is regulated both in disease and during development. Other
animal studies, including the effect of renal failure using the 5/6 nephrectomy model, and the effects of
diabetes on ACE2 expression have been completed. We have developed and validated a method to measure
soluble ACE2 activity in human plasma, thus overcoming problems associated with interfering substances
present in plasma and allowing the detection and measurement of circulating ACE2 for the first time thus
opening the door to the development of a biomarker for hreart disease.
Expected future outcomes:
We will continue these studies to further characterise the mechanisms involved in mediating the shedding of
ACE2 and will pursue the hypothesis that ACE2 could be a potential diagnostic or prognostic indicator of heart
disease.
Name of contact:
Ian Smith
Email/Phone no. of contact:
Ian.smith@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 284234
CIA Name: A/Pr Robert Andrews
Admin Inst: Monash University
Main RFCD: Not Allocated
Total funding: $833,601
Start Year: 2004
End Year: 2010
Grant Type: Established Career Fellowships
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
I am a protein chemist/vascular biologist analysing structure, function and clinical role of platelet adhesion
receptors regulating patho/physiological thrombus formation associated with thrombotic diseases such as heart
attack and stroke.
Research achievements (from final report):
Recent achievements in research have focused on translation of laboratory-based studies of platelet receptors to
analysis of clinical samples from patients with atherothrombotic disease, coagulopathy, cancer, autoimmune
thrombocytopenia or other immunological or haematological defects. Together with colleagues at the
Australian Centre for Blood Diseases, Melbourne, and our national and international collaborators, this
research has included development of new antibody-based tests for platelet receptors that has now been applied
to healthy donors and patients with autoimmune disease, stroke or disseminated intravascular coagulation
(DIC). Other studies defined a new mechanism for inhibiting platelet adhesive function by small molecules by
altering the molecular structure of a key platelet receptor that initiates platelet thrombus formation at arterial
flow rates in the bloodstream. Also as major achievements, my PhD students have won national awards
(including the Australasian Society of Thrombosis and Haemostasis, Scientific Medal, 2009) and presented
their studies internationally, in Auckland NZ, Boston USA, and Kagoshima, Japan. Together, this research
program provides the foundation for developing new blood tests for diagnosis and stratification of
thrombotic/bleeding risk in individuals, or for monitoring treatment.
Expected future outcomes:
Future outcomes of the research include translation of basic laboratory findings towards the development of
new types of diagnostic tests for analysis of platelet dysfunction in individuals or for monitoring response to
treatment. In partnership with the Monash University commercialization office, a provisional US patent was
filed in 2011.
Name of contact:
Robert Andrews
Email/Phone no. of contact:
rob.andrews@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 284250
CIA Name: A/Pr Robert Medcalf
Admin Inst: Monash University
Main RFCD: Gene Expression
Total funding: $318,000
Start Year: 2004
End Year: 2006
Grant Type: NHMRC Project Grants
Title of research award:
Post transcriptional regulation of plasminogen activator inhibitor type 2 gene expressionPost transcriptional
regulation of plasminogen activator inhibitor type 2 gene expression
Lay Description (from application):
The process of wound healing, cell migration and the spread of cancers requires the recruitment of specialised
proteases to the cell surface . These proteases act to degrade other proteins, mainly in the extracellular space,
which in turn allows cells to move around, wounds to close, and blood clots to disappear. The plasminogen
activating system is one of the enzyme systems involved in these events. One of the proteases that cleaves
plasminogen to its active form, plasmin, is urokinase (u-PA) and the activity of u-PA is regulated by its natural
inhibitor called plasminogen activator inhibitor type 2 (PAI-2). u-PA is strongly implicated in the progression
of metastatic cancer and high levels of PAI-2 relative to u-PA is regularly seen as a positive prognostic
indicator for metastatic cancer. In this situation, PAI-2 acts to limit the activity of u-PA thereby restricting the
migration potential of the cancer. PAI-2 is unusual because it exists both inside and outside the cell. Outside
the cell, PAI-2 acts to inhibit u-PA activity, while inside the cell, PAI-2 also plays a role in the inhibition of
cell growth and differentiation. It is therefore important to understand how the production of PAI-2 is regulated
in cells. A significant component of PAI-2 regulation occurs post-transcriptionally, particularly at the level of
mRNA stability. We have identified some of the proteins that bind to PAI-2 mRNA and influence its longevity
in the cell. This project aims to further undertand how these as well as other PAI-2 mRNA binding proteins
influence the expression of the PAI-2 gene.
Research achievements (from final report):
Plasminogen activator inhibitor type 2 (PAI-2) is a serine protease inhibitor that plays a role in metastatic
cancer and skin and placental biology. The PAI-2 gene is highly regulated and part of this occurs at the posttranscriptional level, particularly at the level of PAI-2 mRNA stability. We have identified regions within the
PAI-2 transcript as well as cytoplasmic proteins that influence the post transcriptional regulation of PAI-2. Two
of these proteins included tristetraprolin (TTP), and HuR, that are important regulators of mRNA turnover.
During the course of this project, we redefined the region within the 3'-UTR that was responsible for conferring
mRNA instability. Furthermore, we identified a region within this extended instability element that contained a
putative binding site for a novel mRNA binding protein known as NFAR1 (NF-90). We adapted our mRNA
instability method to use a TET-regulated system that more accurately reflects changes in mRNA stability. We
also used RNA interference to reduce expression levels of these PAI-2 mRNA binding proteins and have
provided further functional evidence for a role for these proteins in the post transcriptional regulation of PAI-2
gene expression.
Expected future outcomes:
We expect to identify new proteins that are critical mediators of post-transcriptional regulation of the PAI-2
gene. These proteins are likely to have a broader significance in this field by regulating the expression of other
transcripts that may ultimately allow for novel approaches to control PAI-2 expression in vivo.
Name of contact:
Robert Medcalf
Email/Phone no. of contact:
robert.medcalf@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 284266
CIA Name: Prof Shaun Jackson
Admin Inst: Monash University
Main RFCD: Haematology
Total funding: $481,500
Start Year: 2004
End Year: 2006
Grant Type: NHMRC Project Grants
Title of research award:
Investigation of mechanotransduction mechanisms in plateletsInvestigation of mechanotransduction
mechanisms in platelets
Lay Description (from application):
Platelets are extremely important cells that stop bleeding by sticking to injured blood vessel walls, forming
blood clots. Excessive clotting can lead to fatal vascular events such as heart attack and stroke. On the other
hand, defects in blood clotting can result in life threatening bleeding problems. Platelets stick to sites of vessel
wall injury through the interaction between cell surface receptors and sticky materials (proteins) that become
exposed to the blood flow when the vessel wall is damaged. The "stickiness" of platelets is controlled by many
proteins (and/or enzymes) inside these blood cells. These proteins transmit messages from platelet receptors on
the surface into the cell interior, thereby controlling platelet behaviour. We are in the process of identifying
several types of proteins/enzymes which are responsible for controlling platelet "stickiness". The studies
proposed in this application will provide better understanding of the complicated pathways regulating platelet
stickiness and clot formation. The knowledge gained may utimately assist in the design of specific drugs for the
prevention and/or treatment of heart attacks and strokes.
Research achievements (from final report):
Platelets are small blood cells critical to stop bleeding. Platelets perform this function by sticking to areas of
blood vessels injury, as well as each other, eventualy forming a blood clot or thrombus. It is critical that platelet
reactivity be finely balanced in order to allow for normal blood clot formation, as insufficient blood clotting
can result in life threatening bleeding problems, while excessive clotting can lead to acute myocardial
infarction (heart attack) and ischaemic stroke. , Excessive clotting, such as that seen in heart attack and stroke,
remains a leading cause of death and disability in western society. This excessive clotting is commonly
precipitated by the sudden rupture of advanced atherosclerotic lesions. A major contributing factor to the
excessive clotting observed in this disease state is the abnormal blood flow environment caused by narrowing
of the lumen of diseased atherosclerotic vessels. Abnormal blood flow patterns, including flow separation, flow
reversal and turbulence, are typically found in narrowed diseased vessels and produce complex, rapid changes
in the blood flow environment. Despite their potential importance for excessive blood clotting, the effects of
such blood flow changes on platelet function remain largely unknown. This grant application aimed to define
the impact of blood flow changes on platelet stickiness and idenfy the responsible proteins (expressed either on
platelet surface or within platelets) which link the blood flow changes to enhanced platelet stickiness.
Expected future outcomes:
We have defined the importance of blood flow changes in regulating platelet stickiness, and identified proteins
responsible for this regulation. These findings will help define differences between haemostasis and
thrombosis, and ultimately contribute to development of better anti-thrombotics to treat thrombosis whilst
reducing bleeding side-effects associated with current anti-platelet drugs.
Name of contact:
Shaun P Jackson
Email/Phone no. of contact:
shaun.jackson@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 284267
CIA Name: Prof Shaun Jackson
Admin Inst: Monash University
Main RFCD: Not Allocated
Total funding: $713,750
Start Year: 2004
End Year: 2008
Grant Type: Established Career Fellowships
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
Blood clot formation is primarily driven by platelets, small blood cells which possess a highly specialised
adhesive ability to stick to areas of blood vessel injury, as well as each other. A precise balance in the level of
platelet 'stickiness' is critical for normal blood clot formation, as insufficient blood clotting can result in life
threatening bleeding problems, while excessive clotting can lead to the formation of pathological blood clots
which restrict blood flow to major organs (thrombosis). Such events precipitate acute myocardial infarction
(heart attack) and ischaemic stroke, major causes of death and disability in the Australian community. A major
focus of our laboratory has been to identify novel, safer and more effective antithrombotic approaches that
regulate platelet 'stickiness'. One such therapeutic target we have identified is the PI 3-kinase (PI3K) family of
enzymes. PI3Ks are classified into 3 distinct groups (Types I-III), with four type I isoforms, (p110alpha,
selective PI3K p110beta inhibitors that are highly effective at preventing pathological blood clot formation
without causing a major increase in bleeding, a common side-effect with current antithrombotics. Moreover,
our recent preliminary studies suggest that these inhibitors may not only have the potential to prevent the
development of life-threatening pathological blood clots, they may also have the potential to assist in the
removal of these blood clots once they have formed. We have successfully performed preclinical and Phase I
clinical trials on several PI3K p110beta inhibitors and demonstrated that they are well tolerated with no
bleeding side-effects, even when administered at high doses.
Expected future outcomes:
Our studies demonstrate that selective targeting of PI3K p110beta may represent an effective antithrombotic
strategy that is devoid of bleeding side-effects. The new class of antithrombotic agents we have developed has
been successfully commercialised to AstraZeneca who is currently evaluating these compounds in Phase II
clinical studies in an ongoing collaborative effort with our laboratory.
Name of contact:
Shaun Jackson
Wshaun Jackson
Email/Phone no. of contact:
Shaun.Jackson@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 284272
Start Year: 2004
CIA Name: Prof Christina Mitchell
End Year: 2006
Admin Inst: Monash University
Grant Type: NHMRC Project Grants
Main RFCD: Neurology and Neuromuscular Diseases
Total funding: $500,750
Title of research award:
Characterization of the FHL protein family in striated muscleCharacterization of the FHL protein family in
striated muscle
Lay Description (from application):
This grant examines the role of a family of muscle proteins, called FHL proteins, in skeletal and heart muscle.
Inherited muscular disorders such as muscular dystrophy and myopathies, cause muscle weakness, which may
be profound and lead to premature death due to respiratory muscle failure, or cause mild weakness later in life.
The proteins which are defective in these muscular dystrophies are structural muscle proteins, which link and
stabilize the contractile fibres in muscle and protect the muscle from the stresses and damage resulting from
repeated muscular contraction. We have identified that the FHL proteins, which are the focus of this grant
application, bind to and potentially regulate muscle proteins, which have been shown to cause forms of
muscular dystrophy and cardiomyopathy. Examination of these interactions will provide insights into the
biological mechanism of these muscle disorders. Furthermore, one of these proteins, FHL1 is significantly
increased in hypertrophic cardiomyopathy, heart muscle thickening, a major cause of sudden cardiac death in
young adults. We are creating transgenic mice, which make increased levels of FHL1 protein in their heart
muscle, to determine whether increased FHL1, by itself is sufficient to promote heart muscle thickening.
These studies should lead to further understanding of the development of diseases of heart and skeletal muscle,
which may lead to novel treatments in the future.
Research achievements (from final report):
We have identified a novel molecular pathway that regulates skeletal muscle hypertrophy and promotes
increased muscle strengh despite ageing. These studies have identified FHL1 and FHL3 as critical regulators of
skeletal muscle mass, and differentiation which is of importance in aging and disease states. In addition we
have with our collaborators identified that FHL1 may be mutated in human disease leading to hereditary
muscle dystophies. These studies will enable further characterization of these human diseases and also enable
future work establishing therapeutic agents to improve muscle strength with ageing
Expected future outcomes:
We will further characterise the molecular basis of human muscle diseases that are caused by mutation in
FHL1 and characterise the role other FHL proteins play in regulating cellular differentiation
Name of contact:
Christina Mitchell
Email/Phone no. of contact:
Christina.mitchell@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 284357
CIA Name: A/Pr Rosemary Horne
Admin Inst: Monash University
Main RFCD: Paediatrics
Total funding: $358,537
Start Year: 2004
End Year: 2006
Grant Type: NHMRC Project Grants
Title of research award:
DEVELOPMENT OF CARDIOVASCULAR CONTROL DURING SLEEP IN HUMAN INFANTS AFTER
PRETERM BIRTHDEVELOPMENT OF CARDIOVASCULAR CONTROL DURING SLEEP IN HUMAN
INFANTS AFTER PRETERM BIRTH
Lay Description (from application):
Infants spend the major part of their life in sleep, and the period between birth and 6 months of age sees
dramatic changes in their sleep organisation. Coincidently, there are dramatic developmental changes in the
infant's heart and blood pressure control systems, and the ability to compensate for stress such as falls of blood
pressure (hypotension) or in the level of oxygen in the blood (hypoxaemia). In infants born preterm, the risks
of hypoxaemia, and even death are significantly greater during sleep than during wakefulness, but why this is
so is uncertain. This study will examine the ability of infants to respond to stress during sleep. Four groups of
infants will be examined: healthy infants born at normal gestation; healthy infants born prematurely (preterm);
preterm infants who have experienced mild hypoxaemia soon after birth; and preterm infants who have
suffered more severe hypoxaemia because of lung disease. Infants will be studied in a sleep laboratory during
day-time sleep, and their ability to control blood pressure will be determined. By contrasting the effectiveness
of blood pressure control between the infant groups we aim to determine whether preterm infants have lasting
problems as a result of their premature birth, or their exposure to hypoxaemia. By contrasting infants in sleep
and wakefulness, we aim to assess whether the risks of poorer blood pressure control are greater in sleep.
Research achievements (from final report):
We have found as expected, that in term infants HR, HRV and AP are altered by both postnatal age and sleep
state. HR and HRV fell with increasing postnatal age whilst AP remained constant. HR, HRV and AP were
higher in active sleep (AS) compared with quiet sleep (QS). In preterm infants however there was no effect of
sleep state on HR until 5-6 months of age. Additionally, autonomic control, as assessed by head-up tilting was
impaired in the healthy preterm infants as it did not follow the same pattern as term infants exhibited at 2-3
months until 5-6 months corrected age (Figure 1). These studies have shown that autonomic control of the
cardiovascular system in maturationally delayed in preterm infants with control substantially differing from
term infants until 5-6 months corrected age. These findings may explain the increased risk of preterm infants to
cardiorespiratory disturbances during sleep and to Sudden Infant Death Syndrome.
Expected future outcomes:
One paper has been published and another submitted. Five papers are currently being written. In addition a
subsequent NHMRC application has been submitted in 2007.
Name of contact:
A/Prof Rosemary Horne
Email/Phone no. of contact:
rosemary.horne@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 284391
Start Year: 2004
CIA Name: Dr Suhasini Kulkarni
End Year: 2006
Admin Inst: Monash University
Grant Type: Early Career Fellowships (Overseas)
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $185,953
Title of research award:
Investigation of the role of phosphoinositide 3-kinases in neutrophil functionInvestigation of the role of
phosphoinositide 3-kinases in neutrophil function
Lay Description (from application):
Not Available
Research achievements (from final report):
The aim of this study was to examine the relative contribution of proteins from the PI3Kinase family (p110b, g
and d) to the ability of inflammatory cells called neutrophils to respond to inflammatory and infectious
situations. The way neutrophils do this is through a series of processes including adhesion (sticking), spreading,
chemotaxis (moving towards inflammation), phagocytosis (eating foreign particles/microbes) and production
of reactive oxygen species (ROS) that destroy microbes. I have found, by using anti-p110b or d drugs and
transgenic mice that lack p110b and/or p110d that these proteins are very important for neutrophil function.
Specifically, these PI3Ks have a big role in responding to antibody mediated inflammation such as would be
found when neutrophils encounter antiody coated foreign objects or autoimmune antibodies in conditions such
as arthritis. Interestingly, if you drug both p110b and p110d concurrently, you get much more significant
impairment in the neutrophil inflammatory response. The siginificance of this study and its results are several
fold: 1) the generation of a p110b knockout mouse now allows us to better understand the function of this
protein; 2) We now know the significance of both p110b and d in normal neutrophil responses involving
antibodies; 3) these data identify p110b as a novel therapeutic target for drugs to treat autoimmune conditions;
and 4) these data suggest that drugging a single PI3K is insufficient to overcome the debilitating effects of
autoimmune antibodies, information that will be invaluable in the design and clinical application of drugs to
treat autoimmune conditions.
Expected future outcomes:
I expect that these data will lead to at least two publications in high impact journals. Scientifically, we will now
try and work out the exact mechanisms by which these PI3Ks are involved in antibody-induced neutrophil
functions leading to a clearer understanding of the role of PI3Ks in general and in neutrophils.
Name of contact:
Suhasini Kulkarni
Email/Phone no. of contact:
suhasini.kulkarni@bbsrc.ac.uk
NHMRC Research Achievements - SUMMARY
Grant ID: 284396
Start Year: 2004
CIA Name: Dr Shanhong Ling
End Year: 2007
Admin Inst: Monash University
Grant Type: Early Career Fellowships (Australia)
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $358,500
Title of research award:
Analysis and development of medicinal herbs for the prevention and management of cardiovascular
diseaseAnalysis and development of medicinal herbs for the prevention and management of cardiovascular
disease
Lay Description (from application):
Although medicinal herbs are widely used in the community for the prevention and management
of cardiovascular disease, to date no systemic, effective methods are available to assess the
physiological effects of these substances. This project will employ advanced bio-cellular and
molecular technologies to develop (i) screening procedures, (ii) standardised chemical analyses
and (iii) bioassays to allow efficient assessment of new herbal pharmaceuticals in relation to
possible cardiovascular activities, side effects, purity and quality.
Research achievements (from final report):
This project has examined the effects of several Chinese herbal medicines and pharmaceutical herbal products
on the cardiovascular physiology and atherosclerosis risk through a range of experimental methods, including
in vitro cultured cardiovascular cells, in vivo atherosclerotic animal models, and clinical trial study. In these
studies it has been found that (1) the medicinal herbs contain compounds (e.g. 3,4-dihydroxyphenyl lactic acid,
protocatechuic aldehyde, salvianoid acid B and tanshinone II-A in Salvia miltiorrhiza) that have multiple
effects on cardiovascular cell physiology; (2) the pharmaceutical preparations derived from medicninal herbs
Salvia miltiorrhiza, Panax notoginseng, Polygonum multiflorum, and Hawthorn inhibit atherosclerosis
development in mice; (3) the herbal preparation reduces several cardiovascular risk factors in hyperlipidemic
patients, and (4) the herbal remedy is generally safe under use at regular dosages, while in some cases, e.g.
under using other medications, such remedy might still have significant side/toxic effects. In particular, the
studies havs found that the effects of the herbal medicines on vascular endothlium, incluiding inhibtion of
cellular adhesion molecule production, reduction of endothelial cell apoptosis, and improvement of endothelial
function are the important mechanisms underlying the anti-athrosclerotic efficacy by the herbal remedy. The
results from these studies have led 3 publications as journal articles, 2 conference publications, and additional 3
papers in manuscript preparation. We believe that these results will be provide useful information for both
herbal users and clinical practioners, and in addition for the development of new therapeutic strategy on
atherosclerotic cardiovascular disease.
Expected future outcomes:
The project has found that Salvia miltiorrhiza has significant inhibitory actions on cellular adhesion molecules
ICAM-1 and VCAM-1. The molecular mechanisms and bioactive components underlying the herb action are
undergoing being studied. Such study may lead to research and develop new medications for the prevention
and treatment of atherosclerosis through specific effects on these molecules.
Name of contact:
Shanhong Ling
Email/Phone no. of contact:
shanhong.ling@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 284399
Start Year: 2004
CIA Name: Dr Sascha Hughan
End Year: 2007
Admin Inst: Monash University
Grant Type: Early Career Fellowships (Overseas)
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $302,955
Title of research award:
Investigation of the role for Syk and PECAM-1 in ITAM and non-ITAM mediated platelet
activation.Investigation of the role for Syk and PECAM-1 in ITAM and non-ITAM mediated platelet
activation.
Lay Description (from application):
Not Available
Research achievements (from final report):
The research undertaken during the tenure of this Fellowship has extended our understanding of two major
routes of platelet activation, notably ITAM and non-ITAM mediated platelet signalling. The study has
identified how these pathways interact and contribute to novel synergistic effects which are of relevance for the
clinical management of thrombosis. In addition, the work has identified in platelets a new family of proteins
that appear to negatively regulate platelet function, in a manner which may be harnessed for therapeutic
intervention in the future. Moreover, the latter study has revealed a need for including new clincial tests within
pathology labs to assist in the diagnosis of patients at increased risk of thrombosis.
Expected future outcomes:
We expect to fully delineate the role for Dok2 and Dok1 adapter proteins in platelets and how these proteins
may be manipulated for therapeutic gain. We anticipate these studies will take a number of years for
completion, but will lead to significant outcomes for the haemostasis and thrombosis community.
Name of contact:
Dr Sascha Hughan
Email/Phone no. of contact:
sascha.hughan@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 299810
CIA Name: Prof Patrick Sexton
Admin Inst: Monash University
Main RFCD: Basic Pharmacology
Total funding: $542,013
Start Year: 2004
End Year: 2007
Grant Type: NHMRC Project Grants
Title of research award:
Molecular pharmacology of receptor activity modifying protein (RAMP) actionMolecular pharmacology of
receptor activity modifying protein (RAMP) action
Lay Description (from application):
The maintenance of optimum health and function of living cells, and consequently that of the whole organism,
depends on how cells respond to a multitude of physical and chemical stimuli that continually bombard them.
The majority of the chemical stimuli such as hormones and neurotransmitters impart their actions not by
directly entering the cell, but instead, by binding to a specific receiver protein at the cell surface called a
receptor. In one class of such receptors called G protein-coupled receptors, the transmission of the message to
the interior of the cell involves yet another protein called G protein. These receptors are the most abundant type
of cell surface receptors and form the targets for nearly 50% of currently used therapeutic drugs. It is, therefore,
extremely important to unravel how each of these components works. To make this process even more
complex, it was recently shown that another newly discovered group of proteins called receptor activity
modifying proteins (RAMPs) too play a critical role in some systems. We have shown that RAMPs interact
with many G protein-coupled receptors and that they have a wider range of actions than has previously been
appreciated. Moreover, it has been shown that the RAMP-receptor interface is a viable target for drug
development. Understanding the extent to which RAMPs interact with G protein-coupled receptors, how they
interact with the receptors and the consequences of this interaction forms the basis of the current proposal.
Such knowledge is central to the unraveling of the processes involved in the maintenance of health,
abnormalities that lead to disease, and in the development of new treatments.
Research achievements (from final report):
Receptor activity modifying proteins (RAMPs) are an important class of accessory proteins that modulate the
location and function of a subset of G protein-coupled receptors (GPCRs), the major class of cell surface
receptors. In particular, RAMPs are key components of the receptors for calcitonin gene-related peptide
(CGRP), a potent vasodilator that is also implicated in the pain of migraine, adrenomedullin, an important
cardiovascular hormone that plays a protective role during ischemia, and amylin, an important hormone
involved in metabolism. We have now performed extensively analysis of peptide agonist (receptor activators)
and antagonist (receptor blockers) behaviour at RAMP-induced receptors. The data identify important tools for
delineating different RAMP-based receptors as well as identifying where such tools are lacking. We have
extended these studies to clarify the role of residues of the RAMP N-terminus in binding of non-peptide (small
molecule) antagonists being trialled as anti-migraine drugs, and also for direct contribution to the binding
pocket for adrenomedullin. Analysis of signalling pathways for free and RAMP-complexed calcitonin
receptors revealed strong evidence for alteration in G protein (the signal transducer of GPCRs) specificity of
the receptor. Analysis of the role of different parts of the RAMP also provided key information on distinct roles
for each domain in , ligand binding, receptor interaction and selectivity of signalling by agonists at the
calcitonin receptor/RAMP complexes.
Expected future outcomes:
Future work will provide information on the role of RAMPs in the behaviour of receptors outside the calcitonin
family of receptors. In particular, how RAMPs modulate signaling of receptors and also how they are regulated
after binding of ligands. Additional work will examine the extent of RAMP-GPCR interaction.
Name of contact:
Prof. Patrick Sexton
Email/Phone no. of contact:
NHMRC Research Achievements - SUMMARY
patrick.sexton@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 299811
Start Year: 2004
CIA Name: Prof Patrick Sexton
End Year: 2007
Admin Inst: Monash University
Grant Type: NHMRC Project Grants
Main RFCD: Protein Targeting and Signal Transduction
Total funding: $596,956
Title of research award:
Molecular mechanisms underlying G protein coupled receptor signalingMolecular mechanisms underlying G
protein coupled receptor signaling
Lay Description (from application):
The maintenance of optimum health and function of living cells, and consequently that of the whole organism,
depends on how cells respond to a multitude of physical and chemical stimuli that continually bombard them.
The majority of the chemical stimuli such as hormones and neurotransmitters impart their actions not by
directly entering the cell, but instead, by binding to a specific receiver protein at the cell surface called a
receptor. In one class of such receptors called G protein-coupled receptors, the transmission of the message to
the interior of the cell involves yet another protein called G protein. These receptors are the most abundant type
of cell surface receptors and form the targets for nearly 50% of currently used therapeutic drugs. It is, therefore,
extremely important to unravel how each of these components works, and in particular to know how they work
in living cells. This project utilizes state-of-the-art methodologies to examine interactions between receptors
and their cognate G proteins, in living cells and in real-time. The work will answer fundamental questions
about the nature of G protein-coupled receptor signaling and will aid in the future development of more
effective therapeutic agents.
Research achievements (from final report):
G protein-coupled receptors (GPCRs) are the largest family of cell surface receptors, playing a major role in
most physiological processes and serving as the most tractable target for drug development. These receptors
impart their primary signal into the cell via transducer proteins, termed G proteins. This project investigated
new aspects of interaction between the GPCR and G proteins. A major finding of the grant was differences in
the way individual drugs acting at the same receptor could activate a different spectrum of signaling pathways.
A further finding was of cell background dependent differences in the capacity of individual receptors in
interact with different G proteins. Both of these findings impact on how we think about drug action. Another
significant outcome of the grant was the development, in collaboration with Prof. Michel Bouvier (Montreal,
Canada), of a new approach to directly examine the interaction between receptors and individual G proteins in
living cells. Finally, in collaborative work we have demonstrated that dimerisation of receptors can alter the
physiological response of receptors for angiotensin and, in separate work, the regulation of vasoactive intestinal
peptide and secretin receptors.
Expected future outcomes:
The technology developed within the grant to examine individual receptor G protein interaction has potential
for identifying novel drug behaviour and may be useful in drug discovery and development applications.
Name of contact:
Prof. Patrick M. Sexton
Email/Phone no. of contact:
patrick.sexton@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 334008
Start Year: 2005
CIA Name: Prof Henry Krum
End Year: 2009
Admin Inst: Monash University
Grant Type: Programs
Main RFCD: Clinical Pharmacology and Therapeutics
Total funding: $4,928,324
Title of research award:
Novel Therapeutic strategies to reduce the burden of chronic heart failureNovel Therapeutic strategies to
reduce the burden of chronic heart failure
Lay Description (from application):
The broad aims of the Program are to develop novel strategies in the prevention and treatment of chronic heart
failure. This will involve investigating new targets for pharmacological therapies, evaluating whether common
co-morbid disease states such as diabetes alter the efficacy of these therapies and investigating the role of stemcell therapy in this setting. The Program will also evaluate the contribution of non-heart failure drugs to the
burden of heart failure, determine the impact of rurality on prescribing for this condition and explore systems
of optimising delivery of best practice to the community.
This research formalises the existing collaborative efforts of a team of investigators that span all aspects of
research into the therapeutics of CHF from basic laboratory research to evaluation of patients in clinical trials
and public health translational aspects of this condition.
The Chief Investigators and Principal Investigators have an existing successful research collaboration which
will be greatly expanded via Program.
Research achievements (from final report):
The main achievements of the Program were:-, o
A series of novel anti-fibrotic agents
have been developed, are currently being tested and have been patented. This preliminary work has resulted in
a successful NIH Rapid Access to Investigational Drugs (RAID) grant for CIA and CIB as well as a successful
NHMRC Development grant for CIB., o
Novel inhibitors of key cells
signaling pathway in heart failure have been developed and are currently in the process of being patented with
a successful NHMRC Development Grant application for CIA having spun off this work., o Clinical studies
of stem cell subtypes in plasma of patients with heart failure has been completed., o
A large cohort
study has commenced which should provide insight into the antecedents to heart failure and its treatment
(SCREEN-HF). Funding has been secured via a further NHMRC Project Grant to follow all 3500 patients for 5
years. This should allow evaluation of transition from risk to overt disease., o
Delineation of
heart - kidney pathophysiological inter-relationship has been pursued with considerable success in identifying
novel pathways and therapeutic targets.
Expected future outcomes:
The pre-clinical and clinical research has significant potential to impact upon the progression of disease to
overt heart failure ie. prevention of disease as well as management of established heart failure. Beneficiaries
would be patients at risk of or currently with this condition, both in terms of novel therapies as well as early
detection approaches.
Name of contact:
Henry Krum
Email/Phone no. of contact:
henry.krum@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 334015
CIA Name: Prof Paul Myles
Admin Inst: Monash University
Main RFCD: Surgery
Total funding: $1,185,000
Start Year: 2005
End Year: 2007
Grant Type: NHMRC Project Grants
Title of research award:
Evaluation of Aspirin and Tranexamic Acid in Coronary Artery Surgery: The ATACAS TrialEvaluation of
Aspirin and Tranexamic Acid in Coronary Artery Surgery: The ATACAS Trial
Lay Description (from application):
This large study will compare two types of drug treatment in 4600 patients undergoing heart surgery, to see
whether either can reduce the risk of death or major complications. The complications after surgery we are
measuring include heart attack, stroke, lung embolism, bleeding around the heart, breathing failure, kidney
failure, major haemorrhage, serious wound infection, and death. The first drug being tested is low-dose aspirin.
It is believed that aspirin can reduce the risk of a further heart attack or stroke in patients with pre-existing
heart disease. There is some evidence that aspirin may have similar effects in people undergoing heart surgery,
but such use is constrained by a concern that there may be an increased risk of bleeding after surgery. For this
reason, most patients having heart surgery are advised to stop their aspirin about one week before surgery. But
patients could be missing out on aspirin's beneficial effects. At present, we do not know whether the benefits
of aspirin could outweigh the risk of excesive bleeding.The second drug being tested is tranexamic acid. This
drug prevents blood clot being broken down at the stitching sites of surgery, and probably reduces the amount
of blood loss during and after heart surgery. It is known that use of this drug reduces the need for a blood
transfusion. It is possible that this could avoid other more serious complications after surgery. Both of these
drugs are being tested individually, but in addition we are testing whether they may have an extra beneficial
effect when used together.The study is being done by a partnership of anaesthetitsts and surgeons at more than
20 hospitals around Australia.
Research achievements (from final report):
oThis research group has been challenged by gaining the collaboration and cooperation of specialists in cardiac
surgery, anaesthesia, intensive care and cardiology, both in Australia and overseas (UK, Malaysia, USA,
India). All are working tohgether to address two key questions in cardaic surgery: (i) should aspirin be
continued up to the day of surgery, (ii) should an antibleeding drug (in this case tranexamic acid) be used as a
routine in cardiac surgery. The latter question has reached heightened awareness over the past two years, with
several studies suggesting excess mortality with one of these drugs (aprotinin)., The study design and rationale
underwent peer review, and has appeared in print in the American Heart Journal (Feb 2008). CIA (Myles) has
been invited to speak at the Society of Cardiovascular Anesthesiologists in Vancouver, Canada, in June 2008,
on large multicentre trials in cardaic anaesthesia.
Expected future outcomes:
Safer cardiac surgery, with a lower rate of complications, and improved survival in the years that follow.
Name of contact:
Prof Paul Myles
Email/Phone no. of contact:
p.myles@alfred.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 334028
CIA Name: Dr Yuping Yuan
Admin Inst: Monash University
Main RFCD: Haematology
Total funding: $292,500
Start Year: 2005
End Year: 2007
Grant Type: NHMRC Project Grants
Title of research award:
Investigation of negative signalling mechanisms in plateletsInvestigation of negative signalling mechanisms in
platelets
Lay Description (from application):
Platelets are specialised blood cells essential for normal blood clotting. We are studying the processes that
control platelets sticking to the exposed vessel wall, to each other and to other cells to form a stable blood clot
at the site of injury to stop bleeding. The same processes, when unchecked, could lead to the formation of
harmful large blood clots that may block blood vessels in the heart or brain, resulting in heart attack or stroke.
Platelets stick to the blood vessel wall and each other through sticky proteins called receptors on the cell
surface. Receptors are able to bind to their specific ligands such as von Willebrand factor (vWf) and collagen
which become exposed following vessel wall damage. The interaction between the ligands and receptors will
trigger many biochemical changes within platelets, called signal transduction, that control platelet stickiness.
The aim of this research project is to investigate the signalling processes that are utilised by the major platelet
receptor called integrin alpha IIb beta 3. We are particularly interested in identifying the negative signalling
process utilised by this receptor to dampen the positive signals required for platelet stickiness, to achieve a
balanced clotting process. The identification of these specific signalling pathways will not only increase our
knowledge of blood clot formation in health and disease, but also help develop potential new therapies for the
prevention of heart diseases and strokes.
Research achievements (from final report):
Platelets are specialised blood cells essential for normal blood clotting and repair of damaged blood vessels.
We are studying the processes that enable platelets to stick to exposed vessl wall, to each other and to other
cells to form a stable blood clot at the site of injury. The same processes, when unchecked, could lead to the
formation of harmful blood clots that may block blood vessels in the heart or brain, resulting in heart attack or
stroke. Platelets stick to the blood vessel wall and each other through sticky proteins called receptors on the cell
surface. Receptors are able to bind to their specific ligands such as von Willebrand factor (vWf) and collagen
which becomes exposed following vessel wall damage. The interaction between the ligand and receptor will
trigger many biochemical changes within a platelet, called signal transduction. The signalling events then
control platelet stickiness. The aim of this research project is to investigate the signalling processes utilised by
the major platelet receptor called integrin alphaIIb beta 3, which is essential for platelets to firmly stick to sites
of damaged vessel wall and clot formation. We are particularly ineterested in identifying the negative
signalling process utilised by this receptor to dampen the positive signals required for platelet stickiness, to
achieve a balanced clot formation. The identification of these specific signalling pathways will not only
increase our knowledge of blood clot formation in health and disease, but also with the potential development
of new therapies for the prevention of heart disease and stroke.
Expected future outcomes:
We have identified a novel negative signalling pathway ultilised by the major platelet integrin alphaIIb beta3.
This pathwat involves the 5-phosphotase SHIP1 and Src kinase Lyn. This grant has allowed several high
impact publications and provided new insights to the regulation of ingerin negative signalling to other relevant
researchers in the field.
Name of contact:
Yuping Yuan
Email/Phone no. of contact:
yuping.yuan@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 334031
CIA Name: A/Pr Kate Denton
Admin Inst: Monash University
Main RFCD: Systems Physiology
Total funding: $393,750
Start Year: 2005
End Year: 2007
Grant Type: NHMRC Project Grants
Title of research award:
Study of the functional consequences of angiotensin II induced increases in renal innervationStudy of the
functional consequences of angiotensin II induced increases in renal innervation
Lay Description (from application):
Hypertension (high blood pressure) is a major public health problem in Australia, being a key risk factor for
cardiovascular diseases such as heart attack and stroke. More ominously, recent WHO reports show that
cardiovascular disease is the major health burden facing developing countries, particularly in our region.
Although some of the burden of cardiovascular diseases may be reduced by effective public health measures
(e.g., to reduce saturated fat intake), hypertension remains largely impervious to preventative public health
measures. While treatment of established high blood pressure can reduce the incidence of cardiovascular
disease, preventing the development of hypertension in the first place is not possible at this time. A major
impediment to the development of effective public health measure is our lack of knowledge of the pathological
mechanisms involved, despite over 100 years of active research effort. The experiments planned in this study
will probe below the surface of two important facts known about hypertension but not previously brought
together - that the kidney's blood vessels and nerves are remodeled in hypertension, and that the kidney's
control of the level of blood pressure must be changed in order for high blood pressure to develop in the first
place. We hope that pursuit of this experimental line of enquiry will provide new clues on where to look for
initiating factors in human hypertension.
Research achievements (from final report):
Angiotensin II is a hormone that controls blood pressure. Our studies demonstrate that one way in which
angiotensin II does this is to alter nerve growth to blood vessels in the kidney. Our work also shows that the
blood pressure response to angiotensin II is different in males and females. Together these studies demonstrate
novel pathways for the action of angiotesin that likely contribute to the development of high blood pressure
Expected future outcomes:
Effective control of blood pressure can prolong life expectany. Our studies have identified potential new
therapeutic targets for controlling high blood pressure
Name of contact:
Kate Denton
Email/Phone no. of contact:
kate.denton@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 334032
Start Year: 2005
CIA Name: Prof John McNeil
End Year: 2009
Admin Inst: Monash University
Grant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $427,500
Title of research award:
Risk and Determinants of Fatal and Non-Fatal Coronary Heart Disease in the Melbourne Collaborative Cohort
StudyRisk and Determinants of Fatal and Non-Fatal Coronary Heart Disease in the Melbourne Collaborative
Cohort Study
Lay Description (from application):
Heart disease is the leading cause of death and ill-health in Australia. Accordingly, it also imposes a significant
cost burden to the community. The key to effective prevention is understanding of the roles of risk factors in
the development of heart disease. These are best defined through the use of large cohort studies, which are
those that follow up a group of individuals over time. Statistical analyses are used to develop prediction
equations to quantify the effects of multiple risk factors in terms of their contributions to risk of heart disease.
The current heart disease prediction equations most commonly used in Australia are based on older overseas
studies, such as the Framingham Heart Study. Other than having low relevance to the current Australian
population, they incorporate only a limited range of traditional risk factors. A spectrum of new risk factors is
emerging. This study aims to develop risk prediction equations for heart disease that are applicable to the
current Australian population, using contemporary data from the Melbourne Collaborative Cohort Study.
Results from this study will allow the future onset of heart disease to be predicted with accuracy and
confidence, which in turn will allow preventive strategies, including expensive drugs, to be utilised in a more
effective manner. Ultimately, the results will lead to a more efficient allocation of limited healthcare resources
in Australia.
Research achievements (from final report):
Using Medical Records, autopsy reports and adjudication, we have verified over 750 fatal cardiovascular
disease (CVD) events that have occurred in the Melbourne Collaborative Cohort Study (MCCS). A process for
linking the MCCS with the Victorian Admitted Episodes Dataset to determine non-fatal CVD events has also
been established. Both these achievements mean accurate ascertainment of CVD outcomes in the MCCS.
These outcomes can then be used to develop new risk prediction equations for Australia., Data on fatal CVD
events has been used in analysis of the relationships between CVD and dietary patterns, and CVD and alcohol
intake, demonstrating the importance of both factors on disease outcomes. Data has also been used in a study of
the association between socioeconomic status and CVD death. This analysis reinforced the signficant role of
both smoking and abdominal adiposity in the social gradient seen in CVD. Finally, baseline data from the
MCCS study has been used to calibrated the SCORE (Systematic Coronary Risk Evaluation) risk chart, which
estimates 10-year risk of cardiovascular death. Recalibration using contemporary risk factor data and national
mortality data enables this equation to be used in other populations other than that from which it was derived.
Expected future outcomes:
Fatal and non-fatal CVD outcomes occurring within the MCCS will be used to develop and validate new
cardiovascular risk prediction equations for Australia.
Name of contact:
Andrew Tonkin
Email/Phone no. of contact:
andrew.tonkin@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 334046
Start Year: 2005
CIA Name: A/Pr Helena Parkington
End Year: 2007
Admin Inst: Monash University
Grant Type: NHMRC Project Grants
Main RFCD: Foetal Development and Medicine
Total funding: $440,250
Title of research award:
Vitamin D deprivation in early life: programming of vascular function in adulthoodVitamin D deprivation in
early life: programming of vascular function in adulthood
Lay Description (from application):
It is becoming increasing evident that appropriate nutrition in fetal/early life is important in programming the
cardiovascular system of the offspring, influencing its function throughout life. Maternal deficiency in vitamin
D is a recently-identified concern world-wide, including in Australian women. We have recently found that
vitamin D deficiency in pregnant rats results in marked hypertension in the offspring, when only 7 weeks of
age. This is associated with impaired endothelium-dependent vasodilator function, increased smooth muscle
tone and increased constriction to nerve stimulation. A combination of intracellular electrophysiological
techniques and tension recordings will be used to investigate detailed mechanisms in arteries isolated from key
vascular beds. In vivo studies will probe the role of vitamin D deficiency in the control of regional blood flow
control, and its influence on the underlying regulatory mechanisms responsible for the cardiovascular
dysfunction that we have observed. We will test whether the cardiovascular dysfunction in the offspring
following vitamin D deficiency is reversible upon repletion, or is "programmed" and thus not reversible with
repletion. Our early results suggest that the deleterious effects are not reversible. From this study we aim to be
in a position of greater confidence from which to inform women as to the importance for their baby of ensuring
adequate vitamin D repletion during pregnancy, to minimise risk of later cardiovascular disease.
Research achievements (from final report):
The aim of this project was to determine whether Vitamin D (VitD) deprivation in early life has permanent
effects on cardiovascular function and to determine underlying mechanisms. VitD insufficiency during
pregnancy and early life was associated with high blood pressure in young rats. There was enhanced sensitivity
of arteries to constrictor agents and reduced capacity to relax, which could explain the high blood pressure.
Following restoration of normal VitD levels, blood pressure and heart rate returned to normal values. Yet there
was persistent and significant impairment in the ability of arteries to relax. We found that the walls of the
arteries were more stretchy, which could explain the normalization of blood pressure. A startling, and
unexpected finding was that nerve activity caused large constriction of arteries in animals that had been VitD
deficient in early life, even though VitD had been restored. We tested heart function and found that it too was
more sensitive to the chemicals released by nerves. Interestingly, these effects were only evident in females.
This study demonstrates that, while early life VitD deficiency does not have a permanent effect on blood
pressure, we have discovered new evidence that early life VitD deficiency has persistent, lifelong effects on the
functions of arteries and heart, possibly rendering the heart of these individuals vulnerable to stress, when
nerves are more active. Thus, it is recommended that VitD deficiency during pregnancy and early life should
be avoided using supplementation to prevent permanent cardiovascular dysfunction. Supplementation is cheap,
safe and readily available.
Expected future outcomes:
The team involved in this project includes an epidemiologist, working in the Royal Women's and Children's
Hospitals in Melbourne. Thus, we can take early steps to implement the outcomes of this study in terms of
advice to pregnant women, to enhance the likelihood of a healthier cardiovascular start to life
Name of contact:
Dr Marianne Tare
Email/Phone no. of contact:
marianne.tare@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 334047
Start Year: 2005
CIA Name: Prof John McNeil
End Year: 2009
Admin Inst: Monash University
Grant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $3,532,500
Title of research award:
Randomised double-blind placebo-controlled trial of aspirin in primary prevention of CVD events or dementia
in the aged.Randomised double-blind placebo-controlled trial of aspirin in primary prevention of CVD events
or dementia in the aged.
Lay Description (from application):
The single most important risk factor for cardiovascular disease is age. All men aged 75 years have a 10-15%
risk of having a stroke or heart attack in the next 5 years. Low dose aspirin has been shown to prevent further
strokes and heart attacks in people who have already had one. It has been also shown to protect people who
have not had a heart attack or stroke but who are at increased risk. Given that the elderly are at increased risk
why do we need to do a trial in this particular group? The reason is that relatively few elderly patients were
included in the previous prevention trials. Also while the elderly may have the most to gain from treatment,
they also have the most to lose because they are more likely to suffer from side-effects. Aspirin prevents heart
attacks by stopping clots forming in blood vessels. This also means that people taking it have an increased
tendency to bleed. Thus though it may prevent strokes due to clots it may also increase the risk of strokes
caused by bleeding. Bleeding from the gut is another major problem as aspirin tends to erode the lining of the
stomach. Minor bleeding from the gut can also lower blood oxygen carrying capacity which may exacerbate
other diseases associated with ageing, e.g. heart failure. Dementia may be caused by repeated clots in small or
large vessels. Dementia is a particular problem in the elderly affecting 10% of 85 year olds. It is a major cause
of loss of quality of life and a significant cost to the community. Aspirin may reduce the progression of such a
disease leading to a maintained quality of life (QOL) for individuals and their families. As our age increases
our years of life remaining decreases. This is self-evident. Thus the potential to add years to life reduces and
the potential of diseases to adversely affect quality of life becomes more important. Thus it may be more
important to prevent a nonfatal stroke that leads to institutionalisation than a fatal stroke. Hence QOL will be
assessed.
Research achievements (from final report):
, This NHMRC project grant initially supported the completion of the ASPREE pilot study, analysing
data from 207 participants on aspirin or placebo for 12 months. Feasibility of methods for the main study was
proven with the pilot study. The grant was primarily awarded to act as leverage to obtain funding for the main
ASPREE trial. This was outstandingly successful. On the back of this seeding grant we obtained the following:,
1)
Funding of 50 million USD (shared
with US colleagues) was awarded late in 2009 by the peak medical research funding organisation of the USA,
the National Institutes of Health., 2)
The final ASPREE grant proposal
received a ranking in the top 2.5 percentile of all grants in that review round in 2008. This was an outstanding
achievement by any standard., 3)
Leverage to obtain funding for
substudies within Australia, e.g., $1.2 million AUD for the neuroimaging substudy ENVISion from NHMRC;
$3.4 million AUD for the establishment of the ASPREE HealHealthy Ageing Biobank from the CSIRO., 4)
Leverage to obtain $1.9 million AUD
funding from the Victorian Government (Victorian Cancer Agency) to establish clinical trial centres in regional
Victoria with ASPREE as the flagship clinical trial. , 5) The capacity to establish a longitudinal study of
healthy ageing in Australia., 6) The main ASPREE primary prevention clinical trial of low dose aspirin versus
placebo in 19,000 older persons is currently being undertaken in Australia and the USA with international
funding (2010-2016). ,
Expected future outcomes:
NHMRC Research Achievements - SUMMARY
Results from the ASPREE clinical trial will have broad implications for clinical outcomes, clinical
management and public health of older persons in Australia and internationally, particularly in the areas of
cardiovascular disease, dementia, physical disability and cancer.
Name of contact:
Dr Robyn Woods
Email/Phone no. of contact:
robyn.woods@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 334049
CIA Name: Prof Marie-Isabel Aguilar
Admin Inst: Monash University
Main RFCD: Basic Pharmacology
Total funding: $389,250
Start Year: 2005
End Year: 2007
Grant Type: NHMRC Project Grants
Title of research award:
Helix VIII of G protein coupled receptors is a lipid-activated signalling sensorHelix VIII of G protein coupled
receptors is a lipid-activated signalling sensor
Lay Description (from application):
G protein-coupled receptors (GPCRs) are the largest superfamily of membrane-embedded receptors and
represent prime targets for drug development. The molecular basis for their activation and regulation is poorly
understood, particularly the contribution of the membrane environment to receptor function. Using a range of
molecular and biophysical approaches and the angiotensin receptor as a model GPCR, studies are proposed to
understand the role of the cell membrane in GPCR activation. The results will provide important new
information on the molecular mechanism of GPCR regulation and exciting new approaches for drug design.
Research achievements (from final report):
This project has characterised the role of the cell wall in the control of G protein-coupled receptors.
Specifically we have identified key components of the cell wall that are important for turing the receptors on
and off. In addition, we have established methods to study how certain parts of the receptor change shape and
orientation at the cell wall, and how this can affect noraml cell function.
Expected future outcomes:
This project paves the way for more detailed analysis of G protein coupled receptor function and may open up
new avenues for drug design that may treat a range of diseases that arise from over-active receptors.
Name of contact:
Marie-Isabel Aguilar
Email/Phone no. of contact:
mibel.aguilar@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 334067
Start Year: 2005
CIA Name: Prof Stephen Holdsworth
End Year: 2009
Admin Inst: Monash University
Grant Type: Programs
Main RFCD: Immunology not elsewhere classified
Total funding: $5,527,670
Title of research award:
Pathogenic mechanisms of inflammatory diseasesPathogenic mechanisms of inflammatory diseases
Lay Description (from application):
This research is directed by a team of medical and basic scientists with expertise in mechanisms of
inflammation relevant to human disease. The program will investigate the molecular and cellular events that
are responsible for inflammation in the kidneys, joints and blood vessels which lead to diseases such as
glomerulonephritis, arthritis and atherosclerosis. The aim of the research is to find new therapeutic targets
which may be specific to certain organs or disease processes, in order to develop more effective and selective
treatments ofchronic inflammatory disease in humans.
Research achievements (from final report):
Theme 1: Mechanisms of nephritogenic immune responses and renal injury, Glomerulonephritis (GN) is a
major cause of renal failure. These studies have revealed many of the molecular events which determine the
generation of immune responses that target the kidney. Inhibition of many of the key molecules involved
prevented or attenuated injury in animal models of human disease. , Theme 2: Glucocorticoid induced
molecules in the control of inflammation and arthritis , Glucocorticoids are widely used in the treatment of
inflammatory diseases. They work through mechanisms which include increasing the production of a number
of proteins that regulate immune system. The function of some of these proteins, including MIF, MKP1,
Annexin 1, and the more recently described GILZ, has been investigated in rheumatoid arthritis and lupus. ,
Theme 3: Pro-inflammatory roles for coagulation proteins and their receptors, Coagulation and inflammation
are closely intertwined in common diseases that affect the kidney, liver and blood vessels. Cellular receptors
for coagulation factors (protease activated receptors (PAR's) and tissue factor) have the potential to modulate
tissue injury in these diseases and are potential therapeutic targets. These studies have demonstrated
coagulation receptors modulate inflammatory tissue injury in an organ and disease specific manner. , Theme 4:
Control of leukocyte recruitment and vascular permeability during inflammation, These studies improved our
understanding of the processes whereby damaging white blood cells infiltrate tissues affected by inflammatory
diseases. A greater understanding of this process may allow development of new approaches to limit the
contribution of white blood cells to inflammatory disease.
Expected future outcomes:
Tissues from diseased patients will be assessed to determine whether molecules found to be critical to the
development of inflammation in relevant animal models are prominent participants in human diseased tissues.
Strategies used to prevent disease in relevant animal models will be assessed for their applicability to human
disease.
Name of contact:
Professor Stephen Holdsworth
Email/Phone no. of contact:
stephen.holdsworth@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 334080
CIA Name: Prof Shaun Jackson
Admin Inst: Monash University
Main RFCD: Haematology
Total funding: $243,000
Start Year: 2005
End Year: 2007
Grant Type: NHMRC Project Grants
Title of research award:
Investigation of a novel role for Factor XIII in regulating the adhesive function of plateletsInvestigation of a
novel role for Factor XIII in regulating the adhesive function of platelets
Lay Description (from application):
Platelets are small specialised blood cells that are extremely important for the normal formation of blood clots
and for the repair of injured blood vessels. We are studying the processes that allow platelets to stick to the site
of vessel injury and to each other to form stable blood clots. If this process proceeds unchecked, harmful blood
clots can form which block blood vessels and cause heart attacks and strokes. There are many factors, both
inside and outside platelets, which control how big and how fast a blood clot grows and whether it becomes
harmful enough to cause a blood vessel blockage. One of these factors is the level of platelet 'stickiness' or
'reactivity'. We are working towards a better understanding of how platelet reactivity is regulated. Specifically,
we believe we have identified a new factor which keeps blood clots at a size that is not harmful to cause blood
vessel blockade. This information will not only increase our knowledge of blood clot formation in health and
disease but also may help in the development of new therapies for the prevention of heart attack and stroke.
Research achievements (from final report):
Platelets are small blood cells critical to stop bleeding. In order to perform this function, platelets possess a
highly specialised adhesive ability, capable of sticking to areas of blood vessel injury, as well as each other, to
form blood clots. A precise balance in the level of platelet 'stickiness' is critical for normal blood clot
formation, as insufficient blood clotting can result in life threatening bleeding problems, while exccesive
clotting can lead to acute myocardial infarction (heart attack) and ischaemic stroke, leading causes of death and
disability. Platelet stickiness and blood clot formation is critically dependent on the major platelet surface
protein called GPIIbIIIa which serves as a bridge between the platelet and the damaged vessel wall, as well as
between platelets, to facilitate the development of a platelet clump to plug the wound. Intensive investigations
have been carried out to understand the mechanisms regulating GPIIbIIIa adhesive function. In work leading to
this grant proposal, we have demonstrate a pivotal role for the elevation of calcium within the platelets in
promoting GPIIbIIIa activation and platelet stickiness. We have identified a novel role for calcium-dependent
enzymes named calpain and transglutaminase coagulation factor XIII (FXIII), in negatively regulating
GPIIbIIIa adhesive function. In this grant application, we aimed to define a role for FXIII in regulating platelet
adhesiveness and blood clot formation.
Expected future outcomes:
This grant has allowed us to define an important role for FXIII in regulating GPIIbIIIa function, and platelet
procoagulant activity. These studies led to several high impact publications, formed basis for future grant
applications and provided new insights to the regulation of platelet adhesiveness.
Name of contact:
Shaun P Jackson
Email/Phone no. of contact:
shaun.jackson@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 334083
Start Year: 2005
CIA Name: Prof Christina Mitchell
End Year: 2007
Admin Inst: Monash University
Grant Type: NHMRC Project Grants
Main RFCD: Protein Targeting and Signal Transduction
Total funding: $454,500
Title of research award:
The role of the inositol polyphosphate 4-phosphatase in cellular signallingThe role of the inositol
polyphosphate 4-phosphatase in cellular signalling
Lay Description (from application):
Cells respond to hormones, stress, growth factors and other environmental stimuli resulting in secretion, cell
growth, cell division and other specialized functions. These cellular responses are dependent on the generation
of intracellular signals that send messages either to the nucleus, the cytoskeleton or membrane compartments
and thereby elicit a specific response. A specific subset of signalling molecules that are localized on membrane
compartments are called phosphoinositides. We plan to investigate the role of a specific lipid called
PtdIns(3,4)P2 that recruits signalling proteins to specific cellular membranes including the inner wall of the
plasma membrane and vesicles found within the cell. We have identified and are currently characterizing a
novel enzyme called the "inositol polyphosphate 4-phosphatase" that terminates the signals generated by
PtdIns(3,4)P2. We are characterizing mice which lack this enzyme. 4-phosphatase deficient mice demonstrate
significant abnormalities in the brain and bone marrow. These mice appear unable to make circulating platelets,
small anucleate cells which are vital in preventing bleeding. We will determine how the 4-phosphatase
functions in regulating platelet production, by examining the bone marrow and blood of these mice. These
studies are significant as platelet production is essential for prevention of blood loss following trauma and also
is of vital importance in conditions associated with blood clotting including heart attack and stroke. Secondly
we have identified a related enzyme to the 4-phosphatase designated P-Rex-1 which is highly expressed in
brain and nerve cells. This proposal aims to determine if P-Rex-1 promotes nerve development.
Research achievements (from final report):
This grant application has investigated the functional role two novel enzymes play neuronal development. We
have shown two novel and related enzymes, 4-phosphatase-1 and P-Rex1 regulate nerve development and have
characterised the molecular mechanisms by which they function in nerve cells. This work has relevance to the
development of neuronal networks in the brain, for developmental brain defects, acquired degenerative
diseases of the brain, and in cancer.
Expected future outcomes:
We predict the 4-phosphatases and related enzymes may be significant therapeutic targets for controlling
cancer cell proliferation and spread.
Name of contact:
Prof Christina Mitchell
Email/Phone no. of contact:
christina.mitchell@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 334098
Start Year: 2005
CIA Name: Prof Michael Abramson
End Year: 2007
Admin Inst: Monash University
Grant Type: NHMRC Project Grants
Main RFCD: Environmental and Occupational Health and Safety
Total funding: $469,250
Title of research award:
Cardiorespiratory effects of ultrafine particlesCardiorespiratory effects of ultrafine particles
Lay Description (from application):
Very high levels of air pollution kill people. Although air quality is quite good in most Australian cities, the
levels of particles are still too high. There are many sources of particles in the air including diesel vehicles and
wood fires. There is a National Environment Protection Measure for particles less than 10 thousandths of a
millimetre in diameter. However some recent overseas studies have suggested that tiny particles less than 0.1
thousandths of a millimetre might have the greatest effects on the heart and lungs. We will conduct the first
Australian study of the health effects of these tiny particles. Particle counts will be measured in Melbourne by
CSIRO using state of the art equipment. Two groups of older subjects will be recruited: patients with chronic
lung diseases such as emphysema and patients with heart disease. They will perform regular breathing tests
and/or have the electrical activity of their hearts recorded. The recordings will be analysed to detect small
variations in heart rate. If we find relationships between particle counts and lung function or heart rate
variability, this will provide new evidence of the health effects of air pollution. When the NEPMs are revised,
new measures may be required for tiny particles. Particle counts can then be reduced by measures such as
better controlling diesel exhaust and more efficient wood stoves.
Research achievements (from final report):
Measurements of ultrafine(UF) or tiny particles were made in South Eastern Melbourne by CSIRO Marine &
Atmospheric Research. Over 2 years, air samples were collected, weighed and chemically analysed. Because
UF particles do not weigh very much, the actual number of particles in each ml of air was also counted. Indoor
measurements were made in a sample of homes with a portable particle counter. The mean indoor
concentration was 14% higher than outdoor concentrations., We recruited 48 patients with heart disease who
had their heart beat monitored for 24 hours on two separate occasions. Despite what is commonly thought,
even a normal pulse is not perfectly regular. There was no simple correlation between UF particle
concentrations and heart rate variability. However more complex statistical analysis suggested that one
measure of heart rate variability was associated with UF after allowing for temperature.,
We also
recruited 131 patients with Chronic Obstructive Pulmonary Disease who recorded their symptoms in a diary
and performed breathing tests every day for a week. A subgroup of subjects had more detailed measurements
of lung function. No relationship was found between UF particle concentrations and these measurements.
Analysis of UF particles, respiratory symptoms and other breathing tests is continuing., The general lack of
relationships between UF particles and measures of heart and lung disease suggest that there may not be
significant adverse health effects at the concentrations which occur in Melbourne air. There is little justification
for establishing a National Environment Protection Measure for this size fraction.
Expected future outcomes:
The final analysis of these data will be presented at relevant conferences and published in scientific journals.
They will inform the next revision of National Environment Protection Measures for ambient air quality.
Name of contact:
Michael Abramson
Email/Phone no. of contact:
Michael.Abramson@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 334162
Start Year: 2005
CIA Name: Dr Harold Coleman
End Year: 2007
Admin Inst: Monash University
Grant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $287,500
Title of research award:
A novel ionic current contributing to spasm of small blood vesselsA novel ionic current contributing to spasm
of small blood vessels
Lay Description (from application):
Vascular smooth muscle can produce strong constrictions or spasms that can severely limit blood flow.
Disorders arising from such spasms include sudden death, neurological deficits, visual and hearing loss or
impairment, Raynaud's phenomenon (painful episodic contraction of the fingers and toes) and intestinal
necrosis. Common mechanisms are likely to underlie the spasms associated with these disparate disorders. In
a recent electrophysiological study of vascular smooth muscle, we discovered a novel membrane current which
we refer to as the "plateau current". This current has a strong depolarizing influence that is likely to make a
major contribution to the spasms, particularly in arterioles and small arteries which are more dependent on
depolarization for contraction. Block of this current is expected to minimize the depolarization and therefore
prevent or ameliorate spasm of the vessels. Thus the plateau current represents a new field of therapeutic
potential for addressing vascular problems that have significant health implications. However, therapeutic
manipulation of the current requires knowledge of its properties. In this project we will determine the
biophysical and pharmacological properties of this current using voltage-clamp techniques. We will then use
this information to assess its functional significance by recording membrane potential with intracellular
microelectrodes simultaneously with contractile activity. We will also compare small vessels obtained from
volunteers with or without the vasospastic disorder of Raynaud's phenomenon. Our previous work using these
techniques was described in J Physiol as "a microelectrode, patch clamp and myograph study of the highest
quality and of supreme technical difficulty" and scored a "Top-Ten hit rate". Since we are the only ones to
record the plateau current, we are in a unique position to make significant progress to our understanding of
contraction, including spasm, in small blood vessels.
Research achievements (from final report):
Strong contraction, spasm, of vascular smooth muscle can severely limit tissue perfusion. In coronary vessels
spasm can totally occlude vessels and result in sudden death. In subjects who experience vasospastic angina,
acetylcholine (ACh) evokes spasm rather than the usual vasorelaxation, particularly in the smaller vessels, and
this is used as clinical diagnostic evidence for vasospastic angina. , Our single-microelectrode voltage-clamp
recordings from short segments of guinea-pig submucosal arterioles revealed the current that gives rise to AChinduced depolarization and consequently constriction. Other physiologically relevant chemicals are also able to
activate the same current, indicating a universal aspect to this current. Under normal conditions, this
depolarizing current is counteracted by an opposing hyperpolarizing current that is evoked by ACh (known as
EDHF [Endothelium-Derived Hyperpolarizing Factor]). However, if this hyperpolarizing current is diminished,
as we have shown can occur in some diseases (eg diabetes), then the depolarizing current can dominate such
that ACh then evokes constriction. Our results indicate that the depolarizing current is dependent on the
presence of an intact endothelium but is unlikely to result from constricting factors such as endothelin or
products of the cyclooxygenase pathway. The applicability of these results to humans is being investigated in
an electrophysiological and contractility study of small subcutaneous vessels from humans in which we are
comparing control vessels with those from sufferers of Raynaud's disease, a disease involving painful coldinduced vasospasm of the periphery. Early exciting results indicate novel mechanisms are likely to underlie
these cold-induced spasms of the blood vessels.
Expected future outcomes:
Block of the ionic current that underlies ACh-induced depolarization and constriction of blood vessels
minimizes constriction of the blood vessels. Thus, our identification of the ionic current means that the ion
NHMRC Research Achievements - SUMMARY
channels that carry the current are potential targets for therapeutic drugs aimed at improving tissue perfusion
and reducing hypertension.
Name of contact:
Dr Harold A. Coleman
Email/Phone no. of contact:
h.coleman@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 334173
CIA Name: Dr Robyn Tapp
Admin Inst: Monash University
Main RFCD: Epidemiology
Total funding: $379,866
Start Year: 2005
End Year: 2009
Grant Type: Early Career Fellowships (Overseas)
Title of research award:
Epidemiology of Microvascular & Macrovascular Complications Associated with diabetes
MellitusEpidemiology of Microvascular & Macrovascular Complications Associated with diabetes Mellitus
Lay Description (from application):
Not Available
Research achievements (from final report):
In 2005 I was awarded the prestigious National Health and Medical Research Council Sidney Sax PostDoctoral Fellowship and as part of this award undertook post-doctoral training at the International Centre for
Circulatory Health, Imperial College London and INSERM France, returning to Australia at the start of 2007.
During this time, I developed extensive expertise in novel non-invasive methods for assessing both the retinal
microvasculature and cardiac structure and function. Additionally, I also developed expertise in life course
epidemiologic methods and the determinants of adult chronic disease. At the start of 2010 I returned to the UK
to further develop my research program 'Life course Epidemiology and Cardiovascular Physiology'. I maintain
strong collaborative links with Australia, but without career funding it has not been possible for me to remain
in Australia. A great disappointment to me.
Expected future outcomes:
Within the Australian context there is no future work, as I did not secure funding in Australia. Consequently I
am now based at the Imperial College London. Its nice to see that since lodging a formal complaint with the
NHMRC independent commissioner in 2009 that the CDF assessment process has been overhauled. It was
devistating to see fellows with limited experience being funded.
Name of contact:
Robyn Tapp
Email/Phone no. of contact:
r.tapp@imperial.ac.uk
NHMRC Research Achievements - SUMMARY
Grant ID: 350327
CIA Name: A/Pr Christopher Sobey
Admin Inst: Monash University
Main RFCD: Basic Pharmacology
Total funding: $560,229
Start Year: 2005
End Year: 2009
Grant Type: Established Career Fellowships
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
Brain arteries were found to normally produce high levels of oxygen radicals compared with arteries from other
parts of the body, in amounts that are likely to be nearly toxic. The function of these radical species remains
largely unknown, but it is higher in males than females and some evidence was found that they may assist in
opening brain arteries to allow increased blood flow under healthy conditions. Under disease conditions, such
as high blood pressure, high cholesterol or stroke, the oxygen radical production by these arteries was found to
further increase to levels high enough to cause damage to the artery and inflammation in the brain. We
identified the protein family that produces such high levels of oxygen radicals in brain arteries to be 'NADPH
oxidase'. While better drugs are needed to be able to block this production, we found that this could be done
experimentally with existing blockers to improve artery health and reduce damage after stroke. We have also
identified two new classes of drugs that could be developed towards clinical use as NADPH oxidase inhibitors
in cardiovascular disease.
Expected future outcomes:
Important information was obtained to clarify NADPH oxidase in the brain and brain arteries as a future target
for therapy, and progress was made towards identifying lead compounds for such a development program.
Name of contact:
A/Prof Christopher Sobey
Email/Phone no. of contact:
chris.sobey@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 350477
CIA Name: A/Pr Christopher Sobey
Admin Inst: Monash University
Main RFCD: Basic Pharmacology
Total funding: $515,813
Start Year: 2005
End Year: 2007
Grant Type: NHMRC Project Grants
Title of research award:
Nox4-containing NADPH-oxidase as a protective enzyme in the cerebral circulationNox4-containing NADPHoxidase as a protective enzyme in the cerebral circulation
Lay Description (from application):
Failure of the cerebral circulation to meet the brain's immediate high nutritive requirements results in a stroke
in just a few minutes. Stroke continues to be a major cause of death and disability, and this major medical
challenge requires urgent research at the basic level to better understand the processes of normal, and then
abnormal, regulation of brain artery function. The project will test the importance of a newly discovered
mechanism for increasing brain blood flow. This involves activation of an enzyme, Nox4-containing NADPHoxidase, to generate oxygen radicals which then relax the wall of blood vessels causing the arteries to let more
blood through. We believe that this process plays an important role in the normal, healthy maintenance of
blood supply to the brain. Furthermore, we propose that the activity of this enzyme is elevated and therefore
protective in brain arteries during high blood presure - which is the major risk factor for stroke. We will
specifically test whether the activity of this enzyme actually helps to limit the amount of brain death following
stroke. We will use a variety of techniques to assess the importance of this enzyme in brain arteries in the
living body, and also in isolated segments of brain artery from animals that are either healthy or have diseased
brain arteries. The results are expected to provide major new insight into processes that help maintain brain
blood flow under normal conditions and after a stroke, and the knowledge gained here should lead to safer
therapies to prevent or treat stroke.
Research achievements (from final report):
We discovered that a protein called NADPH oxidase is present in brain arteries at much higher levels than in
non-brain arteries. This protein is an enzyme that makes oxygen radicals which are normally understood to be
detrimental, but because levels of NADPH oxidase are high in brain arteries of normal healthy animals (in a
range of species), we predicted that it plays a unique signalling role in regulating brain blood flow. Indeed, we
found that when we stimulated the enzyme, oxygen radicals were produced and caused opening of the brain
arteries, which improves brain blood flow. We also found that increasing blood flow through brain arteries
actually activates the enzyme to assist in the opening of the artery. Another interesting observation was that the
enzyme is always more active in males than females, and that this is due to the suppressing effects of
oestrogen. Under disease conditions, such as high blood pressure, we found that in brain arteries the enzyme is
even more active than normal, consistent with it playing a protective role to help maintain brain blood flow
when the risk of stroke caused by artery blockage is increased. Ongoing studies are directly assessing the effect
of NADPH oxidase on outcome after stroke. Together this research, and the spin-off research that has resulted,
should enable an improved understanding of mechanisms that control brain blood flow during health and
disease, and it should also facilitate the development of new and safer therapies for treatment of stroke.
Expected future outcomes:
This research should enable an improved understanding of mechanisms that control brain blood flow during
health and disease, and it should also facilitate the development of new and safer therapies for treatment of
stroke.
Name of contact:
A/Prof Christopher Sobey
Email/Phone no. of contact:
chris.sobey@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 359282
Start Year: 2005
CIA Name: Dr Sophocles Chrissobolis
End Year: 2010
Admin Inst: Monash University
Grant Type: Early Career Fellowships (Overseas)
Main RFCD: Medical Physiology not elsewhere classified
Total funding: $342,589
Title of research award:
Vascular protection of the brain during hypertension: Role of manganese-superoxide dimutase (MnSOD)Vascular protection of the brain during hypertension: Role of manganese-superoxide dimutase (MnSOD)
Lay Description (from application):
Not Available
Research achievements (from final report):
This research uncovered a key protective role of two antioxidant enzymes (manganese superoxide dismutase
and glutathione peroxidase-1) and a new receptor (receptor activity modifying protein-1) against harmful
effects of angiotensin II (Ang II), a hormone found in the body. Mechanisms that contribute to cerebral
vascular dysfunction by another hormone, aldosterone, were also uncovered. During cardiovascular disease,
angiotensin II and aldosterone promote high blood pressure, inflammation and thickening of blood vessels, all
of which are harmful to the body. Since Ang II and aldosterone contribute to high blood pressure, which in turn
is a major risk factor for stroke, and may be important in Alzheimer's disease, it is crucial to identify
mechanisms which contribute to, and protect against, elevated Ang II and aldosterone levels. Understanding
protective mechanisms at this basic level is critical to help guide development of more effective therapeutics in
the treatment of high blood pressure, stroke and Alzheimer's disease. Thus, drugs which can perhaps target
mechanisms to either inhibit or enhance their activity may be used in conditions where Ang II or aldosterone is
known to be the underlying cause of disease.
Expected future outcomes:
By identifying mechanisms that protect in response to a hormone which contributes to disease, this research
may leads to further discovery regarding ways that these mechanisms may be protective, for example in
response to other harmful stimuli. Hopefully such research aids development of specific drugs to help treat
cardiovascular disease.
Name of contact:
Sophocles Chrissobolis
Email/Phone no. of contact:
Sophocles.Chrissobolis@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 367644
CIA Name: Dr Salvatore Pepe
Admin Inst: Monash University
Main RFCD: Surgery
Total funding: $442,093
Start Year: 2006
End Year: 2008
Grant Type: NHMRC Project Grants
Title of research award:
Clinical feasibility study of Omega-3 PUFA therapy for the reduction of post-cardiac surgery atrial
arrhythmiasClinical feasibility study of Omega-3 PUFA therapy for the reduction of post-cardiac surgery atrial
arrhythmias
Lay Description (from application):
The aim of this study is to determine the molecular and clinical impact of omega-3 polyunsaturated fatty acids
(PUFA) pre-treatment 2 weeks before cardiac surgery in 150 patients. The outcome of this proposal will
indicate proof of molecular concepts, clinical feasibility and specific design elements of a future, large scale,
placebo controlled, prospective randomised trial of oral therapy with omega-3 polyunsaturated fatty acids
(PUFA). Recently, omega-3 PUFA via fish diet was reported to be linked to low incidence of AF. The main
aim is to provide a cheap and safe preventative therapy against post-operative atrial fibrillation (AF), a key
heart rhythm disorder that occurs in at least 1 in 4 patients after heart surgery and increases post-operative
complications, limits recovery and increases hospital stay and cost. Biochemical study elements are important
to gain valuable insight into the molecular mechanisms (directly in human heart) that underlie post-operative
heart rhythm disorder and may delineate new more precise molecular targets for therapy. No previous clinical
study has ever examined whether omega-3 PUFA therapy prevents post-operative heart rhythm disorder. Use
of 3g/day omega-3 PUFA pre-treatment in the surgical setting has been shown to be safe in a number of small
studies, including our own. Our preliminary data indicates that therapy increases heart and blood content of
omega-3 PUFA ~2-fold, and reduces the incidence of AF. Post-operative AF is an expensive resource burden
in all cardiothoracic surgery units of Australian hospitals and targets key health priorities. Due to the nonpatentable nature of omega-3 PUFA, significant industry based support for clinical research is limited. A
positive outcome would rapidly pave the way for widespread use in elective surgery. Reduced length of
hospital stay, cost-savings, and the increase in productivity as healthy individuals return to their communities
would nationally repay the investment many fold.
Research achievements (from final report):
Complications after heart surgery are common and are a major impediment to recovery requiring extended
medical support. The goal of this project was to test at a preliminary level whether oral therapy with omega-3
fatty acids (fishoil type) for 2 weeks before elective cardiac surgery, reduced the incidence of post-operative
arrhythmias (incl. atrial fibrillation) and related biochemical pathology in the heart and blood. Although the
clinical study remains in progress until 2010 (due to reduced availability of intensive care beds and thus
scheduling of elective surgery), key laboratory findings to date are: 1.) treatment with omega-3 increases
omega-3 fatty acid content in human heart and red blood cells; 2.) in lab experimental models (which included
animal studies) omega-3 therapy improves recovery of isolated muscle contraction and reduced vulnerability to
arrhythmias that normally arise after oxygen deprivation-related injury; 3.) omega-3 therapy restores efficient
oxygen metabolism and energy production permitting this recovery in dose response fashion; 4) omega-3
consumption prior to oxygen deprivation stress provides the heart with an apparent 'preconditioning' effect
which provides protection against a controlled and sustained period of oxygen deprivation; 5) Preliminary data
indicates omega-3 therapy reduces the incidence of inflammation that normally occurs after oxygen deprivation
and reperfusion.
Expected future outcomes:
The clinical study component (with related biochemical measures), in elective cardiac surgery patients, to
determine whether omega-3 fatty acids limit the incidence of early post-operative arrhythmias (including atrial
fibril1ation) remains in progress until the end of 2010 due to delays in elective surgery schedules.
Name of contact:
NHMRC Research Achievements - SUMMARY
Dr Salvatore Pepe
Email/Phone no. of contact:
Salvatore.Pepe@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 384101
CIA Name: A/Pr Roger Evans
Admin Inst: Monash University
Main RFCD: Systems Physiology
Total funding: $548,878
Start Year: 2006
End Year: 2010
Grant Type: Established Career Fellowships
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
My major achievements include:, Showing how the flow of blood in the inner and outer part of the kidney is
independently controlled, and how changes in these mechanisms could promote the development of high blood
pressure., Showing how the unique layout of the blood vessels in the kidney acts as to protect the kidney from
the toxic effects of oxygen, but at the same time renders the kidney susceptible to damage from inadequate
oxygen delivery., Showing how the kidney responds to changes in oxygen delivery and oxygen consumption.,
Showing that the causes of high blood pressure in settings of severe disadvantage (e.g. rural India) may differ
from those in more affluent settings.
Expected future outcomes:
A new understanding of how low levels of oxygen in the kidney lead to the development of kidney disease. We
hope this work will lead to new ways to treat or even prevent many disease of the kidney., Our work in rural
India will provide a new understanding of the causes of high blood pressure and other cardiovascular disease in
a large population of people who have previously been little studied.
Name of contact:
Roger Evans
Email/Phone no. of contact:
roger.evans@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 384126
CIA Name: Prof Michael Berndt
Admin Inst: Monash University
Main RFCD: Haematology
Total funding: $516,015
Start Year: 2006
End Year: 2008
Grant Type: NHMRC Project Grants
Title of research award:
Regulation of platelet adhesion by the GPIbalpha cytoplasmic tailRegulation of platelet adhesion by the
GPIbalpha cytoplasmic tail
Lay Description (from application):
Platelets are small blood cells that play an essential role in the normal blood clotting process that stops
bleeding following an injury to a blood vessel. In addition to their important role in preventing bleeding, they
are also responsible for the development of harmful blood clots which can sometimes result in a fatal outcome
in the form of a heart attack or a stroke. When platelets stick to sites of blood vessel injury they must respond
very rapidly to ensure the formation of a stable blood clot. Our research studies are aimed at understanding
more closely the factors that regulate the adhesiveness of platelets, since this is an important deteminant not
only in normal blood clot formation but also in the development of harmful blood clots (thrombosis). A better
understanding of these processes will add significantly to our knowledge of how blood clotting is controlled.
This information is relevant to many human diseases including heart attack and stroke.
Research achievements (from final report):
The formation of blood clots is important in preventing excessive blood loss but is also responsible for the
occurence of life threatening heart attacks and stroke. The adhesive function of blood platelets is critical to the
formation of a stable clot, and if not regulated correctly, can result in inappropriate clot formation, causing
vessel obstruction and preventing blood flow to vital organs. The major focus of this grant was to investigate
the physical and functional interaction of two proteins with the cytoplasmic tail of GPIbalpha, namely filamin
A and PI 3-kinase. Building on previous work in transfected cells, which identified specific residues in the
GPIbalpha cytoplasmic tail that were critical for filamin A binding and led to a defect in cell adhesion under
high shear conditions, we generated transgenic mouse models expressing wild type and mutant forms of the
human GPIbalpha receptor. We demonstrated that a specific mutation disrupting the GPIba-filamin interaction
lead to a profound shear-dependent phenotype. In summary, mutant transgenic platelets bound vWf normally
under static and physiological shear conditions, but under elevated shear conditions, platelet adhesion became
highly unstable as did the integrity of the platelet itself. We also identified a direct functional interaction
between the p85 subunit of PI 3-kinase and the GPIbalpha cytoplasmic tail which occurs independent of the
well established association between 14.3.3 and GPIbalpha. These findings serve to improve our knowledge of
how the GPIb/V/IX receptor is involved in platelet activation and regulation of blood clot formation and may,
in the longer term, aid in the development of new therapies for the prevention of arterial thrombosis including
heart attack and stroke.
Expected future outcomes:
The transgenic mice generated here will be used for ongoing examination of the role of GPIb-filamin for in
vivo thrombosis and also to determine the molecular basis of the giant platelet phenotype and
thrombocytopenia characteristic of Bernard-Soulier syndrome. New and important insight into the signalling
functions of the GPIb/V/IX receptor will be gained from the p85-GPIbalpha interaction.
Name of contact:
Michael Berndt
Email/Phone no. of contact:
m.berndt@ucc.ie
NHMRC Research Achievements - SUMMARY
Grant ID: 384142
CIA Name: A/Pr Rosemary Horne
Admin Inst: Monash University
Main RFCD: Paediatrics
Total funding: $324,009
Start Year: 2006
End Year: 2008
Grant Type: NHMRC Project Grants
Title of research award:
Cardiovascular, neurophysiological and neurocognitive assessments to define sleep disordered breathing in
childrenCardiovascular, neurophysiological and neurocognitive assessments to define sleep disordered
breathing in children
Lay Description (from application):
Disruptions to breathing during sleep (snoring), known as sleep disordered breathing occurs in up to 27% of
children and forms a continuum of symptoms ranging from mild to severe. It has previously been thought that
only severe disruptions to breathing, as occurs in obstructive sleep apnoea (OSA), were of clinical significance
requiring intervention, however recent studies have shown that even snoring with no currently used signs of
altered blood oxygenation levels or sleep disruption can have a significant impact on daytime functioning and
school performance. It is also known that cardiovascular disease is a long-term consequence of untreated sleep
disordered breathing in adults, however the long-term effects on the cardiovascular system in children are
unknown. This study will examine both the neurocognitive and cardiovascular effects of a range of severities
of sleep disordered breathing in children and will identify new more sensitive markers of sleep disruption in
order to predict neurocognitive dysfunction. In order to address this most important issue, this project will
combine the expertise of scientists and clinicians in the fields of paediatric sleep, cardiovascular control and
neuropsychological assessment from Monash and Melbourne Universities, and the Monash Medical Centre and
Royal Children's Hospital.
Research achievements (from final report):
Our data suggest that sleep disorderd breathing of all severities elevates blood pressure and heart rate in all
sleep states compared to control children. We also have also found that there is a significant elevation in blood
pressure and heart rate at the termination of central respiratory events which are usually considered benign,
similar to those at the termination of obstructive events. The surges are similar to the blood pressure and heart
rate elevations occur that occur in adults. These repetitive cardiovascular surges may contribute to the overall
hypertension we have observed. Results of behaviour and neurocognitive testing have also shown that
severities of sleep disordered breathing are associated with behavioural and neurocognitive impairments
exhibiting significantly higher rates of total, internalising and externalising behavioural problems compared to
controls and increased rates of behavioural executive dysfunction.
Expected future outcomes:
We have submitted an application in the 2009 round of funding to examine the whether treatment of these
children is effective in lowering blood preaaure and also in improving behaviour and neurocognition.
Name of contact:
Erosemary.Horne@Med.Monash.Edu.Au
Email/Phone no. of contact:
rosemary.horne@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 384163
Start Year: 2006
CIA Name: Dr Grant Drummond
End Year: 2008
Admin Inst: Monash University
Grant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $401,523
Title of research award:
Defining the roles of NADPH oxidases in vascular remodelling and arterial hypertensionDefining the roles of
NADPH oxidases in vascular remodelling and arterial hypertension
Lay Description (from application):
Hypertension (high blood pressure) is a major risk factor for cardiovascular diseases such as heart attacks, heart
failure and stroke - the major causes of death world-wide and a huge burden on the Australian health care
budget. Oxidative stress, resulting from an imbalance in the production and removal of toxic molecules called
free radicals within the blood vessel wall, is a key player in the initiation and progression of these disorders. In
the early stages of hypertension, production of free radicals only just outweighs their removal, resulting in a
mild oxidative stress. However, this is enough to trigger a cascade of downstream events leading to activation
of other, normally dormant, free radical generating systems. At these excessive levels, free radicals attack the
cells of the artery wall leading to blood vessel dysfunction and ultimately cardiovascular disease. A major
source of free radicals in the blood vessel wall are a family of enzymes called NADPH oxidases. It is our
hypothesis that upregulation of onr of these enzymes in the early stages of hypertension is the initial trigger for
many of the downstream effects that ultimately lead to cardiovascular disease. Our group is uniquely poised to
test this hypothesis as we are the only laboratory in the world with access to three different strains of
genetically modified mice, each lacking one of the three known isoforms of NADPH oxidase. Identification of
the specific isoform of NADPH oxidase involved in free radical production in blood vessels is a critical first
step in developing drugs that block vascular free radical production and so remove the molecular link between
hypertension and major cardiovascular events.
Research achievements (from final report):
The major aim of this project was to identify why blood vessels from patients with high blood pressure
generate an excessive amount free radical molecules, and what effects these toxic molecules have in terms of
causing the artery disease that ultimately leads to heart attacks and strokes. We have identified a family of
proteins called Noxes as the major source of free radicals in blood vessels from individuals with high blood
pressure. Furthermore, we have shown that by blocking the activity of these proteins - either by deleting the
gene that encodes them or through the use of experimental drugs - free radical production in the vessel wall is
lowered, as is the elevation in blood pressure. These findings highlight Noxes as promising targets for future
drugs to treat hypertension and its downstream consequences, namely heart attacks and strokes.
Expected future outcomes:
Having established a role for Noxes in hypertension-associated vascular disease, we will now begin testing the
effects of a series of novel chemicals - which we have identified to be inhibitors of NADPH oxidase in cultured
cell systems in a separate research program - for their effectiveness in lowering blood pressure and preventing
vascular disease in a mouse model of hypertension.
Name of contact:
Grant R Drummond
Email/Phone no. of contact:
Grant.Drummond@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 384177
Start Year: 2006
CIA Name: Prof Alexander Smith
End Year: 2010
Admin Inst: Monash University
Grant Type: Established Career Fellowships
Main RFCD: Medical Biochemistry: Proteins and Peptides
Total funding: $664,574
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
The research carried out over the five year period of this fellowship has focused on the trafficking of proteases
through the cell to their final destination on the outer cell surface. This research has identified some of the key
proteins involved in this transport pathway as well as showing that these proteases can be "shed" from the cell
surface. We have shown that this shedding can be both regulated and importantly, we have also shown that the
degree of shedding changes as a consequence of disease. The proteases that we have focused on are expressed
on the surface of the endothelial cells that line blood vessels and their role is to activate or terminate the
function of peptide hormones that regulate blood pressure. Thus by understanding the mechanisms by which
these proteases move to the cell surface and are then shed into the blood system, opens the door to new
therapeutic strategies that might help regulate blood pressure. In addition, in preliminary studies we have
shown that the measurement of these shed proteases in blood or cerebrospinal fluid (CSF) could be predictive
of both vascular and heart disease.
Expected future outcomes:
The interesting finding that levels of the endothelin converting enzyme (ECE) are elevated in the CSF of
patients suffering cerebral ischemia following stroke has been patented as we believe measurement of ECE in
CSF could be a predictor of cerebral ischemia and as such has real clinical utility.
Name of contact:
Professor A. Ian Smith
Email/Phone no. of contact:
ian.smith@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 384207
Start Year: 2006
CIA Name: Prof John Bertram
End Year: 2008
Admin Inst: Monash University
Grant Type: NHMRC Project Grants
Main RFCD: Foetal Development and Medicine
Total funding: $422,265
Title of research award:
Exploring the physiological, morphological and molecular bases of renal developmental
programming.Exploring the physiological, morphological and molecular bases of renal developmental
programming.
Lay Description (from application):
Suboptimal fetal and neonatal development increases our risk of developing a range of diseases in adulthood.
The concept that deleterious events during development can influence adult health is termed 'developmental
programming'. Obtaining A Healthy Start to Life is a priority research goal of the Australian Government. The
kidneys are particularly susceptible to developmental programming. This is in part because the functional units
(nephrons) of the kidneys are all formed before birth in humans. Thus, if fetal development is suboptimal,
babies are at risk of being born with a permanent nephron deficit, with functional and disease consequences.
We have shown in male rats that the offspring of a maternal low protein diet have fewer nephrons and lower
blood pressure than rats fed a normal diet. These rats display a striking sensitivity in adulthood to the feeding
of a high salt diet. We will define the physiological and morphological bases of this sensitivity, and repeat
these studies in females, as increasing evidence shows significant sex differences in developmental
programming. Defining the molecular mechanisms of developmental programming is the greatest challenge
for researchers in the field. We have recently completed the most comprehensive analysis to date of gene
expression in the developing mouse kidney, and have shown for the first time that the mouse programmes
kidney development. We will use the new techniques of genomics and bioinformatics to study the molecular
mechanisms of kidney programming. This mechanistic data will provide an excellent hypothesis engine for
future studies on the specific roles of these molecular pathways in developmental programming in all
mammalian species.
Research achievements (from final report):
There is increasing evidence that growth and development prior to and shortly after birth, can have long term
consequences for our adult health, including cardiovascular (heart, blood vessel) and kidney health. This
phenomenon is referred to as "developmental programming" or the "developmental origins of health and
disease". Many of the common chronic diseases of adulthood may have their genesis before birth., We have
characterized a new model of kidney developmental programming in the mouse. We subsequently examined
the consequences of developmental programming for adult cardiovascular function. We tested the effects of pre
and postnatal protein restriction and salt intake, separately in males and females. In rat studies, we found that
combined pre and postnatal protein restriction renders both systemic arterial pressure and glomerular filtration
pressure sensitive to dietary salt. , We consider the mouse to be a powerful new model for studies on
developmental programming, especially for discovering the molecular/genetic mechanisms responsible for the
fetal changes to tissue/organ development and ultimately the adult outcomes in terms of tissue structure,
function and disease.
Expected future outcomes:
Completion of the gene microarray study of developing kidneys from mouse fetuses exposed to either a normal
maternal diet (normal protein) or a low protein maternal diet. This study will be the most comprehensive to
date on the molecular mechanisms responsible for renal developmental programming, and will provide new
insights into causation and possible therapies.
Name of contact:
Professor John Bertram
Email/Phone no. of contact:
NHMRC Research Achievements - SUMMARY
john.bertram@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 384218
CIA Name: Prof Adrian Walker
Admin Inst: Monash University
Main RFCD: Paediatrics
Total funding: $489,146
Start Year: 2006
End Year: 2008
Grant Type: NHMRC Project Grants
Title of research award:
Novel approaches to assessing cerebral circulation and oxygenation in preterm human infants.Novel
approaches to assessing cerebral circulation and oxygenation in preterm human infants.
Lay Description (from application):
In the first few days after birth, some premature babies develop low blood pressure. It is thought that this
meant that the amount of blood and oxygen going to the brain would also fall. If blood pressure became very
low, this could injure the brain. Drugs are used to prevent low blood pressure, but their effect on blood flow
and oxygen in the brain is uncertain. This study aims to develop simple cotside monitoring procedures that
allow neonatologists to monitor oxygen supply and blood flow in the brain in tiny babies who weigh less than
1000gm, and what happens within the brain when drugs are given to raise blood pressure. We will employ a
new instrument that generates low intensity near infrared light which passes safely into the brain and is
absorbed according to the amount of oxygen present in very small blood vessels. As the methodology is new,
we intend to first validate the measurement in immature lambs. The instrument will then be applied in studies
of babies undergoing intensive care and at risk for low pressure and brain injury, as many as 5000 babies each
year in Australia.
Research achievements (from final report):
Advances in clinical care have improved the survival of very premature babies. However, at least 10 per cent of
very low birth weight babies (<1500g) develop cerebral palsy, and others suffer developmental delay. The
origin of these problems lies with hypoxic-ischaemic injury (HIE) - low brain blood flow and low oxygen
delivery to the preterm brain. Using complementary studies in human infants and an immature lamb model, this
program examined novel approaches to assessing the oxygenation of the brain with novel near infrared (NIR)
technology. , , Newborn lambs. Several methods based on NIR were validated for assessing the level of blood
flow to the brain, the levels oxygen in brain tissue, and the utilisation of oxygen by the brain. The primary
objective was to develop safe, simple and non-invasive (not requiring insertion of catheters) methods suitable
for use at the cotside of critically-ill preterm infants. , , Preterm infants. NIR was employed to continuously
measure brain tissue saturation (TOI). Impaired TOI was associated with lower gestational age, higher clinical
risk scores, and higher risk of death. In ground-breaking studies, we discovered that regulation of blood flow to
meet oxygen requirements of the immature brain (flow-metabolism coupling) was improved by dopamine, an
action that was previously unrecognised.,
Expected future outcomes:
Significance. Development of novel cotside methods for monitoring the brain of immature infants will help to
identify key cause(s) of brain injury. We envisage a new therapeutic role of dopamine; by improving cerebral
flow-metabolism coupling, dopamine may increase the margin of safety against HIE in preterm infants.
Name of contact:
Professor Adrian Walker
Email/Phone no. of contact:
adrian.walker@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 384237
CIA Name: A/Pr Robert Widdop
Admin Inst: Monash University
Main RFCD: Basic Pharmacology
Total funding: $519,279
Start Year: 2006
End Year: 2008
Grant Type: NHMRC Project Grants
Title of research award:
Therapeutic relevance of AT2 receptors in cardiovascular disease and agingTherapeutic relevance of AT2
receptors in cardiovascular disease and aging
Lay Description (from application):
Pharmacological modulation of the renin angiotensin system is a cornerstone of evidence-based cardiovascular
therapeutics. However, their molecular mechanisms are not entirely clear and some therapeutic options have
not been utilized to their full potential. The hormone angiotensin II causes both excitatory and inhibitory
cardiovascular effects via distinct binding sites. Of particular importance to contemporary society is the shift
in the demographic to a more aged population. In Australia in 2002, 13% of the population (~2.5 million) were
aged 65 years or over, and it has been estimated that this number will increase to 18% (~4 million) by the year
2021. While lipid status and smoking are well known risk factors for cardiovascular disease, advanced age by
far confers the greatest risk for cardiovascular disease. In this context, we have found a greater role of the
inhibitory angiotensin II binding site in aging that may result from breakdown products of angiotensin II
having their own unique effects. This project will determine the relative role of various angiotensin products,
and novel compounds that may act similarly, to improve vascular tone and reverse cardiovascular disease in the
elderly, hypertensive population.
Research achievements (from final report):
A hormone called angiotensin II is involved in blood pressure control and overactivity of the angiotensin II
system can exacerbate cardiovascular disease. In this project, we have been studying some of the mechanisms
that are involved in regulating the actions of angiotensin II at the site that initiates many of angiotensin II's
cardiovascular effects. This site is known as the AT1 receptor site and is responsible for the causing blood
pressure to increase as well as causing thickening of blood vessels and the heart itself in cardiovascular disease.
We have shown that there is another receptor site to which angiotesnin II binds, called the AT2 receptor site,
that is involved in opposing the stimulating effects of angiotensin II. In addition, there are 'break down'
fragments of angiotensin II that can also stimulate this AT2 site and cause beneficial effects in cardiovascular
disease such as blood pressure reductions and 'anti-growth' effects on heart and blood vessels. Indeed, we think
that there is a balancing act of various angiotesin peptides in the body to stimulate AT1 and AT2 sites. Our
research has shown that several endogenous peptides can target the AT2 site and there are a number of drugs
under development to selectively stimulate the AT2 receptor binding site, particularly since the AT2 site is
upregulated in cardiovascular disease as well as in aging. Therefore, the potential significance of this work is
that we have highlighted important mechanisms to modify overactivity of angiotensin II in cardiovascular
disease.
Expected future outcomes:
We are targetting the AT2 receptor as a site for novel drug development since stimulation of this site has the
potential to 'protect' the cardiovascular system as well as be an adjunct therapy to other medications in the
treatment of cardiovascular disease.
Name of contact:
Robert Widdop
Email/Phone no. of contact:
robert.widdop@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 384249
CIA Name: Prof Shaun Jackson
Admin Inst: Monash University
Main RFCD: Haematology
Total funding: $507,271
Start Year: 2006
End Year: 2008
Grant Type: NHMRC Project Grants
Title of research award:
Investigate the role of PAF and CD40 ligand in regulating the proinflammatory properties of
plateletsInvestigate the role of PAF and CD40 ligand in regulating the proinflammatory properties of platelets
Lay Description (from application):
The cells of the blood play an important role in maintaining healthy blood vessels. We are interested in two
types of blood cells, platelets and leukocytes, which together play a key role in vessel maintenance, by
promoting blood clot formation and vessel wall repair following injury. However, while critical for normal
blood vessel maintenance, these cells have also been demonstrated to contribute to disease states including
atherosclerosis, thrombosis and inflammatory airway diseases. Underlying the function of both blood cell
types is their ability to stick (or adhere) to each other. However the way in which they coordinate this adhesion
is very complex. New information from our laboratory has demonstrated that the sticky behaviour of each cell
type is spatially and temporally regulated, and may involve may factors both inside and outside of the cells
themselves. Our studies aim to define the key components regulating the 'stickiness' of these blood cells, in
order to undertand how they contribute to maintaining healthy vessel walls, but also how their stickiness may
also contribute to the promotion of diseased vessels. This information will not only increase our knowledge of
the factors that regulate blood clot formation, but may also assist in the development of new therapies to
prevent and/or treat vessel disease.
Research achievements (from final report):
Platelets can stick to sites of injured blood vessels, then stick to each other, eventually forming blood clots to
stop bleeding. Exaggerated clot formation can block blood vessels leading to heart attacks and strokes. Besides
the fundamental role in blood clot formation, platelets are also the key player in inflammatory responses by
recruiting and activating leukocytes to facilitate vessel repair and wound healing, or induce artherothrombosis
(exaggerated blood clot formation in artherosclerotic vessels). As artherothrombotic diseases are a major cause
of mobility and mortality in developed country, understanding the role of platelets in vascular inflammation
and artherosclerosis is an important challenge. In work leading up to this proposal, we have demonstrated that
different platelet activation states can influence their ability to activate leukocytes. More specifically, platelets
that support blood coagulation can selectively enhance neutrophil activation by producing the proinflammatory lipid named PAF. In addition to PAF, platelets also promote leukocyte activation by releasing a
number of chemokines such as CD40L which become expressed on the cell surface and shed during platelet
activaiton. Studies planed in this proposal aim to define for the first time a specific pro-inflammatory function
for platelets, especifically the contribution of PAF and CD40L. Ultimately these studies may provide more
insights into novel targets which may be manipulated to modulate platelet function to reduce atherothrombosis.
Expected future outcomes:
This grant has allowed us to define an important role for PAF in regulating platelet-induced neutrophil
activaiton. These studies have led to several high impact publications, formed basis for future grant
applications and provided new insights to the regulation of leukocyte adhesiveness by platelets.
Name of contact:
Shaun Jackson
Email/Phone no. of contact:
shaun.jackson@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 384299
CIA Name: Dr Niwanthi Rajapakse
Admin Inst: Monash University
Main RFCD: Systems Physiology
Total funding: $303,399
Start Year: 2006
End Year: 2011
Grant Type: Early Career Fellowships (Overseas)
Title of research award:
Roles of L-arginine uptake mechanisms in regulation of renal perfusion kidney function, long-term control
arterial pressRoles of L-arginine uptake mechanisms in regulation of renal perfusion kidney function, longterm control arterial press
Lay Description (from application):
Not Available
Research achievements (from final report):
Nitric oxide is a potent vasodilator in the human body. L-arginine is an amino acid which is needed to produce
nitric oxide in cells. Cellular nitric oxide production depends on functional L-arginine transporters (channels)
located in the surface of cells. The aim of this project was to charachterize L-arginine transport in the kidney
under normal physiological conditions and in hypertension. , Data arising from this project indicate that Larginine transport plays an important role in regulating kidney blood flow and function in health.Importantly, I
found that L-arginine transport in the kidney is impaired in animal models of hypertension. This contributes to
low nitric oxide levels and reduced kidney blood flow observed in this condition. As such, my data provides
strong evidence that L-arginine transporters are a new treatment target in hypertension.
Expected future outcomes:
I am currently investigating whether L-arginine transport over expression can blunt hypertension and my data
provide strong evidence that L-arginine transport over expression can greatly reduce hypertension.Thus, it is
now important in developing pharmacological and/or genetic based approaches which will increase L-arginine
transport.
Name of contact:
Niwanthi Rajapakse
Email/Phone no. of contact:
niwanthi.rajapakse@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 400068
CIA Name: Prof Jennifer Wilkinson-Berka
Admin Inst: Monash University
Main RFCD: Endocrinology
Total funding: $636,288
Start Year: 2006
End Year: 2010
Grant Type: Established Career Fellowships
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
Diabetic retinopathy is the major cause of vision loss and blindness in people of working age. Almost all
people with type 1 diabetes and approximately 65% of people with type 2 diabetes will develop retinopathy,
with some individuals progressing to the severe form of the disease. The current treatments for diabetic
retinopathy are limited as they do not target the early stages of the disease, are invasive and may cause damage
to the retina. Research from our laboratory has established that in animal models of diabetic retinopathy that
blockade of a body hormonal system called renin-angiotensin is a potential treatment for diabetic retinopathy.
In particular, the role of prorenin, angiotensin, renin and aldosterone may play an important role in vascular
and nerve damage in the diabetic retina and hence be a target for treatment. This research fellowship identified
the cellular location of these renin-angiotensin system components in the retina of animals with retinopathy and
evaluated the cellular mechanisms by which they influence retinal cell injury. Using specific inhibitors of these
renin-angiotensin system components, it was identified that protection against retinal injury is possible. Some
of these inhibitors have or are under investigation in clinial trials to determine their relative utility as new
treatments for diabetic retinopathy.
Expected future outcomes:
Given our recent findings and new exciting developments in the area of the renin-angiotensin system and
diabetic retinopathy research, I have developed a research program that evaluates the immunological,
epigenetic and cellular mechansims that contriubte to this disease. This work is now funded by a renewed
NHMRC fellowship, and NHMRC project grants.
Name of contact:
Jennifer Wilkinson-Berka
Email/Phone no. of contact:
Jennifer.Wilkinson-Berka@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 401123
Start Year: 2006
CIA Name: Dr Stephanie De Dios
End Year: 2011
Admin Inst: Monash University
Grant Type: Early Career Fellowships (Australia)
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $327,334
Title of research award:
Endothelial Cell-Leukocyte Interactions: Atomic Force Microscopy StudiesEndothelial Cell-Leukocyte
Interactions: Atomic Force Microscopy Studies
Lay Description (from application):
Not Available
Research achievements (from final report):
The research project conducted during my training fellowship enhanced my knowledge and expertise in the
field of diabetes and cardiovascular disease. The knowledge and techniques acquired from this project has
contributed to the understanding of diabetes and its complications in basic research. The project contributed to
help my understanding of the microvascular complications of diabetes and the basic mechanisms which control
local microvascular haemodynamics. The results from the project indicate that high-density lipoproteins (HDL:
"good cholesterol") has a vasoprotective effect on vascular cells by inhibiting reactive oxygen species
generation. However once HDL is glycated, as in diabetes, its protective effects are reduced. Study results have
shown that albumin suppresses intracellular reactive oxygen species generation, but when modified by
advanced glycation end products, albumin's potency is suppressed. Ultimately, results will lead to further
research and provide rationale for the development of new pharmacological approaches that could be used as
an adjunct to currently used therapies to improve the lives of people with cardiovascular disease and diabetes.
The envisaged drugs are those that may reduce protein modifications, such as advanced glycation end products,
and/or increase vascular endothelial cell resistance to oxidative stress.
Expected future outcomes:
Further understanding of the mechanistic relationship between protein modification, diabetes and
cardiovascular disease.
Name of contact:
Stephanie de Dios
Email/Phone no. of contact:
stephdedios@hotmail.com
NHMRC Research Achievements - SUMMARY
Grant ID: 436606
CIA Name: A/Pr Wayne Hodgson
Admin Inst: Monash University
Main RFCD: Basic Pharmacology
Total funding: $283,110
Start Year: 2007
End Year: 2009
Grant Type: NHMRC Project Grants
Title of research award:
Molecular toxinology of Australian box jellyfish venomsMolecular toxinology of Australian box jellyfish
venoms
Lay Description (from application):
Box jellyfish are an ongoing cause of illness and death for coastal communities and tourist regions in northern
Australia. As well as creating a significant medical problem, the resulting closure of beaches during
boxjellyfish 'season' results in an enormous loss of tourism income and threatens Australia's reputation as a safe
destination. The jellyfish venoms contain toxins with potentially lethal effects on humans. For the first time,
using pure venoms derived from the specialised stinging cells (i.e. nematocytsts), we will isolate and
characterize the major toxins from four species of box jellyfish. Their mechanism of action will be determined
and the effect of various treatments such as antivenom will be investigated. This will also lead to the discovery
of toxins with potentially novel targets and modes of action and increase our understanding of proposed
treatments and prevention of stings.
Research achievements (from final report):
We have completed the first pharmacological examination of Alatina mordens venom. This species of jellyfish
has recently been identified as a cause of 'Irukandji syndrome' (i.e. hypertensive crisis). We have shown that
the venom works by releasing internal stores of catecholamines (e.g. adrenaline and noradrenaline). In addition,
we have shown that CSL Ltd Box jellyfish antivenom recognises the major toxins in box jellyfish venom but is
unlikely to be clinically effective against the 'lethal' toxicns given the speed which the toxins effect the
cardiovascular system. We have identified and isolated the 'lethal' components of box jellyfish venom and are
currently exploring techniques to obtain sufficient quantities to examine their mode of action.
Expected future outcomes:
We will determine the mechanism of action of the lethal components of box jellyfish venom. This will be the
first time these toxins have been isolated and their activity identified.
Name of contact:
Wayne Hodgson
Email/Phone no. of contact:
wayne.hodgson@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 436617
Start Year: 2007
CIA Name: Prof Henry Krum
End Year: 2007
Admin Inst: Monash University
Grant Type: NHMRC Development Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $198,900
Title of research award:
A novel device to improve renal blood flow in cardiorenal syndromeA novel device to improve renal blood
flow in cardiorenal syndrome
Lay Description (from application):
The aim of this project is to assist in the development of a novel device to treat poor delivery of blood to the
kidneys in conditions such as heart muscle weakness (chronic heart failure, CHF). Specifically we aim to build
a prototype and test the device in a relevant animal model of CHF. Chronic heart failure is a major public
health problem affecting >10% of the adult population over the age of 60 years. It is associated with high
morbidity, mortality, frequent hospitalisation and major cost burden on the public health system. Weak heart
muscle results in poor delivery of blood to the kidneys. Poor delivery to the kidneys activates circulating
hormones which in turn further impair cardiac function by adverse effects on the heart. We have developed and
patented a novel catheter based system for improvement of renal function via a purpose built device. Proof-ofconcept studies have shown that the device should improve kidney blood flow in the setting of CHF. Given the
huge public health problem of heart failure and the importance of the kidney in this setting, the commercial
potential for a simple device that can be positioned via a catheter-based approach, permanently implanted is
large. The device is currently being constructed by the Monash University Department of Engineering where
expertise exists with regard to biomedical devices and materials engineering. A series of proof-of-concept
studies will then be performed in sheep, as the vasculature of the sheep roughly approximates the dimensions
of man. Sheep with CHF will have the device inserted percutaneously into the aorta. Measurements will be
made of renal artery flow, relevant circulatory hormones and ultrasound of the heart at baseline (predeployment) and following deployment. We believe the above studies (should they be successful) will be
sufficient to constitute definitive proof-of-concept and thus allow the device to be commercialised, most likely
by a licensing arrangement with a device company.
Research achievements (from final report):
We have established proof-of-concept in rats that a device-based approach to treatment of cardiorenal
syndrome may be of therapeutic benefit. Studies in a sheep model of heart failure using a device modified
based on our initial findings is currently ongoing. We have also modified our end-points to include renal blood
flow as assessed using highly sensitive flow probes., The significance of these findings is that it may provide
an ancillary approach to management of cardiorenal syndrome complementary to that of existing drug therapies
and other device-based approaches.
Expected future outcomes:
The future aims beyond the initial proof-of-concept studies is to develop a device for human use, in particular
one that can be delivered via a percutaneous approach minimising risk and maximising potential benefit.
Name of contact:
Henry Krum
Email/Phone no. of contact:
Henry.Krum@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 436629
CIA Name: Prof David Cooper
Admin Inst: Monash University
Main RFCD: Intensive Care
Total funding: $360,313
Start Year: 2007
End Year: 2011
Grant Type: Established Career Fellowships
Title of research award:
Practitioner FellowshipPractitioner Fellowship
Lay Description (from application):
I am an intensive care physician, clinician and researcher, interested in studying new therapies to improve
outcomes in patienst with acute trauma, sepsis and lung injury. A main focus is independent phase 111 clinical
trials in critically ill patients
Research achievements (from final report):
In 2011, I published two pivotal clinical trials in NEJM, one as first author. I had 70 papers in the past 5 years,
and 23 in 2011. My h-index is 25. Both trials published in NEJM in 2011 (DECRA and PROTECT) have
impacted clinical practice (Marion D. Lancet Neurol. 2011 Jun;10(6):497-8). The publication of the DECRA
trial (N Engl J Med. 2011 April; 364(16): 1493-502) was described as a "fundamental event in the history of
decompressive craniectomy for traumatic brain injury" (Hutchison P, B J Neurosurg 2011; 25(3): 441-442),
and as "one of the most important clinical trials of a novel therapy for severe TBI, and a class 1 study which
should be considered as foundation for an evidence based guideline" (Lancet Neurol. 2011 Jun;10(6):497-8).
DECRA was the first randomised controlled trial of any neurosurgical technique in neurotrauma. It will change
clinical practice and is likely to save Australian health care 1-200 million dollars annually.
Expected future outcomes:
I will lead 2 main research programs: Improving outcomes after traumatic brain injury; and Optimising patient
blood management in critical care. Three NHMRC currently funded multicentre clinical trials (two as CIA) and
the CRE grant (CIA) provide the major components and main funding support for these programs. Organising
an international conference in Italy on clinical trials in intensive care.
Name of contact:
D J (Jamie) Cooper
Email/Phone no. of contact:
jamie.cooper@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 436676
CIA Name: Prof Paul Myles
Admin Inst: Monash University
Main RFCD: Anaesthesiology
Total funding: $360,313
Start Year: 2007
End Year: 2011
Grant Type: Established Career Fellowships
Title of research award:
Practitioner FellowshipPractitioner Fellowship
Lay Description (from application):
Large multicentre clinical trials in anaesthesia and surgery
Research achievements (from final report):
This grant has greatly facilitated the design, conduct and completion of a number of large international
multicentre trials investigating safer treatments for patients undergoing major surgery. Some of these trials
have been completed, and published in the very best medical journals. Others are still in progress. This has led
to international recognition for the investigator as well as for the Trials Group he represents. Invited
presentations and international meetings, journal symposia and textbooks indicate some of this success.
Expected future outcomes:
Improved treatments (at lower cost) for patients undergoing major surgery. Changes in international consensus
guidelines. The development of international research collaborations.
Name of contact:
Prof Paul Myles
Email/Phone no. of contact:
p.myles@alfred.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 436677
CIA Name: Prof Paul Myles
Admin Inst: Monash University
Main RFCD: Anaesthesiology
Total funding: $2,952,623
Start Year: 2007
End Year: 2011
Grant Type: NHMRC Project Grants
Title of research award:
Nitrous oxide anaesthesia and cardiac morbidity in major surgeryNitrous oxide anaesthesia and cardiac
morbidity in major surgery
Lay Description (from application):
Nitrrous oxide is an anaesthtic gas that has been in use for more than 160 years. It has been considered a safe
and cheap drug, but newer anaesthetic drugs and improvements in technology provide alternatives that might
be safer. Our recent research has found some potentialy serious (but rare) complications associated with nitrous
oxide. These are more likely to occur in people with existing heart disease. The purpose of this study is to
investigate the safety of nitrous oxide in such people. When considering its widespread use in about 90% of all
surgery in Australia (and around the world), small differences in outcome would have major implications for
healthcare delivery. A large well-designed study is necessary to answer this question. We plan to study 7,000
patients having major surgery from around the world.
Research achievements (from final report):
This is the largest trial of nitrous oxide ever conducted. To date we have recruited 5436 of 7000 patients, from
46 centres worldwide.
Expected future outcomes:
Expected trial completion June 2013
Name of contact:
Professor Paul Myles
Email/Phone no. of contact:
p.myles@alfred.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 436713
CIA Name: Prof Roger Summers
Admin Inst: Monash University
Main RFCD: Basic Pharmacology
Total funding: $306,843
Start Year: 2007
End Year: 2008
Grant Type: NHMRC Project Grants
Title of research award:
Understanding cell signalling mechanisms activated by relaxin family peptides: targets with therapeutic
potentialUnderstanding cell signalling mechanisms activated by relaxin family peptides: targets with
therapeutic potential
Lay Description (from application):
One of the most powerful ways that the activity of the cells that make up the tissues and organs of the body can
be changed is by the interaction of chemicals with proteins called receptors located at the cell surface. The
commonest type of receptor is called a G-protein coupled receptor as it is linked to mechanisms inside the cell
by the G-proteins. These receptors are the most commonly targeted by pharmaceutical companies that wish to
alter the responses of cells for therapeutic purposes and almost 2/3 of all drugs currently marketed work
through these proteins. This project will examine the mechanisms whereby certain types of G-protein coupled
receptor produce signals in cells and determine what are the critical areas of the receptor for these interactions.
The receptors involved have been discovered only in the last 4 years and little is known of the ways these
change the activity of cells. The substances acting on these receptors have potential for development as targets
for drugs that have the potential to treat fibrosis which is a feature of many diseases including cardiac failure,
kidney failure and lung disease.
Research achievements (from final report):
The project was aimed at achieving a better understanding of how the relaxin family peptides signal to cells.
This has helped to establish how human relaxin 2 produces its effects at RXFP1 receptors which is important
since this peptide has now undergone a successful phase II clinical trial for the treatment of cardiac failure with
phase III expected to begin this year. We have also identified for the first time that multiple isgnalling
pathways can be activated by different relaxin family peptides acting at RXFP3 which will be important for
drug development for the treatment of obesity and anxiety.
Expected future outcomes:
Relaxin has undergone a successful clinical trial for the treatment of cardiac failure and it is to be hoped that
this continues. RXFP3 - the receptor for relaxin 3 is an attractive target for drug development.
Name of contact:
Roger Summers
Email/Phone no. of contact:
roger.summers@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 436721
Start Year: 2007
CIA Name: Prof Euan Wallace
End Year: 2009
Admin Inst: Monash University
Grant Type: NHMRC Project Grants
Main RFCD: Foetal Development and Medicine
Total funding: $513,947
Title of research award:
The effects of maternal glucocorticoid administration in growth restricted fetuses.The effects of maternal
glucocorticoid administration in growth restricted fetuses.
Lay Description (from application):
Antenatal administration of glucocorticoids to pregnant women at risk of preterm delivery has been shown to
enhance fetal lung maturation. However, glucocorticoids such as betamethasone have a range of potentially
deleterious non-pulmonary effects, which include significant alterations in fetal cardiovascular function. This
is important because intrauterine growth restricted (IUGR) fetuses constitute a significant proportion of
pregnancies in Australia, are at risk of preterm delivery and are therefore likely to receive maternal
betamethasone. From both human observations and animal studies, it is well documented that IUGR fetuses
demonstrate a range of cardiovascular adaptations that ensure maintenance of oxygen delivery to vital organs
despite reduced placental perfusion. However, in recent clinical and experimental studies we have
demonstrated that administration of betamethasone to IUGR fetuses induces changes in fetal blood flow that
may be detrimental to the IUGR fetus. Specifically, we believe that glucocorticoids may increase the risk of
both cardivascular and cerebral damage in the growth restricted fetus. The significance of these findings and
the mechanisms regulating these changes remain unclear but they have clear implications for future clinical
management. This proposal represents the further development of preliminary experimental studies to examine
the effects of betamethasone in the ovine IUGR fetus with future clinical care in mind.
Research achievements (from final report):
We have shown for the first time that the treatments we routinely offer women who are likely to give birth
prematurely, to improve the chances of survival of their unborn child, may actually cause harm if the unborn
baby is growth restricted. We have shown that antenatal steroids, given to accelerate fetal lung maturity, causes
surges in blood flow to the brain in growth restricted fetuses and that these surges cause brain injury and
seizures. We have also shown that the blood flow to the heart of growth restricted babies is compromised and
that antenatal steroids may worsen this also. These effects of steroids in the growth restricted baby are not seen
in the normal, healthy baby. These findings suggest that midwives and doctors caring for women with a growth
restricted fetus should consider carefully whether their normal treatments may actually cause harm rather than
good.
Expected future outcomes:
A follow-up project is further examining possible treatments that could protect the fetal brain and heart while
still allowing maturation of the premature lungs. Together, these studies may underpin the development of
entirely new managements for the growth restricted fetus.
Name of contact:
Prof Euan Wallace
Email/Phone no. of contact:
euan.wallace@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 436779
CIA Name: Prof Patrick Sexton
Admin Inst: Monash University
Main RFCD: Basic Pharmacology
Total funding: $362,207
Start Year: 2007
End Year: 2008
Grant Type: NHMRC Project Grants
Title of research award:
Understanding selective drug signaling at G protein-coupled receptorsUnderstanding selective drug signaling at
G protein-coupled receptors
Lay Description (from application):
The maintenance of optimum health and function living cells, and consequently that of the whole organism,
depends on how cells respond to a multitude of physical and chemical stimuli that continually bombard them.
The majority of the chemical stimuli such as hormones and neurotransmitters impart their actions not by
directly entering the cell, but instead, by binding to a specific reciever protein at the cell surface called
receptor. In one class of such receptors called G protein-coupled receptors, the transmission of the message to
the interior of the cell involves yet another protein called G protein. These receptors are the most abundant type
of cell surface receptors and form the targets for nearly 50% of currently used therapeutic drugs. It is, therefore,
extremely important to unravel how each of these components works, and in particular to know how they work
in living cells. This project utilizes state-of-the-art methodologies to examine interactions between receptors
and their cognate G proteins, in living cells and in real-time. The work will answer fundamental questions
about the nature of G protein-coupled receptor signaling, in particular whether new classes of drugs can be
identified that more selectively activate signaling pathways or factors that attenuate signaling. This work has
potential for future development of more effective therapeutic agents.
Research achievements (from final report):
G protein-coupled receptors (GPCRs) are the largest family of cell surface receptor proteins and consequently
are important targets for therapeutic intervention. Recently, new paradigms in GPCR function have been
unravelled and one of these is the capacity of individual ligands (both naturally occuring, and synthetic drugs)
to generate distinct profiles of response, even via the same receptor. This behaviour is termed ligand-directed
signalling. This type of behaviour may well provide a mechanistic basis for why very similar drugs can have
markedly different therapeutic outcomes. , We have established new assays for evaluating response profiles
from individual receptors following ligand treatment. One utilises yeast signaling systems and allows
examination of individual G protein responses. The second uses an assay of proximity, based on resonance
energy transfer, to identify receptor-G protein interactions. These systems have revealed unique liganddependent behaviours. In other work we have shown that a novel class of drug, termed allosteric modulators,
can change the signaling profile of endogenous neurotransmitters or hormones. This work has implications for
current and future drug development.
Expected future outcomes:
The new assays will be applied to elucidating the extent to which ligand-directed signaling occurs for both
physiological ligands and potential therapeutic compounds. This is particularly relevant to understanding
physiological systems with multiple ligands and to understanding the spectrum of activity for novel allosteric
drugs.
Name of contact:
Patrick Sexton
Email/Phone no. of contact:
patrick.sexton@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 436781
CIA Name: Prof Patrick Sexton
Admin Inst: Monash University
Main RFCD: Basic Pharmacology
Total funding: $340,400
Start Year: 2007
End Year: 2008
Grant Type: NHMRC Project Grants
Title of research award:
Molecular characterisation of receptor activity modifying proteins (RAMPs)Molecular characterisation of
receptor activity modifying proteins (RAMPs)
Lay Description (from application):
The maintenance of optimum health and function of living cells, and consequently that of the whole organism,
depends on how cells respond to a multitude of physical and chemical stimuli that continually bombard them.
The majority of the chemical stimuli such as hormones and neurotransmitters impart their actions not by
directly entering the cell, but instead, by binding to a specific receiver protein at the cell surface called a
receptor. In one class of such receptors called G protein-coupled receptors, the transmission of the message to
the interior of the cell involves yet another protein called G protein. These receptors are the most abundant type
of cell surface receptors and form the targets for nearly 50% of currently used therapeutic drugs. It is, therefore,
extremely important to unravel how each of these components works. To make this process even more
complex, it was recently shown that another newly discovered group of proteins called receptor activity
modifying proteins (RAMPs) too play a critical role in some systems. We have shown that RAMPs interact
with many G protein-coupled receptors and that they have a wider range of actions than has previously been
appreciated. Moreover, it has been shown that the RAMP-receptor interface is a viable target for drug
development. Understanding the extent to which RAMPs interact with G protein-coupled receptors, how they
interact with the receptors and the consequences of this interaction forms the basis of the current proposal.
Such knowledge is central to the unraveling of the processes involved in the maintenance of health,
abnormalities that lead to disease, and in the development of new treatments.
Research achievements (from final report):
G protein-coupled receptors (GPCRs) are the largest family of cell surface receptors and form one of the most
important classes of drug targets. Receptor activity modifying proteins are a family of 3 accessory proteins that
interact with specific GPCRs to change their cellular location, spectrum of ligand interaction or how they are
regulated. In this work we have further explored the nature and extent of RAMP interaction with GPCRs to
reveal previously unknown GPCR-RAMP interactions plus also new knowledge on the potential consequence
of this interaction, specifically, the strength of coupling to different intracellular signaling pathways. This work
demonstrates increased breadth in the way that cells can respond to their environment, which may provide
novel opportunity for drug development. Additionally, we have demonstrated that PreProCT and ProCT,
circulating proteins that are highly elevated during sepsis, interact preferentially with RAMP-based receptors
with potential implication for mechanism of action of these peptides in the poor prognosis seen with sepsis.
Expected future outcomes:
Discovery of additional RAMP interacting receptors and elucidation of physiological consequence of these
interactions. This will provide new insight into GPCR diversity and potentially provide scope for new
therapeutic interventions, particularly in relation to diabetes/obesity and migraine.
Name of contact:
Prof. Patrick M. Sexton
Email/Phone no. of contact:
patrick.sexton@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 436784
Start Year: 2007
CIA Name: Prof Alexander Smith
End Year: 2008
Admin Inst: Monash University
Grant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $239,018
Title of research award:
Mechanisms and Regulation of ACE2 SheddingMechanisms and Regulation of ACE2 Shedding
Lay Description (from application):
High blood pressure and heart disease, are a significant health issue affecting more than 25% of the Australian
population. We have recently found that a new enzyme called ACE2 involved in cardiovascular regulation is
greatly increased in heart tissue following heart attack. Furthermore, we have evidence that this enzyme is
released into the blood after a heart attack or as a consequnce of chronic liver injury. The current project aims
to expand on our preliminary data and to understand the basic biology underlying the mechanism of ACE2
secretion in cardiovascular and liver diseases. In addition, the measurement of ACE2 in plasma may provide
useful information on prognosis and knowledge of the mechanism underlying ACE2 secretion may define new
therapeutic targets to treat and prevent cardiovascular and liver disease
Research achievements (from final report):
The major outcomes of this research were to 1) provide evidence that plasma ACE2 could be a biomarker for
heart disease and 2) define the mechanisms by which ACE2 is secrted/shed from the cell surface. In the latter
case, we have defined the cleavage site in ACE2 that is responsbile for the liberation of the enzyme and we
have also identifed some of the key signaling molecules that mediate the shedding event.
Expected future outcomes:
The most likley future outcome will be evidence gathered from a large cohort of partients to show if indeed the
measurement of ACE2 in plasma has clinical utility as a diagnostic and/or progniostic biomarker
Name of contact:
Professor A Ian Smith
Email/Phone no. of contact:
ian.smith@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 436823
CIA Name: A/Pr Robert Widdop
Admin Inst: Monash University
Main RFCD: Basic Pharmacology
Total funding: $512,065
Start Year: 2007
End Year: 2009
Grant Type: NHMRC Project Grants
Title of research award:
Anti-atherosclerotic effects of angiotensin fragments & non-AT1 receptors: Validation as innovative
therapeutic targetsAnti-atherosclerotic effects of angiotensin fragments & non-AT1 receptors: Validation as
innovative therapeutic targets
Lay Description (from application):
In Australia the largest cause of death is coronary heart disease (CHD) leading to heart attacks or stroke and
claiming a staggering 28,000 lives a year. Atherosclerosis is one of the leading causes of cardiovascular
disease, with diseased vessels not able to fully dilate and the plaque that has built up inside these vessels
impeding blood flow and possibly rupturing, resulting in heart attacks and stroke. One of the major players in
the development and progression of atherosclerosis is the hormone, angiotensin II. Angiotensin II has been
found to trigger many factors that cause thickening of the vessel wall, inflammation and imbalances in
vasodilator capacity (e.g. oxidative stress and endothelial dysfunction), all of which contribute to
atherosclerosis. Clinical trials with drugs that inhibit the formation of angiotensin II (ACE inhibitors), or block
the action of angiotensin II (angiotensin receptor antagonists), have demonstrated a significant decrease in
mortality in patients with high risk for cardiovascular disease. However their mechanism(s) of action are not
fully understood as the circulating levels of shorter fragments of angiotensin II (such as Ang IV and Ang (1-7))
are raised in the blood when these drugs are used and may contribute to the protective effects of these drugs.
Importantly, we have found that both Ang IV and Ang (1-7) have protective effects in atherosclerotic blood
vessels. Therefore, we hypothesise that fragments of angiotensin II (such as Ang IV and others) exert antiatherogenic effects via distinct binding sites that oppose the effects caused by angiotensin II, and that these
may be partly responsible for the cardio-protective effects of the ACE inhibitors and angiotensin receptor
antagonists. Thus, information gained in our study will be useful in directing future prescription practices in
clinical management of CHD and stroke, and for designing new therapeutic compounds for the management of
atherosclerosis.
Research achievements (from final report):
The current work supports the hypothesis that shorter angiotensin fragments such as Ang IV and Ang (1-7)
counter-balance the excitatory effects of the parent peptide angiotensin II in the setting of atherosclerosis.,
These data indicate that the hexapeptide angiotensin fragment Ang IV given chronically to adult ApoEdeficient mice on a high fat diet improved endothelial function in this model which is known to exhibit
endothelial dysfunction. The improved endothelial function observed with chronic Ang IV, but not chronic
Ang II, treatment involved increased nitric oxide bioavailability since there was increased eNOS and decreased
superoxide activity in adult and aged mice (Vinh et al 2008a,b). We have also performed analogous
experiments in a more advanced model of atherosclerosis (ApoE-deficient mice on a prolonged high fat diet)
and found that chronic treatment with the N-terminal fragment Ang (1-7) improved endothelial function and
evoked a significant anti-atherosclerotic effect, i.e. a reduction in lesion development in association with
plaque stabalisation (Tesanovic et al 2010).
Expected future outcomes:
This work has found striking vascular protective effects of shorter Ang peptides that were previously
considered to exert minor cardiovascular effects. This work will lead towards identifying novel drug targets to
treat cardiovascular diseases, particularly in the setting of atherosclerosis.
Name of contact:
Robert Widdop
Email/Phone no. of contact:
NHMRC Research Achievements - SUMMARY
robert.widdop@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 436825
CIA Name: A/Pr Christopher Sobey
Admin Inst: Monash University
Main RFCD: Basic Pharmacology
Total funding: $465,210
Start Year: 2007
End Year: 2009
Grant Type: NHMRC Project Grants
Title of research award:
Is NADPH oxidase the trigger for accelerated atherosclerosis caused by bacteria?Is NADPH oxidase the trigger
for accelerated atherosclerosis caused by bacteria?
Lay Description (from application):
Cardiovascular disease is the leading cause of death and morbidity world-wide. However, its incidence is not
fully explained by the presence of conventional risk factors, such as high cholesterol, hypertension, diabetes
and cigarette smoking. Steadily growing evidence indicates that bacterial infection, particularly by Chlamydia
pneumoniae and Helicobacter pylori, is also strongly linked to atherosclerotic lesion formation and increased
risk of a cardiovascular event. This project will investigate a new aspect to the body s defence against bacterial
infection which involves production of oxygen radicals by the blood vessel wall. We propose that although
this response of the artery to bacteria in the blood is beneficial in the short term, it inadverently initiates a
chronic inflammatory process that ultimately accelerates development of artery disease. If this is the case, the
oxygen radical production by the enzyme, NADPH oxidase, in the artery wall may represent the missing link
between bacterial infection and atherosclerosis. We will therefore firstly test whether two bacteria, Chlamydia
pneumoniae and Helicobacter pylori, can acutely induce artery inflammation in this way. We will then
perform definitive studies to test whether mice infected with these bacteria develop accelerated atherosclerosis,
and if so, whether this effect is dependent on NADPH oxidase activity in the artery wall. Finally, we will test
the efficacy and importance of timing of antibiotic therapy to prevent atherosclerotic lesion formation.
Research achievements (from final report):
We have tested whether a bacterium that is associated with artery disease, namely Chlamydia pneumoniae (an
airborne bug), causes oxygen radical production in cells of the artery wall, and whether this results in
inflammation. Our major finding to date is that Chlamydia does indeed cause excessive production of harmful
oxygen radicals by muscle cells from the artery wall. This effect can be blocked by antioxidant molecules or by
a selective blocker of a protein called NADPH oxidase, indicating that this protein is in fact the source of the
damaging molecules. We also found that Chlamydia causes the artery cells to make high levels of
inflammatory markers. Surprisingly, we found that blocking the oxygen radicals produced by Chlamydia
pneumoniae did not prevent the increased production of these inflammatory markers. However, blocking
oxygen radical production in fact increased the ability of the Chlamydia to replicate and continue to infect the
tissue. Our overall conclusion is that while Chlamydia causes harmful radical production, there is a protective
aspect to that response by the artery by limiting the bug's ability to remain in and infect the tissue. Future
antioxidant therapies for artery disease should therefore be avoided if bacterial infection seems likely. Another
observation that we have made is that Chlamydia causes changes to certain proteins of artery muscle cells (e.g.
lipoprotein lipase; scavenger receptors) that are involved in the uptake of lipids. This process may therefore
contribute to how Chlamydia can accelerate artery disease by causing larger blockages by built up fat deposits.
Expected future outcomes:
There should be 3-4 more publications of this work in leading journals for the disclipine in 2010-11. Overall,
the work provides new knowledge suggesting that Chlamydia causes detrimental changes in the artery wall,
including oxidation and lipid accumulation, but that antioxidant therapies may paradoxically prolong the
persistence of the bug.
Name of contact:
Dr Grant Drummond
Email/Phone no. of contact:
grant.drummond@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 436854
Start Year: 2007
CIA Name: Prof Ban-Hock Toh
End Year: 2009
Admin Inst: Monash University
Grant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $458,815
Title of research award:
Atherosclerosis: Molecular action and suppression of NKT cell subsetsAtherosclerosis: Molecular action and
suppression of NKT cell subsets
Lay Description (from application):
Atherosclerosis, or hardening of large arteries, is the underlying cause of up to 50% of deaths in Western
communities from heart attacks and strokes. Today it is considered a chronic inflammatory disease arising
from the influx of fats such as cholesterol into the inner liming of arteries that provide blood supply to organs
such as the heart and the brain. However, the exact role that inflammation plays in the development of this
blood vessel disease is poorly understood. This study is directed towards understanding the role of a subset of
while blood cells known as NKT cells in the inflammatory process. In particular we will examine whether the
activity of NKT cells in promoting atherosclerosis can be controlled either by the administration of drugs that
deprive them of molecules that stimulate their activity and/or by the injection of another population of white
blood cells known as regulatory T cells that may to limit their activity. Our preclinical study of atherosclerosis
in mice has potential for extension to the control of atherosclerosis in humans. Successful translation in this
way can be expected to provide a significant health benefit.
Research achievements (from final report):
Identification of a subset of NKT cells that promote atherosclerosis
Expected future outcomes:
Identification of the molecular mechanisms of action of NKT cells in atherosclerosis
Name of contact:
Professor Ban-Hock Toh
Email/Phone no. of contact:
Ban-Hock.Toh@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 436866
CIA Name: Prof Andrew Forbes
Admin Inst: Monash University
Main RFCD: Epidemiology
Total funding: $188,538
Start Year: 2007
End Year: 2008
Grant Type: NHMRC Project Grants
Title of research award:
Fitness versus fatness: Disentangling their effects on disease outcomes and estimating the population burden of
diseaseFitness versus fatness: Disentangling their effects on disease outcomes and estimating the population
burden of disease
Lay Description (from application):
Overweight and physical inactivity are two of the major risk factors for cardiovascular disease and diabetes.
With increasing population levels of overweight, governments are increasingly advocating public health
measures aimed at increasing physical activity levels or otherwise decreasing weight. There has been much
research concerning which of these factors is the key prognostic factor for adverse health outcomes, but an
ongoing lack of clarity of research findings has led to uncertainty as to the direction of recommendations for
preventive health strategies and population lifestyle changes. In addition, the risks of overweight, in particular,
have been accused of being exaggerated in both the scientific and lay literature. This is often due to the
difficulty of dealing appropriately with time varying confounders which are also intermediate factors (such as
hypertension). To date, no studies have performed careful longitudinal modelling of the joint effects of
physical inactivity and overweight on cardiovascular events and diabetes while taking into account the effects
of factors, such as hypertension or atherosclerosis, that influence both physical activity and overweight as well
as disease, and simultaneously are consequences of these risk factors. Standard statistical methods are known
to produce biased estimates in these situations but we will apply more recently developed statistical techniques
to provide much improved estimation of these effects. After the statistical modelling stage, we will model the
burden of diabetes, cardiovascular disease and mortality associated with given levels of overweight and
physical inactivity. These will be combined with population levels of overweight and inactivity to identify the
fraction of the current and future burden of disease attributable to these risk factors.
Research achievements (from final report):
This project enabled estimation of the effects of physical activity on cardiovsacular disease that is free from
methodological problems of the relationship with obesity and other lifestyle factors or attributes that have
plagued prior studies. Although the finding that physical activity is beneficial for health is not new, the
research has identified how currency, recency and distant or lifetime activity inter-relate to risk.
Expected future outcomes:
These findings reinforce existing strategies for promoting health, and have provided a clearer evidence base for
this.
Name of contact:
Andrew Forbes
Email/Phone no. of contact:
Andrew.Forbes@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 436873
CIA Name: Dr Peter Kruger
Admin Inst: Monash University
Main RFCD: Intensive Care
Total funding: $622,149
Start Year: 2007
End Year: 2008
Grant Type: NHMRC Project Grants
Title of research award:
A phase II randomised controlled trial of atorvastatin therapy in intensive care patients with severe sepsisA
phase II randomised controlled trial of atorvastatin therapy in intensive care patients with severe sepsis
Lay Description (from application):
Infections are common in patients in the intensive care unit and produce inflammation that may spread
throughout the body. Despite improved therapies, when infections cause failure of the body's vital organs, up
to 40% of patients may die. The medication atorvastatin and other "statins" have been used for many years to
treat and prevent conditions such as heart attack and stroke. They act primarily by reducing cholesterol
production. In addition, they also modify inflammation and the immune system which may make them a
useful treatment for patients with established infections. Although the "statin" drugs are usually safe, rare side
effects may affect muscle and the liver. Because of concerns about increased risk of side effects it is currently
recommended that statins should be stopped when patients become unwell. However, a number of studies have
suggested that patients on statins for heart disease are less likely to develop infections and that their infections
are less likely to be severe or result in death. Other studies have suggested that stopping statins in patients that
present with infections (as suggested by current guidelines), may worsen infection outcomes. However, these
studies have not been detailed enough to exclude all factors affecting outcome, such as patient age, severity of
the infection, and the presence of other diseases. We plan to perform a study to assess the effect of atorvastatin
on the outcome of infections in the intensive care unit. We will study 250 patients presenting with severe
infections. We will randomly assign patients to receive either atorvastatin or placebo and monitor the effect on
signs of inflammation and levels of life support. Outcomes and side effects will be carefully monitored. The
study will help us decide whether to perform a larger study to determine if atorvastatin can reduce the risk of
dying from serious infections.
Research achievements (from final report):
Statins are a very commonly used medication in the general population to lower cholesterol. The aim of the
study was to explore the potential impact of the use of statins in patients with severe sepsis (severe, life
threatening infections). This study is the largest randomised trial in the world of statin therapy in patients with
severe sepsis. It has provided an enormous amount of data to explore this topic and inform the medical
community globally. Data analysis is still underway with preliminary results already having been presented at 2
major critical care meetings around the world. As data analysis progresses it is hoped this study may provide
guidance on how best to use these medicines for patients in intensive care with life threatening infection.
Expected future outcomes:
This was a Phase II study and the results of this trial will guide the future direction of research on this topic.
Name of contact:
Dr. peter Kruger
Email/Phone no. of contact:
Peter_Kruger@health.qld.gov.au
NHMRC Research Achievements - SUMMARY
Grant ID: 436879
Start Year: 2007
CIA Name: Dr Robert Andrews
End Year: 2009
Admin Inst: Monash University
Grant Type: NHMRC Project Grants
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $363,098
Title of research award:
Ligand interactions of platelet glycoprotein Ib-IX-V in thrombosisLigand interactions of platelet glycoprotein
Ib-IX-V in thrombosis
Lay Description (from application):
The transition of circulating blood platelets from a fluid-phase, non-adherent state to an adherent, activated and
aggregated state (thrombus formation) is critical in the normal haemostatic response to blood vessel injury and
in thrombotic diseases such as heart attack and stroke. One unique platelet receptor, the glycoprotein Ib-IX-V
complex, is of particular interest, because it initiates platelet aggregate or thrombus formation at high fluid
shear stress in flowing blood, including the pathological shear stress that occurs in a sclerotic coronary artery.
Our published and preliminary results show how GPIb-dependent interaction of platelets with von Willebrand
factor, the major adhesive ligand for GPIb-IX-V, is dependent on the level of shear stress. Using a crossspecies (human to canine) homology-swap approach, where human sequence is replaced by the corresponding
canine sequence within discrete structural domains, a sequence of GPIb has been identified which becomes
increasingly important as hydrodynamic shear stress increases. It is proposed to further define the interactive
surface of GPIb that recognizes von Willebrand factor at increasing shear, and to define the relationship
between the shear-dependent alteration of GPIb conformation and its ability to interact with other prothrombotic or pro-inflammatory binding partners.
Research achievements (from final report):
The platelet-specific receptor, glycoprotein Ib (GPIb), plays a central role in cardiovascular biology, by binding
to the adhesive ligand, von Willebrand factor (VWF), that mediates platelet adhesion and aggregation at
arterial shear rates, and to other binding partners, including leukocyte receptor (Mac-1) and coagulation factors,
Factor XII (FXII) and FXI. Together, these interactions are crucial in the initiation of thrombotic diseases such
as heart attack or stroke, yet there are currently no therapeutics targeting these interactions involving platelet
GPIb, because the molecular basis for ligand binding to GPIb and how this varies as shear increases to
pathological levels is poorly understood. The aims of this proposal are to investigate binding of GPIb to VWF
and other ligands including FXII that are relevant to thrombosis in blocked or diseased arteries, that may
ultimately lead to new safer treatments for thrombotic diseases, without the side-effect of an increased risk of
bleeding, a major problem with current anti-platelet drugs. We have shown that a specific region of GPIb
becomes increasingly important for GPIb-dependent adhesion to VWF as flow rate increases, that an adjacent
region binds to a small-molecule inhibitor of VWF binding, and that blocking the interaction of FXII with
GPIb significantly inhibits FXII-dependent blood clotting in human plasma. Significant achievements include
publishing studies on shear-dependent VWF binding, and the first identification of the crystal structure of a
small-molecule inhibitor of VWF-GPIb binding in complex with the GPIb ligand-binding domain, revealing a
new paradigm for how small molecules can inhibit large protein-protein interactions.
Expected future outcomes:
Future outcomes of these and ongoing studies provide new insights into how platelet GPIb recognizes ligands
under arterial shear conditions, relevant to development of antithrombotic approaches selective for pathological
conditions associated with thrombotic diseases such as heart attack or stroke.
Name of contact:
Robert K Andrews
Email/Phone no. of contact:
rob.andrews@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 443222
CIA Name: Prof Brian Oldenburg
Admin Inst: Monash University
Main RFCD: Preventive Medicine
Total funding: $641,656
Start Year: 2007
End Year: 2009
Grant Type: NHMRC Project Grants
Title of research award:
An implementation trial of a telephone-based care management program for patients following myocardial
infarctionAn implementation trial of a telephone-based care management program for patients following
myocardial infarction
Lay Description (from application):
We are trialling the implementation of an innovative telephone-delivered program for managing people who
have had a heart attack. Cardiac rehabilitation programs are generally based in hospitals in Australia and
people have to be able to attend the programs when they are offered. Even though such programs have been
shown to be very effective in improving outcomes after a heart attack, at least 85% of Australians after a heart
attack are either unable to access and/or unable to attend such programs due to transport and many other
barriers. So, there is an urgent need to identify new, effective, and affordable ways of delivering cardiac
rehabilitation programs to people after a heart attack. The proposed telephone-delivered program will be
particularly appropriate for disadvantaged people, such as those living in rural and remote areas as well as
Indigenous Australians, who do not currently have access to hospital-based cardiac rehabilitation programs.
People who have had a heart attack will be recruited from three of Brisbane's largest public teaching hospitals,
and will then be randomly assigned to the telephone-delivered cardiac rehabilitation program (Care
Management Intervention group) or to a control or Usual Care group. The Care Management Intervention
group will receive regular telephone calls from a highly qualified 'Care Manager' based at the renowned
National Heart Foundation of Australia telephone support service, 'Heartline'. The Care Manager will help
people to manage their heart condition and prevent the reoccurrence of further heart problems. People will also
be encouraged to make necessary lifestyle and behavioural changes with the assistance of the Care Manager
and some Heart Foundation educational and interactive resources to record their progress. We expect that the
program or Care Management Intervention group will have better health outcomes than the control or Usual
Care group at 6 and 12 months follow up.
Research achievements (from final report):
This research study investigated the effectiveness, as well as the cost-benefit, of a novel telephone-delivered
program called ProActive Heart. ProActive Heart was shown to successfully improve important health
outcomes following a heart attack to ultimately reduce the risk of future heart problems. The program was
highly acceptable to study participants and being telephone delivered, has the potential to be delivered
Australia wide using existing telephone support and information services (e.g. Heart Foundation Health
Information Service).
Expected future outcomes:
The research team will be investigating predictors of the observed health outcomes to identify which
participants are more likely to have improved outcomes.
Name of contact:
Brian Oldenburg
Email/Phone no. of contact:
brian.oldenburg@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 454636
Start Year: 2007
CIA Name: Dr Chrishan Samuel
End Year: 2012
Admin Inst: Monash University
Grant Type: Career Development Fellowships
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $479,207
Title of research award:
Investigating the anti-fibrotic properties of relaxin in the normal and diseased heartInvestigating the antifibrotic properties of relaxin in the normal and diseased heart
Lay Description (from application):
Not Available
Research achievements (from final report):
Not Available
Expected future outcomes:
N/A
Name of contact:
Dr Chrishan Samuel
Email/Phone no. of contact:
chrishan.samuel@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 458503
CIA Name: Dr Graeme Polglase
Admin Inst: Monash University
Main RFCD: Systems Physiology
Total funding: $350,508
Start Year: 2007
End Year: 2010
Grant Type: Early Career Fellowships (Australia)
Title of research award:
Influence of intra-luminal pressure on pulmonary haemodynamics in fetal sheepInfluence of intra-luminal
pressure on pulmonary haemodynamics in fetal sheep
Lay Description (from application):
Not Available
Research achievements (from final report):
These studies focused on determing the effect of different resuscitation techniques on lung and heart blood
flow in preterm neonates. Further, we examined how this relationship is affected by exposure of the newborn to
inflammation in the womb during fetal development. We showed the critical relationship between the volume
of air in the lung during resuscitation, and lung and heart blood flow. That is, if we resuscitate preterm neonates
with high volumes of air, we can adversly decrease blood flow to the lung and heart, effectively returning the
newborn to a fetal state. This can have disasterous consequences on morbidity of the preterm newborn. Further,
we showed that this relationship was consistent irrespective of the ventilation modality that was used. We
showed the clinical benefits of using non-invasive Doppler Ultrasound for early detection of adverse blood
flow in the lung, which improved the clinicans ability to treat before the problem became exacerbated. We
found that exposure to inflammation while in the womb had significant adverse effects on the preterm
newborn, which predisposed it to lung and heart disease. We further extrapolated our findings to show that this
had flow-on effects to the brain, which links early clinical care of preterm newborns to potential brain injurry.
The findings of our studies have led to significant changes to clinical practise, with my publications referenced
in the international liason commite on resuscitation 2010 Guidelines.
Expected future outcomes:
We will continue to investigate the link between early clinical care of preterm neonates, and the development
of brain injury. We will investigate how the uterine environment may increase the risk and severity of brain
injury and develop clinical strategies to reduce/prevent resuscitation related brain injury.
Name of contact:
Graeme Polglase
Email/Phone no. of contact:
graeme.polgalse@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 465109
CIA Name: A/Pr Grant Drummond
Admin Inst: Monash University
Main RFCD: Basic Pharmacology
Total funding: $446,617
Start Year: 2007
End Year: 2010
Grant Type: Career Development Fellowships
Title of research award:
Defining the roles of Nadph oxidase iosforms in vascular oxidative stress and pathology in
hypertensionDefining the roles of Nadph oxidase iosforms in vascular oxidative stress and pathology in
hypertension
Lay Description (from application):
Not Available
Research achievements (from final report):
A major focus of my research during this NHMRC Career Development Award has been on identifying disease
pathways within the walls of blood vessels that lead to the formation of arterial occlusions known as
atherosclerotic plaques, which are the major cause of heart attacks and strokes. My team have shown that
conditions such as high blood pressure (hypertension) and high cholesterol (hypercholesterolemia) are
associated with a dramatic increase in the production of oxygen radicals within the artery wall. Oxygen radicals
are highly reactive molecules that are normally generated at low levels by cells as a by-product of aerobic
metabolism. Although cells have evolved to cope with small amounts of oxygen radicals, the high levels seen
in arteries during conditions such as hypertension and high cholesterol are toxic because they overwhelm our
intrinsic antioxidant defences. Toxic effects of oxygen radicals include the breakdown of signalling molecules
required for normal artery function, as well as oxidation of tissue components such as lipids and proteins.
These oxidised molecules act as attractants for white blood cells, which accumulate in the artery wall and lead
to the formation of the atherosclerotic plaque. Using a combination of gene knockout technology and
pharmacological approaches, we have shown that a family of enzymes called NADPH oxidases are the major
source of oxygen radicals in blood vessels during disease. Furthermore, inhibition of these enzymes improves
artery function and reduces atherosclerotic plaque formation in mouse models of hypertension and
hypercholesterolemia, while minimising brain damage following stroke. Hence our studies highlight NADPH
oxidases as novel therapeutic targets for the treatment of cardiovascular disease.
Expected future outcomes:
Having established a central role for NADPH oxidases in cardiovascular diseases, we will now focus on
identifying new drugs that block the actions of these enzymes. Such drugs could have a major impact on
human health by reducing the incidence and impact of heart attacks and strokes in patients with hypertension
and/or hypercholesterolemia.
Name of contact:
Grant Drummond
Email/Phone no. of contact:
Grant.Drummond@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 465147
Start Year: 2007
CIA Name: Dr Don M Sanjaya Kuruppu
End Year: 2010
Admin Inst: Monash University
Grant Type: Early Career Fellowships (Australia)
Main RFCD: Medical Biochemistry: Proteins and Peptides
Total funding: $294,508
Title of research award:
Mechanisms of endothelin converting enzyme shedding, and its role in cardiovascular function.Mechanisms of
endothelin converting enzyme shedding, and its role in cardiovascular function.
Lay Description (from application):
Not Available
Research achievements (from final report):
Endothelin Converting Enzyme (ECE) is essential for the production of the hormone Endothelin which is a
powerful blood vessel constrictor. It is expressed on the surface of cells that line blood vessels. Our research
showed that ECE can be released from the cells that line blood vessels and that this process can be stimulated.
Our data indicate that only the region of the enzyme responsible for activity is released, and occurs as a result
of the action of other enzymes expressed on the cell surface. We have also shown the importance of this
discovery in the progression of diesease states and their associated complications.
Expected future outcomes:
Future studies should aim to discover if ECE exists in human body fluids and its relavance to diseases. A
circulating form of ECE is an excellent candidate to further evaluate for its potential to predict the onset of
cardiovascular and other disease states.
Name of contact:
Sanjaya Kuruppu
Email/Phone no. of contact:
Sanjaya.Kuruppu@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 465150
Start Year: 2007
CIA Name: Dr Klaudia Budzyn
End Year: 2011
Admin Inst: Monash University
Grant Type: Early Career Fellowships (Overseas)
Main RFCD: Medical Physiology not elsewhere classified
Total funding: $325,639
Title of research award:
Defining the role of the T cell NADPH oxidase in angiotesin II-mediated hypertensionDefining the role of the
T cell NADPH oxidase in angiotesin II-mediated hypertension
Lay Description (from application):
Not Available
Research achievements (from final report):
Results from these studies have further strengthened the emerging idea that the immune system plays a
significant role in the development of high blood pressure (hypertension). More specifically, these studies have
demonstrated that specific immune receptors contribute to the inappropriate migration of immune cells into
blood vessels, which is associated with the development of blood vessel dysfunction associated with high blood
pressure. Furthermore, selective targetting of specific immune receptors was shown to result in decreased
hypertension associated with improved vascular function, raising the idea that these novel agents represent a
promising new therapy for tackling high blood pressure and its associated vascular complications.
Expected future outcomes:
Development of novel therapies for treating the underlying vascular disease associated with high blood
pressure.
Name of contact:
Klaudia Budzyn
Email/Phone no. of contact:
klaudia.budzyn@rmit.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 465168
Start Year: 2007
CIA Name: Dr Pascal Wilmann
End Year: 2011
Admin Inst: Monash University
Grant Type: Early Career Fellowships (Overseas)
Main RFCD: Medical Biochemistry: Proteins and Peptides
Total funding: $330,184
Title of research award:
Coagulation factor XI structure, activation, and receptor interactionsCoagulation factor XI structure, activation,
and receptor interactions
Lay Description (from application):
Not Available
Research achievements (from final report):
Determination of the blood coagulation protein Factor XII protease structure from a recombinant system has
been achieved. This novel structure will help the push to develop new anti-coagulants with reduced side
effects, such as stroke and haemoraghe
Expected future outcomes:
Investigations of the FXII protease structure will fuel the discovery of novel anti-coagulants with reduced side
effects, such as stroke and haemoraghe.
Name of contact:
Jonas Emsley
Email/Phone no. of contact:
Jonas.Emsley@nottingham.ac.uk
NHMRC Research Achievements - SUMMARY
Grant ID: 465182
Start Year: 2007
CIA Name: Dr Anna Ahimastos
End Year: 2013
Admin Inst: Monash University
Grant Type: Early Career Fellowships (Australia)
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $319,489
Title of research award:
ACE inhibition - A potntial new therapy for Peripheral Arterial diseaseACE inhibition - A potntial new therapy
for Peripheral Arterial disease
Lay Description (from application):
Media Summary not available
Research achievements (from final report):
Peripheral artery disease (PAD) is atherosclerosis of blood vessels in the legs. Atherosclerosis causes
narrowing or blockage of the vessels, resulting in reduced blood flow. This in turn causes leg pain or heaviness
that develops with walking and is relieved by rest (known as intermittent claudication). This pain often limits
the distance that people can walk, we therefore believe that the major consequence for PAD patients is the loss
of quality of life. As many as 202 million are affected worldwide, while approximately 3 million Australians
suffer from intermittent claudication. Patients with intermittent claudication have a 5 fold increase in
cardiovascular event rates than non-PAD patients. Despite this profile, PAD is currently both under-diagnosed
and under-treated. , We examined the effect of ramipril therapy for 6 months (a medication commonly used to
treat high blood pressure) on walking times in 212 patients with PAD in a randomized clinical trial. , At the
beginning of the trial participants could walk a maximum of 4 mins during a treadmill test. At the end of the
trial, patients who took ramipril could walk a maximum time that was 4.5 minutes longer than that of those
who took placebo; this corresponds to an increase in uphill walking distance of 184 meters which would impact
appreciably on daily life for these patients. Indeed, participants who took ramipril reported large increases in
daily walking distance, walking speed, ability to climb stairs and the physical health aspect of quality of life.
For many people, this could mean the difference between being able to independently perform short errands
close to home or being reliant on a carer.
Expected future outcomes:
Six months of treatment with ramipril improved clinical symptoms and quality of life in people with PAD.
Given that ramipril is off patent, these findings offer medical professionals worldwide an efficacious and
inexpensive agent to dramatically improve clinical symptoms in peripheral artery disease patients with
intermittent claudication.
Name of contact:
Dr Anna Ahimastos
Email/Phone no. of contact:
a.ahimastos@alfred.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 472706
Start Year: 2008
CIA Name: Dr Anthony White
End Year: 2011
Admin Inst: Monash University
Grant Type: Early Career Fellowships (Overseas)
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $383,894
Title of research award:
The cellular origin and nuclear signaling mechanisms of cardiac stem cellsThe cellular origin and nuclear
signaling mechanisms of cardiac stem cells
Lay Description (from application):
Stem cells have special characteristics; they are able to be grown quickly and they have the potential to turn
into different types of cell. These two characteristics indicate the potential to use these cells to repair diseased
organs. Heart disease is an ideal area to investigate the use of such cell-based therapy options. This is because a
weakened heart muscle is very common (especially as we age) and because without assistance, the body is not
able to repair a weakened heart.
Research achievements (from final report):
There were two broad areas of achievement. The first related to a cell preparation known as cardiospherederived cells (CDCs), expanded in vitro beginning with small cardiac biopsy specimens. Work funded by this
fellowship showed that intramyocardial administration of these cells results in functional benefit in pig and
rodent models of myocardial infarction. These pre-clinical data contributed to approval of a Phase I human
clinical trial of these cells, recently completed and published in The Lancet (CADUCEUS study. Makkar et al,
Lancet. 2012). The second field of achievement related to the potential for over-expression or re-expression of
embryonic cardiac trascription factors to promote cardiac differenetiation in adult cells. In particular, the
embryonic trascription factor islet-1 was shown to confer benefit in recovery from myocardial infarction, and
appears to be a good candidate to pursue for clinical translation.
Expected future outcomes:
After the highly encouraging Phase I results, further human clinical testing of cardiosphere-derived cells is
planned. In particular, tests of "off the shelf" donor CDCs are planned, which would be more practical in
everyday clinical practice than waiting 6 weeks to grow autologous CDCs., Further pre-clinical testing of the
efficacy of islet1 in animal models of myocardial infarction is planned.
Name of contact:
Tony White
Email/Phone no. of contact:
Anthony.White@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 490900
CIA Name: Prof James Whisstock
Admin Inst: Monash University
Main RFCD: Enzymes
Total funding: $11,668,789
Start Year: 2008
End Year: 2012
Grant Type: Programs
Title of research award:
Control of proteases in infectious, degenerative and cardiovascular diseaseControl of proteases in infectious,
degenerative and cardiovascular disease
Lay Description (from application):
Proteases are enzymes that control key processes in humans. The research in this program will result in major
discoveries in the field of proteases and their inhibitors, with a focus on inflammatory, cardiovascular and
degenerative disease. The knowledge gained from this strong foundation of fundamental research will underpin
the translational outcomes necessary to combat the debilitating effects of immunological dysfunction,
conformational and cardiovascular disease.
Research achievements (from final report):
Achievements of the team include elucidating the mechanism through which immune cells kill virally infected
and pre-cancerous cells. In a study published in Nature, the team demonstrated how a key immune weapon,
termed perforin, functions by forming large pores in target cells. The pores were shown to be of sufficient size
to permit delivery of a cargo of toxic enzymes (a family of proteases called granyzmes). A second major
achievement of the team was determining the X-ray crystal structure of plasminogen, a major drug target that
functions to dissolve blood clots. Published in Cell Reports, the structural studies revealed how plasminogen
was likely activated against clots, thus suggesting new routes for the development of anticoagulants and "clot
busting" molecules.Work from the program has started to reveal how one of the major branches of the immune
system, the complement system, is switched on by antigens. Using a combination of structural and biophysical
studies, the teams work has shown how a crucial conformational change in the immune protease Complement
Component 1 (C1) leads to activation of major defence mechanisms. The utility of the work includes the
development of small molecules to control unwanted C1 activation in inflammatory disease.Finally, in a series
of studies the team has eluicated how certain key protease inhibitors (the "serpins") incorrectly fold in certain
diseases, including emphysema and liver cirrhosis. Through understanding the detailed mechanism that lies
behind "misfolding disease", it is anticipated that new routes for therapeutic intervention will emerge.
Expected future outcomes:
Expected outcomes include the development of new drugs to treat diseases that impact on society. For example
the structural studies on perfoin have contributed to a major Wellcome Trust funded "Seeding Drug Discovery"
program. The goal of this work is to develop inhibitors to prevent unwanted perforin funciton in immune
driven disease.
Name of contact:
James Whisstock
Email/Phone no. of contact:
James.Whisstock@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 490918
CIA Name: Prof Kate Denton
Admin Inst: Monash University
Main RFCD: Systems Physiology
Total funding: $570,218
Start Year: 2008
End Year: 2012
Grant Type: NHMRC Research Fellowships
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
I am an integrative cardiovascular-renal physiologist determining the role the kidney plays in the regulation of
arterial blood pressure in health and disease.
Research achievements (from final report):
In Australia, cardiovascular disease is one of the leading causes of death and disability. Whilst many therapies
are currently available new and more effective treatments are required. High blood pressure is a major risk
factor for cardiovascular disease. I am building on previous seminal discoveries I have made in the fetal
programming of adult hypertension, the neural control of renal function and the role of the renin angiotensin
system in the control of arterial pressure I am internationally recognised as a leader in cardio-renal research. I
have built world-class research capabilities; including renal micropuncture (only lab in Australia, one of the
few in the world), telemetry, and chronic sympathetic nerve recording. My work has provided significant
insight into important questions.
Expected future outcomes:
To improve cardiovascular health for men and women across their lifespan by building a strong
interdisciplinary and translational research program around the integrative control of arterial pressure. Award
of this fellowship maintains a unique capability in Australia and will help keep Australia at the forefront of
innovative medical research and practice.
Name of contact:
Kate Denton
Email/Phone no. of contact:
Kate.Denton@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 490919
CIA Name: A/Pr Kate Denton
Admin Inst: Monash University
Main RFCD: Systems Physiology
Total funding: $638,526
Start Year: 2008
End Year: 2010
Grant Type: NHMRC Project Grants
Title of research award:
Interaction between estrogen and the renin-angiotensin system in the regulation of arterial pressureInteraction
between estrogen and the renin-angiotensin system in the regulation of arterial pressure
Lay Description (from application):
Women before menopause are protected from cardiovascular disease. Estrogen is thought to provide this
protection. Yet post-menopause estrogen replacement has not always proven beneficial. We are investigating
the idea that estrogen within a narrow window modulates the hormone angiotensin (a major regulator of blood
pressure) to lower blood presssure but outside this range (higher or lower) the benefits are lost.
Research achievements (from final report):
Women of child-bearing age have a lower incidence and severity of cardiovascular disease than males. The
reasons for this gender difference are unknown, though it is suggested that sex-mediated variations in the reninangiotensin system, one of the major regulators of blood pressure, may be involved. Our work demonstrates
that estrogen provides protection against hypertension and cardiovascular disease by counter-balancing the
vasoconstrictor actions of the renin-angiotensin system via an enhanced angiotensin type 2 receptor (AT2R)
mediated mechanism in women. Thus these pathways represent potential new therapeutic targets in the
treatment of hypertension in women.
Expected future outcomes:
Our work in this area continues to define the mechanism of action of the angiotensin type 2 receptor in females
in the regulation of renal function.
Name of contact:
Kate Denton
Email/Phone no. of contact:
kate.denton@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 490920
CIA Name: A/Pr Kate Denton
Admin Inst: Monash University
Main RFCD: Systems Physiology
Total funding: $607,289
Start Year: 2008
End Year: 2010
Grant Type: NHMRC Project Grants
Title of research award:
Altered renal development programs adult hypertensionAltered renal development programs adult hypertension
Lay Description (from application):
If a mother suffers an adverse condition during pregnancy - such as high blood pressure - the development of
the baby is altered, putting it at increased risk of cardiovascular disease in adulthood. Our study in rabbits
examine the role that changes to nerves in the kidney play in the development of high blood pressure later in
life and whether it can be prevented via short-term anti-hypertensive treatment in the postnatal period .
Research achievements (from final report):
Our studies demonstrate that if a mother has high blood pressure during pregnancy the placenta is structually
altered and this is associated with decreases in the hormone renin. Furthermore, our studies in the offspring of
hypertensive pregnancies demonstrate that in the absence of changes in birth weight, kidney development is
altered and the offspring as an adult has increased blood pressure. Our work demonstrates that babies born with
an outward normal appearance at birth can be adversely effected by a poor maternal environment, placing them
at risk of future disease
Expected future outcomes:
Antenatal care of children of hypertensicve mothers should be monitored for signs of kidney health . Future
investigations should focus on the prevention of abormal placental development to protect the child against
adult disease.
Name of contact:
Kate Denton
Email/Phone no. of contact:
kate.denton@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 490938
CIA Name: Prof Susan Davis
Admin Inst: Monash University
Main RFCD: Endocrinology
Total funding: $690,082
Start Year: 2008
End Year: 2012
Grant Type: NHMRC Research Fellowships
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
I am an academic endocrinologist and clinician. I lead a large research program that investigates the links
between hormones and diseases of ageing in women. Thus my research program addresses the contribution of
changes in adrenal and ovarian steroids in
Research achievements (from final report):
I lead and published the largest and longest efficacy and safety study of the use of testosterone therapy for
women, a placebo-controlled RCT of 800 women recruited across 3 continents (NEJM Davis et al 2008). I
established the BUPA Health and Well Being After Breast Cancer Study which recruited 1684 women within
their 1st year of breast cancer (BC) diagnosis 2004-6. This is the largest longitudinal study to report on factors
substantially impacting BC survivors, ranging from sexual dysfunction through to determinants of wellbeing
and patterns of adherence to endocrine therapy. This study has resulted in 18 publications to date and a number
of manuscripts in preparation.My group has reported on the prevalence, incidence and risk factors for urinary
incontinence (UI) in women and the incidence of fecal incontinence in women. I conducted the first study of
UI in young women who have never been pregnant and showed that 1 in8 such women have UI. I developed
the PROSPECT tool for health practitioners to identify the women 70 + years most likely to have
osteroporosis/fracture. I also developed and validated a sexual function questionnaire now used by researchers,
and a menopause stageing questionnaire. I have completed several studies exploring the role of sex steroids on
cognitive performance in women. ?????
Expected future outcomes:
To document the prevalence and severity of menopausal symptoms and of depression in Australian women at
midlife, their use of prescribed and complimentary and alternative therapies, plus a range of other studies of
midlife women's health.
Name of contact:
Susan Davis
Email/Phone no. of contact:
Susan.Davis@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 490968
Start Year: 2008
CIA Name: Prof Andrew Tonkin
End Year: 2010
Admin Inst: Monash University
Grant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $756,559
Title of research award:
The LIPID Study: 16 year outcomes and predictors of risk and their interactions in CHD patientsThe LIPID
Study: 16 year outcomes and predictors of risk and their interactions in CHD patients
Lay Description (from application):
The single most common cause of cardiovascular disease, including heart attack and stroke, is "hardening" of
the arteries. This can largeley be prevented and this research seeks to expand our knowledge of new indicators
of risk and their interaction with the traditional risk factors, such as smoking. With increased understanding, it
is very possible that novel factors will be discovered which will lead to very important new treatments to
prevent problems like heart attack in the future.
Research achievements (from final report):
Linkages of the study cohort with health registers enabled ascertainment of cause-specific mortality and cancer
incidence data during total of 16 years follow-up. Linkage with hospital admission data in West Australia and
New Zealand enabled ascertainment of nonfatal major CVD events in an additional subset. Follow-up of study
participants also was obtained via a questionnaire collecting data on drug use and smoking and diabetic status.
Vital status was obtained for 95% of the cohort, including those whose death was notified., Biomarkers were
assayed in Germany (laboratory of CID Blankenberg) - Lp(a), CRP, Lp-PLA2, BNP, high-sensitivity troponin
I, midregional pro-adrenomedullin, D-dimer, cystatin-C. , The principal findings were that: baseline BNP,
hsCRP, cystatin-C, D-dimer, midregional pro-adrenomedullin and TnI were all significant independent
predictors of CHD events (net NRI 10.3%); change in Lp-PLA2 activity between baseline and 1 year (but not
baseline Lp-PLA2 activity) predicted subsequent CHD events during follow-up, independent of treatment or
LDL-cholesterol; change in hsCRP between baseline and 1 year, although a significant univariate predictor was
not significant in multivariate models after adjustment for traditional risk factors
Expected future outcomes:
Further analyses will address associations of biomarkers with other endpoints including major cardiovascular
(CV) events and determinants other than biomarkers of both long-term CV and non-CV events during 16 years
follow-up.
Name of contact:
Prof Andrew Tonkin
Email/Phone no. of contact:
andrew.tonkin@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 490986
CIA Name: Dr Lauren May
Admin Inst: Monash University
Main RFCD: Basic Pharmacology
Total funding: $324,599
Start Year: 2008
End Year: 2012
Grant Type: Early Career Fellowships (Overseas)
Title of research award:
Allosteric modulation of GPCR-mediated intracellular signalling in human embryonic stem cell derived
cardiomyocytes.Allosteric modulation of GPCR-mediated intracellular signalling in human embryonic stem
cell derived cardiomyocytes.
Lay Description (from application):
Adenosine and muscarinic receptors are cell-surface proteins that represent promising targets for a number of
conditions. However, the mechanisms linking the activation of these receptors to cellular responsiveness have
not been thoroughly investigated in cells of human origin. This study will use novel cutting-edge methods to
measure the effects of different classes of drugs on receptor-mediated intracellular signalling in embryonic
stem cell derived human cardiac cells.
Research achievements (from final report):
Allosteric modulation describes the structural changes occurring within a protein or protein complex upon the
simultaneous occupancy of topographically distinct, but conformationally linked, binding sites. Allosterism is
essential for most signal transduction, and therefore of fundamental importance to life. G protein-coupled
receptors (GPCRs) form a large superfamily of cell surface proteins that propagate extracellular to intracellular
signal transduction via allosteric mechanisms. Given the central role of GPCRs in physiology and disease
progression, a greater understanding of the molecular mechanisms of GPCR allosteric interactions is of critical
importance to multiple disciplines including cell biology, biochemistry, medicinal/synthetic chemistry and
pharmacology. During my NHMRC Training Fellowship, I have been the principal investigator in a number of
studies that have made seminal contributions to the understanding of the molecular pharmacology of GPCR
allosterism. These studies include the first quantification of Family A GPCR allosterism at the single cell level
(Molecular Pharmacology, 2010, 78:511-23), the first identification of Brilliant Black BN as an allosteric
modulator at adenosine receptors (Molecular Pharmacology, 2010, 77:678-86) and the first quantification in
live cells of allosteric interactions between orthosteric binding sites across a homodimeric interface (FASEB J,
2011, 25:3465-3476). In addition, as a postdoctoral research fellow I developed and validated a novel live cell
imaging technique that can quantify allosteric interactions within a GPCR monomer or across a GPCR dimer in
heterologous and endogenous expression systems (The FASEB Journal, 2011, 25:3465-3476). Using this
technique, fluorescent ligand binding and function can be detected simultaneously at the single cell level
(Molecular Pharmacology, 2010, 78:511-23).
Expected future outcomes:
A manuscript will also be submitted in 2014 describing additional studies investigating GPCR allosterism in
cardiomyocytes.
Name of contact:
Lauren May
Email/Phone no. of contact:
lauren.may@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 490998
CIA Name: A/Pr Sophia Zoungas
Admin Inst: Monash University
Main RFCD: Endocrinology
Total funding: $143,661
Start Year: 2008
End Year: 2011
Grant Type: Early Career Fellowships (Australia)
Title of research award:
Glycaemia and cardiovascular disease outcomes in patients with diabetes and CKD: methodology, relationship
andGlycaemia and cardiovascular disease outcomes in patients with diabetes and CKD: methodology,
relationship and
Lay Description (from application):
Diabetes is increasing and now the primary cause of chronic kidney disease (CKD). At present the care of
people with diabetes and CKD aims to achieve normal blood glucose levels in the safest possible way in order
to prevent acute and chronic complications and improve outcomes and quality of life. In this project we will
examine the best means by which to measure, monitor and treat blood glucose levels in such people and
explore the effect of intensive blood glucose control.
Research achievements (from final report):
This research of people with type 2 diabetes sought to identify the optimum method by which to accurately
monitor blood glucose control in those with chronic kidney disease, to assess the effects of glucose lowering on
health outcomes and to determine the safest way to lower glucose levels. The results to date highlight the
importance of self-monitoring of blood glucose levels as well as HbA1c measurement in the day to day
management of people with chronic kidney disease, the important factors that predict vascular comnplications
and the separate and combined beneficial effects of glucose lowering and blood pressure control on vascular
disease and kidney outcomes.
Expected future outcomes:
Ongoing work is examinining the efficacy and safety of glucose lowering therapies in people with diabetes and
chronic kidney disease so that clear guidance on safe prescribing can be provided.
Name of contact:
A/Prof Sophia Zoungas
Email/Phone no. of contact:
sophia.zoungas@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 491001
CIA Name: Prof Rosemary Horne
Admin Inst: Monash University
Main RFCD: Paediatrics
Total funding: $425,703
Start Year: 2008
End Year: 2010
Grant Type: NHMRC Project Grants
Title of research award:
Impact of sleep disordered breathing on cardiovascular, behavioural and neurocognitive function in preschool
childrenImpact of sleep disordered breathing on cardiovascular, behavioural and neurocognitive function in
preschool children
Lay Description (from application):
Studies in school age children have shown that disruption to normal sleep patterns resulting from sleep
disordered breathing (SDB) has severe consequences for both the cardiovascular system and neurocognition.
To date there have been limited investigations of the effects of SDB in pre-school children despite the
knowledge that disruptions to breathing during sleep are maximal at this age and the central nervous system
which is immature and developing at this time, is most vulnerable to injury.
Research achievements (from final report):
Sleep is a major physiological drive which is essential for normal growth and development of both the body
and the brain. During childhood sleep is at a lifetime maximum, with children between the ages of 2 and 5
spending half of each 24 hours asleep. Sleep plays an important role in learning by promoting the consolidation
and integration of memory, and also has a major influence on the developing cardiovascular and respiratory
systems. Studies in school age children have demonstrated that disruption to normal sleep patterns as a result of
sleep disordered breathing (SDB) has severe consequences for both the cardiovascular system and
neurocognition. To date there have been limited investigations of the effects of SDB in pre-school children
despite the knowledge that the prevalence of the condition peaks at this age and the central nervous system
which is immature and developing at this time, is most vulnerable to injury. This study has shown that
preschool children with SDB have significant behavioural problems and thus early treatment may be beneficial
is preventing the cardiovascular and neurocognitive problems exhibited in older children.
Expected future outcomes:
We have completed recruitment with 160 enrolled. We have presented preliminary data on the behavioural and
neurocognitive aspects of this project which are a part of Angela Jackman's PhD and also the cardiovascular
components which are a part of Lauren Nisbet's PhD. We anticipateThe first manuscript is in the final stages of
preparation.
Name of contact:
A/Prof Rosemary Horne
Email/Phone no. of contact:
rosemary.horne@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 491007
Start Year: 2008
CIA Name: A/Pr Michael Hickey
End Year: 2012
Admin Inst: Monash University
Grant Type: Established Career Fellowships
Main RFCD: Immunology not elsewhere classified
Total funding: $570,218
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
I study the mechanisms of inflammatory responses, focussing on the
processes of leukocyte recruitment and vascular injury in the
microvasculature.
Research achievements (from final report):
, The overall thrust of this Fellowship was to broadly examine the processes whereby white blood cells enter
sites of inflammation. White blood cells mediate much of the tissue damage in organs affected by
inflammatory diseases such as glomerulonephritis (inflammation of the kidney), rheumatoid arthritis and the
autoimmune condition, systemic lupus erythematosus. In this Fellowship I used advanced microscopy to
examine tissues and blood vessels in experimental models of inflammation, in order to visualise white blood
cells during their movement from the blood into tissues. This worked spanned several different areas. Particular
emphasis was placed on glomerulonephritis, in which I showed that the process of white blood cell recruitment
to the filtering elements of the kidney (the glomeruli) differed markedly from that which occurs in organs such
as the skin and intestine. Secondly, I investigated in detail the actions of a pro-inflammatory protein called
MIF. This work showed that MIF increased white blood cell recruitment during inflammation, causing proinflammatory changes in both the white blood cells, and the cells lining the blood vessel. I also investigated
white blood cell function in patients with the autoimmune disease, systemic lupus erythematosus, and found
that these cells showed changes in the way they stick to surfaces mimicking inflamed blood vessels. Taken
together, these studies have increased our understanding of the process of white blood cell recruitment under
several inflammatory conditions, and in several organs, illuminating distinctions in the cellular and molecular
biology of this process.
Expected future outcomes:
The increased understanding of the mechanisms whereby white blood cells enter inflamed tissues emerging
from this work will help to direct future research in this area, and potentially identify new targets for therapies
aimed at controlling inflammation, particularly in the kidney.,
Name of contact:
A/Prof. Michael Hickey
Email/Phone no. of contact:
michael.hickey@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 491039
CIA Name: Dr Sascha Hughan
Admin Inst: Monash University
Main RFCD: Haematology
Total funding: $446,832
Start Year: 2008
End Year: 2010
Grant Type: NHMRC Project Grants
Title of research award:
Investigation of Dok2 and Dok1 adapter proteins, in the negative regulation of integrin aIIbb3 platelet
signalling.Investigation of Dok2 and Dok1 adapter proteins, in the negative regulation of integrin aIIbb3
platelet signalling.
Lay Description (from application):
Blood platelets play a key role in blood clot formation, prevention of bleeding and are the principal elements
contributing to thrombosis leading to heart attack and stroke. Numerous studies have defined pathways
promoting platelet activity, however less is known about their negative regulation. In this grant we will
examine the role for proteins, Dok2 and Dok1, in the negative regulation of platelets, hoping this leads to
development of novel therapeutics for prevention of cardiac disease.
Research achievements (from final report):
The central hypotheses of this project grant were that the recently identified adaptor proteins, Dok-2 and Dok1, serve in different signalling capacities within the platelet, and that Dok-2 serves a negative regulatory role in
platelet signalling events downstream of the major platelet receptor, integrin aIIbb3. During the course of the
grant, we identified a novel role for Dok-2 in in vitro and in vivo models of thrombosis and haemostasis,
during which platelets are subject to shear stress, like those encountered in the human vasculature. We
demonstrated that in the absence of Dok-2, platelets are significantly more reactive under shear conditions,
which leads to increased thrombotic and haemostatic events. This effect appeared to be mediated through an
increased length of membrane tethers, thereby implicating tether formation and biomechanical properties in
murine thrombosis. These results have intriguing implications for the study of hyper-reactive platelets and
unexplained thrombotic episodes in the clinical setting. Moreover, they extend our knowledge regarding
membrane tethers and their increasingly important role in haemostasis. Biochemical studies examining 3phosphorylated inositol lipids suggest that Dok2 ablation leads to a subtle upregulation in PI3P suggesting that
one or more lipid 3-phosphatases maybe dysregulated. Ongoing work is focussed on examining 3phosphorylated lipids under both shear flow and static platelet adhesion conditions. Current investigations
using in-house total internal reflection fluorescence microscopy to examine membrane adhesion dynamics are
also underway to elucidate in detail the mechanism of Dok2-/- platelet adhesion.,
Expected future outcomes:
Publication of this work is expected in the high impact factor specialist journal Blood within the next 6 months.
Name of contact:
Dr Warwick Nesbitt
Email/Phone no. of contact:
warwick.nesbitt@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 491042
CIA Name: Dr Michelle Kett
Admin Inst: Monash University
Main RFCD: Systems Physiology
Total funding: $597,579
Start Year: 2008
End Year: 2011
Grant Type: NHMRC Project Grants
Title of research award:
Salt and Cardiovascular Disease: Does Acute Salt-Sensitivity Convey Greater Cardiovascular Risk?Salt and
Cardiovascular Disease: Does Acute Salt-Sensitivity Convey Greater Cardiovascular Risk?
Lay Description (from application):
Salt intake of Australian adults is 10X more than required. Further, salt intake in very young children is
alarmingly high secondary to high consumption of salty snacks and processed food. High dietary salt intake
has been associated with increased cardiovascular disease and death. We will examine the cardiovascular risks
for adults and children on a high salt diet and examine whether switching to a low salt diet ameliorates the high
blood pressure and heart disease caused by high salt diets
Research achievements (from final report):
Salt is a cheap way for food manufactures to increase weight and improve the taste of processed foods.
Approximately 80% of our daily salt intake is hidden in processed foods whilst <20% comes from the salt we
add and that occurring naturally in foods. As our dependence on processed foods increases, as too has salt
intake. The average consumption of salt in industrialised countries is ~10g/day, ~10 times that required. High
dietary salt is associated with increased cardiovascular disease in adults. Disturbingly there has been a rapid
rise in salt intake in young children due to increased consumption of processed foods, particularly salty snacks.
, We examined the impact of a high salt diet in young and old mice. Mice fed diets high in salt from weaning to
young adulthood (10 weeks of high salt diet) did not have high blood pressure but did have increased heart
weights, scarring of the heart, and stiffening of the major blood vessels. We then tested whether placing these
mice on a normal salt diet for 5 weeks improved heart structure and vessel function, however there was no
reversal of vessel stiffening or increased heart weights suggesting that high salt diets during childhood might
have long-term consequences for cardiovascular health., Old mice that were born with small kidneys or one
kidney showed an increase in blood pressure and fall in kidney function when given a high salt diet. This
suggests that those with sub-optimal kidney development are at greater risk for the adverse affects of high salt
diets.
Expected future outcomes:
We hope that our studies will strengthen the call to reduce the salt content of foods particularly those marketed
for children.
Name of contact:
Michelle Kett
Email/Phone no. of contact:
michelle.kett@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 491058
CIA Name: Prof Jennifer Wilkinson-Berka
Admin Inst: Monash University
Main RFCD: Opthalmology and Vision Science
Total funding: $733,841
Start Year: 2008
End Year: 2010
Grant Type: NHMRC Project Grants
Title of research award:
Receptor-mediated Actions of Prorenin in Diabetic RetinopathyReceptor-mediated Actions of Prorenin in
Diabetic Retinopathy
Lay Description (from application):
Despite improvements in patient care, the incidence of diabetic retinopathy is dramatically increasing. Recent
evidence suggests that a component of a hormonal system, called prorenin, may participate in the development
of diabetic organ disease. We will evaluate the role of prorenin in vascular and nerve damage in animal models
of diabetic retinopathy. We will determine if a new inhibitor of prorenin, prevents retinal injury and is a
potential treatment for diabetic retinopathy.
Research achievements (from final report):
Diabetic retinopathy is the major cause of vision loss and blindness in people of working age. Almost all
people with type 1 diabetes and approximately 65% of people with type 2 diabetes will develop retinopathy,
with many individuals progressing to the severe form of the disease. The current treatments for diabetic
retinopathy are limited as they do not target the early stages of the disease, are invasive and may cause damage
to the retina. Research from our laboratory has established that in animal models of diabetic retinopathy that
blockade of a body hormonal system called renin-angiotensin is a potential treatment for diabetic retinopathy.
In particular, the role of prorenin and its receptor, the (pro)renin receptor, may play an important role in blood
vessel and nerve damage in the diabetic retina and hence be a target for treatment. This research grant
identified the cellular location of prorenin and the (pro)renin receptor in the retina of animals with retinopathy
and evaluated the events by which they influence retinal cell injury. Recent evidence published in the highly
respected biomedical journal, Science, has identified further ways in which the (pro)renin receptor may
influence fundamental cell processes in the brain and the retina. This discovery together with our recent
findings has lead to a new avenue of study of prorenin and the (pro)renin receptor in diabetic retinopathy. It is
hoped that this new information will lead to the development of improved treatments for diabetic retinopathy
and possibly other retinal diseases.
Expected future outcomes:
Given our recent findings and new exciting developments in the area of (pro)renin receptor research we have
established a new research program to evaluate the signalling mechanisms by which prorenin and/or the
(pro)renin receptor influence blood vessel damage, inflammation, and neuronal damage in the developing and
diseased retina.
Name of contact:
Jennifer Wilkinson-Berka
Email/Phone no. of contact:
Jennifer.Wilkinson-Berka@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 491099
CIA Name: Prof Christopher Reid
Admin Inst: Monash University
Main RFCD: Preventive Medicine
Total funding: $617,879
Start Year: 2008
End Year: 2012
Grant Type: NHMRC Research Fellowships
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
I am a cardiovascular epidemiologist studying the causes, prevention and management of chronic disease from
an individual and community perspective.
Research achievements (from final report):
The SRF funding has enabled major advancements to be made in the area in improving cardiovascular and
health outcomes from both the individual and population perspectives. My clinical trials research has focussed
on the role of aspirin on the maintenance of healthy active life in 19000 persons over the age of 70 (ASPREE).
The trial has successfully recruited over 12,000 Australian to date and the study will be finished in 2018. The
SCREEN-HF study as recruited 3200 subjects at high risk of heart failure and has demonstrated the importance
of measuring Bnp levels in identifying those with early ventricular dysfunction. The ASPECT trial has also
resulted in an accelerated discharge protocol for chest pain and is being implemented in emergency
departments across Australia. My cardiac registries research program has flourished and has seen the
development of Australia specific risk adjustment models for CABG. In interventional cardiology, my research
has identified an obesity paradox for patient undergoing PCI in terms of long terms clinical outcomes and good
outcomes for patients in cardiogenic shock undergoing PCI. My translational research program has identified
the cost effectiveness of guideline based use of drug eluting stents in public hospitals and also highlighted the
impact and costs associated with lost therapeutic benefit due to non- adherence to guideline based management
of hypertension and high cardiovascular risk patients in the community.
Expected future outcomes:
Clarification of the protective role of aspirin and statins for older persons; improving our understanding of
factors associated with better clinical outcomes in cardiac interventions; determining the cost-benefit of drug
and device based interventions to improve cardiovascular and health outcomes.
Name of contact:
Christopher Reid
Email/Phone no. of contact:
chris.reid@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 491112
CIA Name: Prof Arthur Christopoulos
Admin Inst: Monash University
Main RFCD: Basic Pharmacology
Total funding: $665,498
Start Year: 2008
End Year: 2012
Grant Type: NHMRC Research Fellowships
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
I am a molecular and analytical pharmacologist interested in the mechanisms underlying G protein-coupled
receptor function.
Research achievements (from final report):
N/A
Expected future outcomes:
N/A
Name of contact:
Arthur Christopoulos
Email/Phone no. of contact:
arthur.christopoulos@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 491133
CIA Name: A/Pr Christopher Sobey
Admin Inst: Monash University
Main RFCD: Basic Pharmacology
Total funding: $481,439
Start Year: 2008
End Year: 2010
Grant Type: NHMRC Project Grants
Title of research award:
Does NADPH oxidase link gender, hormone replacement therapy and outcome after stroke?Does NADPH
oxidase link gender, hormone replacement therapy and outcome after stroke?
Lay Description (from application):
This project will assess whether the reduction of a novel mechanism to open brain arteries (i.e. via activation of
'Nox' proteins and generation of oxygen radicals) is a possible explanation of why hormone replacement
therapy (HRT) increases the risk of stroke in postmenopausal women. We will compare brain artery function
of normal mice with those deficient in certain Nox genes in models of menopause, HRT and stroke. This
knowledge should lead to safer stroke therapies in women and men.
Research achievements (from final report):
We found that levels of oxygen radicals are higher in the arteries supplying the brain compared with arteries in
other parts of the body. Moreover, there is a sex difference in this effect, with much higher levels present in
males than females. We identified the protein that is