NHMRC Research Achievements - SUMMARY
END OF GRANT REPORTS
OUTCOMES OF NHMRC FUNDED RESEARCH INTO DIABETES
ENDING 2000 TO 2012
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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
CSIRO Division of Human Nutrition
Curtin University of Technology
Deakin University
Edith Cowan University
Flinders University
Garvan Institute of Medical Research
Howard Florey Institute
International Diabetes Institute Inc
James Cook University
La Trobe University
Macfarlane Burnet Institute for Medical Research and Public
Health
Menzies Research Institute
Menzies School of Health Research
Monash University
Murdoch Childrens Research Institute
Prince Henry's Institute of Medical Research
Queensland Institute of Medical Research
Queensland University of Technology
RMIT University
Royal Melbourne Institute of Technology
Royal Prince Alfred Hospital
St Vincent's Institute of Medical Research
Swinburne University of Technology
Sydney West Area Health Service
The Dr Edward Koch Foundation Limited
University of Adelaide
University of Melbourne
University of New South Wales
University of Newcastle
NHMRC Research Achievements - SUMMARY
University of Queensland
University of South Australia
University of Sydney
University of Tasmania
University of Technology Sydney
University of Western Australia
University of Wollongong
Victor Chang Cardiac Research Institute
Victoria University
Walter and Eliza Hall Institute
NHMRC Research Achievements - SUMMARY
Grant ID: 266505
CIA Name: Prof George Jerums
Main RFCD: Nephrology and Urology
Admin Inst: Austin Hospital Medical Research Foundation
Start Year: 2004
End Year: 2006
Total funding: $288,900.00
Grant Type: NHMRC Project
Grants
Title of research award:
Normoalbuminuric and albuminuric pathways to renal insufficiency in type 2 diabetes
Lay Description (from application):
Up to one third of patients with type 2 diabetes develop kidney disease (diabetic
nephropathy). An increase in protein excretion in the urine (albuminuria) is usually
the first sign of kidney disease. Albuminuria usually progresses from normal levels to
an intermediate phase (microalbuminuria) lasting 5-10 years and is then followed by
overt nephropathy (macroalbuminuria). It has been traditionally believed that onset of
a decline in kidney function, measured as glomerular filtration rate, accompanies the
development of diabetic kidney disease. However, recent studies by our group have
shown that about one quarter of patients with type 2 diabetes have impaired kidney
function without an increase in albuminuria. This raises the possibility that an
alternate non-albuminuric pathway leads to kidney disease in a subgroup of patients
with type 2 diabetes. This study will compare kidney structure and function in
patients with type 2 diabetes and impaired kidney function with or without increases
in albuminuria. The comparison will be accompanied by measurements of the rate of
decline in kidney function over 5 years or more, in subjects with or without increases
in albuminuria in order to confirm that kidney function may decline independently of
albuminuria. The demonstration of alternate mechanisms of renal injury has the
potential to identify new targets for the treatment of kidney disease in patients with
type 2 diabetes.
Research achievements (from final report):
The research that we have performed has highlighted the potential benefits of
accurately detecting kidney dysfunction in people with type 2 diabetes by performing
a blood test and measuring cystatin C levels. This finding is an advancement in the
way that kidney function is monitored. Current methods for estimating glomerular
filtration rate based on the measurement of creatinine are not accurate across the full
spectrum of filtering capacity displayed by the kidneys of people wih diabetes. These
creatinine-based melthods also require a calculation that is based on age and gender.
We have shown for the first time that people wih diabetes and impaired kidney
filering capacity have a greater burden of disease affecting the arateries within the
kidney compared to those with normal filtering capacity. In particular, the intrarenal
arteries of subjects with diabetes and impaired kidney function are "stiffer" than the
arteries in people with normal kidney function. Our preliminary biopsy results
suggest that the structural changes seen within the kidneys of people wilth diabetes
and non-albuminuric chronic kidney disesae (CKD) are different to those seen in
subjects with CKD associated with micro- or macro-albuminuria. Although there is a
fair degree of overlap between the structural changes seen in non-albuminuric and
albuminuric subjects with CKD, we have not seen the classical structural changes of
diabetic nephropathy in non-albuminuric subjects. In contrast, subjects with non-
NHMRC Research Achievements - SUMMARY
albuminjuric CKD have kidney biopsy samples that display changes ranging from
mild to advanced arteriosclerosis. These findings potentially suggest that therapies
targeting arterial disease and arterial stiffness may improve kidney function in people
with diabetes and either albuminuric or non-albuminuric renal insufficiency.
Expected future outcomes:
We expecat that methods for estimating glomerular filtration rate (GFR) based on
cystatin D along with the measurement of urinary albumin excretion (AER) will
emerge as the expected standard of care for monitoring kidney function in subjects
with diabetes. Our findings should also provoke clinical trials of therapies that target
arterial disease and arterial stiffness.
Name of contact: George Jerums
Email of contact: ah-endo@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 385004
CIA Name: A/Pr Zeinab Khalil
Main RFCD: Therapies and Therapeutic Technology
Admin Inst: Austin Hospital Medical Research Foundation
Start Year: 2006
End Year: 2008
Total funding: $407,924.00
Grant Type: NHMRC Project
Grants
Title of research award:
A novel sensory nerve stimulator to improve neuropathy in patients with diabetes
Lay Description (from application):
We have developed a painless, self-applied, cheap, battery powered electrical
stimulation treatment that improves sensory nerve function in some people with
diabetic peripheral neuropathy. We have tested this technique in laboratory animals
and in people with diabetes and have shown it is effective in some. We now propose
to test this technique in a large sample of people similar to the participants in the
successful group of our pilot study - 55-65 year old people with diabetes of shorter
duration. In addition, older people up to 75 years of age, with up to 10 years duration
of diabetes will be included separately. If successful, the electrical stimulation could
improve sensation leading to fewer ulcerations and amputations. Much suffering and
expense would be avoided. - The magnitude of reduction in suffering and expense
can be judged from the fact that people with diabetes have 15 times the risk of
amputation as do people without diabetes. In Australia half of non-traumatic
amputations are done to people with diabetes. Foot ulcers precede amputations in
most cases, and in themselves cause much suffering and expense. Australia needs to
act on this now because, if current trends continue, the number of people with
diabetes will increase as the population ages. -The number of people aged over 65
will increase from around 2.3 million at present to over 6 million in the next half
century. The increase in those over 85 will be even more marked with numbers
increasing four fold to over one million people. Diabetes affects approximately 23%
of people aged 75 or older.
Research achievements (from final report):
By 2051, it is estimated there will be 6 million Australians over the age of 65. Among
people aged 65-74 some 20% are diagnosed with Diabetes Mellitus (DM). Many of
those older patients suffer from the complications of DM, which increase with
increasing duration of DM, with lower extremity amputation (LEA) being a
significant complication of the disease.
The primary aim of this research is to test the a novel treatment, Low Frequency
Sensory Nerve Stimulation (LF-SNS), to reduce neuropathic symptoms in people with
diabetic peripheral neuropathy (DPN), and to improve sensory nerve function thus
reduce DPN and consequently leg ulcers.
We recently finalised data collection (end of May 2009) and broke the study code.
The statistical analyses to date show that the use of the relatively inexpensive, noninvasive, LF-SNS technique for 12 weeks resulted in improvement in:
o
sensory nerve function that is demonstrated by improvements in skin
microvascular blood flow, time to initial flare and area of flare to capsaicin as well as
C fibres perception threshold.
o
diabetic peripheral neuropathy shown by both objective (Neuropathy
impairment score) and subjective (Neuropathy symptoms profile) measures.
NHMRC Research Achievements - SUMMARY
The significance of the project for Australians and the health care system: We were
able to show that the inexpensive, non-invasive, self-applied, sensory nerve
stimulation technique (LF-SNS) improves sensory nerve function and its continuous
use could alleviate much burden of illness. It could potentially prevent the formation
of diabetic foot ulcers, or speed their healing, through preventing or improving DPN.
This would avert much suffering, including LEA, and health care expenditure. This
study therefore provides evidence needed to induce alterations to clinical practice; to
have LF-SNS incorporated into the standard management of such conditions as DPN,
thus improving health outcomes for many Australians and providing enormous health
cost benefits.
Expected future outcomes:
Further research should look more fully into the effects LF-SNS has on aged skin.
Since the current study showed that C-fibre function improves with this therapy and
as these nerves are necessary to maintain skin integrity, then the regular use of LFSNS may well help maintain (if not improve) skin integrity in the older population.
This in turn may help prevent the formation of ulcers.
Name of contact: Zeinab Khalil
Email of contact: zeinab@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 250399
CIA Name: A/Pr Denise Jackson
Main RFCD: Immunology not elsewhere classified
Admin Inst: Austin Research Institute
Start Year: 2003
End Year: 2005
Total funding: $265,500.00
Grant Type: NHMRC Project
Grants
Title of research award:
Regulating tolerogenic signals by inhibitory co-receptors
Lay Description (from application):
Immunoreceptors play an important role in balancing the threshold of cellular
activation is critical in the immune response to tumours, pathogens or allergens, to
arrest autoimmune and infectious disease and to provoke immunological memory to
vaccination. We have discovered that Platelet Endothelial Cell Adhesion Molecule-1
(PECAM-1/CD31) is a new immunoreceptor, that belongs to a very important family
of proteins, the Ig-ITIM superfamily which is a subset of the immunoglobulin
superfamily. We wish to determine if PECAM-1 functions as an inhibitory receptor
in the lymphoid microenvironment using genetically engineered mice which lack the
protein. As some of the functional features may display modest features, we plan to
cross the PECAM-1 deficient mice with hen egg lysozyme transgenic mice to test the
importance of PECAM-1 in peripheral tolerance. We will also define its importance
in T cell function. We will test if the PECAM-1 deficient mice are more susceptible
to the onset of inducible autoimmunde diseases including mouse models of collageninduced arthritis and diabetes. Finally, we will produce transgenic mice expressing
normal and disabled signaling motifs of PECAM-1 to test their requirement in
autoimmunity.
Research achievements (from final report):
Our studies clarified the unique role of a new inhibitory co-receptor, PECAM-1 in the
context of immunity and tolerance.
In PECAM-1-/-.sHEL+/+.IgHEL+/- mice, elevated levels of anti-HEL
immunoglobulin M (IgM) antibodies in the serum of PECAM-1-/- mice transgenic for
both an HEL-specific B cell receptor (BCR) and soluble lysozyme was observed at
six weeks compared to PECAM-1+/+.sHEL+/+.IgHEL+/- mice. Anergic B cells
lacking PECAM-1 showed enhanced B cell proliferation and calcium flux responses
to LPS, IL-4 alone and IgM cross-linking and IL-4 indicating augmentation of antigen
receptor signalling. Thus, PECAM-1 is important in maintaining peripheral tolerance
in anergic B cells.(DJ35).
Specifically, the absence of PECAM-1 results in a modest maturation defect of CD8+
T cells. PECAM-1-/- mice have normal susceptibility to DTH responses induced by
KLH. PECAM-1-/- T cells are hyper-proliferative to anti-CD3 and anti-CD28
stimulation (T cell proliferation and MLR reactions) consistent with involvement of
ITAM-associated TCR signalling pathway. PECAM-1-/- mice show enhanced in
vivo and in vitro deletion of double positive thymocytes following challenge with
anti-CD3 (2C11), dexamethasone and gamma-irradiation treatment consistent with a
role for PECAM-1 in apoptosis (DJ26).
We have demonstrated that PECAM-1 serves a protective role in the early
development of active models but not passive transfer models of collagen-induced
arthritis (DJ31).
NHMRC Research Achievements - SUMMARY
We initially 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 (molecular and protein level) and crossing them onto
PECAM-1 knockout background. These transgenic mice will be used to study
PECAM-1's role in immunity and tolerance.
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 immune responses. Our studies will clarify the
unique role of inhibitory co-receptors in immunity & tolerance.
Name of contact: A/Prof. Denise Jackson
Email of contact: d.jackson@burnet.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 418101
CIA Name: Prof Geoffrey Farrell
Main RFCD: Hepatology
Admin Inst: Australian National University
Start Year: 2007
End Year: 2009
Total funding: $449,592.00
Grant Type: NHMRC Project
Grants
Title of research award:
MECHANISMS OF DISORDERED HEPATIC LIPID PARTITIONING IN NONALCOHOLIC STEATOHEPATITIS
Lay Description (from application):
Fatty liver is the commonest form of liver disease. It is strongly associated with
obesity and maturity onset diabetes. The majority of cases of fatty liver disease cause
no complications, but when inflammation and liver damage also occur, in the
condition of non-alcoholic steatohepatitis or NASH, liver scarring and eventually
cirrhosis or liver cancer can result. The reason why some people with fatty liver
disease develop NASH and others do not ("benign" or "simple steatosis") is unknown
and is the subject of this research. The studies will be performed in a novel mouse
model of obesity and diabetes, the "fat aussie" mouse, in which all animals develop
fatty liver disease after a few months. When fat aussie mice are fed a "Macdonald's
diet" [high in saturated fat] they develop full-blown NASH with liver scarring. Before
NASH develops in fat aussie mice, blood levels of adiponectin (a protein produced
from fat storage cells) fall. Together with high blood insulin and high blood sugar
levels, it is proposed that these changes are what leads to an extraordinarily high build
up of fat (lipid) molecules in the liver, to the extent that the fat ultimately damages the
liver in a process called lipotoxicity. The planned research will first test whether this
hypothesis is correct, and then set about ways to prevent or reverse such a dangerous
build up of fats in the liver. Strategies include a high olive oil diet (which is protective
in another model of steatohepatitis), correction of blood adiponectin levels, lowering
of insulin and blood sugar levels. The anticipated results are a much better
understanding of how complications come about in fatty liver disease, and therefore
insights into how this disorder can be prevented or reversed in those who are
predisposed.
Research achievements (from final report):
1.
Confirmation that the most likely candidate hepatic lipid pool in NASH is free
cholesterol, including documentation of plasma membrane localisation as the most
important subcellular site.
2.
Demonstration that the hepatic lipid (fatty acid and cholesterol) uptake
pathway cluster differentiation protein (CD)36 is pivotal to NASH pathogenesis.
3.
Discovery that genetic background has major modulatory effects on
development of insulin resistance, dyslipidemia and fall in serum adiponectin in mice
with hyperphagic obesity fed a high fat diet.
4."outstanding young investigator" recognition to Derrick van Rooyen at Australian
Gastroenterology Week 2010.
Expected future outcomes:
Understanding the causation of severe forms of fatty liver disease
NHMRC Research Achievements - SUMMARY
Name of contact: Professor Geoff Farrell
Email of contact: geoff.farrell@anu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 366772
CIA Name: Prof Christopher Goodnow
Main RFCD: Humoral Immunology and Immunochemistry
Admin Inst: Australian National University
Start Year: 2007
End Year: 2008
Total funding: $575,948.00
Grant Type: NHMRC Project
Grants
Title of research award:
Genetic and molecular mechanisms dysregulating CD4 T cell tolerance in organspecific autoimmunity
Lay Description (from application):
This project will analyse mechanisms that regulate CD4 T cells and normally prevent
the immune system from attacking parts of our own body. Unknown errors in the
control of T cells result in autoimmune diseases such as Type 1 diabetes, multiple
sclerosis, Addison s disease and thyroid disease, where T cells damage or destroy
vital organs. In order to develop rational, specific methods for treating and preventing
these diseases, it is necessary to identify and understand the genetic and biochemical
mechanisms that normally control T cell responses to self components, and how
inherited defects lead these mechanisms to break down. The project focuses on
defining how CD4 T cell regulation breaks down in a well established but poorly
understood example of polygenic inherited susceptibility to autoimmune disease.
Polygenic diseases are those where susceptibility is inherited in a complex way
involving many different genes either acting together or in opposition, and the
molecular basis for this kind of inheritance is particularly poorly understood. The
project will analyse the basis for this kind of inheritance pattern by analysing the
direct action of diabetes susceptibility genes at the level of the specific T cells
responsible for autoimmune attack and in terms of the biochemical pathways within
the T cells that are dysregulated. By identifying the mechanisms and biochemical
pathways that are dysregulated in autoimmune disorders, the results of this project
will concepts and targets for understanding and diagnosing autoimmune diseases and
for developing new drugs or vaccines to prevent T cells damaging vital organs and
cure these diseases.
Research achievements (from final report):
The study identified a large program of genes whose expression is induced during the
elimination of forbidden clones of T cells within the thymus. This information
advances understanding about how the body normally avoids autoimmune diseases
such as Type 1 Diabetes, thyroid disease, multiple sclerosis, rheumatoid arthritis,
systemic lupus, and many other diseases that collectively affect five percent of
Australians. The study also identified how inherited susceptibility to diabetes and
other autoimmune diseases, in the NOD mouse model of these disorders, results from
faults in the induction of the clone elimination gene program. This result provides a
molecular map for understanding the complex pattern of inherited susceptibility to
autoimmune diseases. This will enable future research to predict individuals at most
risk of autoimmunity, and to tailor prevention or treatment at the underlying cause of
these illnesses.
Expected future outcomes:
NHMRC Research Achievements - SUMMARY
We are continuing to refine the components of the gene program that eliminates
forbidden clones of T cells in the thymus, testing the function of key elements of the
program and how they are altered by subtle inherited differences, and expect to
submit further high impact publications on this during 2009.
Name of contact: Chris Goodnow
Email of contact: Chris.Goodnow@anu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 219167
CIA Name: Prof Christopher Goodnow
Main RFCD: Not Allocated
Admin Inst: Australian National University
Start Year: 2001
End Year: 2006
Total funding: $3,348,000.00
Grant Type: International
Collaborations
Title of research award:
Molecular analysis of pathways in diabetes (MAPDB) study
Lay Description (from application):
The sequence of human genome provides a complete "part-list" of the genes and
proteins that make our bodies. A most unknown subset of these parts work together
in molecular pathways that underpin susceptibility and resistance to Type 1 diabetes
and its complications. The MAPDB study will link patients, families, doctors,
genome experts, immunologists, physiologists, statisticians and data base
programmers together to illuminate these molecular pathways. In particular, the study
will reveal genes and pathways that medicate protection from diabetes and its
complications - either by inhibiting T cell responses to pancreatic beta cells,
protecting or regenerating beta cells in the face of metabolic or immunologic stress, or
protecting eyes and kidneys from the damaging effects of high blood glucose. By
identifying genes and proteins with these functions, the study will enable new
treatments to be developed aimed at augmenting these protective pathways, to prevent
diabetes starting in children at risk, and to preserve beta cell mass, protect
transplanted stem cells or beta cells, and prevent eye and kidney damage in people
already affected by Type 1 diabetes. Genes and proteins that are needed for T cell
attack on beta cells will also be revealed. This information will enable new
treatments to be developed that block these processes, to prevent diabetes from
starting, to preserve beta cell mass and to prevent destruction of transplanted stem
cells or beta cells. The MAPDB study will also identify different versions-alleles- of
many of the genes in the pathways described above. Particular combinations of these
gene alleles will be defines that can identify people at high risk of developing Type 1
diabetes, risk of cell or islet transplantation rejection, or at most risk for eye/kidney
complications. Different gene combinations may be found that allow different kinds
of Type 1 diabetes to distinguished. By creating ways to identify and distinguish
people's individual risk, the study will yield diagnostic tests to enable new treatments
and clinical trials to be targeted.
Research achievements (from final report):
1. Successfully established a unique approach for discovering genes and pathways
regulating diabetes, by combining a sensitised transgenic mouse strain with controlled
variation of the mouse genome sequence.
2. Discovered that the Aire gene is required for thymic deletion of islet-specific T
cells.
3. Discovered a novel ubiquitin ligase gene and peripheral tolerance mechanism,
repressing follicular helper T cells and the costimulatory receptor ICOS, which when
crippled leads to severe diabetes and islet autoantibodies in the sensitised transgenic
strain. That work - published as an Article in Nature - further validates our approach
and provides a unique entry point into new pathways for regulating T cells in lymph
nodes and within islets.
NHMRC Research Achievements - SUMMARY
4. Discovered a gene defect causing Type 2 diabetes, obesity, hypercholesterolemia,
and liver pathology. This gene is an orthologue of a gene recently identified as
causing Type 2 diabetes and obesity in humans, and the mouse strain provides a
unique animal model for understanding the coordination between islet cells and
metabolism.
5. Developed a new theory to explain the pathogenesis of Type 1 diabetes and other
autoimmune diseases.
Expected future outcomes:
The program is continuing with JDRF support, and has spun off a parallel
collaborative project between Australian and Singapore immunologists. These
projects will continue to reveal new pathways and mechanisms for controlling T cell
destruction of islets to prevent and cure diabetes.
Name of contact: Chris Goodnow
Email of contact: chris.goodnow@anu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 418077
CIA Name: A/Pr Christopher Nolan
Main RFCD: Endocrinology
Admin Inst: Australian National University
Start Year: 2007
End Year: 2009
Total funding: $480,828.00
Grant Type: NHMRC Project
Grants
Title of research award:
Biochemical basis of islet beta-cell compensation and failure in normal pregnancy and
gestational diabetes mellitus
Lay Description (from application):
The factors causing the current world-wide crisis of rapidly rising diabetes prevalence
remain poorly understood. Of potential major importance, however, is the hypothesis
that abnormalities in the maternal metabolic environment, as occur in gestational
diabetes (GDM) (diabetes that develops in pregnancy), result in abnormal
development of metabolic systems in the baby resulting in higher risk of adult onset
diabetes in the babies. Therefore, it is of importance to understand the mechanisms
causing GDM, such that effective measures can be developed to counter this passing
on of diabetes risk from mother to baby. It is known that a key factor causing GDM is
failure of maternal pancreatic islet beta-cells to compensate for increased demands for
insulin production in pregnancy. Poorly understood, however, are the cellular
mechanisms of islet beta-cell compensation in normal pregnancy and failure of this
compensation in GDM pregnancy. We have recently shown that there is a pathway of
fat metabolism (triglyceride/ free fatty acid cycle) within the islet beta-cell that has an
important role in amplyfing insulin secretion necessary to maintain normal blood
glucose and protecting the islets from failure in obese rats. The major focus of this
project is to test the hypothesis that this pathway has a key role in the adaptation of
pancreatic islets to normal pregnancy and its dysfunction contributes to the causation
of GDM. Of great interest from preliminary findings is that a "master" regulator of
glucose and fat metabolism, PGC1alpha, is markedly reduced in islets during normal
pregnancy. Studies will also be directed to PGC1alpha's role in islet adaptation to
pregnancy and failure in GDM. We expect that successful completion of this project
will lead to the development of highly targeted counter measures to prevent GDM and
to slow and reverse the current epidemic of diabetes.
Research achievements (from final report):
For SPECIFIC AIM 1, we showed that enhanced islet function in late pregnant rats
can partly be explained by increased augmentation of glucose-stimulated secretion by
fatty acids. Furthermore, increased glucose-stimulated fatty acid esterification and
lipolysis processes, consistent with increased glycerolipid/fatty acid cycling, is
associated with the increased fatty acid effect on secretion. These results are
consistent with alterations in islet lipid signaling processes being involved in beta-cell
compensation for insulin resistance in pregnancy.
For SPECIFIC AIM 2, we confirmed our preliminary data that PGC1α is significantly
reduced in islets in pregnancy.
For SPECIFIC AIM 3, we established a previously described surgical model of
intrauterine growth restriction (IGR) in Sprague-Dawley rats. Our IGR pups are
resistant to developing obesity, gestational diabetes or diabetes compared to controls.
Most interesting, is the recent finding that the IGR rat has severely dysmorphic
NHMRC Research Achievements - SUMMARY
pancreatic islets with evidence of extensive iron accumulation. Pancreatic beta-cell
mass is preserved in this model though, suggesting the islets of our model are very
robust with excellent proliferative capacity. The results are indicative of an effect of
IGR on islet iron metabolism. Iron is known to be highly toxic to the beta-cell, such
this the effects of IGR on increasing the risk of type 2 diabetes later in life could be
due to iron toxicity. This very novel and exciting result is the basis for application for
ongoing NHMRC funding.
Expected future outcomes:
Two further publications are being written. One related to the role of
glycerolipid/fatty acid cycling in islet beta-cell compensation for insulin resistance in
pregnancy. The second relates to the severely abnormal islet morphology and islet
iron accumulation in our model of intrauterine growth restriction.
Name of contact: Christopher J Nolan
Email of contact: christopher.nolan@anu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 224206
CIA Name: Dr Charmaine Simeonovic
Main RFCD: Transplantation Immunology
Admin Inst: Australian National University
Start Year: 2003
End Year: 2005
Total funding: $504,750.00
Grant Type: NHMRC Project
Grants
Title of research award:
Major xenoantigens for neovascularised porcine xenografts: the role of PERV and
MHC in rejection and tolerance
Lay Description (from application):
Cross-species transplants (xenografts) of pig organs which use donor pig blood
vessels are rejected by antibody which recognises a special target (xenoantigen) on
the pig blood vessels; other pig tissue transplants ("cellular" transplants) which use
recipient (not donor pig) blood vessels, are rejected by white blood cells called CD4 T
cells. The pig targets recognised by the xenoreactive CD4 T cells are unknown. We
plan to identify the major target(s) involved in "cellular" xenograft rejection. This
information can then be used to specifically remove or disable only those CD4 T cells
capable of recognising the pig tissue and hence facilitate xenograft survival or
tolerance without immunosuppression. In this way, the remainder of the CD4 T cell
population and immune system is preserved intact. Recent studies have demonstrated
that a pig virus (PERV) can be transmitted from pig tissue xenografts to recipient
tissues. Our studies have also suggested that the process of xenograft rejection and the
immunological recognition of transplant recipient cells infected with the pig virus, are
closely related. We plan to investigate this relationship and ascertain whether the
immunological destruction of the pig tissue xenograft is largely due to an immune
response generated against the pig virus(es) it carries. As an extension of this concept,
we will investigate whether long-term xenograft survival (tolerance) is associated
with lack of immune reactivity to the pig virus and hence a continual capacity for pig
virus to be transmitted to host tissues. This outcome could result in the development
of unwanted disease(s) in transplant patients. To prevent these problems, our studies
will determine whether it will be essential for such pig virus to be eliminated from the
donor pig tissue before transplantation, e.g. by the development of potent anti-viral
agents and/or via the development of pig herds that have been genetically engineered
to be pig virus (PERV)-deficient.
Research achievements (from final report):
This project demonstrated that preimmunisation of mice with PERV virions (Porcine
Endogenous Retrovirus) purified from porcine cells generates a CD4 T cell response
which induces accelerated rejection of porcine thyroid xenografts. The xenografts
were more rapidly rejected following immunisation with porcine PK15 cells than with
pig PBL and this did not correlate with higher Class I MHC levels but with
production of more PERV RNA and high production of PERV virions by the PK15
cells. Using PERV purified from an infected human 293 cell line for
preimmunisation, where the anti-PERV immune response generated was not
complicated by an accompanying immune response to swine MHC, accelerated
rejection of pig thyroid xenografts was observed. Likewise preimmunisation with
purified PERV from porcine cells induced accelerated rejection of xenografts of
PERV-infected human 293 cells, where graft recognition was restricted to PERV
NHMRC Research Achievements - SUMMARY
antigens alone (in the absence of non-PERV porcine antigens e.g. MHC). Using
peptide immunisation for ultimate clarification of the role for PERV xenoantigens,
preimmunisation with PERV peptide was more effective in inducing accelerated
rejection than donor-specific swine MHC peptide. Nevertheless, anti-pig spleen cells
responded equally to each peptide in secondary MLRs. Xenograft tolerance was not
induced after treatment of neonatal mice with PERV (±irradiation), PERV-producing
pig cells (±irradiation) or PERV-ve pig PBL. PERV transmission to host cells
following xenotransplantation was transient, suggesting that PERV-infected host cells
were cleared by the immune system early in the post-transplant period. We conclude
that PERV xenoantigens can function as important transplantation antigens, that MHC
antigens may not be dominant over other cell surface antigens in a xenogeneic system
and that tolerance to xenografts may require non-immunogenic delivery of a range of
porcine cell-surface xenoantigens.
Expected future outcomes:
This study suggests that following clinical xenotransplantation of porcine tissue,
PERV-infected humans cells would be immunologically cleared in underimmunosuppressed patients but not in xenograft-tolerant recipients. Since PERV
produces xenoantigens recognised on pig tissue xenografts and may also infect
transplant recipients, the development of PERV-deficient pig herds should be
beneficial.
Name of contact: Charmaine Simeonovic
Email of contact: Charmaine.Simeonovic@anu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 526639
CIA Name: Prof Josephine Forbes
Main RFCD: Nephrology and Urology
Admin Inst: Baker IDI Heart and Diabetes Institute
Start Year: 2009
End Year: 2011
Total funding: $505,786.00
Grant Type: NHMRC Project
Grants
Title of research award:
Cytosolic oxidative disturbances as a source of mitochondrial dysfunction in diabetic
nephropathy
Lay Description (from application):
There is a critical need to identify new therapies for the growing number of patients
with diabetic kidney disease. Current medicines only retard progressive disease. Our
studies investigate defects in the power houses of the cell, the mitochondria. These
defects cause generation of toxic free oxygen radicals which eventually starve the cell
of energy production. Therefore, reversal of mitochondrial defects in diabetic kidney
disease may be a novel therapeutic target.
Research achievements (from final report):
Not Available
Expected future outcomes:
N/A
Name of contact: Josephine Forbes
Email of contact: jforbes@mmri.mater.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 445300
CIA Name: Prof Mark Febbraio
Main RFCD: Cell Metabolism
Admin Inst: Baker IDI Heart and Diabetes Institute
Start Year: 2007
End Year: 2009
Total funding: $503,426.00
Grant Type: NHMRC Project
Grants
Title of research award:
Role of FoxO proteins in the regulation of skeletal muscle anabolism, catabolism and
insulin sensitivity
Lay Description (from application):
Loss of muscle tissue or muscle wasting is a hallmark of many common health
problems including diabetes, cancer, Cushing's syndrome, sepsis, HIV-Aids and renal
failure. In the past 2-3 years important progress has been made in understanding the
molecular regulation of both catabolism (muscle wasting) and anabolism (muscle
growth) within mammalian skeletal muscles. It has been known for some time that a
certain family of transcription factors, known as FoxO proteins, activate catabolic
pathways. However, recently, we have shown that FoxO proteins also cause muscle
wasting by blocking anabolic pathways. Our new data heighten the importance of
targeting FoxO proteins are therapeutics for human diseases where muscle tissue
wasting occurs. This proposal will investigate methods that will allow for blocking
the action of FoxO proteins in the hope that muscle wasting can be prevented.
Research achievements (from final report):
We have identified that FoxO1increases muscle oxidative capacity when
overexpressed. Moreover, when FoxO1 is deleted from skeletal muscle, mice are
prone to weight gain
Expected future outcomes:
We expect to determine the precise molecular mechanism as to how FoxO1regulates
mitochondrial metabolism
Name of contact: Mark A Febbraio
Email of contact: mark.febbraio@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 418916
CIA Name: Prof Mark Cooper
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Admin Inst: Baker IDI Heart and Diabetes Institute
Start Year: 2007
End Year: 2009
Total funding: $389,522.00
Grant Type: NHMRC Project
Grants
Title of research award:
Role 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 of contact: mark.cooper@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 268904
CIA Name: A/Pr Terri Allen
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Admin Inst: Baker IDI Heart and Diabetes Institute
Start Year: 2004
End Year: 2007
Total funding: $352,000.00
Grant Type: Career
Development Fellowships
Title of research award:
The 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 of contact: terri.allen@baker.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 586691
CIA Name: Prof Josephine Forbes
Main RFCD: Nephrology and Urology
Admin Inst: Baker IDI Heart and Diabetes Institute
Start Year: 2010
End Year: 2010
Total funding: $156,230.00
Grant Type: Career
Development Fellowships
Title of research award:
Synergistic partways contributing to renal dysfunction in diabetes
Lay Description (from application):
Diabetes is the main cause of kidney disease in Australia, which has large social and
economic burdens. Indeed this disorder affects some 400,000 Australians. My
research includes an integrative program to find new targets to combat diabetic kidney
disease in the hope of designing new drugs and producing new biomarkers for early
intervention in this disease.
Research achievements (from final report):
This award was only received for one year after which it was updated to an SRF
fellsohip following the awarding at that level. During this 12 months I completed a
numbr of studies addressing the role of advanced glycation and interconnecting
pathways in the pathogenesis of diabetic kidney disease. Specifically, these included
AGE or AGE-receptor mediated effects on mitochondrial function and interactions
with the renin angiotensin system.
Expected future outcomes:
This research has led to the instigation of a clinical trial in patients with diabetic
kidney disease as well as many follow up studies in humans and in more advanced
mouse models.
Name of contact: Porf Josephine Forbes
Email of contact: jforbes@mmri.mater.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 526619
CIA Name: Prof Mark Febbraio
Main RFCD: Cell Metabolism
Admin Inst: Baker IDI Heart and Diabetes Institute
Start Year: 2009
End Year: 2011
Total funding: $511,295.00
Grant Type: NHMRC Project
Grants
Title of research award:
Can blocking fatty acid transport in myeloid cells prevent insulin resistance?
Lay Description (from application):
Over the past 5 years it has become apparent that blood cells can become inflamed as
people become obese. These inflamed blood cells can contribute to insulin resistance
or "pre-diabetes". Our hypothesis is that these blood cells become inflamed because
they take up fat via fatty acid transporters. Our approach is to knock out one of these
fatty acid transporters specifically in blood cells and reduce inflammation and insulin
resistance due to overnutrition.
Research achievements (from final report):
The general aim of this project was to examine the role of FAT/CD36 in macrophages
on the aetiology of obesity-induced insulin resistance.While CD36 does not appear
important in saturated fatty acid induced macrophage lipid accumulation, our study
uncovers a novel role for CD36 in the migration of pro-inflammatory phagocytes to
adipose tissue in obesity, with a concomitant improvement in insulin action. This
paper was published in Diabetes in 2011 .
Expected future outcomes:
CD36 could be an important molecule to target therapeutically in the treatment of
obesity-induced insulin resistance
Name of contact: Mark Febbraio
Email of contact: mark.febbraio@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 472710
CIA Name: Dr Luciano Pirola
Main RFCD: Endocrinology
Admin Inst: Baker IDI Heart and Diabetes Institute
Start Year: 2009
End Year: 2009
Total funding: $75,250.00
Grant Type: International
Exchange Early Career
Fellowships
Title of research award:
Epigenetic Control in Type 2 Diabetes
Lay Description (from application):
Not Available
Research achievements (from final report):
During this 1-year fellowship, I have learn the foundamental methodologies to
explore the epigenetic control of the chromatin structure. Chromatin
immunoprecipitation (ChIP) techniquers have been applied to study insuli-dependent
transcriptional regulation of candidate genes. Also, ChIP has been used to study the
global histone acetylation profile in endothelial cells treated by prolonged
hyperglycaemia to gain insight into the basic mechanisms underlying the development
of vascular diabetic complications.
Expected future outcomes:
Furher ChIP experiments in endothelial cells will be directed to the definition of
chromatin methylation modifications.
Name of contact: Luciano Pirola
Email of contact: luciano.pirola@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 342115
CIA Name: Prof Mark Febbraio
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Admin Inst: Baker IDI Heart and Diabetes Institute
Start Year: 2005
End Year: 2007
Total funding: $360,750.00
Grant Type: NHMRC Project
Grants
Title of research award:
Novel 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 IL6 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 of contact: mark.febbraio@baker.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 418937
CIA Name: A/Pr Karin Jandeleit-Dahm
Main RFCD: Endocrinology
Admin Inst: Baker IDI Heart and Diabetes Institute
Start Year: 2007
End Year: 2009
Total funding: $460,397.00
Grant Type: NHMRC Project
Grants
Title of research award:
The 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.
NHMRC Research Achievements - SUMMARY
Name of contact: Karin Jandeleit-Dahm
Email of contact: karin.jandeleit-dahm@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 392206
CIA Name: Prof Mark Febbraio
Main RFCD: Cell Metabolism
Admin Inst: Baker IDI Heart and Diabetes Institute
Start Year: 2006
End Year: 2008
Total funding: $602,673.00
Grant Type: NHMRC Project
Grants
Title of research award:
Ciliary Neurotrophic Factor: a novel theraputic agent for the prevention of muscle
insulin resistance
Lay Description (from application):
In 1995 leptin was discovered and scientists world-wide hoped that this was the "great
panacea" in the treatment of obesity related disorders. Alas, from 1995-1997 the
identification of a novel cytokine inducible compound termed suppressor of cytokine
signaling (SOCS) that negatively regulated leptin signalling and lead to "leptin
resistance", quashing hopes for a viable "anti-obesogenic" drug. Recently, however,
work from our group has demonstrated that the neuropoietic cytokine, ciliary
neurotrophic factor (CNTF), can act in an anti-obesogenic fashion in a manner similar
to leptin. However, unlike leptin, when we place rodents on a high fat diet, the effects
of CNTF persist and override induction SOCS proteins. This project will examine the
biochemical pathways that allow the actions of CNTF to persist in the presence of
diet-induced obesity. This is of major significance because in completing this work,
the potential for the development of peripheral tissue drug targets for the treatment of
obesity related diseases are both tangible and realistic.
Research achievements (from final report):
The aim of this project was to elucidate the mechanisms by which CNTF can act as an
anti-obesogenic drug and, in contrast with leptin, overcome the negative effects of
elevated SOCS protein expression. We showed that CNTF can overcome leptin
resistance both centrally and in peripheral tissue . We showed that while STAT3
signalling was not an absolute requirement for gp130 receptor signalling, truncating
the cytoplasmic domain of the gp130 receptor distal to the SHP2 domain (Tyr759)
resulted in a failure for CNTF to adequately signal through the gp130 receptor.
Expected future outcomes:
The second phase of the grant was to design a cytokine that may have better
efficiency than CNTF as a therapeutic strategy. We synthesized a novel protein by
transferring the putative "LIF receptor (LIFR) binding module" from CNTF to IL-6.
We hope that this compound will result in a new drug.
Name of contact: Mark Febbraio
Email of contact: mark.febbraio@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 526606
CIA Name: Prof Mark Febbraio
Main RFCD: Cell Metabolism
Admin Inst: Baker IDI Heart and Diabetes Institute
Start Year: 2009
End Year: 2011
Total funding: $708,267.00
Grant Type: NHMRC Project
Grants
Title of research award:
Novel gp130 receptor ligands to treat metabolic disease
Lay Description (from application):
Over the past decade work from our group has identified that a group of cytokines
termed the gp130 receptor cytokines can lead to weight loss in animals and humans.
Unfortunately, due to side effects, clinical trials using peptides analogues of these
cytokines have failed. We believe that we know why this has occurred and we think
we have developed new peptides that will alleviate these side effects. This application
will test the efficacy of these novel peptides in mammals in vivo.
Research achievements (from final report):
This grant allowed us to make a pivotal discovery. We synthesized a novel protein by
transferring the putative "LIF receptor (LIFR) binding module" from CNTF to IL-6.
Excitingly,we showed that this new cytokine, termed IC7, has similar positive
metabolic effects as CNTF, but may overcome the negative effects experienced bythe
drug Axokine®. CIA Febbraio, together with CIC Rose-John, has filed world wide
patents (60/920822-USA, 2008234408-Australia, 2681935-Canada, 08733275.5-EU)
with claims directed to the use of IC7 to treat type 2 diabetes (T2D) and obesity.
Expected future outcomes:
IC7 could be usedtherapeutically in the treatment of obesity-induced insulin resistance
Name of contact: Mark Febbraio
Email of contact: mark.febbraio@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 292902
CIA Name: Prof Mark Febbraio
Main RFCD: Cell Physiology
Admin Inst: Baker IDI Heart and Diabetes Institute
Start Year: 2004
End Year: 2007
Total funding: $373,000.00
Grant Type: Established
Career Fellowships
Title of research award:
Uncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
In 2000, together with my collaborator Professor Bente Klarlund Pedersen, I made the
vital discovery that muscles produce and secrete cytokines that have biological
reactivity. This formed the basis of my successful SRFB application. During the
period of my fellowship, we made the very important discovery that IL-6 and other
IL-6 family cytokines can be used as anti-obesogenic compounds and this has
culminated in the publications in journals such as Nature Medicine, Journal of
Clinical Investigation, Cell Metabolism, Diabetes, Journal of Biological Chemistry
and FASEB Journal., as well as the filing of a patent for gp130 receptor ligands as
anti-obesity therapies.
Expected future outcomes:
I have recently filed of a patent for the use of gp130 receptor ligands as anti-obesity
therapies. Our expected future outcome is that we will take drugs that activate the
gp130 receptor into clinical trials to treat obesity and insulin resistance.
Name of contact: Ebru Yaman
Email of contact: ebru.yaman@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 526642
CIA Name: Prof Merlin Thomas
Main RFCD: Nephrology and Urology
Admin Inst: Baker IDI Heart and Diabetes Institute
Start Year: 2009
End Year: 2011
Total funding: $453,145.00
Grant Type: NHMRC Project
Grants
Title of research award:
The 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 microand 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 of contact: mthomas@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 367651
CIA Name: A/Pr Karin Jandeleit-Dahm
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Admin Inst: Baker IDI Heart and Diabetes Institute
Start Year: 2006
End Year: 2008
Total funding: $272,000.00
Grant Type: Career
Development Fellowships
Title of research award:
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 of contact: karin.jandeleit-dahm@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 418920
CIA Name: Prof Bronwyn Kingwell
Main RFCD: Endocrinology
Admin Inst: Baker IDI Heart and Diabetes Institute
Start Year: 2007
End Year: 2009
Total funding: $349,683.00
Grant Type: NHMRC Project
Grants
Title of research award:
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.
NHMRC Research Achievements - SUMMARY
.
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 of contact: bronwyn.kingwell@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 268909
CIA Name: Prof Mark Cooper
Main RFCD: Endocrinology
Admin Inst: Baker IDI Heart and Diabetes Institute
Start Year: 2004
End Year: 2008
Total funding: $796,750.00
Grant Type: Established
Career Fellowships
Title of research award:
Uncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
In this period I made significant advances in the area of diabetic complications
extending my original research into renal disease into the major area of diabetic
macrovascular disese. Furthermore, I was able to commence very exciting studies on
the phenomenon of metabolic memory which identified a key role for epigenetic
events in conferring sustained changes on genes as a result of past periods of elevated
glucose levels. These studies have led to new treatments which have intitally been
performed in animal models and clinical studies have just commenced for some of
these treatments. It is hoped that such treatments will ultimately result in a major
decrease in the burden of diabetes, primarily as a result of the kidney and large blood
vessel complications which lead to heart disease and kidney failure.
Expected future outcomes:
We plan to further characterise at a molecular level the changes that occur in response
to glucose in cells. We are prediciting that new targets will be identified to generate
new betetr treatments. It is hoped that such treatments will ultimately result in a
major decrease in the burden of diabetes, specifically its kidney and blood vessel
complications.
Name of contact: Laurel Ring
Email of contact: laurel.ring@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 325645
CIA Name: Dr Clinton Bruce
Main RFCD: Endocrinology
Admin Inst: Baker IDI Heart and Diabetes Institute
Start Year: 2005
End Year: 2009
Total funding: $308,250.00
Grant Type: Early Career
Fellowships (Australia)
Title of research award:
Fatty acid oxidation and muscle insulin sensitivity
Lay Description (from application):
Not Available
Research achievements (from final report):
Understanding the mechanisms that cause obesity and insulin resistance is a key to
understanding the aetiology of, and developing preventative strategies for, Type 2
diabetes. A prominent feautre of obesity and insulin resistance is defective fat
metabolism in muscle which manifests as an inability to burn fat. As a result fat builds
up in muscle which causes insulin resistance and Type 2 diabetes. This project
examined wheter targeting pathways to accelerate the fat burning capacity of muscle
can improve insulin sensitivity. The results obtained from these studies show that
being able to burn more fat prevents the build up of fat within muscle. This leads to
an improvement in insulin sensitvity. Therefore, implementing strategies to increase
fat use is likely to be beneficial in the treatment of type 2 diabetes.
Expected future outcomes:
It is expected that future outcomes will determine exactly which type of fat is causing
the insulin resistance in muscle and whether increasing the ability to burn fat will
prevent these fats from accumulating.
Name of contact: Clinton Bruce
Email of contact: clinton.bruce@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 472650
CIA Name: Prof Mark Febbraio
Main RFCD: Cell Metabolism
Admin Inst: Baker IDI Heart and Diabetes Institute
Start Year: 2008
End Year: 2010
Total funding: $467,720.00
Grant Type: NHMRC Project
Grants
Title of research award:
Activation of HSP70: a therapeutic target to treat obesity-induced insulin resistance
Lay Description (from application):
Type 2 diabetes is a prevalent and serious disease and the development of new
strategies to treat it is warranted. In recent experiments we have been able to show
that by upregulating a particular protein, referred to as a "heat shock protein", we can
reduce the clinical markers of type 2 diabetes by reducing key inflammatory pathways
known to lead to insulin resistance. In this series of studies we will investigate
whether activation of this protein is a target for therapeutic treatment.
Research achievements (from final report):
In studies supported by this NHMRC project grant , we discovered that
overexpression or activation of heat shock protein 72 (HSP72; the inducible form of
the 70kDa family of heat shock proteins) in skeletal muscle reduced obesity-induced
insulin resistance. These findings identified an essential role for HSP72 in preventing
insulin resistance in the context of genetic obesity or high fat feeding. The study
generated excitement amongst the scientific community as evidenced by the fact that
it featured as a research highlight in Nature Medicine, and the observation that a
number of subsequent studies verified our original finding. Importantly, we
demonstrated that a small molecule activator of HSP72, namely BGP-15, was
effective in preventing insulin resistance. This drug has now proceeded to a large
scale human clinical trial.
Expected future outcomes:
We expect to have BGP-15 in the clinic within 5 years
Name of contact: Mark A Febbraio
Email of contact: mark.febbraio@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 268918
CIA Name: Prof Mark Cooper
Main RFCD: Endocrinology
Admin Inst: Baker IDI Heart and Diabetes Institute
Start Year: 2004
End Year: 2006
Total funding: $414,000.00
Grant Type: NHMRC Project
Grants
Title of research award:
Role 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 sugarattached 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 of contact: mark.cooper@baker.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 367620
CIA Name: Prof Mark Cooper
Main RFCD: Nephrology and Urology
Admin Inst: Baker IDI Heart and Diabetes Institute
Start Year: 2006
End Year: 2008
Total funding: $454,023.00
Grant Type: NHMRC Project
Grants
Title of research award:
Role of growth and transcription factors in tubulointerstitial injury in diabetes
Lay Description (from application):
Progressive kidney disease occurs as a result of a range of molecular and cellular
pathways. One of the commonest causes of kidney disease is diabetes and this
appears to be partly related to increased expression and action of certain growth
factors such as CTGF. These factors promote the deposition of scar tissue in the
kidney and one of the ways these promote this scarring is to change a cell s behaviour
so that it now lays down collagen. This proposal will not only focus on how CTGF
promotes scarring but will explore 2 novel factors called Snail and Slug which can act
directly on particular genes such as CTGF to inhibit these deleterious effects. By
further characterising these pathways involving Snail, Slug and CTGF in the kidney it
will be possible to generate new targets and therapies for various forms of progressive
kidney disease including diabetic kidney disease.
Research achievements (from final report):
A common cause of kidney disease is diabetes and is partly related to increased
expression and action of growth factors such as TGFβ and CTGF. These factors
promote the deposition of scar tissue in the kidney by acting on a novel class of
intracellular regulator molecules called microRNAs, to change the cell's
characteristics such that cells begin laying down excess collagen leading to fibrosis in
the kidney. In this study we identified that most of the profibrotic actions of TGFβ
occur via CTGF and that blocking CTGF may in fact be a method by which renal
fibrosis may be controlled. We further observed that the expression of a number of
kidney specific microRNA molecules was altered by these factors in renal cells and
was associated with increased expression of extracellular proteins as happens in renal
fibrosis. Similar observations were also made in a model of experimental diabetes.
Interestingly, restoring the expression of these molecules reversed some of the effects
of TGFβ.
Expected future outcomes:
Confirmation that microRNAs are altered in the kidney as a consequence of diabetic
kidney disease presents us with a unique opportunity to study these novels molecules
in the context of renal fibrosis. This work may potentially lead to the development of
novel strategies for the treatment of diabetic kidney disease.
Name of contact: Phillip Kantharidis
Email of contact: Phillip.Kantharidis@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 472705
CIA Name: A/Pr Chiew Wong
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Admin Inst: Baker IDI Heart and Diabetes Institute
Start Year: 2008
End Year: 2011
Total funding: $210,055.00
Grant Type: Early Career
Fellowships (Australia)
Title of research award:
Effect 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 Renin-Angiotensin-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 of contact: chiew.wong@wh.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 526608
CIA Name: Dr Clinton Bruce
Main RFCD: Cell Metabolism
Admin Inst: Baker IDI Heart and Diabetes Institute
Start Year: 2009
End Year: 2011
Total funding: $450,391.00
Grant Type: NHMRC Project
Grants
Title of research award:
Sphingosine kinase as a target therapeutic for obesity induced insulin resistance
Lay Description (from application):
Obesity is linked to the development of insulin resistance and diabetes, which
represent a significant health issue in Australia. A number of factors contribute to the
development of insulin resistance, including defective fatty acid metabolism. This
study proposes to investigate whether manipulating sphingosine kinase, a key enzyme
in lipid metabolism, affects the development of insulin resistance. These studies may
identify novel targets for the treatment of insulin resistance and diabetes.
Research achievements (from final report):
Obesity is an escalating global health problem. It is associated with a number of
disorders including type 2 diabetes. The prevalence of these diseases has increased
dramatically over the last two decades reaching epidemic proportions. In fact, obesity
and type 2 diabetes are among the most significant health issues in Australia today.
Although the exact causes of type 2 diabetes are not known, it is clear that defects in
the way muscle metabolises fat is involved. In these studies we have identified a
pathway, that once activated, can improve muscle fat metabolism and as a result
prevent insulin resistance, the precursor to type 2 diabetes. More importantly, we
show that a drug which can act on aspects of this pathway is effective in treating
insulin resistance. These results are particularly exciting as this drug has recently
received approval for the treatment of an unrelated disease. The results from these
studies may therefore, provide new strategies for the treatment of obesity and type 2
diabetes.
Expected future outcomes:
Although further studies are required, our intial findings indicated that we may have
identified a novel therapy for the treatment of type 2 diabetes. As this drug is already
in clinical use, rapid translation of these findings is possible.
Name of contact: Clinton Bruce
Email of contact: clinton.bruce@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 367621
CIA Name: Prof Mark Cooper
Main RFCD: Endocrinology
Admin Inst: Baker IDI Heart and Diabetes Institute
Start Year: 2006
End Year: 2008
Total funding: $438,521.00
Grant Type: NHMRC Project
Grants
Title of research award:
Role 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 longterm 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 of contact: assam.el-osta@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 367602
CIA Name: A/Pr Josephine Forbes
Main RFCD: Nephrology and Urology
Admin Inst: Baker IDI Heart and Diabetes Institute
Start Year: 2006
End Year: 2008
Total funding: $333,813.00
Grant Type: NHMRC Project
Grants
Title of research award:
Mediation pathways for the receptor for advanced glycation end products in diabetic
nephropathy
Lay Description (from application):
Excess sugar in the blood from diabetes is detrimental and can accelerate a process
where sugar attaches itself to proteins, fats and DNA. Although facilitated by high
sugar, the reaction occurs happily in the presence of low sugar with high levels of free
oxygen radicals. These complexes are called advanced glycation end products or
AGEs. In addition, we ingest vast volumes of AGES from our diet which are taken
into the blood. These AGEs are known to be involved in the development of kidney
disease in diabetic subjects. AGEs exert most of their effects on the body by
binding to specific proteins, the most common and nasty of which is the receptor for
advanced glycation end products, RAGE. RAGE is a known participant in other
serious diseases such as Alzheimer's disease and evidence is mounting for its central
role in the development of kidney disease in diabetic subjects. There is not much
known about the processes which mediate RAGE which is why this is the aim of this
proposal. This will enable us to stop the relentless progression of kidney disease in
diabetes.
Research achievements (from final report):
Diabetes and specifically its resultant kidney complications affects more than 400,000
Australian. There is no cure for this disease and the only available treatments are
costly and undesirable for patients, including kidnye transplants and dialysis. This
proposal involved a systematic series of studies to explore the modulation of a
protein, RAGE which is known to be involved in the the development of kidney
disease in diabetes. This was explored by changing the interactions of other proteins
with RAGE ligand (by reducing AGEs or the AGE clearance receptor, AGE-R1), by
altering the ratio of good (soluble) to bad (full length) RAGE present in the diabetic
kidney and by modulating cell signalling pathways for RAGE via NF-κB. Each of
these regulatory pathways is a potential therapeutic target to dampen the expression of
full length pathogenic RAGE to halt the progression of diabetic nephropathy. It is
essential that new therapies, which have additive or synergistic actions to current
therpies used for diabetic kidney disease such as RAS blockers, are developed as
diabetic nephropathy continues to provide a significant socio-economic burden on the
community.
Expected future outcomes:
We anticipate that within the next stage of these studies, we will establish whether
activation of other AGE receptors such as AGE-R1, can produce more "good" soluble
RAGE facilitating improvements in kidey disease as the result of diabetes.
Name of contact: Josephine Forbes
NHMRC Research Achievements - SUMMARY
Email of contact: josephine.forbes@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 526685
CIA Name: Prof Mark Cooper
Main RFCD: Nephrology and Urology
Admin Inst: Baker IDI Heart and Diabetes Institute
Start Year: 2009
End Year: 2011
Total funding: $474,619.00
Grant Type: NHMRC Project
Grants
Title of research award:
Role of chromatin remodelling in diabetic renal and vascular complications: in vivo
studies
Lay Description (from application):
Even after diabetics return to improved blood glucose levels after a period of poor
blood glucose control, the kidney and blood vessel complications progress. The cause
of this metabolic memory remains unexplained. This proposal focuses on sustained
changes as a result of prior glucose levels in proteins called histones that are part of
the wrapping of DNA. Using a new technique called carrier ChIP we will study
histone modifications in the blood vessels and kidneys in diabetes.
Research achievements (from final report):
Diabetes is characterised by high blood sugar levels and elevated levels of certain
factors that result in blood vessel damage. This grant explores a phenomenon known
as metabolic memory where the effects of previous episodes of poor glycaemic
control have sustained deleterious effects on organs including blood vesselds in
diabetes. We have identified that a particular enzyme known as Set7 involved in
modification of proteins that wrap DNA in the nucleus called histones plays a central
role in conferring this memory. We explored the regulation of this enzyme in
response to glucose and showed how sugar promotes the shuttling of this enzyme
from the cytoplasm to the nucleus to methylate certain histones thus modulating
expression of genes encoding proteins implicated in the inflammation of blood vessels
as seen in diabetes. This work has now led to a combined genetic deletion and
pharmacological approach to explore if inhibiting this enzyme Set7 will lead to a
reduction in diabetic complications. This work has now been published in a number
of high impact journals and the prominence of this work is further reflected by
multiple international invitations to present this work as well as requests to write
reviews on this subject.
Expected future outcomes:
Our work has identified the critical role of the histone methyl transferase Set7 in
diabetic complications as well as conferring metabolic memory. This work has been
the impetus for considering this enzyme as a potential target for end-organ protective
therapies in diabetes.
Name of contact: Mark E Cooper
Email of contact: mark.cooper@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1040122
Start Year: 2011
CIA Name: Dr Celine Latouche
End Year: 2012
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding:
$74,973.00
Admin Inst: Baker IDI Heart and Diabetes Institute
Grant Type: International
Exchange Early Career
Fellowships
Title of research award:
Novel actions of HDL cholesterol: a potential new strategy for treatment of diabetes
Lay Description (from application):
There are currently in excess of 170 million patients diagnosed with type 2 diabetes
worldwide. Recent studies have identified novel actions of HDL cholesterol in
relation to glucose and fat metabolism which provide a rationale for therapeutic
approaches to raise levels of circulating HDL to manage the metabolic syndrome and
type 2 diabetes. This research will investigate HDL signaling pathways and contribute
significantly to our understanding of the metabolic actions of HDL in Humans.
Research achievements (from final report):
80% of individuals with type 2 diabetes mellitus will die of cardiovascular
complications, such as heart attack or stroke. There are currently approximately
500,000 Australians who have been diagnosed with type 2 diabetes and it is estimated
the same number of Australians remain undiagnosed. To further understand the
mechanisms of metabolic dysfunction in impaired glucose tolerance/impaired fasting
glucose and type 2 diabetes, people free of disease, pre-diabetics, or type 2 diabetics
have been recruited and subjected to a muscle biopsy.
Genes are made of a chemical called Deoxyribonucleic Acid, commonly known as
DNA. DNA is sometimes compared to a set of blueprints because it contains the
instructions for all the other components of cells. In this study, we investigated which
and how genes are switched on and off by factors unrelated to the DNA sequence
itself, especially short ribonucleic acid molecules called microRNA (this kind of study
is called epigenetics).
Our study highlights some of the regulated mechanisms during the progression of
diabetes. We have identified candidate genes, as well as potential microRNAs, which
are likely to contribute to the development of type 2 diabetes and represent potential
new targets for treatment.
Expected future outcomes:
Once identified the mechanisms involved in the progression of diabetes, we will
investigate the effectiveness of a number of drugs (or potential new drugs) which
target these mechanisms. We will also investigate the epigenetic changes that may
occur after treatment with the compounds in development.
Name of contact: Celine Latouche
Email of contact: celine.latouche@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 268928
CIA Name: A/Pr Peter Little
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Admin Inst: Baker IDI Heart and Diabetes Institute
Start Year: 2004
End Year: 2006
Total funding: $500,750.00
Grant Type: NHMRC Project
Grants
Title of research award:
Inhibition 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
NHMRC Research Achievements - SUMMARY
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 of contact: peter.little@baker.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 317810
CIA Name: A/Pr Dmitri Sviridov
Main RFCD: Medical Biochemistry: Lipids
Admin Inst: Baker IDI Heart and Diabetes Institute
Start Year: 2005
End Year: 2009
Total funding: $595,500.00
Grant Type: Established
Career Fellowships
Title of research award:
Uncoupled 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 of contact: Dmitri.Sviridov@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 526614
CIA Name: Prof Dmitri Sviridov
Main RFCD: Medical Biochemistry: Proteins and Peptides
Admin Inst: Baker IDI Heart and Diabetes Institute
Start Year: 2009
End Year: 2011
Total funding: $372,472.00
Grant Type: NHMRC Project
Grants
Title of research award:
Impact 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 of contact: Dmitri.Sviridov@Bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 367628
Start Year: 2006
CIA Name: Prof Peter Little
End Year: 2011
Main RFCD: Medical and Health Sciences not elsewhere classified
Total funding:
$639,194.00
Admin Inst: Baker IDI Heart and Diabetes Institute
Grant Type: Established
Career Fellowships
Title of research award:
Uncoupled 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 of contact: peter.little@rmit.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 431203
Start Year: 2007
CIA Name: A/Pr David Dunstan
End Year: 2009
Main RFCD: Public Health and Health Services not elsewhere classified
Total funding:
$334,955.00
Admin Inst: Baker IDI Heart and Diabetes Institute
Grant Type: NHMRC Project
Grants
Title of research award:
A behavioural intervention for the adoption & maintenance of physical activity in
type 2 diabetes
Lay Description (from application):
For people with type 2 diabetes (T2DM) it is essential that blood glucose levels are
managed well to reduce the risk of developing complications. Physical activity is
essential for maintaining glucose levels because it helps make the muscles use glucose
more effectively. In particular, being active through strength training not only
improves blood glucose levels, but can be very effective for maintaining good
physical functioning, which is known to be reduced by having T2DM. This study
builds on our earlier research which demonstrated significantly improved blood
glucose levels from a strength training program for older adults with T2DM. The
strength training program is to be administered nationally in a research to practice
trial (Lift for Life); however, the original research found that those who did not
complete the program as it was intended (ie, poor adherence) did not show significant
improvements in blood glucose levels. Furthermore, maintenance of strength training
exercises after completion of the program was poor and resulted in return of blood
glucose levels back to pre-starting levels. In people without diabetes, we have
collected pilot data that shows that the use of behavioural strategies based on
behavioural theories whereby each person's motivations and barriers are taken into
consideration is more effective than the traditional one-treatment-fits-all approach.
This study will evaluate the effectiveness of using behavioural strategies for
improving adherence and maintenance to the Lift for Life strength training program
(Enhanced L4L) for older adults with T2DM compared with the Standard L4L
program. It will also follow-up participants 6 months later to determine the extent to
which the changes in behaviour can be maintained. The study will provide
information that will assist in the design, delivery and uptake of programs to improve
treatment strategies in older adults with T2DM through the maintenance of healthier
behaviours and lifestyles.
Research achievements (from final report):
The project has successfully recruited a large community-based sample of 318 older
adults with or at risk of developing type 2 diabetes to establish the impact of adding
regular motivational strategies (including telephone counselling) to a national strength
training program (Lift for Life) on program adoption and maintenance compared to
the existing standard Lift for Life program (ie: without motivational strategies). A
major achievement has been the excellent retention rates during the 6-month
intervention and 6-month follow-up phases, with more than 80% of the participants
completing the 12-month study. The project is the largest study of its kind in the
world to have investigated the effects of strength training in the 'real-world' setting in
people with or at risk of developing type 2 diabetes. It will provide new insights into
NHMRC Research Achievements - SUMMARY
the success of various proven motivational strategies to encourage people to not only
'start-up' their strength training program within local community facilities, but also
whether the addition of these strategies helps people to maintain their strength training
by themselves once the initial intervention has been completed. Additionally, the
effects of the Lift for Life program, both with and without motivational strategies, on
muscle strength and blood glucose levels will be examined.
Expected future outcomes:
The project provides new evidence that will assist in the design, delivery and uptake
of community-based physical activity programs and the maintenance of healthier
behaviours and lifestyles in older adults with or at risk of developing type 2 diabetes.
Name of contact: David Dunstan
Email of contact: David.Dunstan@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 244622
CIA Name: Dr Karen Andrews
Main RFCD: Endocrinology
Admin Inst: Baker IDI Heart and Diabetes Institute
Start Year: 2003
End Year: 2007
Total funding: $267,150.00
Grant Type: Early Career
Fellowships (Australia)
Title of research award:
Endothelial 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 of contact: karen.andrews@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 367629
CIA Name: Prof Bronwyn Kingwell
Main RFCD: Clinical Sciences not elsewhere classified
Admin Inst: Baker IDI Heart and Diabetes Institute
Start Year: 2006
End Year: 2008
Total funding: $357,250.00
Grant Type: Established
Career Fellowships
Title of research award:
Uncoupled 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 of contact: bronwyn.kingwell@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 526663
CIA Name: Prof Mark Cooper
Main RFCD: Nephrology and Urology
Admin Inst: Baker IDI Heart and Diabetes Institute
Start Year: 2009
End Year: 2011
Total funding: $490,202.00
Grant Type: NHMRC Project
Grants
Title of research award:
Growth factors and their effect on microRNAs and transcription factors in
tubulointerstitial fibrosis in diabetes
Lay Description (from application):
A common cause of kidney disease is diabetes and is partly related to increased
expression and action of growth factors such as CTGF. These factors promote the
deposition of scar tissue in the kidney by acting on a novel class of intracellular
regulator molecules called microRNAs, to change the cell's characteristics such that
cells begin laying down excess collagen. This proposal will focus on how growth
factors act on microRNAs and the role of microRNAs in diabetic kidney disease.
Research achievements (from final report):
Diabetes is characterised by high blood sugar levels and elevated levels of certain
factors that result in kidney damage. The most important of these factors is TGF-β1.
The combination of these factors cause the production and accumulation of excess
collagen in the kidney resulting in scaring of the kidney and loss of kidney function.
In our studies we have made several important discoveries that have changed the way
we think of the development of kidney damage that occurs in diabetes.
We have found that TGF-β1 causes a significant decrease in the level of certain
members of a family of small RNA molecules called microRNAs. These molecules
are known to important in normal physiology and disease condition like kidney
scarring. We demonstrated in different experimental diabetes models that
microRNAs-192/214, the microRNA-200 and the microRNA-29 families are all
decreased in the kidney and in kidney cell lines. The result of the decreased levels of
these microRNAs results in elevated synthesis and accumulation of collagens and
other proteins that contribute to scarring and loss of kidney function. Our experiments
have demonstrated that restoring expression of these microRNAs reverses the damage
by preventing the synthesis of collagen by kidney cells and reducing the accumulation
of collagen in the kidney. This work has now been published in 5 papers and another
2 manuscripts are aboout to be submitted for publication.
Expected future outcomes:
Our work has identified the use of microRNAs as a possible alternative treatment
option for dealing with diabetic kidney fibrosis in diabetic patients. Whilst some
hurdles remain as to how to deliver this treatment clinically, a major global effort is
underway to overcome these obstacles.
Name of contact: Mark E Cooper
Email of contact: mark.cooper@bakerdid.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 540107
Start Year: 2009
CIA Name: Prof David Dunstan
End Year: 2012
Main RFCD: Public Health and Health Services not elsewhere classified
Total funding:
$416,597.00
Admin Inst: Baker IDI Heart and Diabetes Institute
Grant Type: NHMRC Project
Grants
Title of research award:
Understanding the acute and cumulative metabolic effects of prolonged sitting in
adults
Lay Description (from application):
Sedentary behaviour (sitting time) has been linked to an increased risk of chronic
illnesses, including type 2 diabetes and obesity, but recent evidence suggests that
light-intensity activity (non-exercise activities of daily living) is associated with
reduced risk. These studies will examine whether breaking up sitting time with
frequent short periods of activity can overcome the negative effects of prolonged
sitting on blood glucose and blood fats in overweight older adults.
Research achievements (from final report):
It is well known that being physically active is important for maintaining good health.
However, evidence has emerged showing that sedentary time (sitting for prolonged
periods) is adversely associated with indicators of poor health (eg. elevated blood
glucose and blood triglycerides), even in the presence of meeting physical activity
guidelines. Observational evidence suggests that the manner in which sedentary time
is accumulated may also be important, since people who break up their sitting time
throughout the day have lower levels of risk markers of diabetes and cardiovascular
disease (eg. blood glucose, insulin and triglycerides) than people who sit for
prolonged periods without activity breaks. This research involved the first ever
clinical study to examine the extent to which interruptions to prolonged sitting
influences metabolic outcomes. In a supervised laboratory setting, this study found
that interrupting a 5 hour period of prolonged sitting with frequent short (2 mins)
bouts of light- or moderate-intensity walking activity every 20 mins reduced
elevations in blood glucose and insulin levels (two risk factors for diabetes) when
compared with prolonged sitting. Furthermore, the effect of the light-intensity
activity breaks was comparable to the moderate-intensity physical activity breaks, the
activity intensity level that is the current focus of public health messages. This
suggests that interrupting sitting time, even with gentle walking, may be useful to
prevent the negative consequences of prolonged sitting.
Expected future outcomes:
We are currently in the process of analysing the data collected from the second study
undertaken as part of this project grant that examined whether prolonged sitting after
repeated days worsened metabolic outcomes and whether this is attenuated by
incorporating intemittent short bouts of light-intensity walking activity.
NHMRC Research Achievements - SUMMARY
Name of contact: David Dunstan
Email of contact: david.dunstan@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 431200
CIA Name: Dr Jeremy Jowett
Main RFCD: Endocrinology
Admin Inst: Baker IDI Heart and Diabetes Institute
Start Year: 2007
End Year: 2009
Total funding: $558,920.00
Grant Type: NHMRC Project
Grants
Title of research award:
Identification of Novel Genes Influencing Development of Type 2 Diabetes
Lay Description (from application):
Type 2 diabetes is usually associated with obesity and is often part of a wider
disturbance affecting an individual's energy metabolism. The number of affected
people with type 2 diabetes has trebled since 1981 in Australia and is still increasing.
Apart from individual suffering, this presents a major public health burden for the
country (approx $3 billion annually). Currently available lifestyle based and
pharmaceutical therapies are inadequate to control the increasing numbers of affected
individuals. Unfortunately the cause of disease is poorly understood, although genetic
factors are known to be important, in other words it "runs in the family". This project
proposes to identify some of these factors (genes) and how they contribute to the
disease. Using "molecular flags" on the DNA (like DNA fingerprinting) we have
previously found that a small region on chromosome 12 is likely to carry one or more
of these disease genes. But there are over 100 genes in the region. To help choose the
most likely candidates first for testing, we have developed an automated computer
database searching program ranked the genes based on what is already known about
them. We have also taken a large number of physiological measures in a large group
of people. Some of these measures are controlled by the same chromosome 12 region
- thus to improve our chances of finding the genes quickly we will look at those that
change the most between people with diabetes and people without diabetes. In this
project we shall investigate the 20 genes most likely affect diabetes based on changes
in physiological measures and what is already known about them.A successful finding
means we will know more about the mechanism of disease development and be able
to better develop new therapies for treatment and prevention. If none of these genes
are the culprit, we would continue examination of the next set of genes likely to be
involved and so on until we are successful.
Research achievements (from final report):
Type 2 diabetes is associated with obesity and is part of a wider disturbance affecting
an individual's energy metabolism. The number of affected people with type 2
diabetes has trebled since 1981 in Australia and is still increasing. Currently available
lifestyle based and pharmaceutical therapies are inadequate to control the increasing
numbers of affected individuals.
Unfortunately the cause of disease is poorly understood, although genetic factors are
known to be important, in other words it "runs in the family". In this project we
sought to dramatically improve our understanding of these factors (genes) and how
they contribute to the disease. We examined over 2,000 variations in over 100 genes
using our advanced lab technology and tested for whether they contribute to type
NHMRC Research Achievements - SUMMARY
diabetes. We were able to see some suggestions that new genes were involved,
however stronger scientific evidence is needed.
The main impediment was the unexpectedly high level of natural variation in human
genes, and this project has taught us that despite using state of the art technology in
2007, this would not appear to be sufficient for the task. Fortunately the project has
allowed us to successfully complete the first test and proof of principle experiments of
an even newer technology that can find and catalog variation far more efficiently and
cost-effectively than previously possible. We have applied for further funding to carry
this important work forward into the next exciting stage that may reveal the genes,
and lay the foundations for new drugs and personalised medicine.
Expected future outcomes:
Our results and those from others on genetic studies to date show that the best
possible approach for gene discovery is in combining new sequencing technology
with family cohorts. We propose to do exactly that in our new application to improve
understanding of disease mechanism for new treatments in the future.
Name of contact: Dr Jeremy Jowett
Email of contact: jeremy.jowett@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 317832
CIA Name: Prof Mark Cooper
Main RFCD: Endocrinology
Admin Inst: Baker IDI Heart and Diabetes Institute
Start Year: 2005
End Year: 2007
Total funding: $453,750.00
Grant Type: NHMRC Project
Grants
Title of research award:
Understanding 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 withinkidney 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 submaximal. 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.
NHMRC Research Achievements - SUMMARY
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 of contact: mark.cooper@baker.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 367625
CIA Name: A/Pr Merlin Thomas
Main RFCD: Nephrology and Urology
Admin Inst: Baker IDI Heart and Diabetes Institute
Start Year: 2006
End Year: 2008
Total funding: $297,523.00
Grant Type: NHMRC Project
Grants
Title of research award:
Circulating 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.
NHMRC Research Achievements - SUMMARY
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 of contact: mthomas@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 367660
CIA Name: Dr Anna Calkin
Main RFCD: Endocrinology
Admin Inst: Baker IDI Heart and Diabetes Institute
Start Year: 2006
End Year: 2012
Total funding: $241,125.00
Grant Type: Early Career
Fellowships (Australia)
Title of research award:
Diabetes-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 non-diabetic
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 of contact: acalkin@mednet.ucla.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 472638
CIA Name: Prof Mark Cooper
Main RFCD: Nephrology and Urology
Admin Inst: Baker IDI Heart and Diabetes Institute
Start Year: 2008
End Year: 2010
Total funding: $483,737.00
Grant Type: NHMRC Project
Grants
Title of research award:
Pathogenic role of CDA1 via its profibrotic action in diabetic nephropathy
Lay Description (from application):
We cloned a CDA1 several years ago and found that it played a major role in
controlling a series of molecular events leading to production and accumulation of
extracellular matrix causing scarring, as seen in diabetic nephropathy. This project
aims to study the biological functions and molecular mechanisms of CDA1 in the
context of diabetic nephropathy, hence allowing us to consider CDA1 as a molecular
target for drug development to treat this condition and related complications.
Research achievements (from final report):
TGF-beta is the key growth factor known to regulate kidney fibrosis in diabetic
nephropathy. We have established the pathological role for CDA1 in promoting the
profibrotic effect of TGF-beta in human proximal tubule cells and in experimental
diabetic as well as non-diabetic nephropathy animal models. We have also identified
an interacting protein for CDA1 (CDA1BP1) and developed several novel short
peptides targeting the CDA1/CDA1BP1 interaction, which is preliminarily shown to
inhibit the profibrotic effect of CDA1 and TGF-beta in cells.
Major findings:
1. Elevation of CDA1 expression levels in two diabetic nephropathy animal models
(SHR and ApoE-/- mice), and interestingly in another non-diabetic model of renal
fibrosis, ischemia/reperfusion injury in both rat and mouse.
2.
Adenoviral delivered CDA1 over-expression robustly enhanced, and retroviral
delivered siRNA knockdown of CDA1 attenuated, TGF-β mediated SMAD signaling
and expression of collagen I and III, as well as other genes including CTGF,
fibronectin and collagen IV.
3.
CDA1BP1, a putative receptor for CDA1, has been identified and appears to
enhance the profibrotic effect of CDA1 in HK-2 cells.
4.
N-, but not C-terminal amino acid residues expanding from the core 6-amino
acid binding site in CDA1BP1 are contributing to protein-protein binding.
5.
Several short peptide designed based on the above findings were shown to
interrupt CDA1/CDA1BP1 interaction in a cell free binding assay. These peptides
were further modified allowing them to enter cells, and inhibited expression of
collagen I and III genes in human proximal tubule cells, HK-2, when added to the
cultured cells.
Expected future outcomes:
We have now generated a CDA1 KO mouse being used to validate CDA1 in DN in
vivo. The newly developed short peptide will further provide validation for CDA1,
ultimately leading to novel therapies for kidney diseases associated with fibrosis such
as DN.
NHMRC Research Achievements - SUMMARY
Name of contact: Mark E Cooper
Email of contact: mark.cooper@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 367652
CIA Name: Prof Merlin Thomas
Main RFCD: Medical Biochemistry: Carbohydrates
Admin Inst: Baker IDI Heart and Diabetes Institute
Start Year: 2006
End Year: 2010
Total funding: $390,260.00
Grant Type: Career
Development Fellowships
Title of research award:
Circulating AGEs; markers and mediators of renal injury in diabetes.
Lay Description (from application):
Not Available
Research achievements (from final report):
Diabetes is the single most common cause of kidney disease in the Australia.
Although a number of factors operate in diabetes, one pivotal pathway appears to be
the formation and accumulation of advanced glycation end products (AGEs). My
research has characterized the role of AGEs in kidney disease associated with diabetes
and hypertension, as well as their impact in cardiovascular complications associated
with these diseases. This research has demonstrated the pivotal role of AGEs in these
complications and the potential utility of targeting them in the prevention of diabetic
complications. This grant has examined novel ways of measuring their accumulation.
In this work, I have described 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. 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. In particular, I have shown
that their ability to activate specific receptors is able to activate a range of pathogenic
pathways, and in the absence of these receptors, complication may not only be
prevented, but potentially detrimental stimuli (like fat and high glucose) can be
transformed into protective mediators. 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. .
Expected future outcomes:
It is anticipated that a better understanding of AGEs 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
products and their detrimental effects on human health.
Name of contact: Prof Merlin Thomas
Email of contact: mthomas@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 586655
CIA Name: A/Pr Barbora de Courten
Main RFCD: Metabolic Medicine
Admin Inst: Baker IDI Heart and Diabetes Institute
Start Year: 2010
End Year: 2012
Total funding: $240,931.00
Grant Type: NHMRC Project
Grants
Title of research award:
Will a reduction in dietary AGEs improve insulin sensitivity and secretion in
overweight individuals?
Lay Description (from application):
Advanced Gycation end-products (AGE) are formed when foods brown during
heating, processing or long term storage. This study will examine the AGE content of
a typical Australian diet. Also, an intervention study will be undertaken to determine
whether an 75% reduction in AGE intake can reduce blood markers of chronic
inflammation, improve insulin secretion and action and thus reduce diabetes and heart
disease risk.
Research achievements (from final report):
The high AGE diet reduced insulin sensitivity by -1.06 mg/kg/min (95% CI,-2.01 to 0.11;p=0.03) while the low AGE diet improved insulin sensitivity by +0.98
mg/kg/min (+0.11 to +1.84; p=0.03). The overall change in insulin sensitivity was
2.04 mg/kg/min (0.99 to 3.08, p=0.001) compared to baseline. Insulin secretion
showed a trend to increase during the high AGE diet (9 mU/l) whereas the low AGE
diet somewhat reduced insulin secretion (-15 mU/l) (both p=ns) with a net difference
between the two diets of 23 mU/l. An association between a change insulin secretion
and change in plasma AGE (CML) concentrations was also seen (r=-0.51, p=0.02).
The diets had no significant effects on any of the AGE parameters tested (ie urinary or
serum AGEs, soluble RAGE, esRAGE plasma concentrations , the expression of
RAGE on PBMC and AGE receptor 1 on PBMC . However, there was a significant
change in AGE-R1 expression on CD14+ monocytes and macrophages following the
high and low AGE diet (p=0.04) in a subset of the study population (n=7) where this
measurement was available.
The diets had no significant effects on any of the plasma inflammation parameters (ie
TNFα, hs-CRP, NF-κB, MCP-1).
Our data support the hypothesis that consuming a diet high in AGE content may
contribute to the development of type 2 diabetes in susceptible populations such as
overweight and obese individuals. In addition, a diet low in AGEs is protective.
Specifically, a 2-week consumption of a high and low AGE diet was able to modulate
insulin sensitivity. The trends for a change in insulin secretion likely represent, at
least in part, a compensation for the changes in insulin sensitivity.
Expected future outcomes:
Future studies are warranted to both explore the mechanisms by which AGEs
influence insulin sensitivity and secretion and to examine the effects dietary AGE
interventions of longer duration in large-scale trials.
Name of contact: Barbora De Courten
NHMRC Research Achievements - SUMMARY
Email of contact: Barbora.deCourten@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 526656
CIA Name: Dr Judy de Haan
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Admin Inst: Baker IDI Heart and Diabetes Institute
Start Year: 2009
End Year: 2011
Total funding: $358,319.00
Grant Type: NHMRC Project
Grants
Title of research award:
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 diabetes-asociated
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
NHMRC Research Achievements - SUMMARY
Email of contact: judy.dehaan@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 268900
CIA Name: Prof Bronwyn Kingwell
Main RFCD: Endocrinology
Admin Inst: Baker IDI Heart and Diabetes Institute
Start Year: 2004
End Year: 2006
Total funding: $283,500.00
Grant Type: NHMRC Project
Grants
Title of research award:
A novel mechanism for manipulation of peripheral glucose utilization in patients with
type 2 diabetes mellitus.
Lay Description (from application):
Significance: Over 600,000 Australians have type 2 diabetes (approximately half are
undiagnosed) and it is estimated that this number will increase substantially to 10% of
the adult population over the next 10 years. At the conclusion of this grant we expect
to understand whether specific signalling molecules might plausibly represent the
basis of a novel therapeutic approach to control blood glucose. If successful, this
work could contribute to improved metabolic control and prevention of diabetic
complications through new blood glucose lowering agents. Hypotheses: Muscle is the
major site of glucose disposal in the body and the two most relevant stimuli for
glucose uptake into muscle are insulin and muscle contraction (exercise). The insulin
pathway is impaired in patients with type 2 diabetes leading to high blood glucose and
complications. Glucose uptake in response to exercise however appears to be normal
in patients with type 2 diabetes. Indeed we have evidence to suggest that this
pathway may compensate for impaired insulin action in type 2 diabetes. We
hypothesise that molecules activated by contraction (exercise) may be useful as
therapies to improve resting glucose control in type 2 diabetic patients. Aims: We
plan a series of three studies to examine whether glucose uptake may be improved
both acutely and chronically at rest by an agent implicated in exercise mediated
glucose uptake.
Research achievements (from final report):
Excess glucose in the blood stream, as occurs in diabetes causes blood vessel damage
which ultimately leads to serious complications in the kidneys, eyes, peripheral blood
vessels and most importantly, the heart. Insulin removes glucose from the blood into
metabolically active tissues including muscle where it can be used as a fuel source.
Recent research has shown that exercise also causes movement of glucose from the
blood into muscle, but via a mechanism which does not involve insulin and may
involve the molecule nitric oxide (NO). The aim of this project was to determine
whether NO donor drugs could represent a new therapeutic approach to the treatment
of diabetes through simulation of the effects of exercise. We have shown that acute
administration of the NO donor drug, sodium nitroprusside increases glucose uptake
into the leg muscle under resting conditions. We expanded this study to examine the
effects of chronic NO administration on glucose metabolism. This involved an initial
pilot investigation to determine which of two nitrate drugs was the best NO donor.
The data from this study suggested that chronic nitrate therapy did not influence
glucose metabolism. Concurrent research within the lab however suggested that good
(HDL) cholesterol may play an important role in glucose and fat metabolism. We
pursued this observation and now have convincing data that HDL increases glucose
uptake and stimulates fat metabolism in cells derived from human muscle. Our
NHMRC Research Achievements - SUMMARY
findings offer a common molecular mechanism explaining the role of low HDL levels
in diabetes and provide a rationale for designing therapies to raise levels of circulating
HDL to address the metabolic syndrome, type 2 diabetes mellitus and obesity.
Expected future outcomes:
Our finding that HDL stimualtes glucose and fat metabolism is being pursued in a
proof of concept clinical trial. If successful, these studies will support a unified
concept describing the aetiology of the metabolic syndrome, and provide a rationale
for therapeutic approaches to raise levels of circulating HDL to manage the metabolic
syndrome, type 2 diabetes mellitus (DM) and obesit
Name of contact: A/Prof Bronwyn Kingwell
Email of contact: bronwyn.kingwell@baker.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 268916
CIA Name: A/Pr Josephine Forbes
Main RFCD: Endocrinology
Admin Inst: Baker IDI Heart and Diabetes Institute
Start Year: 2004
End Year: 2006
Total funding: $431,700.00
Grant Type: NHMRC Project
Grants
Title of research award:
Interactions 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
NHMRC Research Achievements - SUMMARY
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: Josephine Forbes
Email of contact: josephine.forbes@baker.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 511217
CIA Name: Prof Jenny Doust
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Admin Inst: Bond University
Start Year: 2008
End Year: 2012
Total funding: $499,199.00
Grant Type: NHMRC
Strategic Awards
Title of research award:
Implementation 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 overprediction of risk by the Framingham risk equation in recent populations, and recalibration 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
NHMRC Research Achievements - SUMMARY
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 of contact: jdoust@bond.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 520316
CIA Name: Dr Allison Hodge
Main RFCD: Epidemiology
Admin Inst: Cancer Council Victoria
Start Year: 2008
End Year: 2011
Total funding: $304,002.00
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 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 of contact: allison.hodge@cancervic.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 590218
CIA Name: Dr Mohamed Dirani
Main RFCD: Epidemiology
Admin Inst: Centre for Eye Research Australia Ltd
Start Year: 2010
End Year: 2011
Total funding: $109,415.00
Grant Type: Early Career
Fellowships (Australia)
Title of research award:
Identifying the predictors for poor diabetes care and diabetic retinopathy in adults
with type 1 and 2 diabetes
Lay Description (from application):
Diabetes affects 1 million Australians, with 50% of cases still undiagnosed. Diabetes
has associated problems, such as heart failure and sight-threatening eye disease.
Studying patients with diabetes will identify the factors contributing to poor diabetes
care and diabetic eye disease. We also intend to use eye imaging to predict the
development of poor diabetes care and diabetic eye disease. We can then use
preventive measures to reduce the problems associated with diabetes, such as
blindness.
Research achievements (from final report):
Not Available
Expected future outcomes:
My work provides
Name of contact: A/Prof Ecosse Lamoureux
Email of contact: ecosse@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1016698
CIA Name: Dr Ryo Kawasaki
Main RFCD: Ophthalmology
Admin Inst: Centre for Eye Research Australia Ltd
Start Year: 2011
End Year: 2012
Total funding: $107,169.00
Grant Type: Early Career
Fellowships (Australia)
Title of research award:
Novel morphological retinal vascular features as early biomarkers of visionthreatening eye diseases.
Lay Description (from application):
Vision loss is not just a personal health burden, but a huge socio-economical burden.
Management of major vision-threatening eye diseases such as diabetic retinopathy,
age-related macular degeneration and glaucoma will be improved if we can
successfully identified persons at risk of developing the disease before clinical
presentation to benefit from preventive treatment. My research aims to contribute to
the prediction of these blinding diseases using advanced computer imaging analysis
for simple retinal photographs.
Research achievements (from final report):
My research involved clinical data from large population-based cohort studies to
investigate the retinal vascular risk characteristics associated with vision-threatening
eye diseases. I used clinical and epidemiological data collected from population-based
cohorot studies (e.g., the Blue Mountains Eye Study and AusDiab Study), and clinical
study data (e.g., Diabetic Retinopathy Cohort, the Japan Diabetes Complications
Study, Singapore Multi-ethnic cohorts, and Royal Victorian Eye and Ear Hospital
patient database) to address 4 major topics related to my aims. Major results and
findings from this work were:
1. Retinal vascular characteristics associated with ocular diseases;
2. Epidemiology of vision-thretening ocular diseases;
3. Developing new retinal vascular imaging; and
4. Retinal vascular imaging associated with systemic diseases.
Potential benefit of this fellowship can be summarized as (1) identification of new
risk factors for diabetic retinopathy (apolipoprotein subfraction, fruits intake etc.), (2)
potential of retinal vessel signs as a surrogate marker of progression of ocular and
systemic diseases, and (3) development of new retinal vascular imaging system with
standardized and quantitateive parameters.
Expected future outcomes:
Based on newly identified risk characteristcs, more precise risk prediction models for
sight thretening eye diseases such as diabetic retinopathy and age-related maculopathy
will be developed. Automated image grading system to help improve risk prediction
models will be developed in ocular and systemic cardiovascular risk evaluation.
Name of contact: Ryo Kawasaki
Email of contact: rkaw@unimelb.edu.au / rkawasaki@gmail.com
NHMRC Research Achievements - SUMMARY
Grant ID: 475605
CIA Name: Prof Tien Wong
Main RFCD: Endocrinology
Admin Inst: Centre for Eye Research Australia Ltd
Start Year: 2008
End Year: 2010
Total funding: $396,818.00
Grant Type: NHMRC Project
Grants
Title of research award:
Prediction 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 of contact: twong@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 455241
CIA Name: Prof Bernard Tuch
Main RFCD: Endocrinology
Admin Inst: CSIRO Division of Human Nutrition
Start Year: 2011
End Year: 2011
Total funding: $763,317.00
Grant Type: NHMRC Project
Grants
Title of research award:
Xenotransplantation of encapsulated insulin-producing pig cells
Lay Description (from application):
The ideal treatment for insulin-dependent diabetes is the replacement of insulinproducing cells. Currently, this is carried out using a whole pancreas or
experimentally with cells isolated from the pancreas of donor humans. Despite the
success of these procedures, demand for human organs far exceeds supply, thus
driving the search for suitable alternatives. Pigs are physiologically similar to humans,
and insulin-producing cells can be easily isolated from the fetal pig pancreas as isletlike cell clusters; 8% of the cells in the cluster produce insulin and the remaining cells
develop this capability after transplantation. Transplantation requires chronic
immunosuppression with drugs which increase the risk of infection and cancer. To
many people with diabetes, the side effects will be greater than the potential benefit.
Placing cells inside microcapsules made of a biologically inert material may prevent
graft rejection without chronic immunosuppression. The Investigators have
demonstrated that encapsulated insulin-producing pig cells survive and function when
transplanted into diabetic immunodeficient mice, but not when xenografted into
immunocompetent mice. It is hypothesised that this is due to an immunological or
inflammatory response by the host in response to the shedding of molecules by the
encapsulated pig cells. A pre-clinical model to test the efficacy of encapsulated
insulin-producing pig cells is the humanized mouse. It is hypothesized that transient
administration of anti-rejection drugs will be needed to allow the survival of pig cells
xenografted into these mice and normalization of BGL once diabetes has been
induced.The aims of this study are: 1. To assess the nature of the host response when
encapsulated insulin-producing fetal pig cells are transplanted into diabetic BALB/c
mice. 2. To normalize blood glucose levels (BGL) in diabetic humanized mice
transplanted with encapsulated insulin-producing fetal pig cells.
Research achievements (from final report):
Xenotransplantation in the context of treating diabetes in humans requires the
transplantation of animal insulin-producing cells into humans who would normally
administer insulin multiple times each day to stay alive. Placing the pig cells inside
microcapsules made of a product from seaweed was a way of preventing the immune
system of the recipient from recognizing the pig cells as foreign and destroying the
graft.
A mouse recipient model was used to simulate what might occur in human recipients
of porcine tissue.
Within 7 days of mice receiving pig cells, an inflammatory response was observed
around the outside of the microcapsules, with resultant death of the cells inside.
Several strategies were adopted to try and overcome this fibrotic reaction, with human
tissue being substituted for the pig cells, when pig tissue became difficult to obtain.
The only strategy that reduced the inflammatory response was mixing adult rodent
NHMRC Research Achievements - SUMMARY
stem cells, which have anti-inflammatory properties, with the encapsulated insulinproducing cells. Adult human stem cells with anti-inflammatory properties were
unhelpful. Inhibiting activation of immune cells, with genetically modified mice,
showed no benefit. Coating the surface of the microcapsules with the antiinflammatory agent, heparin, also was unsuccessful, although this strategy did reduce
the inflammation observed in rodents transplanted with rodent insulin-producing cells.
Expected future outcomes:
It is expected that strategies to prevent the fibrotic reaction observed when
encapsulated cells are xenografted will be improved, such that the inflammation
observed previously will be prevented, thereby allowing the insulin-producing cells to
function and normalize blood glucose levels.
Name of contact: Dr Bernie Tuch
Email of contact: bernie.tuch@csiro.au
NHMRC Research Achievements - SUMMARY
Grant ID: 229030
CIA Name: Dr Spencer PROCTOR
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Admin Inst: Curtin University of Technology
Start Year: 2003
End Year: 2004
Total funding: $174,288.00
Grant Type: Early Career
Fellowships (Overseas)
Title of research award:
To 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 of contact: spencer.proctor@ualberta.ca
NHMRC Research Achievements - SUMMARY
Grant ID: 400446
CIA Name: Dr Sean McGee
Main RFCD: Neurology and Neuromuscular Diseases
Admin Inst: Deakin University
Start Year: 2006
End Year: 2009
Total funding: $276,750.00
Grant Type: Early Career
Fellowships (Australia)
Title of research award:
Molecular mechanisms mediating contraction-induced metabolic gene expression and
Lay Description (from application):
Not Available
Research achievements (from final report):
This work culminated in discovering a novel signaling cascade involving the AMP
activated protein kinase and histone deacetylase 5 (HDAC5). This signalling
pathways regulates skeletal muscle metabolism by controlling the expression of a
range of genes involved in substrate handling and oxidation. This pathway is activated
by physiological stimuli such as exercise and is conversely dysregulated in disease
states, such as type 2 diabetes. Importantly, this work also showed that inhibitors of
HDAC5 were therefore able to normalise skeletal muscle metabolism in disease states
such as type 2 diabetes. These data highlight that the AMPK-HDAC5 signalling
pathway could be a therapeutic target to combat metabolic disease.
Expected future outcomes:
We expect to find new compounds and small molecules that can be manipulated to
target this siganlling pathway to provide more efficacious treatments for metabolic
diseases like type 2 diabetes.
Name of contact: Sean Mcgee
Email of contact: sean.mcgee@deakin.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 323519
CIA Name: Dr Sarah McNaughton
Main RFCD: Nutrition and Dietetics
Admin Inst: Deakin University
Start Year: 2005
End Year: 2009
Total funding: $275,438.00
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.
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 lifecourse. 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 of contact: sarah.mcnaughton@deakin.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 533824
CIA Name: Dr Juan Carlos Molero-Navajas
Main RFCD: Cell Metabolism
Admin Inst: Deakin University
Start Year: 2009
End Year: 2011
Total funding: $341,884.00
Grant Type: NHMRC Project
Grants
Title of research award:
Transcription-based identification of Insulin Resistance Subtypes
Lay Description (from application):
A key feature of type 2 diabetes is the failure of metabolic tissues such as muscle and
fat to respond to normal levels of insulin. This 'insulin resistance' is caused by a
number of mechanisms. We will use cutting-edge technology to identify small sets of
genes that define each variety of insulin resistance. These gene sets will be used to
diagnose sub-types of insulin resistance and will facilitate the development of
personalised therapies to effectively treat individuals with type 2 diabetes.
Research achievements (from final report):
Presently, there are significant challenges to finding effective therapies for the longterm management of type 2 diabetes. We investigated the hypothesis that insulin
resistance represents a multifactorial series of disorders, in order to target treatment of
individuals according to their subtype(s) of insulin resistance (a personalised medicine
approach to type 2 diabetes). Using a novel, unbiased genomics-based approach to
identify a 'fingerprint' of an individual's biological state, known as a Gene Expression
Signature (GES), we generated and published the first GES based on excess
inflammation (Physiological Genomics, 2011), which we subsequently used as a
screening tool to identify a new anti-diabetic compound (Diabetes, 2012) that is
currently in clinical trials (Verva Pharmaceuticals). Advantage of GESs is that they
provide a global snapshot of the integrated response to an insult, irrespective of the
complexity and interplay involved. We have generated and identified an additonal 3
GESs based on 3 different causes of insulin resistance (excess fat, glucocorticoid or
ER stress), which are being validated in a human cohort to determine if the GESs can
identify insulin resistant subtypes in individuals. Futhermore, we investigated the
functional significance of selected GES genes and our findings highlight an additional
unforseen utility of the GES approach; the potential identification of novel diabetes
candidates. Additionally, pathway analysis has been completed on all 4 models of
insulin resistance to identify the pathways being altered and our findings, coupled
with the identity of the 4 GESs, demonstrate that therapies for type 2 diabetes need to
be individualised.
Expected future outcomes:
Our findings show that GES technology can be used for both the discovery of antidiabetic compounds and the characterisation of patients into subtypes of insulin
resistance, opening the potential to develop optimised medical treatments (i.e.,
personalising medicine) for patients with type 2 diabetes.
Name of contact: Nicky Konstantopoulos
Email of contact: nicky.konstantopoulos@deakin.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 425865
CIA Name: Dr Nicole Stupka
Main RFCD: Cell Physiology
Admin Inst: Deakin University
Start Year: 2007
End Year: 2011
Total funding: $299,189.00
Grant Type: Early Career
Fellowships (Australia)
Title of research award:
Type 2 diabetes and ageing-associated muscle atrophy: role of oxidative stress and
redox sensitive signalling pathways
Lay Description (from application):
Not Available
Research achievements (from final report):
This postdoctoral fellowship enabled me to further my research interests into the
cellular mechanisms in skeletal muscle which promote adaptation to stress and
enhance repair in order to improve tissue structure, function and metabolism. During
the course of the fellowship, I established and developed an independent research
program which is focused on the following two themes:
(1)
To investigate the consequences of nutrient excess on oxidative and
endoplasmic reticulum stress responses in muscle cells, and to characterize the
functional role of a novel selenoprotein (SEPS1) and the thioredoxin antioxidant
system in regulating these responses. SEPS1 and the endogenous inhibitor of the
thioredoxin antioxidant system (TBP-2) are associated with insulin resistance in vivo
and their expression can be dysregulated by excessive nutrients.
(2)
To examine the role of secreted ADAMTS proteinases in connective tissue
remodelling during skeletal muscle repair, and to test the potential of ADAMTS
proteinases as therapeutic targets for muscular dystrophy. There are no effective
therapeutic strategies to prevent or treat fibrosis in muscular dystrophy and
appropriate connective tissue remodelling is essential to prevent scaring and fibrosis
and help maintain functional muscle mass.
I am continuing to grow this research program in my new role as a Lecturer in
Medical Physiology in the School of Medicine, Deakin University.
I have also maintained a productive, cross-disciplinary collaboration with the
Department of Chemistryto develop and validate novel approaches to measure cellular
redox state (e.g. glutathione), and to test the antioxidant potential of biological
compounds in various muscle cell culture systems.
Expected future outcomes:
The fellowship was disrupted by maternity leave and at the conclusion of the
fellowship I began a new role as a Lecturer in Medical Physiology, there is a need to
publish the latter half of my postdoctoral research. The aim for 2012 is to begin work
to validate cell culture findings in transgenic animal models.
Name of contact: Nicole Stupka
Email of contact: nstupka@deakin.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 219125
CIA Name: Prof Neil Thomson
Main RFCD: Not Allocated
Admin Inst: Edith Cowan University
Start Year: 2002
End Year: 2003
Total funding: $50,000.00
Grant Type: SRDC - Research
Title of research award:
Development of a collaborative intervention model to improve diabetes outcomes in a
rural aboriginal community
Lay Description (from application):
Not Available
Research achievements (from final report):
The Noongar Family Diabetes Project (NFDP) aimed to develop a collaborative
family-centred model of diabetes care for the Noongar community in the Central
Great Southern district of WA. The project was based on the principles of Aboriginal
ownership and empowerment of Aboriginal Health Workers (AHWs) to work as
members of the Integrated Diabetes Team (IDT), providing diabetes education and
care for their Noongar clients.
As capacity-building for AHWs was an integral part of the NFDP, a skills audit was
conducted at its commencement. This audit revealed that AHWs possessed a range of
skills and experience, but identified the need for update/development of their
knowledge of diabetes prevention and management. In addressing this need, seven
AHWs completed the 'Health Worker program in diabetes prevention and
management', a nationally recognised competency-based course.
Building on qualitative research undertaken with Noongar residents of Tambellup, the
model of diabetes care developed by the NFDP provides for AHWs to work alongside
clients, to help build self-esteem, and to encourage belief in their own abilities. The
model uses yarning as a consultative technique for working with Noongar clients.
Yarning, described by the AHWs as 'getting alongside people', recognises the
importance of client expertise and sees people as assets to be developed.
The NFDP model describes a collaborative patient-professional partnership that
supports client autonomy in the day-to-day management of their condition as well as
providing traditional clinical care and diabetes education.
Using tools developed to assist AHWs, the development of diabetic action plans with
families addressing identified priorities has commenced.
Full implementation of the model will depend on its use by the district health-care
team, AHWs feeling empowered to take their role as professional members of the
IDT, and on the development and maintenance of cultural competence for mainstream
health workers.
Expected future outcomes:
The NFDP model of diabetes care should enable development of diabetes action plans
by Noongar families. This will depend on: use of the model by the district health-care
team; support for AHWs in their work as Aboriginal Diabetes Health Officers and in
raising the cultural competence of the health workforce; and acknowledgment of
Noongar perspectives in diabetes programs for local Noongar people.
NHMRC Research Achievements - SUMMARY
Name of contact: Professor Neil Thomson
Email of contact: n.thomson@ecu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 375110
CIA Name: A/Pr Xin-Fu Zhou
Main RFCD: Sensory Systems
Admin Inst: Flinders University
Start Year: 2006
End Year: 2008
Total funding: $457,268.00
Grant Type: NHMRC Project
Grants
Title of research award:
Analysis of functional role of the BDNF precursor in sensory neurons
Lay Description (from application):
Neurotrophins, which are generated from their precursors, are essential for the
survival and function of the nervous system. One of neurotrophins, brain derived
neurotrophic factor (BDNF), is made in sensory neurons and transported towards
nerve terminals. Mutation of a single amino acid in the precursor of BDNF disrupts
this transport. This project will examine whether the precursor of BDNF has any
function within sensory nerves. We will examine whether the precursor of BDNF gets
into the nerve via its receptors and whether it plays any role in the development of
pain and maintenance of neuropathic pain after nerve injury. Successful execution of
the project will eludicate mechanisms of pain, especially neuropathic pain, and will
provide important information to assist in the design of drugs for neurological
diseases.
Research achievements (from final report):
BDNF is a critical molecule for the brain development and brain functions. However,
the functions of the precursor of BDNF (proBDNF) are not known. This project
investigates functions of proBDNF. We have made following findings:
1. We found that proBDNF, similar to the mature counterpart, is transported both
anterogradely and retrogradely in the primary sensory neurons.
2. We found that injection of neutralization of antibody to proBDNF can partially
protect sensory neurons from death. Application of furin-resistant exogenous
proBDNF in the nerve stumps exaggerated the death.
3. We found that injection of exogenous proBDNF suppresses the migration of
neurons from external granule layer (EGL) to the internal granule layer whereas the
neutralizing antibody to proBDNF promotes the migration of these neurons.
Exogenous proBDNF suppresses the proliferation of granule cells in EGL whereas the
neutralizing antibody promotes the proliferation of these cells in EGL.
Expected future outcomes:
This work may lead to use proBDNF as a therapeutic target for the treatment of
neurological diseases. For example use of proBDNF antibodies may be
neuroprotective for neurodegenerative diseases and neurotrauma.
Name of contact: Xin-Fu Zhou
Email of contact: zhou0010@flinders.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 375103
CIA Name: Prof Keryn Williams
Main RFCD: Clinical Sciences not elsewhere classified
Admin Inst: Flinders University
Start Year: 2006
End Year: 2010
Total funding: $739,574.00
Grant Type: Established
Career Fellowships
Title of research award:
Uncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
My research is focussed on common eye diseases prevalent in our community, and
spans the interface between the clinic and the laboratory bench. Highlights over the
past 5 years:
35 publications in the international literature;
presentation of 2 named lectures and 10 invited talks at national and international
meetings;
5 PhD student completions;
appointment to the NHMRC Academy, 2008-11;
award of 5 NHMRC project grants and >AUD $9 million in research funding overall.
My group and I have produced clinically-relevant discoveries in the field of gene
therapy to improve corneal graft survival, in the field of new ocular therapeutics and
of biomaterials suitable for use in the eye, and we have started to untangle the basis
for heritable influences in experimental retinopathy of prematurity. Further, a number
of highly-cited publications have emanated from the Australian Corneal Graft
Registry, of which I am scientific director. This clinical database contains archival
records of over 22,000 Australians who have received a corneal transplant, submitted
by over 700 clinicians in a wide variety of practice settings. This Register is widely
acknowledged to contain the most extensive repository of information about clinical
corneal transplantation in the world.
Expected future outcomes:
Two further PhD student completions and a number of publications.
Name of contact: Keryn A Williams
Email of contact: keryn.williams@flinders.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 426711
CIA Name: Prof Thomas Gordon
Main RFCD: Autoimmunity
Admin Inst: Flinders University
Start Year: 2007
End Year: 2009
Total funding: $254,592.00
Grant Type: NHMRC Project
Grants
Title of research award:
An autoantibody in type 1 diabetes that mediates autonomic complications
Lay Description (from application):
Type 1 diabetes is a chronic autoimmune disease characterised by destruction of
insulin producing cells in the pancreas. One of the most common and serious
complications of type 1 diabetes is disruption of the autoimmune nervous system, and
once symptoms appear the 5-year mortalityrate is approximately 50%. Symptoms of
autonomic dysfunction can be extensive, and involve the stomach, intestine, bladder,
heart and reproductive organs. Currently, the management of autonomic dysfunction
remains primative due to our poor understanding of the mechanisms underlaying the
disease. Recent work from our group has identified an excitatory autoantibody (an
antibody against the self) to calcium channels in patients with type 1 diabetes. The
anti-calcium channel autoantibody profoundly disrupts gut and bladder function by
interfering with autonomic regulation of smooth muscle within these organs. The anticalcium channel autoantibody is the first functional autoantibody to be detected in
type 1 diabetes, and represents a conceptual advance in our understanding of immune
mechanisms in this disease. Using animal models and a panel of novel, functional
assays of colon, stomach and bladder we will investigate how the anti-calcium
channel autoantibodies contribute to autonomic dysfunction in type 1 diabetes.
Understanding the mechanisms by which this autoantibody effects autonomic
regulation of organ function will enable the development of new therapeutic strategies
for better management of patients.
Research achievements (from final report):
Type 1 diabetes is an autoimmune disease characterised by the loss of insulin
secreting cells in the pancreas. In addition, patients often develop diabetic autonomic
neuropathy (DAN). DAN affects multiple components of the nervous system,
resulting in dysfunctions of the heart, gastrointestinal tract and urinary bladder.
However, the mechanisms by which DAN alters organ function are largely unknown.
Our laboratory has used a novel approach to identify autoantibodies (antibodies
against self tissues) that contribute to DAN in patients with type 1 diabetes. By using
whole organ preparations, we have discovered an autoantibody that alters the activity
of calcium channels, structures that are vital for normal performance of the smooth
muscle found in many organs, including the gut and bladder. The autoantibody is only
found in the serum of patients with type 1 diabetes, and alters the way in which the
nervous system regulates gastrointestinal and bladder function. A major achievement
of this grant was the development of a cell-based assay for detecting the autoantibody,
which will aid studies to determine the role that these pathogenic autoantibodies play
in the autonomic dysfunction associated with type 1 diabetes, and could lead to
improved clinical management of patients.
Expected future outcomes:
NHMRC Research Achievements - SUMMARY
This research has considerably increased the knowledge of how autoantibodies
contribute to the pathogenesis of type 1 diabetes. In addition, the development of a
cell-based assay for the autoantibody will facilitate screening for the antibody in
patients, and may lead to improved clinical management of symptoms associated with
autonomic dysfunction.
Name of contact: Dr. Michael W. Jackson
Email of contact: michael.jackson@flinders.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 375134
CIA Name: Dr Penelope Lynn
Main RFCD: Peripheral Nervous System
Admin Inst: Flinders University
Start Year: 2006
End Year: 2008
Total funding: $372,390.00
Grant Type: NHMRC Project
Grants
Title of research award:
Sensory innervation of the anal region in normal and diabetic guinea pigs
Lay Description (from application):
Until something goes wrong, we take it for granted that we can empty our bowels on a
regular basis, at a time and place of our choosing. Failure to achieve this is very
distressing and substantially diminishes quality of life, if it occurs regularly.
Disordered defecation, fecal incontinence and constipation are surprisingly common
and their prevalence will continue to increase as our population ages and the
incidence of diseases such as diabetes increases. In many people suffering these
problems, there is a detectable dysfunction of the sensory nerves in the anal region.
These nerves supply information from the anal region to the spinal cord that can cause
us to sense activity in our lower bowel and initiate defecation reflexes. These sensory
pathways are important for clinical gastroenterology, but remarkably little is known
about them. We are now able to investigate what it is the sensory nerves in the anal
region sense, what they look like and where they go to in the spinal cord - in a single
project. To do this we will use simple, but novel techniques that have been developed
in this laboratory in an animal model. Once we know this, we will compare the
function of sensory nerves in the anal region in diabetic animals with normal animals.
This will give us insight into the role of sensory nerves in the development of fecal
incontinence an unpleasant symptom for many people suffering advanced diabetes.
My systematic approach will provide understanding of the basic cellular mechanisms
and nerve pathways that underlie sensation in the anal region, helping both clinicians
and patients understand the cause of defecatory disorders and potentially pointing the
way to new therapies and strategies for diagnosis.
Research achievements (from final report):
Fecal incontinence is distressing. Fecal incontinence can occur from damage to the
nerves innervating the anal region. Prevention of damage and future potential
treatments rely on a good understanding of the nerves that innervate the anal region.
We identified some of the types of nerves that are likely to be responsible for
sensation from the anal region and that give voluntary control over defecation. The
anal region was investigated in the guinea pig for comparison with the well
documented innervation of nearby gut regions. Electrophysiology was used to record
the activity of nerves in response to movement or compression of the anal region. A
group of nerves that responded readily to stretch of the internal anal sphincter was
identified that had both similar function and nerve pathways to a documented rectal
class of nerves, but had quite different endings. The difference in the shape, size and
distribution of these endings suggests different requirements to maintain nerve
function. The external anal sphincter was innervated by different nerves to the internal
anal sphincter. Two functional classes of nerves were identified. The first displayed
similar stretch and compression sensitivity as observed for other parts of the gut,
including the internal anal sphincter. The other displayed phasic responses to
NHMRC Research Achievements - SUMMARY
vibration only, a previously undescribed phenomena in the gut. Together with an
examination of the neurochemical markers nerve endings in the anal region, we
documented some previously unknown differences in the classes of nerves
innervating the anal region of the guinea pig.
Expected future outcomes:
We hope this work will encourage others in the field to pursue a greater understanding
of the physiology and pathophysiology of the anal region neural innervation.
Name of contact: Penny Lynn
Email of contact: penny.lynn@flinders.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 276440
CIA Name: Dr Leonie Heilbronn
Main RFCD: Endocrinology
Admin Inst: Garvan Institute of Medical Research
Start Year: 2005
End Year: 2008
Total funding: $276,447.00
Grant Type: Early Career
Fellowships (Australia)
Title of research award:
Intramyocellular lipid, oxidative stress and insulin resistance
Lay Description (from application):
Not Available
Research achievements (from final report):
The post-doctoral fellowhip enabled my return from a post-doctoral position overseas
to the Garvan Institute in Sydney. This funding contributed to 16 research
publications as well as providing preliminary data for successful 2007 NHMRC
project grant funding and a 2008 Career Development Award.
Expected future outcomes:
This post-doctoral fellowship most likely contributed to my receiving a NHMRC
Career Development Award in 2008 and toghther this will enable me to become an
independent researcher.
Name of contact: Leonie Heilbronn
Email of contact: l.heilbronn@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 427644
CIA Name: Dr Mark Cleasby
Main RFCD: Endocrinology
Admin Inst: Garvan Institute of Medical Research
Start Year: 2007
End Year: 2008
Total funding: $340,400.00
Grant Type: NHMRC Project
Grants
Title of research award:
Role 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.
NHMRC Research Achievements - SUMMARY
Name of contact: Prof Edward Kraegen
Email of contact: e.kraegen@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 481300
CIA Name: A/Pr Jenny Gunton
Main RFCD: Endocrinology
Admin Inst: Garvan Institute of Medical Research
Start Year: 2008
End Year: 2010
Total funding: $362,304.00
Grant Type: NHMRC Project
Grants
Title of research award:
The Role of Hypoxia Inducible Factor 1a in Beta-Cell Function and Diabetes
Lay Description (from application):
HIF1a is a gene which our preliminary data shows is needed for normal beta-cell
function and insulin secretion. When beta-cells cannot release enough insulin, blood
sugar levels rise, and diabetes develops. This research plan will look at the effects of
deletion of HIF1a and of increasing HIF1a to see how this affects function of betacells and / or diabetes development. This work may show that HIF1a is a potential
therapeutic target for the treatment of diabetes in humans.
Research achievements (from final report):
The ideas which led to the grant were confirmed. HIF-1a does appear to play an
important role in beta-cell function and insulin secretion in type 2 diabetes.
This led to a paper published in the Journal of Clinical Investigation.
We identified a drug which is a new therapeutic agent for the treatment of people with
diabetes. It is already in use in people with type 1 diabetes, and we are about to begin
a trial in type 2 diabtes.
Expected future outcomes:
We expect at least 2 more papers from the grant in the near future, and will be starting
a human clinical trial of our drug for the treatment of type 2 diabetes.
Name of contact: Jenny Gunton
Email of contact: j.gunton@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 376020
CIA Name: A/Pr Trevor Biden
Main RFCD: Cell Metabolism
Admin Inst: Garvan Institute of Medical Research
Start Year: 2006
End Year: 2008
Total funding: $510,476.00
Grant Type: NHMRC Project
Grants
Title of research award:
Mechanisms of fatty-acid mediated destruction of pancreatic beta cells
Lay Description (from application):
Type 2 diabetes is associated with obesity, but not all obese individuals develop the
disease. Non-diabetic obese subjects are able to compensate for diminished sensitivity
to insulin (a general feature of obesity) by enhanced output of insulin from the
pancreatic beta-cells of the islet of Langerhans. In diabetics this compensatory
mechanism is disrupted. Obesity and Type 2 diabetes are also associated with
elevated levels of fatty acids (FAs) in the bloodstream. These can be taken up by the
beta-cells where they exert both short and long-term effects. In the longer term FAs
can be toxic to beta-cells and this is thought to be important in the failure of beta-cell
compensation. The project is aimed at a better understanding of the manner by which
different types of FAs influence the susceptibility of beta-cells to destruction. It
builds on our preliminary results suggesting that the capacity of the beta-cell to
convert saturated FAs to unsaturated FAs helps protect them from destruction. Our
aim is to examine the mechanisms underlying this protection.
Research achievements (from final report):
The major achievements were the demonstrations that ER stress occurs in
experimental models of Type 2 diabetes, and most importantly is present in beta cells
of human subjects with the disease. We have additionally shown that ER stress in
necessary for full lipoapoptosis in our cellular model. On a more mechanistic level we
established that a slowing in the trafficking of sectory protein between the ER and
golgi contributes to the induction of ER stress.
Expected future outcomes:
In future studies we are focusing on the mechanisms whereby fatty acids disrupt
protein trafficking and are testing the hypothesis that compartalized increases in
ceramide is a causative factor.
Name of contact: Trevor Biden
Email of contact: t.biden@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 244906
CIA Name: Dr Jenny Gunton
Main RFCD: Gene Expression
Admin Inst: Garvan Institute of Medical Research
Start Year: 2003
End Year: 2007
Total funding: $373,780.00
Grant Type: Early Career
Fellowships (Overseas)
Title of research award:
Gene expression profiles in adipose and liver tissue from insulin receptor substrate
Lay Description (from application):
Not Available
Research achievements (from final report):
The work identified genes which were altered in expression in the islets of people
with type 2 diabetes. This provides new understanding of the causes of beta-cell
failure and thus the devleopment of diabetes. It has led to studies currently underway
to examine the effects of increasing levels of the transcription factors ARNT / HIF-1a
and the effects on diabetes. It is possible that this may lead to a new therapeutic agent
for the treatment of human type 2 diabetes.
Expected future outcomes:
There are further papers currently with journals for review, these will be published in
due course. The patents resulting from this work may lead to human type 2 diabetes
clinical trials. We hope to start a human clinical trial for the treatment of diabetes in
the next year.
Name of contact: Alison Heather
Email of contact: a.heather@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 376024
CIA Name: Dr William Hughes
Main RFCD: Protein Targeting and Signal Transduction
Admin Inst: Garvan Institute of Medical Research
Start Year: 2006
End Year: 2008
Total funding: $509,268.00
Grant Type: NHMRC Project
Grants
Title of research award:
The Role of Phospholipase D in Regulating Insulin Secretion
Lay Description (from application):
Insulin, secreted appropriately by the b-cell of the pancreatic islets of Langerhans,
regulates blood glucose levels through its effects on various tissues throughout the
body. Precise control of insulin secretion from the pancreatic b-cell into the blood is
therefore vital for accurate glucose homeostasis. Type II Diabetes Mellitus is caused
by the inability of pancreatic b-cells to respond adequately to changes in blood
glucose. In the last 18 months we have determined that the enzyme phospholipase D
(PLD) plays an essential role in distally coordinating signals leading to accurately
regulated insulin secretion from the pancreatic b-cell. Through this proposal we now
aim to define the signalling pathways upstream of PLD and identify the mechanism
downstream that allows PLD activity to regulate insulin secretion. We aim to use a
combination of established and novel, biochemical and cell biological, approaches to
characterize the role PKC alpha and beta isoforms and the small GTPase cdc42 may
have in controlling PLD mediated insulin release. We will also use a variety of cell
biological approaches to identify why, where, and when PLD activation is required
for appropriate insulin secretion. We will also correlate these observations with the
role the cell cytoskeleton may have in mediating PKC, cdc42 and/or PLD effects. In
particular we aim to use a state-of-the-art microscope facility recently established at
the Garvan Institute to achieve these aims. In doing this we will gain new insights into
the pathways determining how insulin is released into the bloodstream, further define
cellular processes common to all vesicular trafficking events and also identify
potential targets for pharmacological intervention in the disease Diabetes.
Research achievements (from final report):
The study was aimed at better understanding the mechanisms controlling the secretion
of insulin from pancreatic beta cells. The major achievement from the work is a the
development of novel reagents and techniques to image the insulin secretion process
in live pancreatic beta cells. I have then either genetically or pharmacologically
stimulated or inhibited molecules implicated in regulating insulin secretion and have
visualized precicely which process in the secretory mechanism is defective.
Expected future outcomes:
A better understanding of insulin secretion and which molecules regulate which
precise step in the process.
Name of contact: William E. Hughes
Email of contact: w.hughes@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 376000
CIA Name: Dr Jenny Gunton
Main RFCD: Endocrinology
Admin Inst: Garvan Institute of Medical Research
Start Year: 2006
End Year: 2008
Total funding: $411,798.00
Grant Type: NHMRC Project
Grants
Title of research award:
The Role of ARNT in Beta-Cell Dysfunction and the Pathogenesis of Type 2 Diabetes
Mellitus in Humans and Animal Models
Lay Description (from application):
The importance of type 2 diabetes research is clear, as we are in the midst of both a
global and Australian epidemic; 24% of Australian adults have increased blood sugar
levels, and this already high rate will increase rapidly over the coming years. The
cost to the Australian economy will be enormous. Because diabetes does not develop
until -cell failure is present in the pancreas, and the mechanisms of -cell failure are
not well understood, more studies are needed, particularly using human samples.
Until recently, these samples were simply not available. The advent of reliable islet
isolation techniques, and their availability in Sydney make these studies feasible. My
previous work identified a 90% decrease in ARNT in islets from people with type 2
diabetes, clearly making ARNT function and regulation an important question of
relevance to human disease. It is possible that understanding how ARNT works in cells may lead to new treatments for -cell failure and diabetes. The use of human
islets will allow the important verification that substances having an effect in mice
and cell lines are actually relevant in normal humans.
Research achievements (from final report):
We have identified a decrease of a transcription factor called ARNT in the islets and
livers of people with type 2 diabetes. Transcription factors are 'master regulators' of
many things in living cells and decreased ARNT causes changes in many other
proteins needed for normal cell function. Decreased ARNT impairs insulin release
from the pancreas and insulin action at the liver, and increasing ARNT action may
therefore provide a possible therapeutic target for the treatment of type 2 diabetes.
Expected future outcomes:
We have 1 paper in press and 2 papers currently being considered for publication.
Name of contact: Jenny Gunton
Email of contact: j.gunton@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 276411
CIA Name: Prof Charles Mackay
Main RFCD: Immunology not elsewhere classified
Admin Inst: Garvan Institute of Medical Research
Start Year: 2004
End Year: 2006
Total funding: $465,750.00
Grant Type: NHMRC Project
Grants
Title of research award:
The role of PAC-1 in leukocyte activation and inflammatory responses
Lay Description (from application):
The MAP kinase pathway is fundamental for signalling a variety of cellular
responses. This pathway is particularly important for immune responses ie. cytokine
signalling, chemotaxis, and proliferation. PAC-1, a MAP kinase phosphatase, is an
important regulator of this pathway. Extensive gene profiling of various immune cells
using Affymetrix GeneChips identified PAC-1 as a highly regulated molecule in
activated mast cells. Mast cells are important inflammatory cells, particularly for
rheumatoid arthritis and asthma. We have shown that PAC-1 deficient mice are
highly protected from inflammation and disease in a mouse model of rheumatoid
arthritis. This grant aims to extend these exciting initial findings to other
inflammatory diseases, particularly asthma and type 1 Diabetes, and to establish the
basis for PAC-1 inhibition of disease. This research should establish PAC-1 as a new
and important target for inflammatory disease, provide understanding on
inflammatory processes, and possibly lead to improved therapies for diseases such as
rheumatoid arthritis.
Research achievements (from final report):
Understanding of MAP kinase pathway regulation , identity of a potential new target
for inflammatory diseases. we also published 2 high profile papers, one in Nature
Immunology and another review paper in Nature Reviews Drug Discovery. We
believe that Pac-1 is an exciting new drug target, and any drug that inhibits Pac-1
function should be highly selective and effective for diseases such as rheumatoid
arthritis. Based on our work, Serono initiated a drug screening program for inhibitors
of Pac-1.
Expected future outcomes:
This work has led to new knowledge on how phosphatases regulate the MAP kinase
pathway, and their role in inflammation. A major outcome would be drug targeting of
Pac-1, to achieve better anti-inflammatory therapeutics
Name of contact: Charles Mackay
Email of contact: c.mackay@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 481330
Start Year: 2008
CIA Name: Prof David James
End Year: 2008
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding:
$265,970.00
Admin Inst: Garvan Institute of Medical Research
Grant Type: NHMRC Project
Grants
Title of research award:
Regulation of Energy Expenditure
Lay Description (from application):
The incidence of obesity is increasing alarmingly throughout the world. In this
proposal we aim to explore one side of the energy equation - energy expenditure. We
will conduct a series of detailed studies in genetically modified mice to examine the
role of the brain versus muscle in whole body energy expenditure. These studies
have significant implications for therapeutic management of Type 2 diabetes and
obesity.
Research achievements (from final report):
We have recently obtained floxed c-Cbl mice from Ozgene and we are in the process
of crossing them with whole body Cre animals to verify the previously described
phenotype.
We have already obtained ACC2 floxed animals and crossed these to whole body
Cre's. These animals have been phenotyped and surprisingly do not exhibit a lean
phenotype. This is a very important observation that we have recently submited for
publication.
We have recently obtained floxed ACC1 mice and are preparing to cross these to
whole body Cres.
Expected future outcomes:
These studies will provide a more detailed mechanistic view of how whole body
energy is controlled and the role of substrate switching in this phenomenon. .
Name of contact: Greg Cooney
Email of contact: g.cooney@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 481329
CIA Name: A/Pr Gregory Cooney
Main RFCD: Endocrinology
Admin Inst: Garvan Institute of Medical Research
Start Year: 2008
End Year: 2008
Total funding: $169,695.00
Grant Type: NHMRC Project
Grants
Title of research award:
The role of muscle fatty acid oxidation in regulating intramyocellular lipid
accumulation.
Lay Description (from application):
Obesity and the subsequent accumulation of fat in muscle leads to reduced insulin
action and an increased risk of type 2 diabetes. This project will investigate the
metabolic processes that influence fat accumulation and oxidation primarily in
skeletal muscle, the tissue responsible for most fuel utilization in the body. This
information will help design therapeutic strategies to prevent the development of type
2 diabetes.
Research achievements (from final report):
The work conducted so far on this project clearly shows that increasing fat oxidation
doesn't necessarily mean that there will be fat loss from the body. Body fat can only
be lost if energy expenditure exceeds energy intake. Therefore an increase in fat
oxidation without an increase in energy expenditure or decrease in energy intake
cannot lead to weight loss. Altering fat oxidation via AMPK activation might be
beneficial to a particular tissue but there is no evidence from this study that activation
of AMPK leads to weight loss.
Expected future outcomes:
Understanding of the fact that increased use of fatty acids for energy is not necessarily
linked to reduced fat content (or weight loss).
Name of contact: Gregory Cooney
Email of contact: g.cooney@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 210226
CIA Name: Prof David James
Main RFCD: Protein Targeting and Signal Transduction
Admin Inst: Garvan Institute of Medical Research
Start Year: 2002
End Year: 2006
Total funding: $690,000.00
Grant Type: Established
Career Fellowships
Title of research award:
Uncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
o Characterisation of mechanism of insulin action - this work has identified the major
step regulated by insulin in muscle and fat cells and has transformed the field in terms
of how we think about this problem
o Discovery of a new agent from Traditional Chinese Medicine that results in reduced
body weight and improved insulin action in animal models.
o Identification of a gene that controls energy expenditure in mice - this has resulted
in new knowledge about this important biological pathway and may lead to new
therapeutic manipulations.
o Development of a high throughput assay for one of insulin's major metabolic
actions. This has already resulted in several licence deals with the Pharmaceutical
industry
Expected future outcomes:
o Discovery of new metabolic pathways regulated by insulin
o Dissection of the mechanism by which insulin controls glucose transport in muscle
and fat cells
o Discovery of mechanism of insulin resistance in muscle and fat cells
o Identification of compounds for the treatment of human Type 2 diabetes
Name of contact: David James
Email of contact: d.james@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 230842
CIA Name: Prof David James
Main RFCD: Protein Targeting and Signal Transduction
Admin Inst: Garvan Institute of Medical Research
Start Year: 2003
End Year: 2005
Total funding: $440,250.00
Grant Type: NHMRC Project
Grants
Title of research award:
Mechanism of action of Sec1p-like proteins in Membrane Trafficking.
Lay Description (from application):
One of the most important evolutionary changes that has occurred is the development
of intracellular compartments. All eukaryotic cells possess numerous membraneencased structures which provide the basis for intracellular specialisation. For
example, in order to degrade unwanted components cells have developed degradative
enzymes. It is vital for the cell that these enzymes are sequestered away from other
cellular components to avoid destruction of valuable molecules. In addition, the cell
has developed a complex assembly line of modifications that are added to proteins in
a specific order as they travel to their final destination within the cell. This
necessitates the accurate passage of molecules between compartments, a process
known as vesicle transport. To orchestrate the complex network of vesicular transport
steps between all of the various intracellular compartments it is necessary to employ
complex machinery to guide and check that these steps occur with high fidelity. The
goal of our research proposal is to define the function of one of the molecules
involved in this control process, the so-called Sec1p proteins. The strength of our
proposal lies in the diversity of our approach. We intend to explore the molecular
advantages of a relatively simple eukaryotic organism, a yeast cell, and apply the
findings obtained from this cell to a more complex but highly related vesicular
transport process; that of the insulin-regulated movement of a glucose transporter in
mammalian fat and muscle cells. While we intend to apply our findings to the
treatment of patients with diabetes, it is our ultimate goal to be able to learn more
about this fundamental cell biological process so that we can apply our knowledge to
understanding many different disease states.
Research achievements (from final report):
The movement of proteins within the cell is fundamental to almost all biological
processes. There are now many diseases that appear to be due to disruptions in the
process of protein movement within cells, including Parkinson's disease, Huntington's
disease, as well as various kinds of cancer. Although the function of proteins within
cells is very similar across all organisms, our understanding of the molecular
machinery that governs this function is very rudimentary. In this study, we have
begun to unravel the workings of one of the proteins that is involved in this process,
which we believe will provide us with important clues to fundamental questions about
the relationship between protein movement and disease. .
Expected future outcomes:
In the future we hope to be able to define the function of the protein we have
identified in much greater detail. We hope to solve the atomic structure of this
molecule, and then to use this information to pinpoint exactly how it functions in the
living cell and how this may relate to different disease states.
NHMRC Research Achievements - SUMMARY
Name of contact: Professor David E James
Email of contact: d.james@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 481356
CIA Name: Dr Nigel Turner
Main RFCD: Cell Metabolism
Admin Inst: Garvan Institute of Medical Research
Start Year: 2008
End Year: 2011
Total funding: $380,559.00
Grant Type: Career
Development Fellowships
Title of research award:
Mitochondrial Energy Metabolism and Insulin Action
Lay Description (from application):
Obesity and type 2 diabetes are two major health conditions associated with abnormal
energy metabolism. In this proposal I will investigate the role of important metabolic
proteins in regulating energy expenditure and insulin action in skeletal muscle and
adipose tissue, two crucial tissues for whole-body energy metabolism. These studies
will provide critical insight into the factors leading to obesity and type 2 diabetes and
will assist in identifying possible therapeutic targets.
Research achievements (from final report):
The research conducted with the support of this award has further explored the
relationship between mitochondrial function and insulin action in different tissues.
We have observed that specific types of dietary fats have very different effects on
metabolic pathways in different tissues, with medium chain fatty acids have a
particularly pronounced effect to increase nutrient oxidation in muscle. We have
shown that directly increasing the total capacity of mitochondria to oxidise nutrients
can improve insulin resistance induced by a high fat diet. Finally we have shown a
potential role for a group of mitochondrial enzymes (sirtuins) in acutely regulating
mitochondrial function in response to alterations in nutrient availability.
Expected future outcomes:
Our investigations into the factors regulating mitochondrial nutrient oxidation in
different tissues and have identified a number of interesting proteins and pathways
that may be potential drug targets for treating obesity and type 2 diabetes.
Name of contact: Nigel Turner
Email of contact: n.turner@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 427639
CIA Name: Dr Leonie Heilbronn
Main RFCD: Endocrinology
Admin Inst: Garvan Institute of Medical Research
Start Year: 2007
End Year: 2009
Total funding: $417,197.00
Grant Type: NHMRC Project
Grants
Title of research award:
Short-term effects of overfeeding on metabolic risk in humans
Lay Description (from application):
The prevalence of obesity is rapidly increasing in Australia and other parts of the
world. Obesity is closely associated with insulin resistance and plays a role in the
development of type 2 diabetes. However, the effects of short-term periods of over
nutrition in humans remain unclear. In the proposed study, we will investigate the
effects of short-term weight gain by high fat feeding in lean subjects, in subjects who
are overweight and in subjects who are genetically more likely to develop diabetes
(due to strong family history). The aims are to distinguish physiological and
endocrine characteristics of individuals who store more fat in response to overfeeding.
We will identify differences between these individuals and whether they have defects
in upregulating machinery involved in fat oxidation and energy production in skeletal
muscle that may help them adapt during to energy excess. We will look for changes in
type 2 diabetes risk and we will have the potential to identify defects in factors that
are involved in this response. We will also re-examine indivudals again after calorie
restriction and weight loss. We also plan to confirm the role of the candidate genes
involved in fat oxidation that have been identifieid in human studies by in vivo gene
transfer technology in rodents. This study will determine whether overweight and
lean subjects behave similarly when faced with an overfeeding challenge. We expect
that individuals with a genetic predisposition for T2DM will become more IR, due to
metabolic inflexibility and a decreased ability to upregulate machinery involved in
fatty acid oxidation and mitochondrial function. By characterising the physiological
and endocrine responses to overfeeding, we will establish quantifiable markers
allowing us to distinguish those at risk and identify new targets for pharmacological
or lifestyle intervention.
Research achievements (from final report):
There are studies showing mitochondrial dysfunction and increased oxidative stress in
human obesity and type 2 diabete. Furthermore, these studies suggest that these
factors may be reversed by weight loss and induced by lipids. However, an increasing
number of rodent studies suggest that diet induced obesity increases, not decreases
mitochondrial function. It was unclear what will happen under these conditions. In
this study, we observed a transient increase in mitochondrial biogenesis indicating
that mitocondrial dysfunction is not causal in development of weight gain induced
insulin resistance. Furthermore, we observed a significant increases in systemic and
muscle markers of oxidative stress. Further work is now required to determine
whether increased reactive oxygen species production in muscle causes insulin
reistance in animal and human models.
Expected future outcomes:
NHMRC Research Achievements - SUMMARY
We are using this high fat overfeeding model to now study individuals who were
conceived through in-vitro fertilisation. There is some animal evidence, and some
cross-sectional studies to suggest that these individuals are at increased risk of
developing insulin resistance and type 2 diabetes. But this is has not been well studied
to date.
Name of contact: Leonie Heilbronn
Email of contact: leonie.heilbronn@adelaide.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 325644
CIA Name: Dr Nigel Turner
Main RFCD: Cell Metabolism
Admin Inst: Garvan Institute of Medical Research
Start Year: 2005
End Year: 2008
Total funding: $271,500.00
Grant Type: Early Career
Fellowships (Australia)
Title of research award:
The role of Dysfunctional Mucscle Mitochondria in Lipid-induced Insulin Resistance
Lay Description (from application):
Not Available
Research achievements (from final report):
This research involved an examination of the relationship between muscle
mitochondrial metabolism and insulin resistance. The major findings were 1) showing
that an excess intake of calories does not cause obesity and insulin resistance by
reducing the capacity of muscle to burn fuel substrates; 2) demonstrating that a
number of anti-diabetic agents have their beneficial effects in part by influencing
mitochondrial function; 3) identifying that improved mitochondrial capacity is present
in association with reduced fat mass and enhanced insulin action in mice with a
knockout of the c-Cbl gene. These results have provided novel insight into the
complex link that exists between mitochondrial function and insulin action, and
indicate that targeted manipulation of mitochondrial metabolism may be a fruitful
approach for the treatment of insulin resistance and diabetes.
Expected future outcomes:
The current study has identified mitochondrial pathways which appear to be
associated with insulin action. Future research will be aimed at testing whether
specific manipulation of these pathways can improve insulin action.
Name of contact: Nigel Turner
Email of contact: n.turner@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 427629
CIA Name: A/Pr Trevor Biden
Main RFCD: Endocrinology
Admin Inst: Garvan Institute of Medical Research
Start Year: 2007
End Year: 2007
Total funding: $157,375.00
Grant Type: NHMRC
Development Grants
Title of research award:
Therapeutic Strategies and Screening Methods for PKC epsilon antagonists in the
treatment of Type 2 diabetes
Lay Description (from application):
Type 2 diabetes is a chronic disease affecting over a million Australians and hundreds
of millions of people worldwide. Its prevalence is rising due to several factors such as
an increase in caloric intake, the aging of the population, and the common sedentary
lifestyle of Western civilization. Type 2 diabetes occurs when the pancreas is unable
to produce enough insulin for the body to cope with rising blood glucose levels after a
meal, and has been strongly linked to obesity. We have now shown that an enzyme
found in the pancreas becomes inappropriately activated under conditions of fat
oversupply, and plays an important role in the development of defects in insulin
release from the pancreas in response to glucose. Excitingly, we have also shown that
inhibition of this enzyme can partly reverse these defects once they have been
established. We now intend to further validate this enzyme as a drug target by
determining the optimum dosing regimen for the treatment of type 2 diabetes in a
mouse model, and testing whether this approach can be used in conjunction with
previously-developed drugs which promote insulin action, to improve blood glucose
handling better than either treatment alone. This would promote the enzyme as a
therapeutic strategy in the treatment of Type 2 diabetes. We also plan to develop a
high throughput screen to identify novel inhibitors of the enzyme, which will further
increase the attractiveness of the project to pharmaceutical companies, who are better
able to implement full commercialization of our findings.
Research achievements (from final report):
The major achievement of this grant was extension of knowledge on the mechanism
of action of PKCe. We made use of the peptide inhibitors to demonstrate a specific
action of PKCe in the amplification pathway of insulin secretion. This study was
undertaken using islets of Langerhans isolated from mice, and now provides us with
the crucial baseline measurements for comparison with identical studies to be
undertaken with human islets. We also developed crucial reagents for undertaking the
high throughput screen and demonstrated proof of principle of the basis of our assay.
This led us into extended discussions and potential collaborations with industry
partners. Unfortunately funding for the undertaking the screen was not forthcoming.
More productively, we have negotiated with a biotech firm for a joint investigation of
their PKCe inhibitors in our model systems. An agreement has now been signed.
Expected future outcomes:
We will perform the assays under the terms of our joint agreeement, and depending
on outcomes, treatments for Type 2 diabetes based around inhibition of PKCe will be
developed clinically. Our partner has already conducted trials for their inhibitors for
other applications, so use with diabetes could be potentially fast-tracked.
NHMRC Research Achievements - SUMMARY
Name of contact: Trevor Biden
Email of contact: t.biden@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 325631
CIA Name: A/Pr Katherine Samaras
Main RFCD: Endocrinology
Admin Inst: Garvan Institute of Medical Research
Start Year: 2005
End Year: 2009
Total funding: $162,400.00
Grant Type: Career
Development Fellowships
Title of research award:
Modulation of insulin resistance and metabolic syndrome.
Lay Description (from application):
Not Available
Research achievements (from final report):
As this was a Career Development Award, I am reporting achievements relative to
objectives of
career development, rather than scientific discovery.
1. A considerable research output, measured by a body of original papers published,
invited reviews and book chapters, invited plenaries and conference presentations.
2. Successful grant funding obtained through NHMRC and non-government funding
bodies to
permit (most) desired projects to come to fruition.
3. Establishment of a clinical database-biological tissue bank with prospective data on
a large
number of people with type 2 diabetes undertaking bariatric surgery.
4. Establishing a presence or representation on government bodies or cooperatives
defining or
influencing policy, as a clinical science researcher ( for example, government
treatment guidelines
on HIV, NSW Health bariatric surgery guidelines, Federal Government Obesity
Enquiry, American Heart Association Scientific Consenus on cardiovascular risk in
HIV, cardiovascular Research
Network-as part of 45 and Up)
Expected future outcomes:
N/A
Name of contact: Katherine Samaras
Email of contact: k.samaras@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 427600
Start Year: 2007
CIA Name: Prof David James
End Year: 2011
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding:
$765,883.00
Admin Inst: Garvan Institute of Medical Research
Grant Type: Established
Career Fellowships
Title of research award:
Uncoupled Research Fellowship
Lay Description (from application):
I am a cell biologist studying the molecular mechanism of insulin action
Research achievements (from final report):
Type 2 Diabetes and obesity are major risk factors for most life threatening diseases
of modern humans. Because diabetes and obesity could be essentially eliminated by
dietary restriction this places an enormous emphasis on food as a public health risk.
Our work has been attempting to define how food excess contributes to life
threatening diseases by studying systems as they transition from one dietary state to
another. We have been placing quite a bit of emphasis on intracellular stress pathways
as we postulate that food intake is intimately linked with these pathways. Another
major area of interest is to examine not just the relationship between absolute amounts
of food and biological outcomes but also the time of exposure to food. We believe
that ultimately, research of this kind will lead to the development of personalized
treatments for a range of diseases based on individualized nutritional requirements.
Such treatments may have broad impact on the onset of a range of diseases that are
now increasing in incidence throughout the world.
Expected future outcomes:
Over the next 5 years we aim to gather much more data that define system response to
food and then using sophisticated computational approaches we aim to decipher from
these data those pathways that define long term health of mammals.
Name of contact: David James
Email of contact: d.james@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 376003
CIA Name: Prof Ken Ho
Main RFCD: Endocrinology
Admin Inst: Garvan Institute of Medical Research
Start Year: 2006
End Year: 2008
Total funding: $379,143.00
Grant Type: NHMRC Project
Grants
Title of research award:
The Metabolic Effects of Oestrogens and SERMs: Regulatory interactions with the
GH-IGF-system in health and disease
Lay Description (from application):
This project extends work aimed at understanding how GH and sex hormones work
together to optimise physical health in women and men. It addresses the benefits and
safety of oestrogen compounds in relation to their effects on body fat and muscle
(body composition). Oestrogen compounds are among the most widely used
medicines and include tradition oestrogens (female hormone) and synthetic
oestrogens called SERMs. Oestrogens are used in young women as oral contraception
and in the postmenopause for replacement therapy. Body composition is an
important determinant of fitness and health. Obesity reduces fitness and increases the
risk of diabetes and heart attacks while muscle loss causes weakness and frailty. GH
is a major regulator of body composition; it acts by breaking down fat and building
muscle mass. We discovered that oestrogens, when taken as a tablet interferes with
the action of GH and causes detrimental changes in body composition. On the positive
side, we have exploited the GH blocking action to treat acromegaly. This is a
debilitating disease of excessive GH production from a pituitary tumour and for which
available drug treatments are very expensive and require injection. The effects of
SERMs on body composition are unknown. SERMs are interesting compounds
because they act like oestrogens in some but as oestrogen blockers in other tissues.
These are widely used in the treatment of breast cancer and osteoporosis. The extent
to which they interfere with the action of GH has not been studied. They may exert
additional effects because they act on the pituitary gland to reduce the secretion of
GH. They may also prove to be effective in acromegaly which could extend their
usefulness to men. In summary, the work will provide important information on the
long-term benefits of SERMs in patient groups that tend to be frail. It may also prove
to be a simple and inexpensive treatment for acromegaly.
Research achievements (from final report):
This proposal addresses whether SERMs, commonly used oestrogen compounds
affect the secretion and action of growth hormone (GH), an important regulator of
body metabolism, composition and function. This project investigates whether
SERMs which block the action of oestrogen, lead to a reduction in the release and in
the action of GH.
Our studies show that two synthetic oestrogen compounds, raloxifene and tamoxifen
which interfere with the action of natural oestrogens in the brain, markedly reduces
GH secretion in both men and women. Both these compounds also interfere with the
ability of the liver to make a growth-promoting hormone called IGF-1, which is
normally produced in response to the action of GH.
NHMRC Research Achievements - SUMMARY
Our findings show unequivocally that SERMs interfere with both the secretion and
action of GH which in the longer term may be detrimental to health. As these agents
are used to treat a variety of conditions where alternatives are available, our findings
call for more judicious use of these compounds which are increasingly used for long
periods in a frail and aging population.
Expected future outcomes:
Future studies are expected to confirm the negative effect of these compounds on the
ability of GH to burn body fat and to build muscle which are currently being
addressed in detailed metabolic studies.
Name of contact: Professor Ken Ho
Email of contact: k.ho@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 481335
CIA Name: Prof Roger Daly
Main RFCD: Protein Targeting and Signal Transduction
Admin Inst: Garvan Institute of Medical Research
Start Year: 2008
End Year: 2010
Total funding: $617,256.00
Grant Type: NHMRC Project
Grants
Title of research award:
Regulation of body composition and glucose homeostasis by the adaptor protein
Grb10.
Lay Description (from application):
Resistance to the hormone insulin underlies the development of Type 2 Diabetes.
Loss of muscle mass in the elderly contributes to insulin resistance. Recently we
identified Grb10 as a new regulator of insulin action and muscle mass. In this
proposal, we aim to study how Grb10 affects development and growth of muscle and
fat, and the underlying molecular mechanisms. This may lead to new strategies for
improving body composition and treating the insulin resistance associated with Type
2 Diabetes.
Research achievements (from final report):
Skeletal muscle accounts for 40% of our body mass and is important not only for
strength but also for regulating our body glucose metabolism. Changes in muscle
mass or the ability of muscle to respond appropriately to circulating hormones
contributes significantly to metabolic health. In obesity there is an inappropriate
'spillover' of fats out of fat storage tissue and into muscle, as well as other tissues
important for insulin function. This leads to insulin resistance in the tissues and
predisposes to diabetes. With ageing, there is a loss of muscle mass and metabolic
health is also compromised. Therefore, investigations into the mechanisms regulating
muscle mass are an important part of understanding whole body metabolism. This
project examined the role of a particular protein, Grb10, in reremained muscular
throughout their life, and additionally possessed reduced fat stores. This increase in
muscle mass was due to an increase in muscle fibres. Furthermore, the metabolic
profile of the mice was improved. This work identifies Grb10 as a potential
therapeutic target for improving body composition and metabolism.
Expected future outcomes:
We expect to understand the mechanisms underpinning the muscle phenotype in
Grb10-deficient mice and to determine whether Grb10 regulates muscle wasting.
Name of contact: Prof. Roger Daly
Email of contact: r.daly@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 376012
CIA Name: A/Pr Gregory Cooney
Main RFCD: Cell Metabolism
Admin Inst: Garvan Institute of Medical Research
Start Year: 2006
End Year: 2010
Total funding: $607,101.00
Grant Type: Established
Career Fellowships
Title of research award:
Uncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
This 5 year Fellowship Grant was used to pursue studies that have highlighted the
importance of fuel metabolism and energy expenditure in different tissues to the
accumulation of fat and the development of insulin resistance and type 2 diabetes.
These studies have involved significant collaborations and publications with other
researchers interested in the regulation of metabolism in muscle. The studies
supported by this Fellowship have demonstrated tissues switch fuels to match energy
demands and that changes in energy intake or expenditure are necessary for fat loss.
Other studies have determined that mice with a deletion of the Grb10 protein have
greater muscle mass, less fat and better insulin action which is relevant to muslce loss
with ageing as well as type 2 diabetes. Finally there ahs been considerble focus on the
circadian changes in metabolism that regulate that we sleep at night and eat and work
during the day. Studies have determined that making animals eat when they normally
sleep has significant effects on energy metabolism and can lead to metabolic
abnormalities similar to those now being reported ins hift workers. All thee studies
have a major impact on how to deal with the increasing incidence of obesity and its
complications.
Expected future outcomes:
The successful research outcomes of this Fellowship Grant have resulted in a renewal
of my Fellowship and the next 5 years will be used to significantly contribute to
understanding how obesity develops and causes metabolic disease.
Name of contact: Greg Cooney
Email of contact: g.cooney@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 325638
CIA Name: Dr Jerry Greenfield
Main RFCD: Endocrinology
Admin Inst: Garvan Institute of Medical Research
Start Year: 2005
End Year: 2008
Total funding: $384,870.00
Grant Type: Early Career
Fellowships (Overseas)
Title of research award:
Detailed Phenotypic charaterisation of Human Melanocortin 4 Receptor Deficiency &
Othr Monogenic Forms of Severe Obesity
Lay Description (from application):
Not Available
Research achievements (from final report):
During the research fellowship, I undertook a number of research studies examining
the causes and metabolic consequences of increased body fat in humans, particularly
type 2 diabetes. Specifically, the studies performed in the UK provided new
information regarding the genetics of obesity and the abnormalities present in humans
who develop obesity due to defects in a single gene. This work was published in the
New England Journal of Medicine. A second groups of studies is being performed to
investigate obese people who remain sensitive to insulin despite having increased
body fat. These individuals appear not to develop diabetes as commonly as other
obese people. We are studying the mechanisms of apparent protection from metabolic
diseases in an attempt to devise new therapies that may target these pathways. This
paper will be sumitted to the Journal of Clinical Investigation shortly. A third line of
work, which started in the UK and is ongoing in Australia (funded by an NHMRC
Project Grant) is examining a novel therapy for treatment of high glucose levels.
Glutamine, an amino acid, appears to lower blood sugar levels in people with diabetes
via a hormone secreted from the gut. Two studies have been published from this work
(in the American Journal of Clinical Nutrition and the Journal of Nutrition).
Expected future outcomes:
The expected future outcomes relate to the discovery of new therapies for obesity and
its metabolic accompaniments, particularly insulin resistance and type 2 diabetes.
Name of contact: Dr Jerry Greenfield
Email of contact: j.greenfield@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 276419
CIA Name: A/Pr Gregory Cooney
Main RFCD: Nutrition and Dietetics
Admin Inst: Garvan Institute of Medical Research
Start Year: 2004
End Year: 2006
Total funding: $579,000.00
Grant Type: NHMRC Project
Grants
Title of research award:
The role of stress response and circadian genes in the link between excess lipid and
muscle insulin resistance
Lay Description (from application):
Obesity and its associated conditions of heart disease, reduced insulin action, fatty
liver and type 2 diabetes are increasing at an alarming rate worldwide. The epidemic
of these conditions appears to be due to an interaction between genetic background
and changes in the environment such as reduced physical activity and increased
availability and consumption of high energy food. The relationship between genes and
environment is very complex but it seems clear that increased intake of high fat foods
can cause body tissues to accumulate excess fat. This interferes with the way that the
hormone insulin controls body glucose utilisation although how this happens has not
been fully defined. This grant application will test two possible mechanisms that
could help explain the link between increased dietary fat intake and decreased insulin
action in muscle. Using microarrays to examine the activity of genes in normal and
insulin resistant muscle, we have identified two groups of genes that may be involved
in how fat causes insulin resistance. One group of genes is normally associated with
stress and we will determine if fats control these genes directly or if fats increase
other stress factors which increase the activity of these genes. We will then use novel
gene therapy techniques to see if these genes cause insulin resistance in muscle of
experimental animals. The second group of genes is related to the mechanisms which
regulate daily cycles in the body such as sleep/wake cycles, blood pressure, and eating
behaviour. We will examine the activity of these genes over a 24 hour period in
muscle from normal animals and insulin resistant animals to determine if disruption of
these gene cycles contributes to insulin resistance. We will then perform experiments
to establish what processes these genes control. The successful outcome of this grant
will determine if these groups of genes can be targeted to help treat lipid-induced
insulin resistance in muscle.
Research achievements (from final report):
Significant progress has been made in both parts of this project.
1. We have undertaken microarray analysis of gene expression in cultured L6 muscle
cells treated overnight with fatty acid and shown that acute fatty acid treatment upregulates expression of several of the same stress genes up-regulated by fat-feeding in
muscle. We have established the utility of using siRNA constructs to reduce gene
expression using electroporation in a collaborative study in which siRNA for nurr77
was introduced into mouse muscle with the effect of reducing genes of fatty acid
oxidation.
2. We have documented significant differences in the expression of circadian rhythm
and metabolic genes in muscle and liver of fat-fed rats. The circadian transcription
factor dbp had altered expression in liver and muscle from fat-fed rats. We have
measured significant alterations in the expression of metabolic genes in muscle and in
NHMRC Research Achievements - SUMMARY
the diurnal variation of plasma fatty acids and intracellular lipids. These results
indicate that the diurnal metabolism of glucose and lipid are significantly altered by a
high fat diet in a temporal fashion with key differences only evident at specific times
of the 24 hour cycle. It is possible that interventions at specific times of the day may
have the most benefit for the treatment of metabolic disease.
Expected future outcomes:
The outcomes of the work funded by this grant will be several journal articles
documenting key differences in the metabolism of glucose and lipid at specific times
during the 24 hour cycle that are important in the development of metabolic disease.
Name of contact: A/Prof Greg Cooney
Email of contact: g.cooney@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 230820
CIA Name: A/Pr Amanda Sainsbury-Salis
Main RFCD: Systems Physiology
Admin Inst: Garvan Institute of Medical Research
Start Year: 2003
End Year: 2005
Total funding: $329,625.00
Grant Type: NHMRC Project
Grants
Title of research award:
Investigation of the role of hypothalamic Y1 receptors in obesity
Lay Description (from application):
The worldwide prevalence of obesity alarming, and is a major risk factor for diseases
such as type 2 diabetes. Although the benefits of weight loss in overweight subjects
are undisputed, there currently exists no effective long-term treatment for obesity.
Therefore pharmacological interventions for obesity could dramatically reduce the
burden of this disease. There is much interest in the development of treatments for
obesity that prevent the action of proteins in the brain that are thought to lead to
increased food intake and gain of body fat, such as neuropeptide Y and its receptor
Y1, both of which are found in the hypothalamus in regions known to regulate body
fat. However, the true role of Y1 receptors in regulating body weight in the
hypothalamus is currently unclear, since there are no known pharmacological tools
that can specifically block or activate this receptor in order to demonstrate its
function. To circumvent this problem we have developed genetically modified mice
that enable us to specifically delete the Y1 receptor from the hypothalamus of adult
mice, and therefore determine its role in regulating body weight. This project will
demonstrate whether hypothalamic Y1 receptor deletion can reduce food intake and
body fat in mice in the long-term, and whether it can cause other changes in
metabolism that might also contribute to reducing body fat. We will also show
whether the obesity that results from either a high-fat diet, from an excess of the stress
hormone corticosterone, or from genetic mutation in mice, can be prevented or
reversed by deletion of hypothalamic Y1 receptors. The results will be instrumental in
deciding whether developing medicines that specifically block Y1 receptors in the
hypothalamus will be of significant benefit for the long-term treatment of human
obesity, which is caused by multiple genetic and environmental factors.
Research achievements (from final report):
It is known that food restriction (e.g. dieting) leads to elevated expression of
neuropeptide Y (NPY) in the hypothalamus, contributing to increased hunger, reduced
metabolic rate, and difficulty to attain and maintain a healthy body weight. We know
that NPY exerts these effects via a variety of different Y receptors, but we don't know
which one(s) is(are) the most important in mediating this NPY-induced "famine
reaction". Using state-of-the-art technology to delete Y1 receptors specifically from
the hypothalamus of the brain, we showed that under normal conditions Y1 receptors
are not involved in reguating food intake or fat storage, but contribute to behaviours
related to feeding, notably food grinding and aggression. However, under situations of
increased NPY levels in the brain (such as during food restriction), Y1 receptors are
partly responsible for mediating the increased propensity to store fat. Whereas
deficiency of Y1 receptors resulted in a mild decrease in body fat levels under some
circumstances, we showed that deficiency of Y2 and Y4 receptors results in even
greater and synergistic reductions in body fat. These data show that strategies aimed
NHMRC Research Achievements - SUMMARY
at reducing the function of Y2 and Y4 receptors could help reduce the tenacity of the
human "famine reaction", thereby increasing effectiveness of lifestyle changes for
weight loss.
Expected future outcomes:
These findings will provide valuable targets for pharmacotherapy for obesity.
Name of contact: Dr Amanda Sainsbury-Salis
Email of contact: a.sainsbury-salis@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 427616
CIA Name: Dr David Ross Laybutt
Main RFCD: Endocrinology
Admin Inst: Garvan Institute of Medical Research
Start Year: 2007
End Year: 2009
Total funding: $537,110.00
Grant Type: NHMRC Project
Grants
Title of research award:
Mechanisms of beta-cell failure in diabetes
Lay Description (from application):
The current epidemic of type 2 diabetes represents a major global health problem,
with over 7% of the Australians suffering the disease. While there is a wellestablished relationship between obesity and insulin resistance, the majority of
overweight individuals do not develop type 2 diabetes because their pancreatic betacells compensate with enhanced insulin secretion. It is the failure of beta-cell
compensation that is fundamental to the development of diabetes. The beta-cell is a
highly specialised cell with a unique metabolic profile and differentiation specifically
geared towards making these cells able to sense fluctuations in circulating glucose
levels and secrete insulin accordingly. We propose that in susceptible individuals, a
gradual rise in blood glucose (hyperglycaemia) and lipid levels resulting from
increasing obesity and insulin resistance leads to a loss of the unique expression
pattern of genes necessary for appropriate insulin secretion. This exacerbates
hyperglycaemia, which causes further beta-cell dedifferentiation and eventually the
death of beta-cells by apoptosis. We have recently found evidence in several models
of diabetes that supports this hypothesis. We propose to use animal studies and cell
culture systems to investigate the following hypotheses important for our
understanding of beta-cell failure and progression to diabetes: 1)Hyperglycaemia
plays a critical role regulating the progression to beta-cell dedifferentiation. 3) The
overexpression of key candidate gene products play an integral role linking
hyperglycaemia to the loss of beta-cell secretion. 4) Endoplasmic reticulum stress is
necessary for beta-cell death in diabetes. Our studies will make a major contribution
to our understanding of why beta-cells fail in diabetes and aim to provide novel
therapeutic targets in the treatment of diabetes.
Research achievements (from final report):
Diabetes occurs as a result of pancreatic beta cell failure. In both type 1 and type 2
diabetes, beta cell failure is characterised by insulin secretory defects, loss of insulin
content and beta cell destruction. In type 1 diabetes, this is mediated by cytokines that
are produced as a part of an autoimmune and inflammatory process. In type 2
diabetes, elevated lipid and glucose levels occurring as a result of high fat diets,
obesity and insulin resistance are thought to contribute. The beta cell is a highly
specialised cell with a unique metabolic profile and differentiation specifically geared
towards making these cells able to sense fluctuations in circulating glucose levels and
secrete insulin accordingly. Our research showed that beta cell secretory defects in
diabetes and in islet transplants are associated with a loss of the specialised expression
pattern of genes that optimises insulin secretion. The molecular and cellular
mechanisms responsible for this loss of beta cell differentiation were investigated.
Stress within the endoplasmic reticulum (ER) compartment of the cell was a focus of
investigation. Pancreatic beta cells possess a highly developed ER, which is required
NHMRC Research Achievements - SUMMARY
for the processing, folding and export of vast quantities of newly synthesised insulin.
We investigated ER stress as an exciting potential mechanism for beta cell
dysfunction and destruction in type 1 and type 2 diabetes.
Expected future outcomes:
We will further investigate potential mechanisms of beta-cell failure in type 1 and
type 2 diabetes.
Name of contact: Ross Laybutt
Email of contact: r.laybutt@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 376022
CIA Name: Dr Carsten Schmitz-Peiffer
Main RFCD: Endocrinology
Admin Inst: Garvan Institute of Medical Research
Start Year: 2006
End Year: 2008
Total funding: $627,148.00
Grant Type: NHMRC Project
Grants
Title of research award:
Investigation of the Roles of Protein Kinase C epsilon in Insulin Secretion and Insulin
Clearance
Lay Description (from application):
The rise in blood insulin levels after a meal normally reduces blood sugar levels by
increasing glucose uptake and storage in certain tissues, especially muscle. Type 2
diabetes is characterized in part by a failure of the pancreas to produce adequate
insulin in response to increases in blood sugar. This loss of insulin secretion has been
strongly linked to increases in the availability of fat, although the reasons for this are
not clear. We have recently found that mice lacking a specific enzyme (protein kinase
C epsilon) are much less susceptible to the problems in dealing with blood sugar that
are caused by a high fat diet. We showed that this is due partly to improved insulin
secretion, and also to a slower breakdown of insulin by the liver, which increases its
availability to target tissues. The aim of this project is to investigate the mechanisms
occurring in the liver and in the pancreas by which this enzyme contributes to
improved insulin action. Firstly, we will examine insulin uptake in liver cells, to
investigate how the enzyme controls this process. Secondly, we will determine the
mechanism through which the activation of the enzyme, upon increased fat supply to
pancreatic beta-cells, reduces insulin secretion in response to glucose. Finally, will
assess the relative importance of these two actions of the enzyme in improving the
control of blood sugar levels. This work will lead to a better understanding of the
mechanisms by which fat oversupply, and hence obesity, can play a role in the
development of Type 2 diabetes, so that they can be targeted both for the development
of new and more effective treatments for the disorder and for prevention of its onset.
Research achievements (from final report):
This project resulted in a high profile publication in a top scientific journal (Cell
Metabolism), because the work described a novel drug target for the treatment of
Type 2 diabetes. We showed that the enzyme known as protein kinase C epsilon
(PKCe) plays an inhibitory role in the beta cells of the pancreas to reduce glucosestimulated insulin secretion in the face of increased fat accumulation, as occurs during
obesity. Inhibition of this enzyme improves glucose intolerance in mice fed a high fat
diet. In addition, we found that PKCe reduces the availability of insulin in the body by
promoting its uptake and degradation by the liver. Thus drugs designed to inhibit
PKCe would enhance insulin secretion as and when needed as well as reduce its
clearance. These effects counteract the insulin resistance also occuring in Type 2
diabetes, improving blood glucose levels. In addition to these key findings we also
addressed the mechanisms involved in these actions of PKCe. On the one hand, the
enzyme affects lipid metabolism in beta cells to amplify their response to glucose and
thus enhance insulin secretion. On the other hand, PKCe affects the internalization of
the insulin receptor in liver cells which are responsible for insulin clearance. These
findings are significant advances in our understanding of the effects of PKCe, and
NHMRC Research Achievements - SUMMARY
also shed light on the regulation of glucose-stimulated insulin secretion and insulin
uptake.
Expected future outcomes:
Our work is the subject of an international patent application currently under
examination. In addition we have recently signed an agreement with a commercial
partner to test PKCe inhibitory molecules in our models of type 2 diabetes. The
ensuing intellectual property may be licensed for development of PKCe inhibitors to
treat diabetes in humans.
Name of contact: Carsten Schmitz-Peiffer
Email of contact: c.schmitz-peiffer@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 376008
CIA Name: Prof David James
Main RFCD: Protein Targeting and Signal Transduction
Admin Inst: Garvan Institute of Medical Research
Start Year: 2006
End Year: 2008
Total funding: $505,523.00
Grant Type: NHMRC Project
Grants
Title of research award:
The Role of AS160 in Insulin Action
Lay Description (from application):
Obesity and diabetes are increasing in our community at an alarming rate. When one
considers that Diabetes is a major cause of heart disease, stroke and kidney disease
these diseases represent one of the most threatening for the future health of our nation.
At the heart of these diseases is a disorder known as insulin resistance, or the inability
of insulin to function correctly. The explosion in biological outcomes over the past
decade has brought us closer than ever before to solving some of the key questions
associated with this problem. This proposal represents an exciting step forward in this
area because our recent research combined with information from our international
colleagues have led us to propose a new concept concerning the mechanism of insulin
action. In this proposal we have formulated a series of molecular experiments to test
this hypothesis which if correct will both change the way we think about this problem
and provide new prospects for therapeutic design.
Research achievements (from final report):
This research has enhanced our understanding of how insulin regulates one of its
fundamental steps namely the import of glucose into muscle and fat cells. This step is
considered to be one of the most important in determining the removal of glucose
from the bloodstream after a meal and indeed it becomes disrupted in individuals who
are at risk of developing type 2 diabetes. Over the period of the award we have
identified essential elements of how the protein AS160/TBC1D4 and its family
members work in fat cells. AS160 is a RabGAP that is phosphorylated by Akt. We
have made the following achievements:
1. Identified two Rabs that specifically bind to AS160
2. Established molecular mechanisms for AS160 dimerisation
3. Developed methods to show that phosphorylation and 14-3-3 binding per se are
key to the function of AS160 in response to insulin
4. Performed systems analysis of AS160 combined with other key Akt substrstes to
show that AS160 is phosphorylated by Akt at the plasma membrane.
5. Used mass spectrometry to identify novel AS160 binding partners.
In a separate body of work we have begun to study the role of other TBC family
proteins in insulin action. Specifically we have found that another protein TBC1D13
binds to Rab10 and when over expressed in adipocytes profoundly inhibits insulin
dependent GLUT4 trafficking.
These studies have provided novel insights into this important biological process.
Expected future outcomes:
Mutations in TBC1D4 and a related protein TBC1D1 have recently been identified in
families with obesity and Type 2 diabetes. However, the mechanism for this is not
yet known. Our work will provide a deeper understanding of this linkage and as to
NHMRC Research Achievements - SUMMARY
how the regulation of glucose transport in muscle and fat cells is so closely linked to
whole body energy homeostatsis and metabolism.
Name of contact: Jacky Stoeckli
Email of contact: j.stoeckli@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 325614
CIA Name: A/Pr Gregory Cooney
Main RFCD: Protein Targeting and Signal Transduction
Admin Inst: Garvan Institute of Medical Research
Start Year: 2005
End Year: 2007
Total funding: $484,500.00
Grant Type: NHMRC Project
Grants
Title of research award:
Regulation of glucose homeostasis and insulin signalling by Grb10 and Grb14.
Lay Description (from application):
The hormone insulin is a critical regulator of blood glucose levels. Defective insulin
action, also known as insulin resistance, underlies the development of Type 2
Diabetes, which is major health problem worldwide. Understanding how insulin
action is regulated may lead to new treatments for this disease. Insulin mediates its
effects by binding to a receptor on the cell surface that transmits signals to the interior
of the cell. Depending on the cell type, these signals can instruct the cells to take up
glucose from the bloodstream (muscle and fat) or decrease glucose production (liver).
We have identified a new regulator of insulin signalling in cells, a protein termed
Grb14. This was accomplished by generating mice in which the Grb14 gene was
removed, so that the animals no longer produced Grb14. These animals responded
better to insulin, indicating that Grb14 normally inhibits insulin action. However, it is
likely that another closely related protein, Grb10, functions alongside Grb14 to
regulate insulin signalling. Therefore, we will use mice in which the Grb10 and Grb14
genes have been removed, singly and in combination, to define the roles of these two
proteins in regulating blood glucose levels and insulin signals inside the cell. We will
also use cells isolated from the mice to analyse the molecular events underlying the
effects of Grb10 and Grb14 on insulin signalling. The significance of these studies is
that defining the functional role and mode of action of Grb10 and Grb14 may lead to
novel therapeutic approaches aimed at blocking their function. Such approaches could
be used to overcome the insulin resistance associated with Type 2 Diabetes.
Research achievements (from final report):
The major aim of this project were to define the effects of deleting the Grb10 gene on
glucose metabolism in mice. A secondary aim was to compare any effects with those
previously described in a mouse model with a gene deletion for the related adaptor
protein Grb14 and to examine the metabolic phenotype of mice lacking both Grb10
and Grb14. The investigation of the Grb10 gene-deleted mice revealed a novel
phenotype of increased muscle mass in the absence of any increase in other organ size
(kidney, heart, liver, spleen). The increased muscle mass was accompanied by a
reduced amount of adipose tissue which suggested that, because increased fat mass is
normally associated with insulin resistance and poor glucose metabolism, the higher
fat free mass in Grb10 gene-deleted mice could be advantageous from a metabolic
viewpoint. Grb10 gene-deleted mice had improved glucose tolerance and the double
knockout mice (Grb10 and Grb14) maintained the phenotype of Grb10 mice having
larger muscles and less fat tissue. These findings suggest that Grb10 might have a
negative effect on signalling pathways that control the growth of muscle tissue and
that manipulating the amount of Grb10 might be useful for increasing or maintaining
muscle mass in elderly people. Other experiments suggest that neither Grb10 or
NHMRC Research Achievements - SUMMARY
Grb14 deletion protect against the detrimental effects of a high-fat diet but that the
double knockout may have some beneficial effects.
Expected future outcomes:
Elucidating the pathways by which Grb10 influences muscle and fat depots could lead
to new therapies to combat excess fat tissue and reduced muscle mass which are both
problems of an ageing population.
Name of contact: A/Prof. Greg Cooney
Email of contact: g.cooney@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 535934
CIA Name: Dr Cecile King
Main RFCD: Autoimmunity
Admin Inst: Garvan Institute of Medical Research
Start Year: 2009
End Year: 2011
Total funding: $489,060.00
Grant Type: NHMRC Project
Grants
Title of research award:
The role of Interleukin-21 in the pathogenesis of autoimmune diabetes
Lay Description (from application):
Interleukin-21 (IL-21) is a soluble protein that is produced by cells enabling them to
communicate with other cells. IL-21 helps cells to clear viruses and bacteria from the
body. However, our studies show that IL-21 also generates T cells that destroy beta
cells and cause diabetes. IL-21 is produced at abnormally high levels in an important
murine model of spontaneous type-1 diabetes (T1D) and if we block IL-21 we prevent
diabetes. This projects' aims assess IL-21 as therapeutic target for T1D.
Research achievements (from final report):
Tissue types have their own individual molecular signatures. If tissue from one
individual is transplanted into another individual, the "mis-matched" tissue is rapidly
rejected by the immune system. This process is known as allograft rejection and along
with existing autoimmunity, poses a huge hurdle for successful islet transplantation.
Our study demonstrated that preventing IL-21 from accessing immune CD8+ T cells
prevented both the allo-rejection of islet cells from other strains of mice as well as the
recurrence of the existing autoimmunity that destroyed the islets in the first place.The
cells that make IL-21 in the inflamed lesion of the pancreas are also increased in the
blood of Sjogrens patients, suggesting that IL-21-producing T cells are important for
the development of autoimmune diseases that affect the accessory organs of the
digestive system.
Thus, neutralizing the effects of IL-21 could prevent both autoimmunity and allograft
rejection of islets-the two major hurdles to successful replacement of islet tissue in
type 1 diabetes. This reagent worked as well in our model as drugs that are currently
in clinical trials for islet transplantation. If this approach works in people as it has in
mice, then they would only have to take the drug for a brief time-window after
surgery and the transplant would be fine for life.
These findings are relevant to understanding the chronic inflammation in autoimmune
disease and to islet transplantation in human type 1 diabetes.
Expected future outcomes:
Neutralizing the effects of IL-21 could prevent both autoimmune and allograft
rejection of islets-the two major hurdles to successful replacement of islet tissue in
type 1 diabetes. If this approach works in people as it has in mice, then they would
only have to take the drug for a brief time-window after surgery and the transplant
would be fine for life.
Name of contact: Cecile King
Email of contact: c.king@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 481317
CIA Name: Dr Carsten Schmitz-Peiffer
Main RFCD: Endocrinology
Admin Inst: Garvan Institute of Medical Research
Start Year: 2008
End Year: 2010
Total funding: $504,097.00
Grant Type: NHMRC Project
Grants
Title of research award:
Dilinoleoyl phosphatidic acid as a novel mediator of insulin resistance in muscle
Lay Description (from application):
We have identified a novel fat molecule in muscle which may play an important role
in causing insulin resistance during obesity, a major factor in the development of
Type 2 diabetes. We will now examine whether depletion of this molecule,
dilinoleoyl-phosphatidic acid, can improve insulin action in muscles and in obese
mice, and investigate the mechanisms by which it may act. This work may indicate
new strategies for the treatment of diabetes.
Research achievements (from final report):
Insulin resistance in skeletal muscle is a major characteristic of Type 2 diabetes, and
is strongly linked to increased fat availability, although the mechanisms involved are
not well understood. This project examined the role of specific lipid mediators in the
generation of insulin resistance caused by different high fat diets and whether
inhibition of enzymes involved in their accumulation in muscle could improve insulin
action. We showed that although different dietary fatty acids had been associated with
distinct inhibitory mechansims in cultered cells or acute in vivo models, oversupply of
both saturated or unsaturated fatty acids in fat-fed mice both caused the content of a
particular intermediate, ceramide, to increase in muscle. Furthermore, ceramide
accumulation was best prevented using the anti-inflammatory agent lisofylline, rather
than myriocin, an inhibitor of ceramide biosynthesis, which agreed with the more
potent effect of lisofylline in improving gluucose homeostasis. This is the first
indication that lisofylline could be used to treat Type 2 diabetes in humans. Finally,
lipidomic analysis of muscle by mass spectrometry revealed that changes in specific
ceramide species, rather than the most abundant forms, correlated ewith changes in
insulin sensitivity, which suggests that inhibition of specific ceramide synthases may
represent a more targeted approach to the treatment of insulin resistance. These
findings were published in the specialist journal Endocrinology.
Expected future outcomes:
The potential use of lisofylline to treat diabetes has led to a research collaboration
with Diakine Therapeutics, Inc. which hold the IP on this drug and its orally-available
derivatives. We will be investigating the use of these compounds to improve insulin
resistance in further studies. In addition we are determine the contribution of different
ceramide synthases which represent novel targets.
Name of contact: Carsten Schmitz-Peiffer
Email of contact: c.schmitz-peiffer@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 262013
CIA Name: Dr Pablo Silveira
Main RFCD: Autoimmunity
Admin Inst: Garvan Institute of Medical Research
Start Year: 2003
End Year: 2007
Total funding: $270,305.00
Grant Type: Early Career
Fellowships (Australia)
Title of research award:
B cell tolerance defects as a potential contributor to Type 1 diabetes
Lay Description (from application):
Not Available
Research achievements (from final report):
A class of white blood cell in the immune system, termed T cells, are responsible for
destroying the insulin producing cells leading to Type 1 Diabetes (T1D). However,
another class of immune cell, called B cells, also play an important role in T1D as a
mouse model made deficient in these cells no longer develops this disease. B cells are
one of the few cell types which are able to take up and present protein fragments from
other cells in a form recognizable to T cells. Normally, this only leads to the
activation of T cells recognising foreign cells such as viruses or bacteria, resulting in
clearance of infection. We have identified an aberrant population of B cells that arise
in mice prone to T1D that specifically take up proteins from insulin producing cells.
Using these proteins, B cells can activate T cells that subsequently become armed to
recognise and destroy insulin producing cells. B cells that recognize the body's own
cells such as those producing insulin are normally eliminated or suppressed in healthy
individuals. This project has identified faulty immune mechanisms that allow T1Dpromoting B cells to escape elimination and suppression. We have also identified
sections of DNA containing genes which control the generation of this T1Dpromoting B cell population. By understanding how dangerous B cells are generated
in mice, we hope to form the basis of new therapies aimed at inhibiting these cells
from forming in T1D susceptible humans, thus preventing disease at an early stage.
Expected future outcomes:
In future, we hope to develop a more complete understanding the the faulty genes and
proteins leading to the development of diabetes promoting B cells. Such studies could
potentially reveal new drug targets that could avert diabetes by preventing the
development of dangerous B cells.
Name of contact: Pablo Silveira
Email of contact: P.Silveira@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 325604
CIA Name: Prof David James
Main RFCD: Protein Targeting and Signal Transduction
Admin Inst: Garvan Institute of Medical Research
Start Year: 2005
End Year: 2007
Total funding: $469,500.00
Grant Type: NHMRC Project
Grants
Title of research award:
Molecular regulation of GLUT4 targeting.
Lay Description (from application):
Insulin resistance (the inability of ordinarily insulin-sensitive tissues such as muscle
and adipose tisse to respond to insulin) contributes to a number of diseases including
diabetes and obesity. A key metabolic step in these tissues is the uptake of glucose
from the blood stream. This step is accelerated by insulin thus allowing efficient
clearance of glucose from the bloodstream after a meal. Our laboratory has played a
major role in showing that insulin regulates glucose uptake into muscle and adipose
tissue by stimulating the movement of a glucose transport protein from inside the cell
to the cell surface. The purpose of this proposal is to dissect the molecular
mechanisms by which this glucose transporter can be held inside the cell in the
absence of insulin and then allowed to be released from this site moving to the surface
in the presence of insulin. Our studies over the past 5 years have brought us much
closer to understanding this process in detail. The identification of the molecules
responsible for this regulatory step will not only aid our understanding of this process
but it will also provide a valuable target for development of therapeutic agents that
can be used to combat insulin resistance.
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.
NHMRC Research Achievements - SUMMARY
Expected future outcomes:
Once conditional mice have been received we will be in a strong position to map the
tissue specificity for the c-Cbl metabolic phenotype by creating adipose tissue,
muscle, liver and brain specific c-Cbl knock out mice.
Name of contact: David James
Email of contact: d.james@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 402727
CIA Name: Dr Pablo Silveira
Main RFCD: Autoimmunity
Admin Inst: Garvan Institute of Medical Research
Start Year: 2006
End Year: 2008
Total funding: $163,756.00
Grant Type: NHMRC Project
Grants
Title of research award:
Identifying the underlying mechanisms responsible for the generation of pathogenic B
cells in Type 1 Diabetes
Lay Description (from application):
Type 1 diabetes (T1D) occurs when the body's own immune system mistakenly
attacks and destroys all the beta cells of the pancreas which produce insulin, a
hormone essential for regulating sugar levels in the blood. The non-obese diabetic
(NOD) mouse develops a form of T1D closely resembling the human disease, and as
a model, has led to numerous important insights into its cause. Based on studies in
NOD mice, it is now well accepted that a class of cell in the immune system, termed
T cells, are responsible for most of the damage to the beta cells in T1D. Recent work
in this model, however, has demonstrated that another class of immune cell, termed B
cells, also play an important role in T1D as NOD mice made deficient in these cells
no longer develop disease. In addition to producing antibodies, B cells are one of the
few cell types which are able to take up and present protein fragments in a form
recognizable to T cells. Normally, this only leads to the activation of T cells
recognising foreign insults, like viruses or bacteria, resulting in their destruction. We
have shown that a dangerous population of B cells can arise in NOD mice that can
specifically take up beta cell proteins and present them to the T cells, which
subsequently become armed to recognise and destroy the beta cells. Just like T cells,
B cells that recognize the body's own proteins are normally eliminated in healthy mice
and human individuals. This research proposal aims to determine the faulty immune
mechanisms that give rise to the beta cell specific B cells in NOD mice. We have also
set out to identify the diabetes susceptibility genes which control the generation of
this dangerous population of B cells in this model. By understanding how these
dangerous B cells are generated in NOD mice, we hope to form the basis for new
therapies aimed at inhibiting these cells from forming in T1D susceptible humans,
thus preventing the disease at an early stage.
Research achievements (from final report):
Aim 1: We have performed experiments in which we have obtained complete genetic
profiles of B cells from diabetes-prone mice as well as non-diabetes prone mice at
various stages of their development. By comparing these genetic profiles, we have
been able to identify new defective molecular pathways responsible for generating
self-reactive B cells that facilitate development of disease.
Aim 2:
We have produced genetically engineered diabetes prone and non-diabetes prone mice
in which all B cells recognize a transgenic pancreatic beta cell protein. Using these
mice we have been able to confirm that self-reactive B cells specific for beta cell
proteins are normally functionally inactivated and subsequently eliminated. However,
in diabetes prone animals, these self-reactive B cells can be rescued upon interaction
NHMRC Research Achievements - SUMMARY
with T lymphocytes, whereas those in non-diabetes prone backgrounds are not. This
study provides an interesting insight into how self-reactive B cells are able to be
rescued and recruited into beta cell specific response in individuals predisposed to
Type 1 Diabetes.
Aim 3:
We identified two genetic regions housing diabetes susceptibility genes in mice which
control the ability of B cells to participate in the autoimmune response against beta
cells. We have revealed that the genes in both of these regions increase the capacity of
self-reactive B cells to escape being functionally inactivated in diabetes susceptible
mice. We are currently performing studies to identify the specific genes responsible
for these diabetes promoting B cell attributes.
Expected future outcomes:
Elucidation of the cellular and molecular basis for defective B cell tolerance in NOD
mice will pave the way for translational studies to determine whether dysregulation of
similar pathways characterize Type 1 Diabetes patients. These studies may yield
novel targets in B lymphocytes for intervention protocols which may ultimately
prevent or reverse T1D in susceptible human subjects.
Name of contact: Pablo Silveira
Email of contact: P.Silveira@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 427642
CIA Name: Prof David James
Main RFCD: Protein Targeting and Signal Transduction
Admin Inst: Garvan Institute of Medical Research
Start Year: 2007
End Year: 2009
Total funding: $303,510.00
Grant Type: NHMRC Project
Grants
Title of research award:
Dissection of Insulin Regulated Phosphorylation in the Adipocyte
Lay Description (from application):
Obesity and diabetes are increasing at an alarming rate throughout the world. These
diseases are part of a constellation of disorders that includes cardiovascular disease
and kidney disease, which are collectively referred to as the metabolic syndrome. A
disorder referred to as insulin resistance is at the heart of the metabolic syndrome.
This represents the inability of insulin to function correctly in target cells like muscle
and fat. In this project we are attempting to undertake a large scale effort to
understand the complex circuitry that gets turned on within cells when they become
exposed to insulin. This project involves a collaboration between the Garvan Institute
and the University of New South Wales Mass Spectrometry Facility allowing us to
bring a combination of very sophisticated technologies to bear on this very significant
health care problem. This project will provide major new insights into our
understanding of insulin action yielding new possibilities for therapeutic
development.
Research achievements (from final report):
The output of a biological system is an integrated response of numerous finely tuned
regulatory events involving millions of components. Large-scale studies have begun
to define the components. The challenge is to ascertain how they cooperate in a living
cell and how they respond to perturbation. The metabolic system is ideal as it adapts
to environmental change and is relevant to many human diseases. Diabetes represents
a disease where this adaptive network becomes disrupted and the body is unable to
cope with incoming nutrients appropriately. The hormone insulin is at the heart of this
regulatory circuit. It is secreted every time we eat to coordinate the distribution of
nutrients. One of the major facets of insulin's actions is to change the activity of
intracellular proteins by a modification called phosphorylation. To completely
understand how this system works it is essential to map all of these phoshorylation
events. The goal of this proposal was to discover new insulin regulated
phosphoproteins in the hope of better understanding how insulin works. We
developed novel high resolution methods using a technique known as mass
spectrometry to identify phosphoproteins. In addition to identifying many of the
known insulin regulated phosphoproteins we were able to identify 4 novel proteins.
We focussed our efforts on one of these known as Edc3 and this led us to unveil a
completely new pathway regulated by insulin. This will have major impact on future
work in this area because this pathway may have a lasting effect on the ability of cells
to regulate metabolism.
Expected future outcomes:
Our work has revealed 4 new proteins phosphorylated by insulin. They control RNA
repression, autophagy, DNA methylation and cell movement. This will catalyse many
NHMRC Research Achievements - SUMMARY
new studies in each of these important areas. Also we are now using this approach to
map even more insulin-regulated events. This will lead to the most comprehensive
insulin regulated phosphomap.
Name of contact: David James
Email of contact: d.james@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 276431
CIA Name: Prof Donald Chisholm
Main RFCD: Endocrinology
Admin Inst: Garvan Institute of Medical Research
Start Year: 2004
End Year: 2006
Total funding: $335,800.00
Grant Type: NHMRC Project
Grants
Title of research award:
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
NHMRC Research Achievements - SUMMARY
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: Prof.Donald Chisholm
Email of contact: d.chisholm@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 188829
CIA Name: Dr David Ross Laybutt
Main RFCD: Not Allocated
Admin Inst: Garvan Institute of Medical Research
Start Year: 2002
End Year: 2006
Total funding: $425,000.00
Grant Type: Career
Development Fellowships
Title of research award:
Islet B-cell growth, differentiation and function in typpw 2 diabetes:
Lay Description (from application):
Not Available
Research achievements (from final report):
In Australia over 7% of the population have type 2 diabetes. This epidemic represents
a major health problem. The majority of overweight individuals do not develop
diabetes because their insulin-secreting pancreatic beta-cells adequately compensate
with over-secretion. It is the failure of this so called, beta-cell compensation, that is
fundamental to the development of diabetes. We proposed that in susceptible
individuals, a gradual rise in blood glucose levels resulting from obesity and insulin
resistance leads to beta-cell failure and overt diabetes. This project investigated the
mechanisms responsible for beta-cell failure in a mouse model with a similar timedependent progression to obesity and type 2 diabetes as that seen in humans. db/db
mice progress from a pre-diabetic phase of insulin over-secretion, obesity and insulin
resistance to a diabetic state characterised by the appearance of high blood glucose
and lipid levels and the loss of insulin secretory capacity.
Our findings suggest that chronic exposure of islets to elevated glucose and fatty acids
can, independently, lead to changes in gene expression consistent with a loss of betacell phenotype. Since both conditions lead to a loss of glucose-responsive insulin
secretion, these data support our theory that the dedifferentiation of beta-cells
underlies the insulin secretory defect in diabetes. Islets from db/db mice show an early
loss of several genes implicated in glucose sensing whereas transcript levels of betacell hormones are better maintained. We showed that hyperglycaemia was a critical
factor regulating the progression to β-cell decompensation in db/db mice.
Expected future outcomes:
Fuure studies will be aimed to identify the transcription factors responsible for
hyperglycaemia-induced beta-cell dedifferentiation and dysfunction.
Name of contact: Ross Laybutt
Email of contact: r.laybutt@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 325618
CIA Name: Dr David Ross Laybutt
Main RFCD: Endocrinology
Admin Inst: Garvan Institute of Medical Research
Start Year: 2005
End Year: 2007
Total funding: $389,250.00
Grant Type: NHMRC Project
Grants
Title of research award:
Pancreatic beta-cell dysfunction in diabetes
Lay Description (from application):
In Australia over 7% of the population have type 2 diabetes. This epidemic represents
a major health problem. The majority of overweight individuals do not develop
diabetes because their insulin-secreting pancreatic beta-cells adequately compensate
with over-secretion. It is the failure of this so called, beta-cell compensation, that is
fundamental to the development of diabetes. We propose that in susceptible
individuals, a gradual rise in blood glucose levels resulting from obesity and insulin
resistance leads to beta-cell failure and overt diabetes. This project will investigate the
mechanisms responsible for beta-cell failure in a mouse model with a similar timedependent progression to obesity and type 2 diabetes as that seen in humans.
C57BL/KsJ db/db mice progress from a pre-diabetic phase of insulin over-secretion,
obesity and insulin resistance to a diabetic state characterised by the appearance of
high blood glucose and lipid levels and the loss of insulin secretory capacity. With
age, there are also a reduced number of beta-cells because of increased cell death.
db/db mice will be studied at different stages in their natural progression to diabetes to
fully characterise the secretory dysfunction and the changes in beta-cell phenotype
over the time-course of diabetes development. The use of laser capture
microdissection will allow us to study selectively the actual beta-cells without
contamination from the other cells of the pancreas. The mice will also be treated with
an agent that lowers blood glucose levels without affecting lipids to test the influence
of hyperglycaemia itself in the development of beta-cell dysfunction. We will also test
if the changes observed in the mice are regulated independently by high glucose
levels in cell culture systems. The role of one candidate protein called ID-1 will be
investigated as a potential link between hyperglycaemia and the development of betacell dysfunction.
Research achievements (from final report):
In Australia over 7% of the population have type 2 diabetes. This epidemic represents
a major health problem. The majority of overweight individuals do not develop
diabetes because their insulin-secreting pancreatic beta-cells adequately compensate
with over-secretion. It is the failure of this so called, beta-cell compensation, that is
fundamental to the development of diabetes. We proposed that in susceptible
individuals, a gradual rise in blood glucose levels resulting from obesity and insulin
resistance leads to beta-cell failure and overt diabetes. This project investigated the
mechanisms responsible for beta-cell failure in a mouse model with a similar timedependent progression to obesity and type 2 diabetes as that seen in humans. db/db
mice progress from a pre-diabetic phase of insulin over-secretion, obesity and insulin
resistance to a diabetic state characterised by the appearance of high blood glucose
and lipid levels and the loss of insulin secretory capacity.
NHMRC Research Achievements - SUMMARY
Our findings suggest that chronic exposure of islets to elevated glucose and fatty acids
can, independently, lead to changes in gene expression consistent with a loss of betacell phenotype. Since both conditions lead to a loss of glucose-responsive insulin
secretion, these data support our theory that the dedifferentiation of beta-cells
underlies the insulin secretory defect in diabetes. Islets from db/db mice show an early
loss of several genes implicated in glucose sensing whereas transcript levels of betacell hormones are better maintained. We showed that hyperglycaemia was a critical
factor regulating the progression to β-cell decompensation in db/db mice.
Expected future outcomes:
Fuure studies will be aimed to identify the transcription factors responsible for
hyperglycaemia-induced beta-cell dedifferentiation and dysfunction.
Name of contact: Ross Laybutt
Email of contact: r.laybutt@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 481303
CIA Name: Prof Edward Kraegen
Main RFCD: Endocrinology
Admin Inst: Garvan Institute of Medical Research
Start Year: 2008
End Year: 2010
Total funding: $604,793.00
Grant Type: NHMRC Project
Grants
Title of research award:
Adiponectin: key factors determining its metabolic actions and influences on insulin
sensitivity
Lay Description (from application):
Diabetes and obesity are growing at alarming rates due to poor lifestyle and other
factors. Adiponectin is a complex molecule secreted by fat tissue that may help to
burn fat in other tissues such as muscle and liver. We investigate what are the main
determinants of adiponectin action and how these might counteract defective insulin
action caused by excessive fat intake. This promises to provide new therapeutic
targets to lessen the metabolic derangement associated with diabetes and obesity,
Research achievements (from final report):
A hormone released from adipose tissue, adiponectin, has been implicated in
counteracting insulin resistance, a major perturbation in the Metabolic Syndrome and
Type II Diabetes, although the mechanisms are not well understood. One putative
pathway influenced by adiponectin is the AMP kinase (AMPK) pathway. Our overall
objective was to determine the contribution of adiponectin oligimers, adiponectin
receptors and adapter proteins and AMPK in the ability of adiponectin to influence
fuel metabolism and insulin action. Our work focussed particularly on the role of the
adiponectin receptors (AdipoR1 and AdipoR2), the important adaptor protein APPL1,
and on the extent of involvement of AMPK as a downstream component of
adiponectin action. Using in vivo gene manipulation techniques we demonstrated
roles for AdipoR1 and APPL1 in skeletal muscle glucose disposal, and their overexpression (OE) increased glycogen accumulation. APPL1 OE also increased muscle
glucose uptake and partially ameliorated high fat diet-induced insulin resistance.
Furthermore insulin signalling (IRS1) was activated by APPL1 OE and this finding
provides a potential mechanism for the insulin sensitising effect of adiponectin in
muscle. Regarding liver, we demonstrated in collaboration with the AI Assoc/Prof
Aimin Xu, that APPL1 potentiates insulin-mediated inhibition of hepatic glucose
production. These studies, reported in Cell Metabolism, suggest that in liver APPL1
principally enhances insulin signalling by blocking an inhibitory effect of Tribbles 3
(TRB3) on Akt activation. Thus, in both liver and muscle, our studies of APPL1
suggest it is of physiological importance in enhancing insulin action.
Expected future outcomes:
Our findings provide potential mechanisms for the insulin sensitising effect of
adiponectin in muscle and liver and suggest the possibility of further insulin and
AMPK-independent actions of adiponectin in regulating glucose metabolism. This
provides a positive impetus for investigating activation of adiponectin or its
downstream effectors in counteracting insulin resistance.
Name of contact: Edward Kraegen
NHMRC Research Achievements - SUMMARY
Email of contact: e.kraegen@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 481355
CIA Name: A/Pr Amanda Sainsbury-Salis
Main RFCD: Medical Physiology not elsewhere classified
Admin Inst: Garvan Institute of Medical Research
Start Year: 2008
End Year: 2011
Total funding: $420,872.00
Grant Type: Career
Development Fellowships
Title of research award:
Improving long-term weight loss by deactivating the famine reaction with molecular
or lifestyle means
Lay Description (from application):
Dr Amanda Sainsbury-Salis’ research will clarify which hormones and natural brain
chemicals interact in the hypothalamus of the brain to control the famine reaction, the
survival mechanism that slows your weight loss when you are on a diet. By knowing
precisely which natural chemicals mediate the famine reaction and how they interact,
it will be possible to weaken them by pharmaceutical and / or lifestyle means, thereby
enabling more people to reap the benefits of being lean and healthy.
Research achievements (from final report):
Non-surgical obesity treatments are ineffective for most, in part due to adaptive
responses to energy restriction that increase appetite & reduce metabolic rate. Not
only do these adaptations oppose ongoing weight loss, they may also adversely affect
body composition via hormonal changes that favor abdominal fat accretion with loss
of muscle mass & bone. Thus, current obesity treatments may inadvertently increase
the risk of metabolic diseases such as atherosclerosis, as well as that of structural
diseases such as sarcopenia & osteoporosis. My long-term objective is to find ways to
attenuate these adaptive responses so that more people can attain & maintain a healthy
body weight & composition. During this Career Development Award, my research
team and I identified brain pathways mediating these adaptive responses and their
effects on fat, muscle & bone, predominantly using transgenic mice at the Garvan
Institute. For example - and as seen in the titles of publications arising from this work
- we demonstrated that Y4 receptors in the brain play a critical role in the ability of
the gut satiety hormone, pancreatic polypeptide, to reduce food intake in mice, as well
as demonstrating the pathways via which this occurs. This finding has important
implications for the development of anti-obesity treatments based on administration of
agents that act similarly to pancreatic polypeptide. We also demonstrated the role of a
natural brain chemical called neuropeptide Y in the development of obesity in
response to estrogen deficiency. This has potential future implications for
management of the weight gain that many women experience in the peri-menopausal
time of their lives.
Expected future outcomes:
I now hold 2 NHMRC project grants in order to apply this knowledge to clinical
practice for more immediate benefit to human health. Pending further NHMRC
Research Fellowship funding, my team will determine the consequences of adaptive
responses to energy restriction on body composition in obese patients, and will also
test the utility of intermittent energy restriction for improved weight loss.
NHMRC Research Achievements - SUMMARY
Name of contact: Amanda Sainsbury-Salis
Email of contact: amanda.sainsbury-salis@sydney.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 230846
CIA Name: Prof Edward Kraegen
Main RFCD: Medical Physiology not elsewhere classified
Admin Inst: Garvan Institute of Medical Research
Start Year: 2003
End Year: 2007
Total funding: $779,500.00
Grant Type: Established
Career Fellowships
Title of research award:
Uncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
Obesity, the Insulin Resistance Syndrome and Type 2 Diabetes are major health care
problems and are reaching global epidemic proportions. Despite this there are few
internationally competitive research teams working in this area in Australia. We have
built up an international reputation in the study of lipid-related insulin resistance and
research has focussed on this area, particularly on how fatty acids and other lipids
could interfere with insulin action in muscle, arguably the most important target for
insulin in the body. There was a need to develop new techniques to manipulate
(overexpress or inhibit) individual target muscle proteins in animal models to
understand key factors in generating insulin resistance and suggesting new therapeutic
targets. This was achieved by the use of in vivo electrotransfer (IVE) techniques to
locally introduce DNA constructs to muscle, and since our publication the technique
has generated widespread interest. Using this and related techniques we have been
able to clarify the role of several proteins in the insulin signalling pathway (eg Akt
isoforms). In a separate line of investigation we were the first to show the ability of
the AMP-activated protein kinase pathway to counteract lipid induced insulin
resistance in a tissue-selective manner. We established the importance of AMPK
activation as a contributing mechanism to actions of thiazolidinediones and metformin
(common anti-diabetic drugs) in liver and muscle. In addition studies were started to
identify new anti-diabetic compounds based on traditional Chinese medicines.
Collectively these open the way for development of new anti-diabetic therapies that
might help overcome limitations in current therapeutic approaches.
Expected future outcomes:
We have development a number of unique methodologies for application to the
preclinical area of new drug development for diabetes and related metabolic disorders.
These have helped clarified metabolic actions of current "insulin sensitising" agents
and should prove extremely valuable in the future to explore new therapeutic
approaches.
Name of contact: Prof Edward Kraegen
Email of contact: e.kraegen@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 325625
CIA Name: Prof Edward Kraegen
Main RFCD: Endocrinology
Admin Inst: Garvan Institute of Medical Research
Start Year: 2005
End Year: 2007
Total funding: $454,500.00
Grant Type: NHMRC Project
Grants
Title of research award:
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
NHMRC Research Achievements - SUMMARY
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 20082010 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.
Name of contact: Edward Kraegen
Email of contact: e.kraegen@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 535949
CIA Name: A/Pr Jerry Greenfield
Main RFCD: Endocrinology
Admin Inst: Garvan Institute of Medical Research
Start Year: 2009
End Year: 2012
Total funding: $397,444.00
Grant Type: NHMRC Project
Grants
Title of research award:
Effect of oral glutamine on GLP-1 and insulin secretion and glycaemia in humans.
Lay Description (from application):
Diabetes is an ever increasing problem with serious complications. We will
investigate whether glutamine, one of the most common amino acids (protein building
blocks) in the body, has a beneficial effect on blood glucose and insulin levels in the
body in people who have type 2 (non-insulin dependent) diabetes. If so, glutamine
supplementation may represent a novel, cheap and palatable way of improving
outcomes and preventing the development of complications in people with type 2
diabetes.
Research achievements (from final report):
Insulin is secreted from the beta cells in the pancreas in response to a meal. In type 2
diabetes patients, the insulin secretory response to a meal is impaired. Incretins are
hormones secreted from the gut in response to a meal that potentiate secretion of
insulin from the pancreas. One such incretin is glucagon-like peptide-1 (GLP-1).
Increasing GLP-1 in the bloodstream in type 2 diabetes is a way of lowerring glucose
levels. The amino acid glutamine has been reported to increase secretion of GLP-1
from cells and, in a previous project, we demonstrated that ingestion of glutamine
increased GLP-1 release in obese and non-obese humans with and without type 2
diabetes. Interestingly, the concentration of glutamine in the blood is low in type 2
diabetes patients compared with healthy individuals. In one study, which has already
been published, we found that glutamine, when given with a low-fat meal to patients
with type 2 diabetes (n = 15), decreased glucose excursions in parallel with increases
in insulin and GLP-1. In another study of 13 well-controlled type 2 diabetic patients,
we demonstrated that glycaemic control was improved when glutamine was
administered twice daily for a month. This effect may be attributed to: (i) increasing
the time to release nutrietnts from the stomach to the blood stream; and/or (ii) a direct
effect on the pancreas to secrete more insulin. We are currently finalising a third
study, in which we are investigating the effect of glutamine on insulin secretion in
type 2 diabetes patients. In 2 other studies, performed with our collaborators in
Adelaide, we have studied the effect of glutamine on how fast the stomach empties
and which part of the gut is important in mediating the effects of glutamine in relation
to GLP-1 secretion.
Expected future outcomes:
The expected outcome of the project is to demonstrate the naturally-occurring amino
acid glutamine to be a novel method of stimulating secretion of GLP-1 and perhaps,
improving glycaemic control in type 2 diabetes.
Name of contact: Jerry Greenfield
Email of contact: j.greenfield@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 276430
CIA Name: Prof Edward Kraegen
Main RFCD: Endocrinology
Admin Inst: Garvan Institute of Medical Research
Start Year: 2004
End Year: 2006
Total funding: $481,500.00
Grant Type: NHMRC Project
Grants
Title of research award:
Role 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 lipidassociated 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 over-
NHMRC Research Achievements - SUMMARY
expressed 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 Akt-1 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.
Name of contact: Prof Edward Kraegen
Email of contact: e.kraegen@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 358307
CIA Name: Dr Cecile King
Main RFCD: Autoimmunity
Admin Inst: Garvan Institute of Medical Research
Start Year: 2005
End Year: 2007
Total funding: $519,000.00
Grant Type: NHMRC Project
Grants
Title of research award:
The role of Interleukin-21 in the pathogenesis of autoimmune diabetes
Lay Description (from application):
T cells are a component of our blood (white blood cells) and a major component of
the body's defense system against infection, known as immunity. Without T cells, we
would fail to resist infection by foreign agents, such as viruses, bacteria and fungi.
Autoimmune (type 1) diabetes is a disease in which T cells attack our own pancreatic
islet self tissues as if they were foreign. T cells that react against the islets of the
pancreas cause destruction of the insulin producing beta cells so that the pancreas can
no longer make insulin. Diabetes is a life-threatening disease because insulin is a
hormone that enables people to get energy from food. Type 1 diabetes is usually
diagnosed in childhood and insulin must be administered daily by injection or through
a pump in order to survive. Unfortunately, taking insulin doesn t cure diabetes and
people continue to suffer from an extensive list of complications affecting most vital
organs. Interleukin-21 (IL-21) is a soluble protein that is produced by cells enabling
them to communicate with other cells. IL-21 helps cells to produce factors that cause
inflammation and assist in clearance of viruses and bacteria from the body. However,
our studies show that IL-21 is a major factor in the development of the T cells that
destroy beta cells and cause diabetes. Our studies show that IL-21 is over-expressed in
an important murine model of spontaneous type-1 diabetes. We have isolated the T
cells that cause diabetes and show that they are distinguished from other T cells by
very high levels of the receptor for IL-21. This project focuses on the IL-21responsive T cells that cause diabetes and aims to determine the mechanisms by
which the cytokine IL-21 causes destructive immune responses and ways to modulate
its production. This project applies basic science to the important public health issue
of type 1 diabetes for the development of therapeutic intervention strategies.
Research achievements (from final report):
The cytokine growth factor interleukin-21 (IL-21) has an important role in both
immunity and autoimmunity.
Our data has shown that IL-21 is a growth/survival factor for a specialised subet of
cells known as T follicular helper cells.
T follicular helper cells orchestrate the production of high affinity antibodies by B
cells in specialised structures in lymphoid organds known as germial centers.
Our data suggests that potentiating the effects of IL-21 may improve vaccination
protocols and inhibiting its actions may be useful in autoimmune diseases that have
dysregulated antibody production (such as Lupus).
Data obtained from this grant proposal demonstrate that IL-21 is important in organspecific autoimmune disease: the type-1 diabetes-susceptible NOD mouse produces
abnormally large amounts of IL-21.
The abundance of IL-21 produced was due to a mutation in thepromoter region IL-21
gene that ensured increased expression.
NHMRC Research Achievements - SUMMARY
Production of IL-21 was increased in T cells in the blood and pancreas just before the
onset of diabetes. This suggests that the measurement of IL-21 could be a predictive
marker for the onset of T1D.
We have demonstrated for the first time that short-term neutralization of IL-21
abolishes immune cell infiltration in the islets and prevents diabetes in the NOD
mouse. The ability of short-term blockade of a single cytokine to have this profound
effect is very impressive.
The inhibition of IL-21 signaling through its receptor starves diabetes-causing T cells
of their growth/surival factor IL-21.
Both the production of IL-21 by CD4+ T cells and receptiveness to IL-21 by CD8+ T
cells were found to be necessary for the destruction of insulin-producing islets and
subsequent diabetes.
These studies reveal a network in which IL-21 produced by CD4+ T cells provides a
soluble helper signal that ensures the survival of self-tissue destrcutive CD8+ T cells
in non-lymphoid tissues.
Expected future outcomes:
IL-21 has equivalent effects on the immune system in mouse and humans. Therefore,
we think that neutralization of IL-21 has great therapeutic potential in humans for (1)
the treatment of T1D and (2) the protection of transplanted islets. In addition (3)
boosting IL-21's effects has potential application as a vaccine adjuvant.
Name of contact: Dr Cecile King
Email of contact: c.king@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 427610
CIA Name: Prof Trevor Biden
Main RFCD: Protein Targeting and Signal Transduction
Admin Inst: Garvan Institute of Medical Research
Start Year: 2007
End Year: 2011
Total funding: $618,722.00
Grant Type: Established
Career Fellowships
Title of research award:
Uncoupled Research Fellowship
Lay Description (from application):
I am a biochemist/cell biologist primarily investigating pancreatic beta cell biology
and diabetes as a function of signal transduction pathways.
Research achievements (from final report):
Firstly, we have identified ER stress as a major and unexpected response, accounting
for >20% of the total alterations in gene expression occurring following exposure to
palmitate but not oleate. Using a variety of techniques we confirmed that ER stress
does indeed occur, not only in vitro, but also in pancreatic islets of db/db mice, a
model of T2D. In addition, by performing immunohistochemistry on archival
pancreatic tissue, we showed for the first time that ER stress occurs in human T2D.
Because only saturated FAs are cytotoxic, whereas both unsaturated and saturated
FAs cause secretory dysfunction, we believe that our results are profoundly relevant
to the processes whereby b-cell mass is decreased in T2D. This paper has received
more than 220 citations. Subsequent studies in this area demonstrated that a selective
block in ER-to-golgi protein trafficking contributed mechanistically to the induction
of ER stress, and this was secondary to alterations in sphingolipid metabolism as
assessed via a comprehensive lipidomic screen.
With regard to secretory alterations, we made the unexpected finding that ablation of
PKCe reverses the effects of chronic lipid exposure. These findings were made using
in vivo, and ex vivo approaches, and were confirmed using a small molecule inhibitor
of PKCe in the db/db mouse model of T2D. This was a major discovery with
implications regarding both our understanding of the mechanisms underlying b-cell
dysfunction, and the development of new therapies to treat T2D. Subsequently we
demonstrated that alterations in neutral lipid turnover (esterification and lipolysis)
contributed to the mechanism of action of PKCe deletion.
Other studies focused on the mechanism of action of PKCd in both pancreatic islets in
models of Type 1 diabetes, and in liver in models of Type 2 diabetes. In both
instances results suggest that inhibition of this PKC might be therapeutically
beneficial.
Expected future outcomes:
We are uniquely placed to elaborate defects in pancreatic beta cell dysfunction in the
areas of both insulin secretory failure and loss of beta cell mass. Firstly, we have
generated mice for selectively deleting PKCe in different tissues and will use these to
further characterize underlying mechanisms. Secondly, we are pursuing the nexus
between sphingolipid metabolism, ER stress and apoptosis.
NHMRC Research Achievements - SUMMARY
Name of contact: Trevor Biden
Email of contact: t.biden@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 145702
CIA Name: Prof Patrick Sexton
Main RFCD: Basic Pharmacology
Admin Inst: Howard Florey Institute
Start Year: 2001
End Year: 2003
Total funding: $392,037.00
Grant Type: NHMRC Project
Grants
Title of research award:
G-protein receptor interaction
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. It is extremely important to unravel how each of
these components, the stimulating agent, the receptor and G protein, works in order to
understand how the cells respond to various chemical signals. 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. Understanding what actually is the role of these new players, and
how they team-up with the other components to elicit a specific response to a
chemical stimulus, forms the basis of this 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):
This work led to new understanding on the importance of accessory protein
interaction with G protein coupled receptors (the major sites of pharmaceutical drug
interaction). Further work will include examining the mechanisms that underlie
RAMP-induced changes in signalling. This work is important for understanding how
this important class of receptors function.
Expected future outcomes:
N/A
Name of contact: N/A
Email of contact: N/A
NHMRC Research Achievements - SUMMARY
Grant ID: 145703
CIA Name: Prof Patrick Sexton
Main RFCD: Basic Pharmacology
Admin Inst: Howard Florey Institute
Start Year: 2001
End Year: 2003
Total funding: $227,037.00
Grant Type: NHMRC Project
Grants
Title of research award:
Analysis of calcitonin - receptor interactions
Lay Description (from application):
Receptors form a basic intermediary as the acceptor site for signals that are
transmitted between the cells that make up our body. Modulation of receptors,
therefore, forms a key target in our ability to treat disease. The largest class of
receptors is the superfamily of G protein-coupled receptors (GPCRs), which transmit
signals within a cell via proteins called G proteins. GPCRs form between 1 and 5% of
the entire repertoire of human genes. One group of GPCRs provide the target for
small protein molecules that circulate through the body. One such circulating
molecule is calcitonin, a peptide that plays an important role in maintaining
circulating calcium levels in the body, which is essential for proper maintenance of
the skeleton. As a consequence of this action, calcitonin is an important clinically
used tool in the treatment of bone disease such as osteoporosis and Paget's disease.
Due to the molecular nature of calcitonin and its receptor (and other related receptors)
that have a broad, complex mechanism of interaction, we have very little definitive
information on how calcitonin interfaces with its receptor to signal to target cells. The
current project utilises a novel method of permanently linking calcitonin to its
receptor, allowing identification of how the two components come together. This
information provides important fundamentals for understanding how this and related
receptors work and the potential for rational design of improved therapeutic tools.
Research achievements (from final report):
The work has provided advances in knowledge of how calcitonin peptides (which are
used therapeutically to treat bone diseases including osteoporosis and Paget’s disease)
interact with their cognate receptors. This, together with ongoing work, is contributing
to dynamic models of how peptide hormones interact with receptors (which is poorly
understood due to lack of high resolution structural information). It has implications
for the mode of action of both calcitonin peptides, but also more broadly for the mode
of action of other related peptide hormone receptors.
Expected future outcomes:
N/A
Name of contact: N/A
Email of contact: N/A
NHMRC Research Achievements - SUMMARY
Grant ID: 233200
CIA Name: Prof Paul Zimmet AO
Main RFCD: Epidemiology
Admin Inst: International Diabetes Institute Inc
Start Year: 2003
End Year: 2007
Total funding: $2,677,855.00
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 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
NHMRC Research Achievements - SUMMARY
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 of contact: jonathan.shaw@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 226911
CIA Name: Prof Alan Baxter
Main RFCD: Immunogenetics
Admin Inst: James Cook University
Start Year: 2003
End Year: 2005
Total funding: $235,500.00
Grant Type: NHMRC Project
Grants
Title of research award:
Functional genomic analysis of the NKT cell control locus Nkt1 and the Bana3/Babs2
lupus susceptibility locus
Lay Description (from application):
The major populations of white blood cells responsible for "learned" immunity are the
B cells, which make antibody against microorganisms like bacteria, and the T cells,
which kill virally infected cells and help B cells produce antibody. The T and B cells
occasionally attack the body's own tissues, resulting in autoimmune diseases such as
lupus, in which antibodies are deposited in the tissues causing inflammation in organs
such as the brain, skin and especially the kidneys. Another population of white blood
cells, termed NKT cells, plays an important role in keeping the T and B cells in check,
and we have found that these cells are deficient in an inbred mouse strain, NOD mice,
which develop lupus after exposure to a particular type of bacteria, called
mycobacteria. We have found that one of the major genes conferring susceptibility to
lupus in these mice lies in the same genetic region as the major gene controlling NKT
cell numbers, raising the possibility that the deficiency in NKT cells in this strain
predisposes it to developing lupus. The experiments proposed for this project are
divided into two groups. The first group test whether increasing NKT cell numbers by
either injecting them, or else transferring genes that allow more to develop naturally,
can affect the risk of developing lupus. The second group of experiments examine the
potential roles of two specific genes which are in the genetic region of interest, and
which we think might control both NKT cell numbers and lupus susceptibility. The
approach to be used involves sophisticated techniques of genetic analysis, such as the
use of mutant mice which carry genetic mutations near the relevant genes, and
congenic mice, which are like NOD mice, but carry in addition to NOD genes, genetic
regions from a non-autoimmune strain.
Research achievements (from final report):
Congenic and mutant mouse lines bearing genes affecting risk of developing diabetes
and lupus were produced and analysed.
Expected future outcomes:
Improved characterisation of genetic control of FasL expression, a factor that may
affect disease susceptibility.
Name of contact: Alan Baxter
Email of contact: Alan.Baxter@jcu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 137811
CIA Name: Prof Alan Baxter
Main RFCD: Autoimmunity
Admin Inst: James Cook University
Start Year: 2001
End Year: 2005
Total funding: $692,040.00
Grant Type: NHMRC Project
Grants
Title of research award:
Functional Genomic Analysis of NK and NKT Cell Immune Control of
Autoimmunity
Lay Description (from application):
The major populations of white blood cells responsible for learned immunity to are
the B cells, which make antibody against microorganisms like bacteria, and the T
cells, which kill virally infected cells and help B cells produce antibody. The T and B
cells occasionally attack the body s own tissues, resulting in autoimmune disease.
These diseases include type 1 diabetes, lupus, and anaemia, and collectively represent
the third commonest cause of morbidity and mortality in humans. The major reason
why autoimmunity occurs is thought to be due to a failure in the mechanisms
responsible for controlling such unwanted responses. Two other populations of white
blood cells are involved in this regulation, termed NK and NKT cells, each of which
release important cell hormones. The current project is designed to test whether
defects in NK and NKT cells lead to autoimmune disease. For this purpose a special
strain of mice (NOD mice) will be used. The reasons for their selection are: 1) they
are highly susceptible to a range of autoimmune diseases including diabetes, lupus
and anaemia, and 2) we and others have found that they are deficient in both NK and
NKT cells. The proposed experiments are divided into two groups, one designed to
characterise the nature of the defects in these cells and the other to identify the genes
responsible for them. In this way it should be possible to shed light on the genetic
basis of autoimmune diseases in general. The approach to be used involves
sophisticated techniques of genetic analysis, which require production of special
congenic lines of mice. These mice are like NOD mice but carry in addition to NOD
genes genetic regions from a non-autoimmune strain with the potential to correct the
defects in NK and NKT cells. In this way, it should be possible to pinpoint the disease
susceptibility genes involved in causation of autoimmunity and to work out how they
affect NK and NKT cells.
Research achievements (from final report):
The aim of this project was to characterise the genes that control the numbers and
function of lymphocytes of the innate immune system, termed NK and NKT cells. A
series of congenic mouse stocks were generated and analysed. These studies provided
an improved understanding of the regulation of these cell types and provided the basis
of ongoing studies to identify and sequence the genes involved.
Expected future outcomes:
Cloning and sequencing of immune control genes.
Name of contact: Alan Baxter
Email of contact: Alan.Baxter@jcu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 279408
CIA Name: Prof Jonathan Golledge
Main RFCD: Surgery
Admin Inst: James Cook University
Start Year: 2004
End Year: 2006
Total funding: $299,250.00
Grant Type: NHMRC Project
Grants
Title of research award:
Role 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 buildup. 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 of contact: jonathan.golledge@jcu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 279402
CIA Name: Prof Robyn McDermott
Main RFCD: Epidemiology
Admin Inst: James Cook University
Start Year: 2004
End Year: 2007
Total funding: $1,493,700.00
Grant Type: NHMRC Project
Grants
Title of research award:
Follow-up study of Indigenous adults in north Queensland: Chronic diseases and
sexual health
Lay Description (from application):
This study aims to follow up a cohort of Indigenous adults in rural and remote north
Queensland communities who participated in the "Well Persons Health Check"
(funded by OATSIH) during 1998-2000. Out of the 2,862 Indigenous participants,
2,503 (87.5%) agreed to have another Check in a few years time. A follow-up study
is proposed for the consenting WPHC participants (any any other adults who wish to
participate). This study will have 5 main objectives: 1. Estimate the incidence rate of
chronic disease conditions (diabetes, renal disease, CVD) and the main determinants
of these in the north Queensland cohort (It is expected that Torres Strait Islanders will
have different patterns to Aborigines), 2. Estimate the change over a 5 year period
in risk factors and complications (including hospitalisations) of those with existing
chronic conditions 3. At a community level, evaluate the effectiveness of local
interventions aimed at health improvement (e.g. one community has drastically
changed rules about alcohol availability, other communities have significantly
improved the supply of fresh fruit and vegeta4. Estimate whether the early detection
of chlamydia and gonorrhoea (using routine urine PCR testing) has lowered the
community prevalence of bacterial STIs, and bles, still others have commenced
family savings programs which improve the availability of money over the week and
enable savings to buy fridges etc). 5. Evaluate the effectiveness of local health
promotion programs (e.g. tobacco control initiatives, healthy weight programs). The
study will be undertaken in collaboration with Apunipima Cape York Health Council,
the Torres Strait Health Council and relevant local community organisations. It will
involve skills development for local Indigenous researchers and practitioners. Results
will be given back to communities and individuals, with opportunities for further
planning.
Research achievements (from final report):
The Adult Health Check+ was a study that followed up Indigenous adults in 19
remote communities that had a health check under the Well Persons Health Check
(WPHC) program between 1998-2000. The purpose of the study was to look at
changes in health status that occurred since the Well Persons Health check. The
project commenced in 2004 and was completed in 2007. A total of 719 people or 40%
of the participants targeted for a follow up had a health check. 8% or 178 people who
participated in the WPHC screen have passed away since the WPHC study and 712 or
32% of people had moved away from the area. The study found:
o Ninety-nine (99) new cases of diabetes
o One hundred (100) new cases of high blood pressure.
o Fifty-five (55) new cases of renal disease.
NHMRC Research Achievements - SUMMARY
o
Younger people gained more weight and had a greater increase in waist size
than did older people.
o
The rate of smoking in the Adult Health Check+ cohort is more than twice the
Australian rate.
o Over half of the people who said they drank alcohol were risky drinkers.
o
People increased their intake of vegetables, but on average are still eating
much less fruit and vegetables than is recommended for good health.
o
Overall people have increased their physical activity but a only about half are
doing enough physical activity for good health.
These results will help the individual participants make decisions about their own
health and inform planning for service development.
Expected future outcomes:
o
This research evidence will continue to inform Indigenous health policy and
chronic disease strategies for Queensland's remote communities
o
Feedback to individuals enables their active participation in prevention and
management of chronic and communicable diseases.
o
Two Indigenous PhD students will base their studies on this research data.
Name of contact: Professor Robyn Mcdermott
Email of contact: robyn.mcdermott@unisa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 487311
Start Year: 2008
CIA Name: Dr Hamsa Puthalakath
End Year: 2011
Main RFCD: Cell Development (incl. Cell Division and Apoptosis)
Total funding:
$558,189.00
Admin Inst: La Trobe University
Grant Type: NHMRC Project
Grants
Title of research award:
DETERMINING 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 of contact: h.puthalakath@latrobe.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 365225
Start Year: 2006
CIA Name: Prof David Power
End Year: 2008
Main RFCD: Nephrology and Urology
Total funding: $401,523.00
Admin Inst: Macfarlane Burnet Institute for Medical Research and Public Health
Grant Type: NHMRC
Project Grants
Title of research award:
AMP-activated protein kinase (AMPK) in acute renal failure
Lay Description (from application):
Acute renal failure is a common complication of any severe illness. Generally, it is the
lack of blood flow, or "food" that leads to this problem. People who are ill are unable
to provide adequate blood flow to their kidneys, so the kidneys become diseased and
fail to function. This can be fatal. There are, however, mechanisms in the kidney that
are designed to avoid this shortage of energy. The aim of these studies is to find out
what these protective mechanisms usually do in the kidney, and understand why they
are not more active. We hope to find ways to switch them on earleir, using drugs, so
as to protect the kidneys from injury.
Research achievements (from final report):
We have identified a novel site for a protein that senses the amount of energy in the
body, called AMPK. We found that it helps to control the way that the body deals
with salt; how it conserves and excretes it. This research suggests that conserving salt
should be seen as 'work' that the kidney performs to maintain a normal blood pressure.
The link between energy conservation and salt excretion by the kidney also suggests a
new way that blood pressure and metabolic diseases such as obesity might be linked.
In a separate line of enquiry, we have also found that this protein called AMPK can be
bad when the kidney is stressed. Whether this has anything to do with the ability of
high blood pressure to damage the kidney is unknown, but something that we are
interested in studying.
Expected future outcomes:
We might be able to devise new ways to reduce blood pressure by ddsigning drugs
acting on AMPK.
Name of contact: David Power
Email of contact: david.power@austin.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 544923
CIA Name: Prof Alison Venn
Main RFCD: Epidemiology
Admin Inst: Menzies Research Institute
Start Year: 2009
End Year: 2011
Total funding: $360,326.00
Grant Type: NHMRC Project
Grants
Title of research award:
Inter-relationships 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 of contact: Alison.Venn@utas.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 457603
CIA Name: Prof Michael Clark
Main RFCD: Endocrinology
Admin Inst: Menzies Research Institute
Start Year: 2007
End Year: 2009
Total funding: $433,973.00
Grant Type: NHMRC Project
Grants
Title of research award:
Central 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:
NHMRC Research Achievements - SUMMARY
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 of contact: S.Rattigan@utas.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 361617
CIA Name: Prof Kerin O'Dea
Main RFCD: Indigenous Health
Admin Inst: Menzies School of Health Research
Start Year: 2005
End Year: 2005
Total funding: $8,318.00
Grant Type: International
Collaborations
Title of research award:
Community 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 of contact: kod@medstv.unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 545202
CIA Name: A/Pr Louise Maple-Brown
Main RFCD: Nephrology and Urology
Admin Inst: Menzies School of Health Research
Start Year: 2009
End Year: 2012
Total funding: $959,349.00
Grant Type: NHMRC Project
Grants
Title of research award:
To improve the accuracy and precision of estimated GRF (eGFR) measurements in
Indigenous Australians
Lay Description (from application):
There is an overwhelming burden of chronic disease in Indigenous Australians. In
order to attempt to improve kidney disease in this high-risk population, it is vital that
we are able to accurately measure kidney function. This study will provide evidence
to accurately assess kidney function in Indigenous Australians. This will then enable
development of appropriate clinical guidelines and more effective monitoring of
future interventions to slow progression of kidney disease.
Research achievements (from final report):
We have reported that the standard test of kidney function (estimated Glomerular
Filtration Rate, eGFR) is accurate in Indigenous Australians. In particular, the
recently recommended formula to be used for eGFR (known as the CKD-EPI
formula) was found to be an accurate and reliable test of kidney function in
Indigenous Australians, similar to reports that it is accurate and reliable in nonIndigenous Australians. Thus, health care providers can use the kidney function test
across Australia with confidence and in addition, can now more accurately track the
progression of kidney disease. In the United States, the formula includes a correction
factor for African Americans, however we have reported that this correction factor
should not be used in the assessment of kidney function in Indigenous Australians.
Further work is in progress to assess whether the eGFR equation could be improved
by incorporation of a measure of fat-free mass, and/or use of an alternative
biochemical measure such as creatinine.
Expected future outcomes:
The eGFR Study cohort of 600 Indigenous Australians was established by this grant
and work is now in progress to follow-up this cohort 2-4 years after baseline. Thus
future outcomes include work assessment of progression of kidney damage in this
high risk population.
Name of contact: Dr Louise Maple-Brown
Email of contact: louise.maple-brown@menzies.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 436011
CIA Name: Dr Gurmeet Singh
Main RFCD: Indigenous Health
Admin Inst: Menzies School of Health Research
Start Year: 2007
End Year: 2009
Total funding: $505,213.00
Grant Type: NHMRC Project
Grants
Title of research award:
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.
NHMRC Research Achievements - SUMMARY
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 age-matched nonAboriginal males and females living in Darwin.
Name of contact: Gurmeet Singh
Email of contact: gurmeet.singh@menzies.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 124319
CIA Name: Prof Kerin O'Dea
Main RFCD: Indigenous Health
Admin Inst: Menzies School of Health Research
Start Year: 2001
End Year: 2004
Total funding: $1,699,292.00
Grant Type: NHMRC Project
Grants
Title of research award:
Community-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 communitydriven 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
NHMRC Research Achievements - SUMMARY
and the major providers of food in the community (store, take-aways, 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: Kerin O'dea
Email of contact: kod@medstv.unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 236207
CIA Name: A/Pr Joan Cunningham
Main RFCD: Indigenous Health
Admin Inst: Menzies School of Health Research
Start Year: 2003
End Year: 2004
Total funding: $1,116,053.00
Grant Type: NHMRC Project
Grants
Title of research award:
The DRUID Study: Diabetes and related disorders in urban Indigenous people in the
Darwin region.
Lay Description (from application):
Indigenous Australians suffer a high burden of ill health from diabetes and related
conditions, but very little is known about the burden of diabetes and its complications
among Indigenous people in urban areas, and how to reduce it. Unlike Indigenous
people in rural and remote areas, Indigenous people in urban areas (the majority of
Indigenous Australians) have rarely been the subjects of health research and have
even more rarely been the drivers of such research. The DRUID Study (Diabetes and
Related Disorders in Urban Indigenous People in the Darwin Region) is a partnership
between researchers and members of the Darwin Indigenous community to: examine
the health of adults aged 15 years and over; refer people with disease to appropriate
health care and related services; follow people over time to collect information on the
state of their health and their use of health services; and test the effectiveness of a
program to improve dietary quality, increase physical activity and reduce tobacco
smoking among those at highest risk for diabetes. The results will be of significant
value to policy-makers, health practitioners, researchers, and, most importantly,
Indigenous people and organisations. The study will provide the first-ever data on the
burden of diabetes and related conditions in an urban Indigenous population. This
information can be directly compared with recently collected national data from the
AusDiab study, and used to inform the development and implementation of strategies
for reducing the impact of diabetes and related conditions. The study will provide an
important vehicle for the training and development of Indigenous researchers, and the
central involvement of Indigenous people in the study will promote improved local
awareness and understanding of diabetes among Indigenous people and increase the
capacity of Indigenous people and service providers to manage diabetes and related
disorders.
Research achievements (from final report):
The DRUID Study was the largest research study to date on the health of urban
Indigenous adults in Australia, with over 1,000 Aboriginal and Torres Strait Islander
adults participating. The Study provides new information on the health and social
circumstances of a group about which little information has been available and which,
as a consequence, has been easy to ignore. DRUID participants underwent an
extensive health check, which included a diabetes test, measurement of body size and
blood pressure, several blood tests, a urine test, and a test for heart disease. They also
answered questionnaires about various topics including their health history, health
risk factors, psychosocial factors, and sociodemographic characteristics. People with
diabetes, whether previously known or newly diagnosed, had extra tests to see
whether they had developed complications of diabetes. All participants received
feedback on their own results, plus specifically targeted health information, and were
NHMRC Research Achievements - SUMMARY
referred to a health care provider as necessary. With permission, we also provided
results to the participant's own doctor or clinic, so they could discuss the results
together. In addition to providing people with important health information, the study
also provided training, employment and educational opportunities for 14 Indigenous
staff members and one Indigenous PhD student, some of whom have continued on in
research. We have presented the preliminary results to partner organisations,
community groups and participants, and have begun extensive analysis of the data.
We will work closely with health policy-makers and service providers over the
coming months and years to use the results of the study in a positive way to improve
the health and wellbeing of Indigenous people in the Darwin region and beyond.
Expected future outcomes:
Analysis of this extremely rich data set about the health and social circumstances of
Indigenous adults in an urban area is expected to yield increased understanding in a
diverse range of areas, including chronic diseases, women's reproductive health,
discrimination and stress, health behaviours, etc. It also provides a platform for
targeted interventions in this population.
Name of contact: Joan Cunningham
Email of contact: joanc@menzies.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 384149
CIA Name: Prof Tony Tiganis
Main RFCD: Protein Targeting and Signal Transduction
Admin Inst: Monash University
Start Year: 2006
End Year: 2010
Total funding: $548,878.00
Grant Type: Established
Career Fellowships
Title of research award:
Uncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
One of our key findings in the last five years has been in delineating the potential
beneficial effects of reactive oxygen species in insulin sensitivity and consequentially,
the potentially detrimental effects of antioxidants in the development of type 2
diabetes.
Expected future outcomes:
Delineating the precise nature by which reactive oxygen species can be both good and
bad.
Name of contact: N/A
Email of contact: Tony.Tiganis@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 427620
CIA Name: Prof Charles Mackay
Main RFCD: Autoimmunity
Admin Inst: Monash University
Start Year: 2007
End Year: 2011
Total funding: $16,509,154.00
Grant Type: Programs
Title of research award:
Molecular and cellular studies of the adaptive immune response in health and disease
Lay Description (from application):
Immune responses protect us against pathogens such as viruses and bacteria.
However inappropriate immune responses can result in autoimmune conditions such
as systemic lupus erythmatosus, multiple sclerosis, type I diabetes, asthma as well as
immunodeficiencies. The aim of our proposal is to gain a thorough understanding of
how all the cells of the immune system function and interact with each other, and
what goes wrong when inflammatory diseases develop. We plan to do this using
state-of-of-the-art technologies, including genetically modified mice, gene
microarrays, monoclonal antibodies, and flow cytometry. We have brought together
Australia's leading immunologists with complimentary expertise and research
interests in specific areas of immunology including cytokines, cell migration,
inflammatory diseases, autoimmunity and cell-cell interactions. One aspect of the
application is to understand the genetic and molecular basis of immunological
diseases. However we also wish to move on from an understanding to treatment of
immunological diseases through the development of novel therapeutics. We will form
collaborations with biotech and pharmaceutical companies (including our own spin
off companies) to advance important new therapeutics for autoimmune and allergic
diseases. These conditions represent a significant health burden to Australia.
Research achievements (from final report):
The team has achieved numerous high impact publications on mechanisms
contributing to immune responses including inflammatory responses such as
autoimmunity (lupus, MS, rheumatoid arthritis etc). This may have considerable
significance, as this information may feed through to the development of new
therapies for these diseases.
Expected future outcomes:
We have uncovered important mechanistic insight into the pathogenesis of
autoimmune diseases and other inflammatory diseases. Expected outcomes will be
new treatments for autoimmune diseases and allergy/asthma, and several programs
with pharmaceutical companies are progressing, partcularly around C5aR
Name of contact: Charles Mackay
Email of contact: charles.mackay@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 491123
CIA Name: Prof Leon Bach
Main RFCD: Endocrinology
Admin Inst: Monash University
Start Year: 2008
End Year: 2010
Total funding: $493,221.00
Grant Type: NHMRC Project
Grants
Title of research award:
The role of ezrin-radixin-moesin proteins, novel binding proteins for advanced
glycation endproducts, in kidney cells
Lay Description (from application):
High glucose levels in diabetes react with proteins to form AGEs and it is thought that
this reaction may lead to kidney damage, which is one of the complications of
diabetes. However, how this damage occurs is not completely understood. Cells
need to maintain their shape and position for an organ to stay healthy. We have
shown that AGEs affect kidney cells by interacting with and disturbing the function of
proteins that maintain cell shape. We now want to study how this occurs.
Research achievements (from final report):
We have defined the nature of an interaction between proteins that are modified by
the high glucose levels in diabetes and another protein that regulates important
cellular functions in kidney cells. Glucose-modified proteins interfere with the actions
of the regulatory protein and increase its breakdown. This interaction may contribute
to kidney damage caused by diabetes.
Expected future outcomes:
If the role of the above interaction in diabetic kidney disease is confirmed, it may
lead to new treatments for this condition.
Name of contact: Leon Bach
Email of contact: leon.bach@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 436866
CIA Name: Prof Andrew Forbes
Main RFCD: Epidemiology
Admin Inst: Monash University
Start Year: 2007
End Year: 2008
Total funding: $188,538.00
Grant Type: NHMRC Project
Grants
Title of research award:
Fitness 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 of contact: Andrew.Forbes@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 384146
CIA Name: A/Pr Tony Tiganis
Main RFCD: Endocrinology
Admin Inst: Monash University
Start Year: 2006
End Year: 2008
Total funding: $503,776.00
Grant Type: NHMRC Project
Grants
Title of research award:
Regulation of insulin signalling & glucose homeostasis by protein tyrosine
phosphatases
Lay Description (from application):
Type 2 diabetes has reached epidemic proportions afflicting roughly 6% of the adult
population in Western society. Although the underlying genetic causes & the
associated pathological symptoms are heterogenous, a common feature is high blood
glucose due to peripheral insulin resistance. The molecular basis of insulin resistance
is believed to be attributable to defects in insulin receptor (IR) signalling. The IR is a
protein tyrosine kinase that phosphorylates itself & downstream substrates on tyrosine
in response to insulin. Protein tyrosine phosphatases (PTPs) that dephosphorylate the
IR & its substrates might be important targets for therapeutic intervention in type 2
diabetes; inhibition of specific PTPs may allow for enhanced insulin-induced
signalling to alleviate insulin resistance. This proposal will examine the roles of PTPs
and in particular TCPTP in IR signalling in vivo. Our studies will shed light on the
molecular mechanisms of IR regulation & function & may provide important insights
into novel strategies for enhancing insulin sensitivity in type 2 diabetes.
Research achievements (from final report):
The liver is an important tissue for the control of blood glucose levels during periods
of starvation and fasting. The liver generates glucose during periods of starvation.
This study has demonstarted that the enzyme TCPTP acts in the liver to control
glucose generation. Our studies suggest that inhibiting TCPTP in the liver in type 2
diabetes may provide a means by which to lower blood glucose levels and attenuate
the fasting hyperglycemia that characterises this disease.
Expected future outcomes:
Identify TCPTP as an important regulator of hepatic gluconeogenesis and as
therapeutic target for the treatment of type 2 diabetes
Name of contact: Tony Tiganis
Email of contact: Tony.Tiganis@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 545945
CIA Name: Prof Jennifer Wilkinson-Berka
Main RFCD: Endocrinology
Admin Inst: Monash University
Start Year: 2009
End Year: 2011
Total funding: $511,295.00
Grant Type: NHMRC Project
Grants
Title of research award:
Aldosterone inhibition and diabetic retinopathy: Treatments and mechanisms of
action
Lay Description (from application):
The World Health Organization predicts that by 2030, more than 360 million people
will have diabetes. Despite almost all patients developing retinopathy, current
treatments do not prevent disease progression. One strategy being evaluated is
blockade of a hormone called angiotensin II. We have new evidence that a related
system called aldosterone exists in retina and contributes to damage. This project will
determine if aldosterone blockade is a potential treatment for diabetic retinopathy.
Research achievements (from final report):
We made the novel discovery of a local aldosterone system in the retina, and that
nhibition of this system at various levels including the mineralocorticoid receptor and
aldosterone production reduced retinal vascular pathology. These findings may be
important for the development of improved treatments for retinopathy which involve
blockade of the renin-angiotensin aldosterone system. We have also evaluated the
mechanisms by which aldosterone influenced retinopathy and have on-going studies
in this area.
Expected future outcomes:
The expected future outcomes of this work is to identify the various actions of
aldosterone in the retina which are likely to include both physiological and
pathophysiological processes. Whether inhibition of aldosterone or the
mineralocorticoid receptor is a useful adjunct treatment for retinal vasculopathy is still
to be fully understood and is being evaulated in on-going studies.
Name of contact: Jennifer Wilkinson-Berka
Email of contact: jennifer.wilkinson-berka@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 436740
CIA Name: Dr James Whisstock
Main RFCD: Enzymes
Admin Inst: Monash University
Start Year: 2007
End Year: 2009
Total funding: $500,460.00
Grant Type: NHMRC Project
Grants
Title of research award:
Structural and Functional Studies on Glutamate Decarboxylase.
Lay Description (from application):
This proposal aims to determine the molecular structure of the two known isoforms of
Glutamate Decarboxylase (GAD65 and GAD67). GAD in an essential human
enzyme that is responsible for synthesising the primary inhibitory neurotransmitter
gamma-aminobutyric acid (GABA). GABA functions in the human Central Nervous
System (CNS) to "dampen down" excitatory signals. Proper control of GABA
synthesis is important and perturbations in GABA levels lies behind human diseases
such as intractable epilepsy, depression and schizophrenia. As a result of this role,
numerous common therapeutics (for example benzodiazepines) target proteins
involved in the GABA neurotransmitter system. The goal of this proposal is to use
the molecular structures of GAD to understand how to achieve fine control of GABA
production. In addition to its role in the CNS, GAD is an important human
autoantigen. Antibodies to one isoform of GAD, GAD65, are found in most patients
with type I diabetes as well as certain patients with the movement disorder stiff person
syndrome and related diseases of the CNS. It is suggested that the development of
auto-antibodies may play a key role in the pathophysiology of these conditions.
Despite sharing >80% sequence similarity with GAD65, autoantibodies to the other
isoform of GAD, GAD67, are rarely found in patients with disease. The aim of this
grant is to characterise the region of GAD that is targetted by autoantibodes. These
data will allow us to understand why certain autoantibodes are able to inhibit GAD
enzyme activity and why GAD65, but not GAD67 is recognised by autoantibodes.
Research achievements (from final report):
We have determined the structure of both forms (GAD65 and GAD67) of the enzyme
that in humans produces the inhibitory neurotransmitter GABA. These data are the
subject of a number of high quality publications (including a paper in Nature
Structural and Molecular Biology as well as a patent (PCT)).
Perturbations in GABA levels are linked to important diseases, including depression
and anxiety disorders. Our structural data suggest that it may be possible to modulate
(increase) the activity of GAD65 with small molecule therapeutics and that GAD65
may be an important drug target.
Expected future outcomes:
We have estabished a crucial assay that will permit us to screen for small molecule
activtators of GAD65. We have recently obtained funding to perform this screen with
the long-term goal of developing a new class of drugs for the treatment of anxiety
disorders.
Name of contact: James Whisstock
NHMRC Research Achievements - SUMMARY
Email of contact: James.Whisstock@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 490998
CIA Name: A/Pr Sophia Zoungas
Main RFCD: Endocrinology
Admin Inst: Monash University
Start Year: 2008
End Year: 2011
Total funding: $143,661.00
Grant Type: Early Career
Fellowships (Australia)
Title of research award:
Glycaemia 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 of contact: sophia.zoungas@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 502607
CIA Name: Prof Matthew Watt
Main RFCD: Cell Metabolism
Admin Inst: Monash University
Start Year: 2008
End Year: 2010
Total funding: $323,453.00
Grant Type: NHMRC Project
Grants
Title of research award:
Adipose triglyceride lipase: regulation and implications for the aetiology of insulin
resistance
Lay Description (from application):
Obese individuals have elevated fat levels in the blood and muscle, which contributes
to the development of other diseases such as type 2 diabetes. A newly discovered
protein named adipose triglyceride lipase (ATGL) is essential for fat breakdown. This
project aims to identify how ATGL operates and determine whether defective ATGL
function leads to type 2 diabetes. These studies will assist in the development of
strategies aimed at reducing fatty acids in blood and muscle.
Research achievements (from final report):
We have shown that the protein adipose triglyceride lipase (ATGL) is important for
fatty acid metabolism in skeletal muscle and liver. Specifically, ATGL breaks down
triacylglycerol, resulting in reduced hepatic steatosis (fatty liver) and mild
improvement of liver insulin sensitivity, an effect that is sufficient to improve wholebody insulin resistance. Thus, ATGL may be a viable therapeutic target to reverse
fatty liver disease.
We have also identified novel phosphorylation sites in ATGL, which result in
activation of ATGL. This fundamental information is important for understanding
how the protein works and ways in which it could be manipulated to increase fat
break down.
Expected future outcomes:
These studies contribute to understanding how ATGL works and will provide insight
into designing therapies aimed at activating ATGL to enahnce fat breakdown.
Name of contact: Matthew Watt
Email of contact: matthew.watt@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 546027
CIA Name: Prof Matthew Watt
Main RFCD: Cell Metabolism
Admin Inst: Monash University
Start Year: 2009
End Year: 2011
Total funding: $358,319.00
Grant Type: NHMRC Project
Grants
Title of research award:
Circulating ceramides, inflammation and insulin resistance
Lay Description (from application):
Ceramides are a type of fat that are stored in the body. When people store too many
ceramides in their muscles and liver they no longer respond normally to insulin,
which leads to the development of type 2 diabetes. Ceramide levels are increased in
the blood of people with type 2 diabetes. The aim of the this project is to determine
whether ceramides in the blood contribute to type 2 diabetes and whether reducing
ceramide levels in the blood improves health.
Research achievements (from final report):
We have shown that a type of lipid (or fat) called ceramide circulates in the blood.
Ceramide is elevated in the low-density lipoporteins (LDL) of blood of patients with
type 2 diabetes compared with lean or obese people without diabetes. When ceramide
is infused into lean, healthy mice, these mice developed hallmarks of type 2 diabetes
including resistance to the actions of insulin and low grade inflammation. In addition,
we have shown that the liver is a major source of this ceramide. These newly
identified roles of blood ceramide suggest that strategies aimed at reducing liver
ceramide production or reducing ceramide packaging into LDL may improve some
features of diabetes pathologies.
Expected future outcomes:
Ongoing work will examine how to reduce blood ceramide production and also to
validate whether ceramides contained in high density lipoproteins a detrimental to
health.
Name of contact: Matthew Watt
Email of contact: matthew.watt@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 236869
CIA Name: A/Pr Tony Tiganis
Main RFCD: Endocrinology
Admin Inst: Monash University
Start Year: 2003
End Year: 2005
Total funding: $425,250.00
Grant Type: NHMRC Project
Grants
Title of research award:
Protein tyrosine phosphatases in the regulation of insulin receptor signalling and
glucose uptake
Lay Description (from application):
The key pathological feature of type II diabetes is the lack of cellular response to
normal levels of circulating insulin. Insulin binding to its cell surface transmembrane
receptor initiates a cascade of events known as cellular signalling that results in
amongst other things in the uptake of glucose. Protein tyrosine phosphatases (PTPs)
are key negative regulators of insulin-induced signalling events and their inhibition
with broad based chemical inhibitors can mimic several actions of insulin and lower
blood glucose levels in both normal and diabetic rats. This proposal will examine the
roles of PTPs and in particular TCPTP and PTP1B in insulin receptor-mediated
signalling and glucose uptake. Moreover we will explore the role of TCPTP in
alternate insulin receptor-independent processes for glucose uptake. Our studies will
shed light on processes important for the regulation of glucose uptake. Moreover our
studies may lead to the development of drugs capable of inhibiting PTPs such as
TCPTP, that may allow for enhanced glucose uptake and have therapeutic use in the
treatment of type II diabetes.
Research achievements (from final report):
Type 2 diabetes has reached epidemic proportions afflicting roughly 6% of the adult
population in Western society. Although the underlying genetic causes & the
associated pathological symptoms are heterogenous, a common feature is high blood
glucose due to peripheral insulin resistance. The molecular basis of insulin resistance
is believed to be attributable to defects in insulin receptor (IR) signalling. Protein
tyrosine phosphatases (PTPs) that antagonise IR signalling might be important targets
for therapeutic intervention in type 2 diabetes; inhibition of specific PTPs may allow
for enhanced IR signalling to alleviate insulin resistance.Our studies have identified
the roles of two key PTPs in insulin signalling.
Expected future outcomes:
N/A
Name of contact: Tony Tiganis
Email of contact: Tony.Tiganis@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 491169
CIA Name: Dr Dana Hutchinson
Main RFCD: Basic Pharmacology
Admin Inst: Monash University
Start Year: 2008
End Year: 2008
Total funding: $105,590.00
Grant Type: NHMRC Project
Grants
Title of research award:
Understanding the mechanisms used by G-protein coupled receptors to regulate
insulin-independent glucose transport
Lay Description (from application):
In type 2 diabetes, stimulation of glucose transport in fat cells and skeletal muscle by
insulin is impaired. As a result there is great interest in identifying insulinindependent mechanisms that increase glucose transport. Several G-protein coupled
receptors (GPCRs) regulate glucose transport independently of insulin but the
mechanisms involved in these effects are largely unknown. This project investigates
how GPCRs regulate glucose transport for potential as treatments.
Research achievements (from final report):
Obesity and type 2 diabetes is increasingly more prevalent in our society and at
present there is no definite treatment for either disease. Insulin is an important
mediator for the regulation of glucose homeostasis and glucose uptake, but these
processes can be regulated independently of insulin by activation of G proteincoupled receptors. This work has identified novel targets activated by adrenergic
stimuli in skeletal muscle, adipose tissue and brain that will assist in the
understanding of mechanisms likely to be important for the development of novel
treatments for type 2 diabetes and obesity. This work has advanced our understanding
of how adrenoceptors and other G protein-coupled receptors affect glucose
metabolism in tissues important for glucose homeostasis.
Expected future outcomes:
This work has advanced our knowledge of the mechanisms whereby adrenoceptors
stimulate glucose uptake in cells. This work has the potential to identify novel ways
of treating obesity and type 2 diabetes by G protein-coupled receptor activation.
Name of contact: Dr Dana Hutchinson
Email of contact: dana.hutchinson@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 436797
CIA Name: Dr Velandai Srikanth
Main RFCD: Epidemiology
Admin Inst: Monash University
Start Year: 2007
End Year: 2009
Total funding: $510,223.00
Grant Type: NHMRC Project
Grants
Title of research award:
A study of mechanisms of cognitive decline in Type 2 diabetes mellitus
Lay Description (from application):
Diabetes mellitus and dementia are major public health problems. Diabetes may
increase the risk of dementia. This study aims to uncover the mechanism by which
diabetes may increase dementia risk. This may lead to finding new ways to prevent or
treat diabetes-related dementia and thus reduce the public health burden of dementia.
Research achievements (from final report):
The primary aim is to study mechanisms of cognitive decline in Type 2 diabetes
mellitus, postulating an important role for cerebrovascular disease, neurodegeneration
and advanced glycation endproducts (AGEs).The recruitment of 300 people with
Type 2 DM has been finally completed and measurements have all been undertaken.
Currently we are in the process of cleaning data, completing grading of carotid
measurements and beginning the analyses to answer the primary study hypotheses.
The recruitment of the entire sample took longer ~6-8 months longer than predicted.
Hence the analytical phase and publication preparation will occur this year. In the
meanwhile there have been two articles published, an editorial comment and a review
article and 2 conference presentations in the final year of the grant.
Expected future outcomes:
Completion of data cleaning, analyses and publication are occurring this year (2010)
Name of contact: A/Prof Velandai Srikanth
Email of contact: velandai.srikanth@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 546131
CIA Name: Dr Zane Andrews
Main RFCD: Central Nervous System
Admin Inst: Monash University
Start Year: 2009
End Year: 2011
Total funding: $400,885.00
Grant Type: NHMRC Project
Grants
Title of research award:
Ghrelins novel neuroprotective effects in Parkinsons disease are mediated by AMPactivated protein kinase (AMPK).
Lay Description (from application):
Studies show that body mass index, midlife adiposity and diabetes are associated with
Parkinson's disease (PD). During obesity there is a dramatic change in nutritional
information, such as hormones, sugars and fats, carried in the blood. This proposal
explores how this altered nutritional information in obesity kills the brain cells
associated with PD. It will examine how ghrelin, a metabolic hormone inversely
related to obesity, influences and protects brain cell activity in models of PD.
Research achievements (from final report):
Ghrelin is a hormone that stimulates appetite and body weight under conditions of
low food avavilability. We discovered that ghrelin also prevents degeneration of
dopamine brain cells associated with Parkinson's disease. It is well known that mild
calorie restriction improves behavioural and cognition fucntion in humans and in
animal models of Parkinson's disease. In this grant we discovered that ghrelin
mediates the beneficial effects of calorie restriction in Parkinson's disease. Further, we
showed that diet-induced AMPK activation prevents degeneration of dopamine brain
cells. These discoveries have significant implications for human treatment of
Parkinson's disease. Since starting this grant i have joined the Cure Parkinson's Trust
as an advisor and we are currently conducting feasibility analyses for a human trial for
Parkinson's disease
Expected future outcomes:
We expect to show that ghrelin activates AMPK in dopamine neurons to induce
neuroprotection. Further we hope to show that ghrelin improves quality of life in
human Parkinson's disease patients.
Name of contact: Zane Andrews
Email of contact: zane.andrews@moansh.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 491094
CIA Name: Prof Bryan Williams
Main RFCD: Autoimmunity
Admin Inst: Monash University
Start Year: 2008
End Year: 2010
Total funding: $630,622.00
Grant Type: NHMRC Project
Grants
Title of research award:
Role of the IFN-induced helicase IFIH1 in type 1 diabetes
Lay Description (from application):
Type 1 diabetes (T1D) is presently the most common chronic disease of childhood
and is increasing, with incidence in children under five doubling over the last five
years. Recent findings indicate the ifih1 gene is important in T1D. Our research aims
to establish the contribution of this gene to the disease. It is hoped that recognition of
relevant pathological molecules will allow identification of risk factors for disease
development and, ultimately, targets for therapeutic intervention.
Research achievements (from final report):
We have demonstrated that IFIH1 mediates the immune response to rotovirus, which
is considered an etiological agent for the development of type-I diabetes. In addition,
we show that genetic polymorphisms associated with the risk of developing type-I
diabetes affect the function of IFIH1, thereby establishing a potential innate immune
mechanism in defects that may lead to autoimmunity. We show that impaired IFIH1
function affects the induction of type-I interferons in response to rotavirus,
implicating this cyokine as part of the mechanism of autoimmunity. We also
recognised that gene polymorphisms associated with the risk of developing type-I
diabetes do not simply translate to lost protein function, as initially presumed, but to
regulation of protein activity. This alters the manner in which it had been envisaged
that mutations in IFIH1 might induce autoimmunity.
Expected future outcomes:
Our findings indicate an alternative consequence to IFIH1 function to that anticipated,
changing our perception of how this gene product modulates autoimmune disease. In
addition, we believe we have identified a novel antiviral activity that may be
important in lentivirus infections.
Name of contact: Professor Bryan Williams
Email of contact: bryan.williams@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 545878
CIA Name: A/Pr Peter Tipping
Main RFCD: Nephrology and Urology
Admin Inst: Monash University
Start Year: 2009
End Year: 2011
Total funding: $487,067.00
Grant Type: NHMRC Project
Grants
Title of research award:
The role of the cytoplasmic domain of tissue factor in maintenance of the glomerular
filtration barrier.
Lay Description (from application):
This research aims to understand mechanisms of normal kidney function and the
development of chronic kidney damage associated with diseases such as nephritis and
diabetes. These diseases represent a significant burden of illness in Australia.
Research achievements (from final report):
Leakage of protein into the urine (albuminuria) is an early sign of kidney in a number
of human diseases (eg, diabetes, hypertension, glomerulonephritis). The presence of
albuminuria accelerates kidney damage and development of chronic kidney failure.
These studies explored novel roles for a protein (tissue factor: known to be critical for
blood clotting) in kidney filtering functions that prevent protein leakage under normal
conditions. Theses demonstrated that tissue factor helped to maintain of the
functional and structural integrity of cells (podocytes) that are crucial to normal
filtering function. In the absence of tissue factor, albumin leakage and production of
potentially injurious chemicals (cytokines) such as tumor necrosis factor was
increased. This knowledge may assist in understanding the mechanisms and
preventing the development of albuminuria in the future.
Expected future outcomes:
Improved knowledge of mechanisms of albuminuria may lead to more effective
therapy of this adverse influence on renal function in common diseases such as
diabetes and hypertension.
Name of contact: In The Absence Of Tissue Factor, Podopeter Tipping
Email of contact: peter.tipping@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 334173
CIA Name: Dr Robyn Tapp
Main RFCD: Epidemiology
Admin Inst: Monash University
Start Year: 2005
End Year: 2009
Total funding: $379,866.00
Grant Type: Early Career
Fellowships (Overseas)
Title of research award:
Epidemiology 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 Post-Doctoral Fellowship and as part of this award undertook postdoctoral 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 of contact: r.tapp@imperial.ac.uk
NHMRC Research Achievements - SUMMARY
Grant ID: 546018
CIA Name: E/Pr Paul O'Brien
Main RFCD: Indigenous Health
Admin Inst: Monash University
Start Year: 2009
End Year: 2012
Total funding: $600,855.00
Grant Type: NHMRC Project
Grants
Title of research award:
THE CONTROL OF TYPE 2 DIABETES THROUGH WEIGHT LOSS IN
INDIGENOUS AUSTRALIANS: THE FEASIBILITY AND ACCEPTABILITY OF
LAGB
Lay Description (from application):
Our recent clinical trial showed that 3 out of every 4 obese people with type 2
diabetes who undergo substantial weight loss have their diabetes go into remission. In
this project we recognise in the Indigenous people specific cultural and socioeconomic factors and family and community approach to health care and seek to test
if the Lap-Band procedure is acceptable to them and if it is feasible to achieve
substantial weight loss and control of diabetes as was seen in a European population.
Research achievements (from final report):
The central aim of this study is to achieve a substantial and durable weight loss. The
primary outcome is the frequency of remission of type 2 diabetes in response to this
weight loss.
30 candidates were entered into the study. They had a mean BMI of 44.3 kg/m2 and
they had a mean duration of diabetes of 4.3 years.
All patients had placement of a Lap-Band at the Goulburn Valley hospital as an
outpatient or with an overnight stay
A mean weight loss of 28.2kg was achieved. BMI reduced from 44.3 to 34.3 kg/m2, a
change of 10 BMI units. Diabetes remission had occurred in 20 (77%) of the 26 who
completed the follow up and final assessments. When calculated on the basis of
intention to treat, so including the four who have not completed final assessment, 66%
of study participants are known to be in remission.
The involvement and education of the local Aboriginal Health service enabled the
continuation of medical care following the 2 year period.
Expected future outcomes:
The study has been completed according to the protocol and has shown that this
approach to therapy is equally effective in a rural Indigenous population as it was in
an urban Western population. It will provide a strong endorsement of the value of
direct efforts at weight loss as a path to better control of diabetes for Indigenous
Australians
Name of contact: Prof Paul O'brien
Email of contact: paul.obrien@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 384137
CIA Name: Prof Christina Mitchell
Main RFCD: Protein Targeting and Signal Transduction
Admin Inst: Monash University
Start Year: 2006
End Year: 2008
Total funding: $505,523.00
Grant Type: NHMRC Project
Grants
Title of research award:
Characterization of the phosphoinositide 5-phosphatase SKIP.
Lay Description (from application):
Growth factors and insulin stimulate a complex array of signals inside the cell, which
are important for both cell survival and metabolism. A central intracellular signaling
enzyme that initiates lipid messages that promote glucose uptake into the cell and
promote cell survival is that generated by the PI3-kinase. This enzyme has increased
activity in many cancers, and is also important in diabetes when the enzyme may be
suppressed. Our grant proposes to investigate the function of another enzyme called
SKIP which acts within the cell to oppose the functions of the PI3-kinase. Several
lines of evidence indicate SKIP may be important in both development and cancer.
SKIP has been identified as a putative candidate gene for a developmental disorder
known as Miller Dieker syndrome. This disease is associated with facial and
significant brain abnormalities. In addition the SKIP gene is located on a chromosome
that is frequently deleted in breast and colon cancer. SKIP is an enzyme that
functions to remove phosphate molecules from PI3-kinase signaling molecules. SKIP
has been shown to prevent glucose uptake into the cell by breaking down PI3-kinase
signals. We have recently demonstrated SKIP phosphatase activity can be inhibited by
binding to another protein called suppressor of death domains (SODD). We plan to
investigate the effects this complex has on SKIP enzyme activity, and how this
complex plays a role in regulating PI3-kinase signals that promote glucose uptake.
Secondly, we plan to investigate the function of SKIP in an intact animal by making
mice which lack SKIP(knock out mice). Given SKIP is implicated in a developmental
syndrome and insulin signaling, we can delineate the functional significance of SKIP
and the molecular pathways regulated by this enzyme.
Research achievements (from final report):
This study has characterised a novel signal terminating enzyme called SKIP, that
regulates the actin cytoskeleton and thereby cell migration and in addition regulates
insulin stimulated glucose uptake. The inositol polyphosphate 5-phosphatase SKIP,
opposes an important intracellular pathway generated by the PI3-kinase. SKIP
exhibits increased activity in certain cancers and may promote cancer cell migration
and invasion. SKIP is also implicated in a number of other human diseases including
developmental defects of the human cerebral cortex, perhaps as a result of abnormal
cell migration. This grant has characterised the role SKIP plays in regulating the actin
cytoskeleton revealing it may function to regulate the migration and invasion of both
normal cells and tumours. In addition the grant has demonstrated that SKIP is
essential for normal embryonic development and mice which lack SKIP die mid
gestation. These studies have identified a novel gene that is important in human
development.
Expected future outcomes:
NHMRC Research Achievements - SUMMARY
We predict SKIP may play an important role in regulating the normal migration of
brain cortex cells during embryonic development and in future studies will develop
mouse models with targeted and inducible deletion of SKIP in specific tissues during
embryonic development
Name of contact: Prof Christina Mitchell
Email of contact: christina.mitchell@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 436781
CIA Name: Prof Patrick Sexton
Main RFCD: Basic Pharmacology
Admin Inst: Monash University
Start Year: 2007
End Year: 2008
Total funding: $340,400.00
Grant Type: NHMRC Project
Grants
Title of research award:
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:
NHMRC Research Achievements - SUMMARY
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 of contact: patrick.sexton@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 236824
CIA Name: Prof Christina Mitchell
Main RFCD: Protein Targeting and Signal Transduction
Admin Inst: Monash University
Start Year: 2003
End Year: 2005
Total funding: $440,250.00
Grant Type: NHMRC Project
Grants
Title of research award:
SHIP-2 regulation of the actin cytoskeleton
Lay Description (from application):
Following a meal glucose circulates in the blood and is taken up into cells via
movement of an intracellular glucose transporter from the inside of the cell to fuse
with the cell membrane and subsequent transfer of the glucose into the cell. This
process is triggered by insulin. One of the commonest diseases resulting from a failure
of this cellular process is diabetes. A common form of diabetes which occurs in many
adults in Australia results from insulin resistance, whereby the effects of insulin are
diminished and cells become increasingly unable to uptake glucose. Recent studies
have demonstrated that a novel enzyme known as SHIP-2 may play a role in
regulating insulin action in cells. Deletion of SHIP-2 in mice results in these animals
have increased sensitivity to insulin, low blood glucose levels, and a greatly enhanced
ability to take up glucose in cells in response to low dose insulin. Our laboratory has
been working on the cellular mechanisms regulating SHIP-2 function. We have
recently revealed the intracellular location of SHIP-2 and also demonstrated how
SHIP-2 is localized in the cell. These studies have shown that SHIP-2, via interactions
with other proteins, regulates the actin cytoskeleton immediately beneath the cell
membrane and this may be a mechanism for facilitating cellular glucose uptake. This
research proposal aims to determine how SHIP-2 facilitates glucose uptake into cells.
We will make cell lines and transgenic animals which express high levels of this
enzyme and determine the functional consequences on insulin stimulated glucose
uptake. Collectively these studies in the long term may facilitate better treatment
strategies for diabetic patients.
Research achievements (from final report):
Cells respond to hormones, stress, growth factors and other enviromental stimuli
resulting cell movement, cell growth, cell division and other specialized functions.
These cellular responses require the generation of a multitude of signals including
those generated on specific membrane compartments of the cell called
phosphoinositides. We have characterized the SHIP-2 5-phosphatase which regulates
phosphoinositide signals and have demonstrated that in fat cells this enzyme
negatively regulates the glucose transporter protein required for the uptake of glucose
into cells. We have investigated two possible molecular mechnisms by which SHIP-2
may regulate the glucose transporter. First, our results demonstrate that SHIP-2
regulates the actin cytoskeleton which is essential for the transport of the glucose
transporter to sites of glucose uptake into cells. Secondly, we have demonstrated that
SHIP-2 binds to, and inhibits the actions of a protein called SODD which enhances
the transport of the glucose transporter to the cell membrane, even in the absence of
insulin. These studies provide novel targets for the treatment of insulin-resisitant
diabetes.
NHMRC Research Achievements - SUMMARY
Expected future outcomes:
These studies provided identification of potential novel targets for the treatment of
insulin-resistant diabetes.
Name of contact: Christina Mitchell
Email of contact: christina.mitchell@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 436779
CIA Name: Prof Patrick Sexton
Main RFCD: Basic Pharmacology
Admin Inst: Monash University
Start Year: 2007
End Year: 2008
Total funding: $362,207.00
Grant Type: NHMRC Project
Grants
Title of research award:
Understanding 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-theart 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 ligand-dependent 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.
NHMRC Research Achievements - SUMMARY
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 of contact: patrick.sexton@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 299974
CIA Name: A/Pr Jennifer Wilkinson-Berka
Main RFCD: Endocrinology
Admin Inst: Monash University
Start Year: 2004
End Year: 2007
Total funding: $481,500.00
Grant Type: NHMRC Project
Grants
Title of research award:
Vascular and neuro-glial dysfunction in diabetic retinopathy
Lay Description (from application):
The retina is responsible for sight. Vision occurs by interactions between blood
vessels, neurons (cells that transmit electrical signals for vision) and glia (cells that
support the retina). In diabetes, high amounts of glucose in blood increases certain
factors within retinal cells. These factors slowly cause damage, such that after 15
years of diabetes all patients will have some retinal disease and many will loose sight.
Indeed, diabetes is the leading cause of blindness in working people. The main
treatment for diabetic retinal disease is to burn away damaged blood vessels, however,
this treatment has problems. Firstly, the burns destroy healthy retina and the disease
continues, secondly, the treatment is performed late in the disease and therefore does
not prevent the early changes in retinal cells, and thirdly, changes in neurons and glia
are often not considered. Therefore, there is an urgent need to understand how blood
vessels, neurons and glia interact with each other to threaten vision in diabetes, with
the intention of developing safer and more effective treatments. This will be the focus
of the current project.Currently, there are no studies that have examined the sequential
changes in retinal blood vessels, neurons and glia in diabetes. This is mainly due to
the lack of an experimental rodent model that progresses from mild to severe diabetic
retinal disease. In 2003, we established such a model in the diabetic Ren-2 rat. In this
project the diabetic Ren-2 rat will be used to study retinal cell changes and also to
identify the factors that damage these cells. We suggest that angiotensin, bradykinin
and VEGF are involved. These factors are present in the normal retina and are
increased in diabetes. We will block these factors with specific drugs with the
intention of understanding how these factors affect retinal cells in diabetes, and also to
develop new drug therapies for the treatment of both early and late diabetic retinal
disease.
Research achievements (from final report):
Retinopathy is the most feared complication of diabetes and is the leading cause of
blindness in the working population. Current treatments for diabetic retinopathy
involve burning away damaged blood vessels with a laser. This procedure although
providing some benefits, is associated with damage to healthy retina and the disease
continues despite intensive treatment. New treatments for diabetic retinopathy are
actively been sought. One of these is blockade of a hormonal system called
angiotensin. Our laboratory has played a key role in establishing a role for angiotensin
in diabetic retinal disease. This project grant is an extension of these studies as we
aimed to determine the relationship between blood vessels and neurons in diabetic
retinopathy and whether angiotensin affects the viability of these cell populations.
Using blockers of the angiotensin system and animal models of disease, we were able
to report that this treatment improves overall retinal health in diabetes and other
retinal pathologies. These findings are directly relevant to diabetic patients, as
NHMRC Research Achievements - SUMMARY
currently a large worldwide study comprising over 5000 patients is evaluating the
effect of angiotensin blockade on the progression of diabetic retinopathy (DIRECT
study).
Expected future outcomes:
Our evaluation of how retinal blood vessels and neurons communicate in diabetes,
and how abberations in comunication leads to disease is a major focus. Using state-ofthe-art microscopy (multiphoton) we will evaluate how molecules such as angiotensin
influence these cells in the living retina. This fundamental knowledge will impact on
future treatment strategies.
Name of contact: Jennifer Wilkinson-Berka
Email of contact: Jennifer.Wilkinson-Berka@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 334032
CIA Name: Prof John McNeil
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Admin Inst: Monash University
Start Year: 2005
End Year: 2009
Total funding: $427,500.00
Grant Type: NHMRC Project
Grants
Title of research award:
Risk 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 10year 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.
NHMRC Research Achievements - SUMMARY
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 of contact: andrew.tonkin@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 236872
CIA Name: Dr Sharyn Fitzgerald
Main RFCD: Systems Physiology
Admin Inst: Monash University
Start Year: 2003
End Year: 2005
Total funding: $225,500.00
Grant Type: NHMRC Project
Grants
Title of research award:
Role 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.
NHMRC Research Achievements - SUMMARY
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 of contact: sharyn.fitzgerald@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 384215
CIA Name: A/Pr John Dixon
Main RFCD: Paediatrics
Admin Inst: Monash University
Start Year: 2006
End Year: 2008
Total funding: $481,906.00
Grant Type: NHMRC Project
Grants
Title of research award:
A randomised control trial of medical treatment versus the placement of the Lap Band
in severely obese adolescents.
Lay Description (from application):
There has been a substantial rise in the number of overweight and obese adolescents
in our community. While prevention of obesity is the ultimate goal, effective
stratagies for the management of obese adolescents must be sought. Unfortunately
there are few studies that have focused on this problem in adolescents and success has
been very limited. Modern obesity surgery is the only reliable method of achieving
and sustaining major weight loss in severely obese (body mass index > 35 kg/m2)
adults and there are now several small studies that demonstrate its effectiveness in
adolescents. Modern obesity surgery involving the keyhole placement of an
adjustable band around the very upper part of the stomach has proven to be safe and
effective and requires one 24 hr stay in hospital. In this collaborative study,
involving the Monash University Centre for Obesity Research and Education and the
Royal Children's Hospital, we propose to formally test, for the first time, the
effectiveness of a weight loss program that includes adjustable band surgery, and
compare this with a comprehensive "best care" behavioral program, over a period of
2-years in severely obese adolescents. We estimate that suitable subjects will come
from the top 1% for body mass index in our community. After thorough assessment
50 suitable candidates with ages ranging from 14 to 18 years will be randomly
allocated to one of the two treatment programs. The intensity of each program will be
similar. A broad range of measues including: weight, health status, physical disability,
psychological status, body image and quality of life, will be performed before and at
completion of the 2-year programs. In addition we will compare the complications,
compliance and cost of the two programs. This study will help us assess and compare
the effectiveness of the 2 programs and provide vital information regarding the role of
modern keyhole obesity surgery for the management of severely obese adolescents.
Research achievements (from final report):
Adolescent obesity is common and is associated with multiple health problems, poor
quality of life and reduced life expectancy. We performed a randomized controlled
trial comparing laparoscopic adjustable gastric banding (LAGB) with a program of
behavioral therapy.
50 adolescents aged between 14 and 18 years with a BMI>35. They were randomly
allocated to a supervised behavioral intervention of the LAGB procedure and
followed for two years. 24 of 25 LAGB participants and 18 of 25 non-surgical
patients completed the study.
Outcomes - LAGB participants lost an average weight of 34.9kgs compared with an average of
3kgs for the non surgical participants.
NHMRC Research Achievements - SUMMARY
- At entry, the metabolic syndrome was present in 9 of the surgical group and 10 of
the non-surgical group. After 24 months, none of the surgical group had the metabolic
syndrome, while 4 of the 18 completers in the non-surgical group still fullfilled the
criteria for the metabolic syndrome.
- The surgical complication, gastric pouch dilitation, was more frequent in this
population than expected in an adult population
We concluded LAGB was more effective than the non-surgical program in achieveing
weight loss amd improving health. LAGB may be considered in the severely obese
adolescent who have failed a comprehensive non-surgical treatment program.
Expected future outcomes:
This study provides a strong level of evidence for the effectiveness of LAGB in
adolescents with severe obesity. This is the first demonstration by RCT of such an
effect and should directly help clinicians determine the best option for adolescents.
Refinements to the surgical program may reduce complications.
Name of contact: A/Prof John Dixon
Email of contact: john.dixon@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 400068
CIA Name: Prof Jennifer Wilkinson-Berka
Main RFCD: Endocrinology
Admin Inst: Monash University
Start Year: 2006
End Year: 2010
Total funding: $636,288.00
Grant Type: Established
Career Fellowships
Title of research award:
Uncoupled 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 reninangiotensin 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 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
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding:
$327,334.00
Admin Inst: Monash University
Grant Type: Early Career
Fellowships (Australia)
Title of research award:
Endothelial 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 of contact: stephdedios@hotmail.com
NHMRC Research Achievements - SUMMARY
Grant ID: 443214
CIA Name: Prof Brian Oldenburg
Main RFCD: Preventive Medicine
Admin Inst: Monash University
Start Year: 2007
End Year: 2011
Total funding: $708,607.00
Grant Type: NHMRC Project
Grants
Title of research award:
Using conversational computer technology to improve diabetes management: A
randomised controlled trial
Lay Description (from application):
The diabetes epidemic is a growing challenge for the Australian health care system
with over 1 million Australians living with diabetes. The impact on individuals' lives
and the whole of Australian society is very substantial indeed. There is very good
evidence that this impact would be reduced by developing new approaches to manage
the disease and facilitate improved self-management. Recent developments in
information and communications technologies offer some promising new ways and
tools for achieving this. This research will evaluate a computer-controlled, interactive
telephone system for improving the management and self-management of Type 2
diabetes in addition to routine care. Patients with Type 2 diabetes will be recruited
from Brisbane and each patient will be randomly assigned to receive either this new
program or just their usual care from their doctor or Diabetes Clinic. The first group
will call the system weekly for six months using a regular phone or a mobile phone if
they wish. During the call, they will answer questions by speaking into the phone,
listen to feedback and strategies for improving management of their diabetes and then
"discuss" their next targets and behavioural actions. They will receive systematic and
tailored advice on blood glucose testing, nutrition and physical activity, as well as
medication taking and foot care. The system individualises conversations according
to the user s answers and responses over all the interactive sessions. The trial will
formally evaluate the clinical impact on blood glucose control and the adoption and
maintenance of the targeted health habits, as well as the intervention s costeffectiveness and users satisfaction with the system. This project s significance lies in
the excellent potential of using this new technology to provide a 'low cost' but
effective program to help people better manage Type 2 diabetes.
Research achievements (from final report):
The impact of the diabetes epidemic on individuals and society is severe but can be
reduced by improving diabetes self-management. This research evaluated an
automated interactive telephone system designed to improve type 2 diabetes selfmanagement. The system, called TLC diabetes, consists of a computer equipped with
speech recognition, pre-recorded conversation statements and a database in which
users' answers are stored to be used in future conversations. Adults with type 2
diabetes who accessed the TLC Diabetes programme significantly improved their
diabetes management compared to the group receiving routine care only. The
programme was also shown to improve quality of life. Importantly, user adoption was
very good. Users, of average age 58.4 years, found the system easy to use. They
completed 75% of the expected weekly calls. These results show that this information
and communication technology provides a potential solution to the increasing demand
placed on the health systems by the growing number of people diagnosed with
NHMRC Research Achievements - SUMMARY
diabetes every day. It can assist people better manage their condition from the comfort
and the privacy of their home at a time that is convenient for them. A large scale
implementation of this type of teleheath could help address the urgent need for
effective, inexpensive and easily accessible resources for self-management of chronic
conditions.
Expected future outcomes:
Future work will concentrate on integrating this low cost and effective telephonedelivered program with other information and communication technologies such as
mobile and web applications and explore options to link it to patients' electronic care
plans. This will enhance the program's sustainaility and ability to complement
government efforts to improve the management of chronic conditions .
Name of contact: Professor Brian Oldenburg
Email of contact: brian.oldenburg@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 406620
Start Year: 2006
CIA Name: Dr Adam Hart
End Year: 2008
Main RFCD: Cell Development (incl. Cell Division and Apoptosis)
Total funding:
$491,768.00
Admin Inst: Monash University
Grant Type: NHMRC Project
Grants
Title of research award:
The regulation of pluripotency and self-renewal in embryonic and germline stem
cells.
Lay Description (from application):
Regulation of self-renewal and developmental potential in embryonic and germline
stem cells. The capacity of some stem cells to self-renew and under specific
conditions, give rise to all adult cell types, a property known as pluripotency , is the
key to unlocking the potential of cell based therapies. The development of stem cell
based therapies promises to revolutionize the treatment of many common human
diseases. For instance, in neurodegenerative conditions such as Parkinsons disease,
normal embryonic stem cells grown in culture could be used to replace the lost or
disabled neurons in the patient. Many other conditions including diabetes, cystic
fibrosis, myocardial infarction (heart attack) and stroke could potentially be treated
with stem cell based therapies. Understanding the molecular regulators that govern
establishment and maintenance in culture of stem cell lines derived from embryos and
from germ cells is the primary goal of this study. We will use well-established
techniques to genetically manipulate mouse embryonic stem cells and embryos to
examine the role of a specific gene, NANOG. Named after the Celtic legend of Tir
NaNog (land of the ever young). When NANOG was forced to remain active,
embryonic stem cells were able to grow in media deficient in factors usually required
for self-renewal and did not lose their pluripotency even when treated with chemical
agents that usually induce differentiation. Understanding the full capacity of NANOG
to influence stem cell self-renewal and elucidation of the underlying molecular
pathways regulated by this gene will provide valuable insights into the establishment
and manipulation of stem cell lines from embryonic and adult tissues.
Research achievements (from final report):
The pluripotency homeobox gene NANOG was identified as an early genetic marker
of human germ cell tumors. This marker can be now be used to reliably diagnose the
earliest forms of testicular and metastatic germ cell tumor, enabling more rapid
identification and treatment of this life threatening disease (Hart, AH., et. al., 2005).
We investigated the role of the NANOG gene in normal development and cancer
using genetically manipulated cell lines and mice, demonstrating that this gene is
essential for stem cell survival in the early embryo. The genetically manipulated stem
cells and mouse lines haveyielded an important insight into the molecular basis of
stem cell survival and self renewal. These tools will now enable further research into
the molecular regulation of embryonic and adult stem cells and the pathogenesis of
germ cell tumours and some other forms of cancer.
Identification and manipulation of nanog and other key stem cell genes will provide a
theoretical basis for the manipulation of embryonic and adult stem cell lines prior to
NHMRC Research Achievements - SUMMARY
application in cell based therapies in a range of acute and chronic degenerative
diseases.
The genetically manipulated mice represent a valuable resource for further
investigation of the putative cancer stem cell that is thought to be the originating cell
of many tumor types, including mammary, colorectal, germ cell. leaukemias and lung
cancer.
Expected future outcomes:
1. The germ cell tumor marker Nanog will be used in the clinical identification and
classification of testicular and metastatic tumours of germ cell origin. The Nanog
mutant mice will be used to identify and analyse adult stem cells.
Name of contact: Adam Hart Phd
Adam Hart
Email of contact: adam.hart@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 143664
CIA Name: Dr Marie Gibbs
Main RFCD: Neurosciences not elsewhere classified
Admin Inst: Monash University
Start Year: 2001
End Year: 2003
Total funding: $241,018.00
Grant Type: NHMRC Project
Grants
Title of research award:
Investigation of the mechanisms involved in consolidation of memory by beta 3
adrenoceptoragonists.
Lay Description (from application):
The inability to form new memories is a major and increasingly prevalent health
problem for an aging population. In addition to aging, the inability to form new
memories is associated with serious medical conditions including Alzheimer's Disease
and diabetes. Common to these conditions is the inability to consolidate memories.
Memories are intact for a short while (30 minutes) after the event to be remembered,
but memory does not pass on into permanent storage. We have been able to achieve
memory consolidation in a particular learning task, which is not normally
remembered, by injection of drugs acting on novel receptors (beta 3 adrenoceptors) in
the brain of day old chicks. These drugs mimic the action of noradrenaline at beta-3
adrenoceptors. There are a number of ways in which memory consolidation can be
enhanced, and we will compare the effects of beta-3 drugs with other potential drugs
acting at other types of noradrenaline receptors. One of the actions of beta-3 agonists
is related to the uptake of glucose into cells in the brain. We will investigate whether
the mechanism of beta-3 enhancement of memory involves the uptake of glucose in
brain tissue and studies in cultures of individual cell types will show us which cells
are involved. Although this work is done using young chicks, there is no reason to
suppose that the basic memory mechanisms at the level of the nerve cell should be
different in birds or mammals. There are distinct advantages to using chicks in this
research as they can form a long lasting memory for an experience lasting only 10
seconds, and they will discriminate between different colours as part of their learning.
This research is aimed at understanding the processes involved in and influencing
memory formation. If we are going to develop drugs to alleviate the cognitive
problems of old age and more serious cognitive diseases, we need to understand more
about the basic mechanisms of memory formation in the normal animal.
Research achievements (from final report):
One of the two major chemical transmitters in the body is noradrenaline.
Noradrenaline is ubiquitous in its distribution in the body with particularly high
concentrations occurring in the brain. It has been known for some years that there are
many different types pf receptors for noradrenaline and we have been able to establsh
a role for many of these receptors in the different stages of memory. Our recent grant
has focussed on the role of a new receptor, the beta 3-adrenoceptor and we have
elucidated its role in memory and the cellular effects it is producing in the neurons
and astrocytes (specialized brain cells). We have established the role of the beta 3receptor in relation to the other noradrenergic receptors and the location of the action
in the brain. Although this work has been carried out in the young chick, the results
are proving to be very similar to the limited knowledge of the mammalian systems
with respect to nnoradrenaline and the adrenergic receptors. Memory deficits occur in
NHMRC Research Achievements - SUMMARY
many diseases such as Alzheimer's disease and Parkinsons disease and this research
opens up the exciting possibility that some adrenoceptr drugs may be able to alleviate
the memory deficits seen in these. We have extended the work into understanding
the cognitive disorders that may come about through hypoxia before birth, and have
shown that stimulation of the beta 3-adrenoceptor is able to alleviate the deficits
caused by prenatal compromise.
Expected future outcomes:
we hope that we will be able to extend this work at least to rodents to demonstrate the
universality of our findings and explore the usefulness of the beta 3-adrenergic
receptor drugs in alleviating cognitive problems in both neurodevelopmental and
neurodegenerative diseases.
Name of contact: Dr Marie Gibbs
Email of contact: marie.gibbs@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 237019
CIA Name: Dr Sharyn Fitzgerald
Main RFCD: Systems Physiology
Admin Inst: Monash University
Start Year: 2003
End Year: 2004
Total funding: $166,421.00
Grant Type: Early Career
Fellowships (Australia)
Title of research award:
Cardiovascular 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 of contact: sharyn.fitzgerald@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 436780
CIA Name: Prof Patrick Sexton
Main RFCD: Protein Targeting and Signal Transduction
Admin Inst: Monash University
Start Year: 2007
End Year: 2008
Total funding: $382,821.00
Grant Type: NHMRC Project
Grants
Title of research award:
Analysis of calcitonin receptor binding and function
Lay Description (from application):
Receptors form a basic intermediary as the acceptor site for signals that are
transmitted between the cells that make up our body. Modulation of receptors,
therefore, forms a key target in our ability to treat disease. The largest class of
receptors is the superfamily of G protein-coupled receptors (GPCRs), which transmit
signals within a cell via proteins called G proteins. GPCRs form between 1 and 5% of
the entire repertoire of human genes. One group of GPCRs provide the target for
small protein molecules that cirulate through the body. One such circulating molecule
is calcitonin, a peptide that plays an important role in maintaining circulating calcium
levels in the body, which is essential for proper maintenance of the skeleton. As a
consequence of this action, calcitonin is an important clinically used tool in the
treatment of bone disease such as osteoporosis and Paget's disease. Due to the
molecular nature of calcitonin and its receptors (and other related receptors) that have
a broad, complex mechanism of interaction, we have very little definitive information
on how calcitonin interfaces with its receptor to signal to target cells. The current
project utilises a novel method of permanently linking calcitonin to its receptor,
allowing identification of how the two components come together. Furthermore, the
project will explore the functional consequence of naturally occuring genetic variation
(genotype) and also examine whether the occurence of specific calcitonin receptor
genotype is correlated with disease markers for osteoporosis and obesity. This
information provides important fundamentals for understanding how this and related
receptors work and the potential for rational design of improved theraupeutic tools.
Research achievements (from final report):
G protein-coupled receptors (GPCRs) are major targets for therapeutic intervention. A
major subfamily of GPCRs is the family B group of peptide hormone receptors that
includes receptors for calcitonin, amylin, secretin and the glucagon-like peptides. This
family of receptors contains important targets for potential treatment of bone disease,
diabetes and obesity. We have been studying polymorphic and splice variants of the
calcitonin receptor as they are implicated in a variety of conditions including
osteoporosis and body weight control. We have established stable cell lines for all 4
calcitonin receptor variants and preliminary data suggests that the polymorphic
variants may contribute to altered signaling in a cell-dependent manner. Additional
work has centered on unravelling the mechanism of CT interaction with the receptor.
For this we have been developing methods in collaboration with Prof. Larry Miller
(Mayo Clinic) for generating molecular models of the CT receptor. Initial work
towards this has utilised the secretin receptor as a model system. This has led to the
development of new methods to predict peptide-receptor interactions that can
subsequently be applied to models of the CT receptor. Other work has demonstrated
that CT precursor peptides, which are elevated during sepsis, actually bind
NHMRC Research Achievements - SUMMARY
preferentially to RAMP1 complexed receptors, over the CT receptor expressed alone,
contrasting to the interactions of the mature CT peptides. This work has implications
for pathology of sepsis.
Expected future outcomes:
Future work should elucidate whether there are real mechanistic differences in the
behaviour of CT polymorphic variants and also lead to the generation of models of the
CT receptor that may have benefit in future drug development.
Name of contact: Prof. Patrick Sexton
Email of contact: patrick.sexton@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 519502
CIA Name: Prof Edouard Stanley
Main RFCD: Endocrinology
Admin Inst: Monash University
Start Year: 2008
End Year: 2010
Total funding: $540,075.00
Grant Type: NHMRC Project
Grants
Title of research award:
Expansion, Differentiation and Functional Analysis of In Vitro Derived Pdx1+
Pancreatic Progenitors
Lay Description (from application):
Type 1 diabetes is a condition that arises when the body's immune system destroys
insulin-producing beta cells within the pancreas. Recent studies have shown that
normal glucose control can be restored by replacing the missing beta cells by
transplantation of cells from deceased donors. However, the demand for transplant
material outweighs supply. The work described in this application seeks to define
how insulin-producing beta cells can be derived in the laboratory from embryonic
stem cells .
Research achievements (from final report):
Type 1 diabetes is an autoimmune disease characterised by loss of β cell mass,
compromised insulin production and persistent high levels of blood glucose. Despite
the success of insulin control regimes, people with type 1 diabetes suffer
complications which result from deficiencies in the fine control of blood glucose
levels afforded by exogenously administered insulin. This fine control can be
corrected by islet transplantation, although the availability of this treatment option
will always be limited by the scarcity of donor-derived islets. Pancreatic β cells
derived from the in vitro differentiation of human embryonic stem cells (ESCs)
potentially represent an inexhaustible supply of therapeutically effective cells for the
treatment of type 1 diabetes. However, before such cells can be used, further
understanding of the processes by which these cells are generated is required. In our
project we used mouse embryonic stem cells as a model system to examine
characteristics of the precursors that give rise to pancreatic β cells. We correlated the
results of gene expression studies, morphological analyses and growth characteristics
with the ability of progenitors to generate branching pancreatic organoids. We found
only specific progenitors were able to generate organoids that resembled those arising
from fetal pancreatic explants. Our studies provide additional criteria for classifying
pancreatic progenitors made from ESCs and will facilitate strategies for generating
insulin producing β cells for the treatment of type 1 diabetes.
Expected future outcomes:
Results obtained with mouse embryonic stem cells (ESCs) will be applied to our
human ESC experiments. Specifically, this work provides valuable clues as to how to
determine if pancreatic cells made in the laboratory from human ESCs represent a
genuine and functional insulin producing β cells.
Name of contact: Ed Stanley
Email of contact: ed.stanley@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 491058
CIA Name: Prof Jennifer Wilkinson-Berka
Main RFCD: Opthalmology and Vision Science
Admin Inst: Monash University
Start Year: 2008
End Year: 2010
Total funding: $733,841.00
Grant Type: NHMRC Project
Grants
Title of research award:
Receptor-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 of contact: Jennifer.Wilkinson-Berka@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 606553
CIA Name: Prof Helena Teede
Main RFCD: Reproduction
Admin Inst: Monash University
Start Year: 2010
End Year: 2011
Total funding: $416,116.00
Grant Type: NHMRC Project
Grants
Title of research award:
Insulin resistance in Polycystic Ovary Syndrome and the role of skeletal muscle and
adipose tissue
Lay Description (from application):
11% of women have polycystic ovarian syndrome(PCOS), characterised by insulin
resistance, irregular periods and infertility. These women are prone to obesity,
diabetes and potentially, heart disease. Treatments include lifestyle modifications +/medical therapy. Lifestyle is first line, yet the best diet/exercise prescription is
unclear. This study will provide insights into the cause of PCOS, will inform on the
role of exercise in therapy and may identify targets for future therapies.
Research achievements (from final report):
The research award has afforded us the opportunity to take a multidisciplinary
approach to address a number of important clinical and scientific questions
surrounding a major Australian health issue, Polycystic Ovary Syndrome (PCOS) that
impacts as many as 1 in 5 young Australian women. PCOS is a complex condition
with cardio-metabolic (insulin resistance and a 4-7 fold higher risk of cardiovascular
disease and type 2 diabetes), reproductive (anovulatory infertility) and psycho-social
problems. In this project we focused on insulin resistance (IR) due to the potential
central role of insulin in PCOS. Specifically we looked at potential mechanisms of
insulin resistance in PCOS and the role of exercise in alleviating it. We studied 4
groups of women, lean with and without PCOS, and overweight to obese women with
and without PCOS, examining insulin sensitivity by insulin clamp, body composition,
mitochondrial biogenesis/ function, and insulin signalling in skeletal muscle to
determine if women with PCOS were intrinsically more IR. We also exercise trained
the overweight groups for 3 months. The results show that women with PCOS do
have an intrinsic PCOS related IR which does not appear to be related to
mitochondrial biogenesis/function but more likely to body lipid storage and or insulin
signalling. Furthermore, in the overweight women exercise improved but did not
completely alleviate their IR when compared to matched controls. This work
provides important advances in understanding the aetiology of IR in PCOS and
informs clinical practice on the impact of exercise in PCOS with inclusion in national
evidence based guidelines.
Expected future outcomes:
This work has provided a number of new hypothesis-driven clinical and basic science
research questions and projects in PCOS, new multidisciplinary national and
international collaborations, has informed practice and with completion and analysis
of insulin signalling data, should provide greater ins9ights itno IR in obesity generally
and in PCOS.
Name of contact: Prof Helena Teede
NHMRC Research Achievements - SUMMARY
Email of contact: helena.teede@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 491031
CIA Name: A/Pr Lisandra Martin
Main RFCD: Pharmaceutical Sciences and Pharmacy
Admin Inst: Monash University
Start Year: 2008
End Year: 2011
Total funding: $445,011.00
Grant Type: NHMRC Project
Grants
Title of research award:
Long acting Insulin: Drug design, in vitro activity through to animal model efficacy
Lay Description (from application):
This research will develop novel insulins that possess improved stability and activity
for diabetic patients. The improved pharmacological actions of the modified insulins
offer increased treatment options for patients eg. enabling less frequent or invasive
medication. Our cross-disciplinary team will (i) design & synthesise insulin
derivatives, (ii) explore the activity of the modified insulins by biophysical activity
profiles in vitro, (iii) evaluate the in vivo stability and clinical effects.
Research achievements (from final report):
The new dicarba-insulin analogues generated and evaluated in this project possess
superior metabolic: mitogenic profiles, biostability and formulation stability to
currently available insulin preparations and will have immediate and significant
impact on the global diabetes market, including the Australian population of
diabetes/pre-diabetes sufferers, estimated to be 3.2 million people. These analogues
have been generated using novel, state of the art catalytic and peptide chemistry and
have been designed to cover fast and slow onset formulations. The resultant novel
dicarba insulins possess unrivaled metabolic-mitogenic profiles: Full metabolic
activity is observed in in vitro binding and activation studies and in vivo activity is
also comparable to human insulin preparations. The synthetic modifications, however,
prevent activation of the IGF receptor, a target that has long been associated with the
potential for adverse mitogenic activity. Towards this end, we have generated a
dicarba glargine analogue, a long acting analogue with cancer concerns, with full
metabolic activity devoid of mitogenic activity mediated via the IGF receptor. The
dicarba insulins have also been assessed for their physical stability and shown to be
stable without the need for refrigeration. This is a significant finding which will
facilitate the distribution of insulins to remote and under-resourced communities. The
dicarba substitution is also offering insight into the key determinants responsible for
the activation of the insulin receptor. Full knowledge of this elusive mechanism of
action will provide much needed information for the design of non-proteinogenic
mimetics of human insulin.
Expected future outcomes:
More than 20 dicarba insulin analogues were synthesized and evaluated in this
project. The molecules have performed beyond all expectation. IP protection has been
sought and several international pharmaceutical companies are interested in the
research. Publications were therefore delayed in order to file provisional patents.
Name of contact: Andrea J Robinson
Andrea Robinson
Email of contact: Andrea.Robinson@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 143665
CIA Name: Dr Tony Rowe
Main RFCD: Protein Targeting and Signal Transduction
Admin Inst: Monash University
Start Year: 2001
End Year: 2003
Total funding: $212,037.00
Grant Type: NHMRC Project
Grants
Title of research award:
Analysis of the Role of Vesicle Docking/Fusion Proteins in Trafficking of the Glut4
Glucose Transporter in Adipocytes
Lay Description (from application):
The objective of these studies is to understand the molecular mechanisms that are
involved in the control of blood glucose levels by the hormone insulin. Elevated blood
glucose levels following a meal stimulate the pancreas to release insulin into the
circulation. Insulin acts to reduce blood sugar levels by stimulating the uptake of
glucose into fat and muscle and suppressing glucose production by the liver. Defects
in insulin action in these tissues are the primary cause of Type II diabetes. The
debilitating effects of Type II diabetes, the dramatic increase its incidence, and the
expense of treating the symptoms of diabetic complications have lead to the
realization that the disease represents a major health problem requiring substantial
research and development efforts. The project will focus on insulin regulation of
glucose uptake in fat cells. Insulin promotes glucose uptake into fat by activating an
intracellular signaling pathway that triggers the translocation of a unique glucose
transporter protein (Glut4) from storage sites inside the cell to the cell surface. Glut4
translocation is mediated by small membrane vesicles that function to sequester the
glucose transporter inside cells in the absence of insulin, and to shuttle Glut4 to the
cell surface in response to the hormone. Despite the central importance of this event
to the maintenance of normal blood glucose levels, it is poorly understood. The
studies will be directed towards investigating the cellular machinery involved in the
latter stages of insulin-stimulated glucose uptake- the vesicle-mediated delivery of
Glut4 to the cell surface. The objective of these studies is to better understand the
molecular basis for Glut4 translocation, and regulation by the insulin signaling
cascade. Accomplishment of this goal may suggest potential drug intervention
strategies aimed at enhancing insulin-stimulated Glut4 translocation and promoting
improved control of blood glucose levels in Type II diabetes.
Research achievements (from final report):
The project focused on analysis of proteins that are involved in the movement of a
glucose transporter protein called Glut4 from the inside to the surface of fat cells
(referred to as Glut4 translocation). This process is defective in Type II diabetes, and
therefore the proteins that mediate Glut4 translocation are potential therapeutic targets
for the disease. Three main achievements were made during the course of this
research award. First, a protein called Snapin was found to associate with another
protein, SNAP23 that is involved in Glut4 translocation. Second, a novel association
was discovered between Sec15 (a component of a protein complex called the
exocyst), and another protein, Rab11. Rab11 belongs to a family of proteins (Rabs)
that cycle between active and inactive states, and thereby act as molecular switches
controlling the movement of proteins inside cells. We discovered that Sec15 interacts
specifically with the activated form of Rab11. Since the exocyst is implicated in Glut4
NHMRC Research Achievements - SUMMARY
translocation, these results suggest that the interaction between Sec15 and activated
Rab11 is involved in this process. Third, a novel protein was discovered that interacts
with a protein known as VAMP2 that is also involved in Glut4 translocation. The
novel protein was shown to promote the conversion of certain Rabs (including Rab11)
from the active to the inactive state. The identification of these three novel
interactions has led to an increased understanding of the molecular mechansisms that
control Glut4 translocation. In addition to this potential benefit, students working on
these projects gained valuable experience in medical research science during the
course of the award.
Expected future outcomes:
The achievements made during this award are anticipated to new research directions
focusing on the potential roles of the novel protein-protein interactions we have
discovered in Glut4 translocation. These studies are likely to lead to publications in
peer-reviewed scientific journals, as well as presentations at major international
conferences.
Name of contact: Tony Rowe
Email of contact: Tony.Rowe@biogenidec.com
NHMRC Research Achievements - SUMMARY
Grant ID: 491181
CIA Name: Prof Christopher Porter
Main RFCD: Pharmaceutical Sciences and Pharmacy
Admin Inst: Monash University
Start Year: 2008
End Year: 2011
Total funding: $398,157.00
Grant Type: NHMRC Project
Grants
Title of research award:
Recognition of macromolecular complexes by cell surface receptors: A novel
mechanism of lipid and drug absorption
Lay Description (from application):
A clear understanding of the mechanisms by which orally ingested materials are
absorbed from the gastrointestinal tract is critical in areas such as nutrition, drug
development and toxicology. The current project aims to evaluate the role of specific
receptor types in the intestine in the absorption of both dietary lipids and drug
molecules, with a view to providing a means to better regulate lipid absorption and to
more effectively facilitate the design of improved drug delivery systems.
Research achievements (from final report):
Despite the discovery of many drug candidates with great potential, relatively few
successfully progress through clinical trials and become marketed medicines. There
are myriad reasons for this failure- but one common problem is that the molecules that
are most active are often very poorly soluble in water. Since molecules must pass into
solution in fluids of the gastrointestinal tract prior to being absorbed, this is a
significant problem for drugs that are intended to be given orally (by mouth). To
combat this, ourselves and others have shown that effective absorption (and therefore
treatment) can be supported by administering drugs with small quantities of lipids
(fats). However, not all types support absorption and the mechanisms by which
different lipids facilitate absorption are not well understood. In the past this has
limited the ability to 'tailor' the design of formulations such that good exposure can be
maintained. In this project a number of novel mechanisms by which lipids and drugs
are absorbed have been uncovered. In particular, we have confirmed that high
concentrations of drugs and lipids may be incorporated into lipid complexes inside the
intestine, that the nature of these complexes is critical and that depending on structure,
maximal absorption is attained by lipid complexes that are able to specifically release
the drug near the intestinal membrane, ready for absorption. Subsequently, proteins
within intestinal cells aid in cellular transport and promote drug and lipid uptake into
the body via two pathways: the intestinal blood supply and the intestinal lymphatic
capillaries. Better understanding of these mechanisms has the potential to facilitate
more efficient delivery of new drugs and also the 'recovery' of old drugs that
previously failed to have an impact due to low absorption.
Expected future outcomes:
Improved elucidation of the mechanisms by which lipids promote drug absorption
will allow the rational design of formulations that promote drug absorption for
compounds that otherwise might never have been usable. Identifying novel
mechanisms of lipid absorption in this project might also provide the first steps
towards identifying new drug targets for diabetes, obesity, and/or heart disease.
NHMRC Research Achievements - SUMMARY
Name of contact: Chris Porter
Email of contact: Chris.Porter@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 219172
CIA Name: Prof Andrew Elefanty
Main RFCD: Endocrinology
Admin Inst: Monash University
Start Year: 2002
End Year: 2006
Total funding: $4,260,000.00
Grant Type: International
Collaborations
Title of research award:
Creating b-cells to cure type 1 diabetes
Lay Description (from application):
They aim to create insulin-secreting B cells by identifying their progenitor cells and
the moleculaes normally required for their development, in order to restore B-cell
function in the people with type 1 diabetes. Mouse and human multipotent embryonic
stem (ES) cells and fetal mouse panceas and adult pancreas duct cells will be used as
sources of progenitor B cells. Comparative studies will provide a more complete
picture of human B-cell ontogeny. Culture systems developed for ES cells/embryoid
bodies (EB) / EB-derived cells, fetal pancreas and adult pancreas duct cells, will be
employed to screen for and identify novel growth/differentiation factors and to
optimise parameters for creating B cells in vitro or (re) generating B cells in vivo.
Genetic constructs allowing regulated expression of fluorescently-tagged marker
genes and growth/transcription factors will be introduced into cultured cells or
transgenic mice to enable progenitor B cells to be tracked and isolated. Progenitor B
cells will be typed with panels of known novel markers molecules at the gene and
protein level, and gene expression profiles of tissue yielding B cells will be analysed
across time to reveal further candidate markers. Molecules and methods effective in
mouse systems will be applied to human ES cell-derived or pancreatic duct cells. The
capacity to progenitor cells or insulin-secreting cells to ameliorate diabetes when
transplanted into the testis, under the kidney capsule or into the pancreas of mouse
models would represent proof-of-concept. Functional B cells derived from human
ERS cells or pancreas duct cells, or growth factors that regenerate B cells in vivo,
could together with appropriate immunotherapy restore B-cell function in people with
type 1 diabetes.
Research achievements (from final report):
The aim of this grant was to create insulin-producing cells from several possible
sources, with the long term goal of restoring pancreatic insulin secretion in people
with type 1 diabetes. The arms of the program encompassed endeavours to grow these
insulin producing cells from either mouse or human embryonic stem cells or from
stem cell populations present in the adult pancreas, again using the mouse as a model
system.
Our studies with mouse embryonic stem cells utilised genetic engineering
technologies that enabled us to modify the stem cell lines such that we could visualise
early pancreas cells by their green fluorescence and more mature insulin producing
cells by a red fluorescence. These powerful new tools enabled us to develop growth
conditions that allowed the mouse embryonic stem cells to turn into insulin producing
cells in the laboratory that had the ability to reduce the blood glucose when they were
tranplanted into diabetic mice. If this study can be recapitulated with human
embryonic stem cells, the potential is there for a new therapy that could benefit
NHMRC Research Achievements - SUMMARY
patients with diabetes. In fact, the development of precursor cells part of the way
along the pathway to pancreatic cells was already achieved in the more modest human
embryonic stem cell component of this program.
Another area of achievement in this program related to improvements in the methods
of identifying and isolating stem cells from the adult pancreas with the eventual aim
to direct these cells to making new insulin producing cells for patients. As a result of
our studies we were able to isolate and grow these cells more successfully than
previously.
These results have provided the springboard for a second successful program grant
application that commenced in 2008 with the express aim of translating these results
to human cells.
Expected future outcomes:
These studies have laid the groundwork for a currently funded program that will aim
to translate the succeses with the mouse embryonic stem cell experiments to human
embryonic stem cell experiments with the long term goal of making insulin producing
cells to treat patients with diabetes.
Name of contact: Andrew Elefanty
Email of contact: Andrew.elefanty@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 334100
Start Year: 2005
CIA Name: Prof Andrew Elefanty
End Year: 2010
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding:
$652,378.00
Admin Inst: Monash University
Grant Type: Established
Career Fellowships
Title of research award:
Uncoupled Research Fellowship
Lay Description (from application):
I am a stem cell scientist working on the biology of human embryonic stem cells and
their differentiation into cells of mesodermal (blood, endothelium and cardiomyocyte)
and endodermal (pancreatic islet cells) lineages.
Research achievements (from final report):
Research in the laboratory that I jointly head with Prof Ed Stanley is focused on the
study of human pluripotent (hESC and hiPSC) stem cells. Our core interest lies in the
regulation of human pluripotent stem cell differentiation to mesoderm and endoderm
lineages, as exemplified by blood and heart and pancreatic islet cells, respectively.
In order to facilitate this work, our laboratory has generated genetically modified
human ES cell lines into which reporter genes have been inserted by homologous
recombination in gene loci that are expressed at specific developmental stages or in
specific lineages. We have targeted approximately 10 different genes in multiple
hESC lines to date. Therefore, this has enabled us to more readily identify cells
developing into blood, heart, pancreas, lung, thymus and neural cell types. Our
research has been published in high quality scientific journals and we have
successfully obtained ongoung research funding ofor our laboratory.
We have also devised a reproducible differentiation protocol for human ES cells ('spin
EBs'), complemented with an animal product free, recombinant human protein
containing medium (APEL) that will facilitate optimisation of human ES cell
differentiation in the presence of appropriate growth factors. This cell culture medium
has been commercialised and is now being sold by a biotechnology company,
STEMCELL Technologies.
Our work has generated unique opportunities for the study of early stages of human
development, the generation of laboratory models for human diseases, the testing of
pharmaceuticals and other therapeutic products and eventually we hope to be able to
produce transplantable cells for tissue repair and regeneration. The ability to
genetically modify human ES cells may translate into an ability to correct genetic
abnormalities in patient derived iPS cells in some cases.
Expected future outcomes:
A major goal of our work is to realise some of the scientific and therapeutic potential
that pluripotent cells promise. We hope to continue to develop platforms for testing of
therapeutic products and the generation of cells for replacement therapies.
Name of contact: Andrew Elefanty
Email of contact: andrew.elefanty@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 436634
CIA Name: Prof Richard Boyd
Main RFCD: Autoimmunity
Admin Inst: Monash University
Start Year: 2007
End Year: 2011
Total funding: $5,554,618.00
Grant Type: Programs
Title of research award:
Innovative stem cell-based strategies to establish immune tolerance and tissue repair
Lay Description (from application):
Diseases such as autoimmune gastritis, multiple sclerosis and diabetes arise because a
"rogue" immune system has turned inwards to attack our organs. The organ
destruction follows from recognition by the immune system of specific molecules in
these organs. These
"autoimmune" diseases are incurable and controlled mainly by long-term
administration of substances that suppress the immune
system, often with serious side-effects. A rational approach is to render the rogue
immune system harmless by removing the cells that
recognize these particular molecules. This can be achieved by a "Trojan horse"
approach in which the molecules are delivered to the
immune system such that that the immune cells that recognize them are removed. To
deliver these molecules to the immune system we
will genetically engineer bone marrow stem cells, or embryonic stem cells that
generate these stem cells, because they are precursors of
mature immune cells. Rejection of organ transplants arise in a similar way and also
require long-term immunosuppression. A similar
approach can therefore be taken to promote acceptance of foreign organ grafts. In the
aged, we will combine these approaches with
rejuvenation of the immune system by blockade of sex steroid production and/or by
creation of a new immune organ.
Research achievements (from final report):
One of the greatest challenges in the clinic is the treatment of autoimmune disease.
Being the result of abnormal immune responses, the clinical handling of these
conditions is typically through a form of chemotherapy. This has achieved some level
of success but there are two major problems: by definition, the level of chemotherapy
or anti-inflammatory drugs necessary to stop disease progression almost by definition
creates a potentially even greater clinical problem- generalised immune suppression.
This lack of immunity can lead to outbreak of severe infections, which can be lethal.
The secret to overcoming these issues is to hijack the normal mechanisms of selftolerance and apply them to the treatment of autoimmunity. This has at its essence the
thymus, which creates all T cells necessary for immune responses but eliminates those
which are potentially autoreactive. The reason it has not been manipulated to treat
autoimmunity is because this organ undergoes severe atrophy early in life. This
program made a major advance to the field - it developed a means of reactivating the
seemingly dormant thymus and combined this with bone marrow transplantation and
a very low dose-conditioning regime. It also established the technology for identifying
thymus stem cells and then creating them from pluripotential stem cells as a means of
growing a completely new thymus. By combining these collective studies with that of
intense research in neural development and disease, we now have a unique platform
NHMRC Research Achievements - SUMMARY
for treating autoimmunity - particularly multiple sclerosis. The program also produced
a number of invaluable reagents and technologies for other studies on the immune
and neural systems, and for the general field of preventing rejection of donor
transplants. We have thus established a unique platform for firstly understanding how
self tolerance is broken to allow development of disease and then exploring new ways
of treating autoimmunity.
Expected future outcomes:
There are several very important application of this research, particularly clinically.
We can trial restoration of a functional thymus and immune capacity and combine this
with donor haemopoietic and therapeutic stem cells to generate new T cells which are
both donor and self tolerant. The ability to create a thymus from stem cells can be
applied to many immunological diseases.
Name of contact: Professor Richard Boyd
Email of contact: richard.boyd@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 545846
CIA Name: Prof Tony Tiganis
Main RFCD: Endocrinology
Admin Inst: Monash University
Start Year: 2009
End Year: 2011
Total funding: $542,462.00
Grant Type: NHMRC Project
Grants
Title of research award:
Regulation of insulin signalling and glucose homeostasis by protein tyrosine
phosphatases
Lay Description (from application):
A common feature of type 2 diabetes is high blood glucose due to peripheral insulin
resistance. Protein tyrosine phosphatases (PTPs) that antagonise insulin signalling
might be important targets for therapeutic intervention in type 2 diabetes; inhibition of
specific PTPs may allow for enhanced IR signalling to alleviate insulin resistance.
This proposal will examine the roles of PTPs and in particular TCPTP in insulin
signalling and glucose homeostasis.
Research achievements (from final report):
Type 2 diabetes has reached epidemic proportions in both developed & developing
nations afflicting some 220 million people worldwide. Insulin resistance (diminished
cellular response to circulating insulin) is a key pathological feature of type 2
diabetes. Inhibiting protein tyrosine phosphatases (PTPs) that antagonize insulin
signaling may provide a means for promoting insulin sensitivity and alleviating
insulin resistance. This proposal examined the role of the PTP known as TCPTP in
insulin sensitivity and glucose homeostasis. We generated mice lacking the protein in
eithet muscle, liver, fat or brain, the principal tissues that response to insulin in teh
control of glucose homeostasis. Our studies identified TCPTP as a key regulator of
glucose homeostasis and body weight in liver and the brain. Our studies have
identified TCPTP as a potential therapeutci target for the treatment of obesity and
type 2 diabetes.
Expected future outcomes:
Our ongoing studies will define the molecular mechanisms by which PTPs regulate
body weight and contribute to the development of obesity and type 2 diabetes.
Name of contact: N/A
Email of contact: Tony.Tiganis@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 546425
CIA Name: Prof Anne-Louise Ponsonby
Main RFCD: Epidemiology
Admin Inst: Murdoch Childrens Research Institute
Start Year: 2009
End Year: 2011
Total funding: $342,795.00
Grant Type: NHMRC Project
Grants
Title of research award:
Investigating low sun exposure and other possible early life determinants of type 1
diabtes mellitus
Lay Description (from application):
Type 1 diabetes mellitus is becoming more common among Australian children. The
project explores aspects of the modern child's environment that may increase the risk
of type 1 diabetes. In particular it aims to assess whether very low sun exposure in
early life is adverse. Low sun exposure may be adverse because sun exposure derived vitamin D is vital for the developing child's immune system. We need to
know what level of sunlight and vitamin D children need to prevent disease.
Research achievements (from final report):
The achievements for the Early Environment and Type 1 Diabetes Prevention Project
so far are the publishing of two papers. For the first paper, the sample consisted of
children with T1DM and their sibling (n = 42). Cases were significantly more likely
to have lighter skin pigmentation at the upper arm (AOR 0.69 [95% CI: 0.52, 0.90]; P
= 0.01). Low infant sun exposure was imprecisely associated with a two-fold increase
in T1DM risk (AOR 2.43 [95% CI: 0.91, 6.51]; P = 0.08 for under 1 hour of winter
sun exposure per leisure day). The VDR gene promoter was completely unmethylated
in both cases and siblings. The previously demonstrated association between light
skin pigmentation and T1DM risk was evident even in this comparison across sibling
pairs. The second paper assessed levels of glutamic acid decarboxylase 65 islet cell
antigen (GADA) and anti-insulin antibodies (IAA) in 247 incident T1DM cases
presenting <15 years of age. 58.9% (142/241) of cases were GADA seropositive and
42.3% (94/222) were IAA seropositive. Factors associated with elevated IAA
antibodies included younger age and red hair phenotype. Factors associated with
elevated GAD antibodies included lower birthweight and recent eczema. Intriguingly,
low recent or past sun exposure was only associated with elevated GADA levels
among children presenting at age <5 years, not older (difference in effect, p<0.05 for
4 of 5 associations). These findings show that environmental and phenotypic factors
are associated with autoantibody levels at time of presentation for T1DM.
Expected future outcomes:
This ultimate goal is to improve public health guidelines on lifestyle or environment
to prevent the development of T1DM. This project aims to investigate the role of
early life risk factors for T1DM onset in childhood, with an emphasis on the role of
low sun exposure.
Name of contact: Anne-Louise Ponsonby
Email of contact: anne-louise.ponsonby@mcri.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 334354
CIA Name: A/Pr Fergus Cameron
Main RFCD: Endocrinology
Admin Inst: Murdoch Childrens Research Institute
Start Year: 2005
End Year: 2007
Total funding: $416,000.00
Grant Type: NHMRC Project
Grants
Title of research award:
Insights into the acute cerebral lesion of childhood diabetes and it's
neuropsychological sequelae
Lay Description (from application):
Type 1 diabetes in childhood is a major cause of morbidity with an Australian
prevalence of approximately 20 per 100,000 children under 15 years of age. The
leading cause of death in type 1 diabetes in children and adolescents is diabetic
ketoacidosis complicated by cerebral oedema (brain swelling), the origins of which
remain unknown. This research is aimed at providing an insight into changes in the
brain of children with diabetic ketoacidosis (DKA) and the relationship of these brain
changes to short and long term neuropsychological functioning. The major aim of
this project is to provide an insight into brain changes of children with diabetic
ketoacidosis (DKA) and the relationship of these brain changes to subseuqent brain
function. This is a study where we will simply observe differences between newly
diagnosed type 1 diabetic patients with no ktoacidosis, ketoacidosis or ketoacidosis
with brain swelling over 6 months. We will measure brain function using various
techniques includiung: magnetic resonance imaging (MRI), magnetic resonance
spectroscopy (MRS), electrophysiology (EEG) and neuropsychological tests. The
significance of this project is that it will provide insight into the brain impairment of
diabetic patients with and without DKA, and with brain swelling in the context of
DKA. By further clarifying the nature of brain impairment we will provide early
intervention strategies to improve psychological development of the young patients
with diabetes. In addition to this we hope to better understand the origins of brain
swelling during DKA and design treatment protocols that will prevent this devastating
complication.
Research achievements (from final report):
The sample recruited between 2004 and July 2008 includes 58 children aged between
six and 18 years of age, presenting to the RCH with newly diagnosed type 1 diabetes.
Preliminary neuropsychology subset data analyses have been conducted on 13 DKA
and 21 non-DKA children. We found a trend for poorer intellectual functioning in the
DKA group compared with the non-DKA group. All children exhibited disrupted
mental status, learning, attention and inhibitory control in the acute phases of
diagnosis. Some improvements in cognitive functions were observed over the first 6
months, although not always to age expected levels. A pattern of persisting deficits in
complex skills such as divided attention was observed.
Preliminary electroencephalographic subset data analyses have been conducted
acutely on 6 DKA and 10 non-DKA children. Reversible encephalopatic changes
were evident on both the DKA and non-DKA group with higher degree of disruption
in the DKA group. Epileptiform discharges were identified in 2 of 6 DKA patients
and 1 of 10 non DKA patients, persisting in all cases on follow up EEGs. This finding
is unrelated to DKA and most likely indicate a genetic or developmentally determined
NHMRC Research Achievements - SUMMARY
predisposition to seizures. Further correlation analysis is on the way and until such
takes place we are unable to further comment in details
Preliminary analysis of spectroscopy on 33 completed subset studies shows some
significant differences in metabolite concentration between non-DKA and DKA
subjects. In particular frontal grey matter, N-acetylaspartate, myoinositol and taurine
are increased in DKA, relative to non-DKA, at 28 days but not at other time points. In
DKA subjects, frontal white matter taurine and glycerophosphocholine were
decreased at day 1 and increased at 6 months follow up, relative to non-DKA subjects.
Further correlation analysis is essential on the whole cohort of patients upon
completion of data collection.
Expected future outcomes:
Ongoing clinical recruitment and further correlation data analysis to be done.
Name of contact: A/Professor Fergus Cameron
Email of contact: fergus.cameron@rch.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 198712
CIA Name: Dr Greg Tesch
Main RFCD: Nephrology and Urology
Admin Inst: Prince Henry's Institute of Medical Research
Start Year: 2002
End Year: 2004
Total funding: $451,980.00
Grant Type: NHMRC Project
Grants
Title of research award:
Macrophages in diabetic nephropathy.
Lay Description (from application):
Kidney disease occurs in up to 50% of patients with insulin-dependent (type 1) and
non-insulin-dependent (type 2) diabetes. The increasing rate of diabetes in our
community has made it a major cause of kidney disease and a growing health
problem. Despite clinical attempts to control blood glucose and blood pressure levels,
kidney disease in most diabetic patients progresses towards a complete loss of kidney
function. In severe cases, the survival of the patient is dependent upon lifelong
dialysis or transplantation, which are costly and complicated treatments. Therefore,
there is an urgent need to improve treatment stategies in diabetic patients to avoid
kidney failure. Recent evidence in human and experimental models of diabetic
kidney disease has indicated that macrophages infiltrate the kidney during the disease
process. Our previous knowledge from other inflammatory kidney diseases suggests
that macrophages play an important role in promoting the progression of disease and,
in some of these diseases, treatment strategies which block macrophage function and
accumulation have been shown to be effective in inhibiting the disease. The overall
aim of these studies will be to determine the importance of macrophages in the
pathogenesis of diabetic kidney disease and identify the mechanisms regulating their
recruitment and activation within the diabetic kidney. This will be achieved by
examining the progression of kidney disease in type 1 and type 2 diabetic mice which
have been genetically modified to prevent macrophage accumulation and activation
within the kidney. These studies will provide valuable information into the
pathogenesis of diabetic kidney disease and will identify whether therapeutic
strategies targeting macrophages can help prevent kidney loss in diabetes.
Research achievements (from final report):
In this project, we examined the importance of macrophages to the development of
diabetic nephropathy, the major cause of end-stage renal failure.
In conclusion, the findings of this project provide substantial evidence that
macrophages promote the progression of type 1 and type 2 diabetic nephropathy. Dr
Fiona Chow was awarded the 2004 ANZSN Young Investigator Award for her
contribution to the studies.
Expected future outcomes:
These findings have helped identify potential mechanisms by which macrophages
may contribute to the development of renal fibrosis during diabetic nephropathy.
Name of contact: N/A
Email of contact: N/A
NHMRC Research Achievements - SUMMARY
Grant ID: 388902
CIA Name: Dr David Nikolic-Paterson
Main RFCD: Nephrology and Urology
Admin Inst: Prince Henry's Institute of Medical Research
Start Year: 2007
End Year: 2008
Total funding: $425,921.00
Grant Type: NHMRC Project
Grants
Title of research award:
Lefty - a novel anti-fibrotic molecule for the treatment of kidney disease
Lay Description (from application):
Patients with progressive forms of kidney disease go on to develop end-stage renal
failure which requires intensive medical support of dialysis or organ transplantation.
This is an increasingly common condition in Australia, and the Western world in
general. It is devastating for the individual and it places an enormous economic strain
upon our healthcare system. In addition, renal failure is a strong and independent risk
factor for cardiovascular disease. Current treatments can at best slow the rate of
progression of kidney disease, but cannot prevent the relentless progression to endstage renal failure. Thus, there is a major medical need to be able to halt, and
hopefully reverse, this relentless disease. Scarring of the kidney (termed fibrosis) is
the common final pathway leading to end-stage renal failure regardless of the nature
of the underlying kidney disease. Our preliminary studies have shown that a naturally
occurring protein called Lefty can act to inhibit renal fibrosis in cell culture and
animal studies. These very promising results have lead to the hypothesis that Lefty
can halt, and perhaps even reverse, scarring of the kidney in progressive kidney
disease. We will test this hypothesis by using Lefty as a treatment in animal models of
renal fibrosis. Further cell culture studies are also planned to examine the mechanisms
by which Lefty modulates renal fibrosis. If successful, these studies will provide
critical data to support the development of Lefty as a clinical treatment for patients
with progressive forms of kidney disease.
Research achievements (from final report):
These studies have examined the mechanisms involved in fibrosis (or scarring) of the
damaged kidney, a process generally considered to be the final pathway leading to
complete loss of kidney function that requires treatment by dialysis or kidney
transplantation. We have identified a novel, naturally occurring protein that appears to
have potential anti-fibrotic actions when used in cell culture studies and has indicated
some promise in animal studies. This anti-fibrotic molecule appears to operate via a
novel mechanism and represents a potential therapy for the treatment of chronic
kidney disease. However, much work remains to be done before this molecule could
be used in clinical trials.
Expected future outcomes:
We hope that these exciting findings can be translated into clinical trials in patients
with renal disease, although this possibility is still some time away.
Name of contact: David Nikolic-Paterson
Email of contact: david.nikolic-paterson@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 338517
CIA Name: Dr Greg Tesch
Main RFCD: Nephrology and Urology
Admin Inst: Prince Henry's Institute of Medical Research
Start Year: 2005
End Year: 2007
Total funding: $454,500.00
Grant Type: NHMRC Project
Grants
Title of research award:
Role of JNK and p38 MAPK signalling in diabetic nephropathy
Lay Description (from application):
Renal failure is a major health problem in our community. Patients who progress to
end-stage renal failure are dependent upon lifelong dialysis or transplantation (an
expensive and complex treatment). The past decade has seen a dramatic increase in
the number of patients developing end-stage renal failure, mainly due to increasing
rates of diabetic kidney disease. Indeed, the recent AusDiab nationwide survey that
identified diabetes or glucose intolerance (a precursor to diabetes) is now present in
up to 25% of the adult Australian population. Around 50% of diabetics develop
kidney disease and, despite recent advances in better control of blood glucose and
blood pressure, kidney disease in most diabetic patients will inexorably progress to
end-stage renal failure. Therefore, there is an urgent need to improve treatment
strategies in diabetic patients to avoid kidney failure. We have identified a group of
proteins (enzymes called JNK and p38) within cells that play a causal role in the
development of non-diabetic forms of kidney disease. Most recently, we have shown
that an increase in the activity of these proteins (JNK and p38) is associated with the
development of human and experimental diabetic kidney disease. Therefore, this
project will block the action of JNK and p38 using two complementary approaches
(pharmaceutical drugs and genetically modified mice) to determine whether targeting
these proteins can suppress the development of diabetic kidney disease. In addition,
there is evidence to suggest that blockade of these proteins may have a beneficial
impact upon insulin resistance and elevated blood glucose in type 2 diabetes. If these
postulates are proven, this will provide a well-defined therapeutic target for the
treatment of diabetic kidney disease, and perhaps diabetes itself. Furthermore, since
inhibitors of these proteins are already in clinical trials for other indications, targeting
this mechanism in diabetic kidney disease is a realistic goal.
Research achievements (from final report):
This project has shown that intracellular signalling via JNK1 or MKK3 promotes the
development of pancreatic injury, islet destruction and hyperglycaemia in the
multiple-low dose model of streptozotocin-induced type 1 diabetes in mice.
Furthermore, we have identified that signalling via JNK1 or JNK2 is critical for the
development of type 2 diabetes in obese db/db mice. In contrast, MKK3 signalling
was not required for the induction of type 2 diabetes in db/db mice, but was important
for the subsequent development of diabetic nephropathy in these animals. These
studies indicate that therapeutic targeting of the JNK or MKK3 signalling pathways
may be beneficial in the treatment of diabetes or diabetic nephropathy.
Expected future outcomes:
Our findings provide the foundation for future research examining how JNK
signalling contributes to the development of type 2 diabetes and may also lead to the
NHMRC Research Achievements - SUMMARY
development of specific kinase inhibitors which target these signalling pathways in
order to suppress the development of diabetes or diabetic nephropathy.
Name of contact: Dr Greg Tesch
Email of contact: greg.tesch@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 388930
CIA Name: Dr Greg Tesch
Main RFCD: Nephrology and Urology
Admin Inst: Prince Henry's Institute of Medical Research
Start Year: 2006
End Year: 2010
Total funding: $462,290.00
Grant Type: Career
Development Fellowships
Title of research award:
Macrophage-mediated injury - potential therapeutic targets for preventing diabetic
nephropathy and insulin resistance.
Lay Description (from application):
Not Available
Research achievements (from final report):
During this fellowship, I have performed genetic mutation and pharmacological
studies in animal models of disease which have demonstrated that tissue accumulation
of a particular type of inflammatory cell, known as a macrophage, is a major
contributor to the development of obesity-related diabetes and diabetic kidney injury.
These studies have determined some of the critical molecular mechanisms by which
macrophages cause tissue injury during obesity and diabetes. They have also
identified specific molecules that can be blocked therapeutically to prevent the tissue
injury caused by macrophages, and have shown that this strategy can be used to
prevent the progression of kidney damage during diabetes. However, the therapeutic
strategies identified for blocking macrophages so far are not ideal for clinical use in
chronic disorders such as obesity or diabetes. Therefore, more investigations are
required to identify better strategies for macrophage blockade that will be more
appropriate for potential use in patients.
Expected future outcomes:
The findings made during my CDA have facilitated the development of new research
projects and collaborations with pharmaceutical companies. These ongoing studies
aim to identify molecules that are better therapeutic targets for selectively preventing
the development of inflammatory responses which cause obesity-related diabetes or
diabetic nephropathy.
Name of contact: Dr Greg Tesch
Email of contact: greg.tesch@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 494823
CIA Name: Dr Greg Tesch
Main RFCD: Endocrinology
Admin Inst: Prince Henry's Institute of Medical Research
Start Year: 2008
End Year: 2010
Total funding: $519,715.00
Grant Type: NHMRC Project
Grants
Title of research award:
Therapeutic targetting of MIF in type 2 diabetes
Lay Description (from application):
In this study, mouse models of disease will be used to determine the mechanisms by
which the proinflammatory molecule called MIFpromotes the development of insulin
resisitance and type 2 diabetes. We will also test whether therapeutic blockade of MIF
can prevent the progression of disease in mice with established type 2 diabetes.
Studies on tissue samples obtained from human patients will be used to confirm the
human relevance of these findings.
Research achievements (from final report):
This project has identified a role for a circulating pro-inflammatory molecule
(macrophage migration inhibitory factor - MIF) and two types of intracellular
signaling molecules (JNK1 and JNK2) in the development of type 2 diabetes in obese
db/db mice. Our studies showed that MIF was increased in the abdominal fat and
liver of obese db/db mice and was inducible in cultured fat cells by increasing levels
of free fatty acids, which are present during obesity. Genetic deficiency of MIF
protected db/db mice from inflammation of the fat tissue, loss of insulin sensitivity
and the development of type 2 diabetes without reducing obesity. We also examined
the role of intracellular JNK signaling as a downstream mediator of MIF-induced
inflammation and insulin resistance. Genetic deficiency of either JNK1 or JNK2 were
found to protect db/db mice from the development of obesity-related type 2 diabetes.
JNK1 deficiency resulted in improved insulin sensitivity in db/db mice. In contrast,
JNK2 deficiency had no clear effect on insulin sensitivity but altered fat distribution
in db/db mice. These findings indicate that blockade of MIF or JNK signaling with
specific inhibitors has significant therapeutic potential for preventing the development
of insulin resistance and type 2 diabetes in obese patients.
Expected future outcomes:
Our analysis of 3 animal model studies is approaching completion and we expect to
publish these studies within the next 12 months. These studies are expected to identify
mechanisms by which MIF, JNK1 and JNK2 promote the development of type 2
diabetes.
Name of contact: Dr Greg Tesch
Email of contact: greg.tesch@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 338501
CIA Name: Prof Chen Chen
Main RFCD: Cell Physiology
Admin Inst: Prince Henry's Institute of Medical Research
Start Year: 2005
End Year: 2007
Total funding: $256,500.00
Grant Type: NHMRC Project
Grants
Title of research award:
Regulation of pancreatic beta-cell number and function by adipocyte-released
hormones, free fatty acids and ghrelin.
Lay Description (from application):
The disease diabetes mellitus comprises a heterogeneous group of disorders all
characterised by high blood glucose levels. Beta-cells in the pancreas, which secrete
insulin, are central to the pathophysiology of the disease. Type 1 or insulin-dependent
diabetes mellitus results from an absolute deficiency of insulin due to auto
immunological destruction of the pancreatic beta cell, and accounts for 5-10% of total
diabetes mellitus. In the more common type 2 or non-insulin-dependent diabetes
mellitus, liver, muscle and fat cells are resistant to the action of insulin and
compensatory mechanisms that are activated in the beta-cell to increase insulin
secretion are not sufficient to maintain normal blood glucose levels. In Western
countries including Australia, type 2 diabetes currently affects around 2% of the
whole population and about 6% of adults (10% of over 60-y) and continues to grow at
around 6% per annum. Type 2 diabetes often occurs in obese patients and a direct link
between obesity and type 2 diabetes has been strongly suggested by research to date.
It has also been found that a progressive loss of beta-cell function throughout the
course of the disease results in the reduction of insulin secretion. The contribution of
excessive fat tissue in obese patients to the progress of type 2 diabetes is not clear.
Certain hormones from fat cells, metabolic regulatory hormone, and fatty acids have
been demonstrated to influence the function of beta-cells in previous studies,
including our own. We now aim to investigate in detail the effect of these on cultured
beta-cells with molecular and cell biology techniques. We expect to identify a factor
or factors which stimulate or inhibit the progress of beta-cell dysfunction, with the
potential to identify therapeutic targets in the treatment of type 2 diabetes.
Research achievements (from final report):
Diabetes mellitus is a heterogeneous group of disorders characterised by high blood
glucose levels. The pancreatic beta-cell and its secretory product insulin are central in
the pathophysiology of the disease. Type 2 diabetes counts for 90-95 % of total
diabetes. In type 2 or non-insulin-dependent diabetes mellitus, liver, muscle and fat
cells are resistant to the action of insulin and compensatory mechanisms that are
activated in the beta-cell to secrete more insulin are not sufficient to maintain blood
glucose levels within a normal physiological range. Type 2 diabetes occurs often in
obese patients and a direct link between obesity and type 2 diabetes has been strongly
supported. The contribution of excessive adipose tissue in obesity patients to the
progress of beta-cell dysfunction has been studied in this project. Adipocyte-derived
hormones and free fatty acids have been demonstrated to damage the function of betacells in insulin synthesis and secretion. Membrane ion channels and signalling
systems have been studied. We found that FFA influenced beta cell function through
both membrane receptor and intracellular metabolism pathways. We also found that
NHMRC Research Achievements - SUMMARY
insulin resistance in beta cells was responsible for beta cell dysfunction. These new
discoveries lead to a new project proposal submitted for further investigation.
Expected future outcomes:
The results from this study lead to a further study on cell function of pancreatic islet
cells under the influence of FFAs through receptor and metabolite pathways. It will
clarify the mechanism of FFA-induced beta cell dysfunction and will also lead to new
ways to delay the process of diabetes.
Name of contact: Chen Chen
Email of contact: chen.chen@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 338510
CIA Name: Dr Margaret Jones
Main RFCD: Cell Metabolism
Admin Inst: Prince Henry's Institute of Medical Research
Start Year: 2005
End Year: 2007
Total funding: $361,200.00
Grant Type: NHMRC Project
Grants
Title of research award:
THE METABOLIC SYNDROME, RISK FACTORS AND ESTROGEN
Lay Description (from application):
The Metabolic Syndrome is a group of closely related risk factors that contribute to
the onset of diabetes and heart disease. The risk factors include obesity, (especially
when fat accumulates around the waist), insulin resistance and high blood pressure.
There is an important but as yet not fully understood relationship between estrogen
and the development of these risk factors. The Metabolic Syndrome has been
estimated to affect some 20-30% of the middle-aged population and prevalence
appears to be increasing in the world population with increasing obesity and sedentary
lifestyle. Therefore it is of great importance to be able to understand the mechanisms
regulating the development of, and the interrelationships between, the risk factors of
the syndrome, particularly the integral role played by estrogen. By utilising a mouse
model that cannot make its own estrogen, we are able to study how estrogen
contributes to maintaining the body's balance of fat tissue, sensitivity to insulin and a
healthy heart. We will be looking at how genes important to these systems are
affected when estrogen is not available and what the downstream consequences of any
gene changes are. We also plan to monitor the mouse's sensitivity to insulin in the
absence of estrogen, then again when estrogen is given back. Similarly, we will study
the mouse's cardiovascular system, checking blood pressure, heart health and
sensitivity to salt (which can affect blood pressure). By completing this body of
work, we will better understand how estrogen can best be used as a therapy to prevent
the development of the risk factors for the Metabolic Syndrome.
Research achievements (from final report):
Estrogen has an important role to play in energy homeostasis in both men and mice.
Lack of estrogen results in the development of a metabolic syndrome in humans and
rodents, including excess adiposity, hepatic steatosis (in male but not female
Aromatase Knockout (ArKO) mice) and insulin resistance. Estrogen replacement
results in a prompt reversal of the energy imbalance symptoms associated with
estrogen deficiency. A corollary to the perturbed energy balance observed in the
ArKO mouse is the death by apoptosis of dopaminergic neurons in the hypothalamic
arcuate nucleus of male ArKO mice, an area of the brain pivotal to the regulation of
energy uptake, storage, and mobilisation. An extension of our work exploring the
relationship between estrogen and adiposity has been to examine the role played by
androgens in energy balance. We have demonstrated that an increased androgen to
estrogen ratio can promote visceral fat accumulation in the rodent by inhibiting
AMPK activation and stimulating lipogenesis. Therefore understanding the
regulation of energy homeostasis is becoming an increasingly fascinating challenge,
as the number of contributors, their communications, and the complexity of their
interactions, involved in the preservation of this equilibrium continues to increase.
NHMRC Research Achievements - SUMMARY
Models of aromatase deficiency, both naturally occurring and engineered, will
continue to provide valuable insights into energy homeostasis.
Expected future outcomes:
Features of the Metabolic Syndrome, including 1) abdominal obesity and
dyslipidemia, 2) insulin resistance and 3) hypertension, constitute significant risk
factors for Type 2 diabetes and cardiovascular disease. Our research is continuing to
make significant inroads into understanding the role of estrogen in the development of
these features.
Name of contact: Dr Margaret Jones
Email of contact: Margaret.Jones@princehenrys.org
NHMRC Research Achievements - SUMMARY
Grant ID: 338500
CIA Name: Prof Chen Chen
Main RFCD: Endocrinology
Admin Inst: Prince Henry's Institute of Medical Research
Start Year: 2005
End Year: 2007
Total funding: $350,250.00
Grant Type: Established
Career Fellowships
Title of research award:
Uncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
I have established and sustained a strong international profile in endocrine cell
biology and expanded our research into cardiology and cancer research during this
fellowship support. I have made a substantial contribution to my working field,
having published 27 papers in high quality journals including J Physiol,
Endocrinology, Am J Physiol, Human Mol Genet, etc. It should be noted that this
support was only for 3 years with an early promotion to Principal Research Fellow
starting 2008. A number of published papers have been seminal contributions with
impact beyond my specific field, e.g. demonstration of FFA's action on receptor and
ion channels in beta cells, role of oestrogen in pituitary GH cells, effect of ghrelin on
cardiac myocytes, role of ghrelin in endometrium, etc. This substantial body of highquality work is clearly continuing to make an international impact in my discipline,
confirmed by the high impact factor of journals in which I published, the frequent
citation of my papers, frequent invitations to give plenary lectures, symposium chair
and presentation, and to be in the organizing committees of several scientific
conferences and societies. It is also reflected in the number of invitations to join the
Editorial Boards of international journals, including leading endocrine journal,
Endocrinology. I have also been invited to review grant proposals for a number of
funding agencies. I was offered a Professorship title by the University of Queensland
with significant start-up funds to relocate my laboratory to Brisbane early 2008.
Expected future outcomes:
In the next 5 years, my group is expanding into several new researdch areas including
diabetes research, single cell exocytosis with multiple photon microscope, single cell
contraction and signal image analysis, and cancer development. Our research will be
related to type 2 diabetes, heart failure, obesity, and endometrium cancer.
Name of contact: Chen Chen
Email of contact: chen.chen@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 494822
CIA Name: A/Pr David Nikolic-Paterson
Main RFCD: Nephrology and Urology
Admin Inst: Prince Henry's Institute of Medical Research
Start Year: 2008
End Year: 2010
Total funding: $537,704.00
Grant Type: NHMRC Project
Grants
Title of research award:
TAK1 - a novel regulator of renal inflammation and fibrosis.
Lay Description (from application):
Renal failure is a major health problem in our community. Recent in vitro studies
have identified a protein that plays a critical role in the induction of inflammation and
fibrosis - processes central to the progression of kidney disease. This project will use
a genetic-based approach to determine if this regulator plays a critical role in the
pathogenesis of experimental kidney disease. If successful, these studies will identify
a new therapeutic target for the treatment of kidney disease.
Research achievements (from final report):
We have examined the function of a specific gene, called TAK1, in the development
of inflammation, fibrosis and cell death in experimental kidney disease. Using mice in
which that TAK1 gene has been deleted in different cell populations, we have been
able to define several distinct functions of the TAK1 gene. Specific deletion of the
TAK1 gene from particular white blood cell populations (macrophages and
neutrophils) showed that this gene is not required macrophage development. As
postulated, we found that TAK1 deficient macrophages exhibit a severely diminished
response to various pro-inflammatory stimuli. In vivo, these mice were partially
protected in a model of endotoxin-induced acute renal injury (albuminuria). In a
separate study, general deletion of the TAK1 gene in adult mice was shown to protect
against fibrosis in a model of kidney scarring, although the lack of TAK1 did enhance
cell death in the kidney which limits the potential usefulness of blocking TAK1
function as a treatment of kidney scarring. Finally, deletion of TAK1 in a key cell
type in the glomerulus (the filtering unit of the kidney) called the podocyte
demonstrated that TAK1 is not required for normal kidney development; however,
TAK1 deletion made these mice more susceptible to immune-mediated podocyte
injury resulting in more severe kidney disease. In summary, we have identified TAK1
as a key regulator of inflammation, fibrosis and cell death in kidney disease.
However, our studies indicate that TAK1 is not a suitable therapeutic target in kidney
disease because TAK1 exhibits both protective and detrimental functions in kidney
disease depending upon the nature of underlying renal injury.
Expected future outcomes:
Our studies have indicated that two of the three key signalling pathways activated by
TAK1 (called p38 and JNK) are potential therapeutic targets in kidney disease,
whereas the third major pathway activated by TAK1 (called NF-kB) plays an
important role in protecting the kidney from cell death. We anticipate that these
findings will shape the design of future clinical trials.
Name of contact: Dr David Nikolic-Paterson
Email of contact: david.nikolic-paterson@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 441102
CIA Name: Prof Vincent Harley
Main RFCD: Genetic Development (incl. Sex Determination)
Admin Inst: Prince Henry's Institute of Medical Research
Start Year: 2007
End Year: 2011
Total funding: $618,722.00
Grant Type: Established
Career Fellowships
Title of research award:
Uncoupled Research Fellowship
Lay Description (from application):
I am a molecular biologist investigating the role of SRY/SOX transcription factors in
the formation and function of the gonad, and to a lesser extent, of bone, the brain and
the pancreas. I also identify and functionally characterise other factors causing
Research achievements (from final report):
A COMMON FAILURE IN SEVERAL FORMS OF 46XY DSD Human mutations
in the SRY (sex determining region on Y), SOX9 (SRY-related HMG box 9) or SF1
(steroidogenic factor 1) genes cause DSDs. These factors function during gonadal
development around SOX9 as a hub gene, with different genetic causes of 46,XY
DSD due to a common failure to upregulate SOX9 transcription.
ATRX, AN IMPORTANT REGULATOR OF SPERMATOGENESIS Infertility
affects about one in 20 Australian men, and is a common experience for men with
DSDs. Studies of the molecular action of the ATRX gene are providing a better
understanding of some underlying causes of male infertility. We have discovered that
the ATRX protein is an important regulator of androgen actions, as well as playing a
key role in the survival of testicular cells.
THREE NOVEL CAUSES OF DSD IDENTIFIED 1. Whole-genome analysis of a
46,XY DSD patient that identified the WWOX gene, supporting a role for WWOX in
human gonad development. 2. Genomic rearrangements within the SOX3 regulatory
region are a relatively common cause of XX DSD in cases lacking the SRY gene. 3. A
testis enhancer region of the SOX9 gene was identified where gain or loss of this
region was associated with 46,DSD or 46, XY DSD, respectively.
ROLE OF SRY IN THE HUMAN MALE BRAIN We have recently has
demonstrated that SRY protein also co-localises with dopamine neurons in the ventral
tegmental area in human males. This challenges the dogma in brain sex differentiation
that hormones control sex differences.
GENETICS OF GENDER IDENTITY DISORDERS Our genetic study of male-tofemale transsexuals was the first to link a gene, androgen receptor with this
condition. This has stimulated genetic research worldwide.
Expected future outcomes:
We will have identified causative genes in DSD and their normal functions in gonadal
development.
We will have demonstrated that SRY, a gene found only in males, plays key roles in
the regulation of dopamine in the normal brain and its misregulation in men with
Parkinsons disease is a symptom. Moreover, agents that lower SRY expression have a
protective effect.
NHMRC Research Achievements - SUMMARY
Name of contact: Vincent Harley
Email of contact: vincent.harley@princehenrys.org
NHMRC Research Achievements - SUMMARY
Grant ID: 496688
CIA Name: A/Pr Naomi Wray
Main RFCD: Preventive Medicine
Admin Inst: Queensland Institute of Medical Research
Start Year: 2008
End Year: 2010
Total funding: $269,371.00
Grant Type: NHMRC Project
Grants
Title of research award:
Accurate prediction of individual risk to disease from genome-wide association
studies
Lay Description (from application):
Risk for many complex diseases (such as psychiatric disorders or heart disease) has a
substantial genetic component, however few specific high risk variants have been
identified. Evidence is mounting that there are likely to be hundreds of risk loci each
individually conferring a very low increase in relative risk for disease. We aim to
develop methods that utilise information from multiple genetic risk variants
simultaneously to create a 'genomic profile' of risk.
Research achievements (from final report):
We have made significant developments in the methodology for using genome-wide
genotype data for prediction of genetic risk to disease. At the moment, accurate
prediction is not possible because effect sizes at individual loci are small and very
large sample sizes are required to detect them with accuracy. In the long run it it is
highly likely that clinically useful predictors based on genome-wide genotypes will be
available for some complex disorders, but probably not others. This will depend on
the true genetic architecture of the disorders (i.e., number or risk loci, distribution of
effect sizes of risk alleles, distribution of frequency of risk alleles). The methods we
have developed can be used to understand and quantify the genetic architecture of
complex genetic disease. Our analyses applied to schizophrenia and bipolar data sets
provide direct empirical evidence for a shared genetic etiology between these
disorders. Our methods have been used to determine the proportion of variance that is
tagged by SNPs, and we have partitioned this variation by chromosome, by minor
allele frequency of the genotyped SNPs and by function. Results of these analyses
have considerably enhance our understanding of the genetic architecture of complex
disorders and contribute to planning of future research. We have developed
methodologies for quantifying the efficacy of a genomic predictor, these methods
account for the oversampling of cases into case-control studies compared to the
general population.
Prediction of genetic risk for common complex genetic disorders could provide a
valuable screening tool allowing early intervention strategies to reduce the risk of
onset of disease. These predictors will be probabilistic rather than deterministic but
could contribute to life choice options.
Expected future outcomes:
The progress we have made in this 3 year grant has been recognised by having
secured an NHMRC project grant supporting two full-time post-doctoral researchers.
We hope to extrapolate our methods to more complex data and situations and ultimate
to provide clinically useful predictors of genetic risk.
NHMRC Research Achievements - SUMMARY
Name of contact: Naomi Wray
Email of contact: naomi.wray@qimr.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 339718
Start Year: 2005
CIA Name: A/Pr Gavin Turrell
End Year: 2006
Main RFCD: Public Health and Health Services not elsewhere classified
Total funding:
$429,000.00
Admin Inst: Queensland University of Technology
Grant Type: NHMRC Project
Grants
Title of research award:
A multilevel study of socioeconomic position and physical activity: environmental
and individual-level determinants
Lay Description (from application):
Regular physical activity offers many health benefits, whereas inadequate activity is a
leading cause of premature death and disability and a major contributor to the
increasing prevalence of overweight and obesity. Socioeconomically disadvantaged
groups are least likely to be physically active, and they experience higher rates of
death and morbidity for conditions directly linked to inactivity. Currently, our
understanding of why socioeconomic groups differ in their physical activity is limited,
and very little research has investigated this issue. This study will investigate why
socioeconomic groups differ in their physical activity, by examining the influence of
neighbourhood and individual-level factors. Neighbourhood factors include people's
access to recreational facilities such as swimming pools, tennis courts, golf clubs,
gyms, local parks, walking and bicycle paths; prices for entry to recreational facilities
and opening hours; physical characteristics of the neighbourhood including public
transport, presence of footpaths and street lighting, speed limits on local streets,
availability of local services such as shops and schools, and; aesthetic characteristics,
such as the presence and size of parks and green spaces, and traffic density. Individual
factors include personal enjoyment, knowledge, confidence, type of occupation and
hours worked, family responsibilities, age, health status, and whether other family
member or friends engage in physical activity. A major aim of the study is to
determine whether environmental or individual factors are more important in
influencing participation in physical activity. The study will produce new knowledge
to inform future public health strategies directed at increasing physical activity among
socioeconomically disadvantaged groups, and these will have the potential to reduce
socioeconomic health inequalities, as well as contribute to an overall reduction of the
disease burden attributable to chronic conditions.
Research achievements (from final report):
The HABITAT study is unique internationally and has a number of strengths
including its multilevel design and its focus on area- and individual-level
socioeconomic determinants of physical activity (PA). The new knowledge generated
will inform public health strategies directed at increasing PA among
socioeconomically disadvantaged groups, and these will have the potential to reduce
health inequalities, as well as contribute to an overall reduction of the disease burden
attributable to chronic conditions. Also, this research will inform the development of
intervention trials with different socioeconomic groups. Preliminary output from the
project has been presented at a number of national conferences.
Expected future outcomes:
NHMRC Research Achievements - SUMMARY
The HABITAT Project (baseline) was completed in 2007. Currently we are writing
manuscripts for publication in international journals. Future collections of HABITAT
data will occur in May 2009 and 2011.
Name of contact: Gavin Turrell
Email of contact: g.turrell@qut.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 497230
CIA Name: Prof Nathan Efron
Main RFCD: Endocrinology
Admin Inst: Queensland University of Technology
Start Year: 2008
End Year: 2011
Total funding: $540,372.00
Grant Type: NHMRC Project
Grants
Title of research award:
A longitudinal study of nerve morphology in diabetic neuropathy using novel noninvasive ophthalmic surrogate markers
Lay Description (from application):
This research project will use two new ophthalmic instruments - the corneal confocal
microscope and non-contact corneal aesthesiometer - to directly monitor changes in
corneal nerves and corneal sensitivity, over a 5 year period, in diabetic patients
suffering from a painful condition of the arms and legs known as diabetic neuropathy.
This study will generate important new information that could allow diabetic doctors
to more accurately monitor the progression of the disease.
Research achievements (from final report):
Diabetic peripheral neuropathy is a debilitating condition that affects about 50% of
diabetic patients. The symptoms of neuropathy include numbness, tingling or pain in
the arms and legs. If left untreated, patients with numbness may develop foot ulcers
which may ultimately require foot amputation. Currently the only method of directly
examining peripheral nerves is to conduct skin punch biopsies, which are
uncomfortable and invasive. Indirect methods include quantitative sensory testing
(assessing responses to heat, cold and vibration) and nerve electrophysiology. This
project has demonstrated the utility of using ophthalmic markers to assess diabetic
neuropathy. Specifically, it has been demonstrated that corneal nerve structure and
function can be assessed using corneal confocal microscopy and non-contact corneal
aesthesiometry. Using these techniques, it has been demonstrated that diabetic
neuropathy - assessed using conventional techniques - is associated with altered
morphology of corneal nerves and reduced corneal sensitivity. Initial findings of this
study establish these ophthalmic markers as rapid, painless, non-invasive, sensitive,
reiterative and cost-effective means of screening for early detection and diagnosis of
diabetic peripheral neuropathy, and for monitoring the progression and quantifying
the severity of this debilitating condition.
Expected future outcomes:
Corneal confocal microscopy and non-contact corneal aesthesiometry could be
employed in diabetes clinics as simple screening tests of diabetic neuropathy and/or
for ongoing monitoring of this condition.
Name of contact: Professor Nathan Efron
Email of contact: n.efron@qut.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 535930
CIA Name: Prof Jiming Ye
Main RFCD: Therapies and Therapeutic Technology
Admin Inst: RMIT University
Start Year: 2009
End Year: 2012
Total funding: $574,076.00
Grant Type: NHMRC Project
Grants
Title of research award:
Investigation of Novel Triterpenoids as New Potent AMPK Activators for the
Treatment of Insulin Resistant States
Lay Description (from application):
Type 2 Diabetes has major economic and health implications. Current medications
are inadequate or have serious adverse effects. Triterpenoids have been used in
traditional medicines for various diseases. This project builds on our recent discovery
of novel triterpenoids with antidiabetic properties to investigate their efficacy and
mechanisms of action. The results will provide valuable information about this class
of molecules as potential new therapeutics for Type 2 diabetes.
Research achievements (from final report):
This Project has made a number of significant achievements in three aspects. At the
scientific level, our studies have identified CaMKK as the upstream mechanism
leading to the activation of triperpenoids on AMPK. This finding indicates that the
triterpenoid has the potential as a new class of anti-diabetic compounds by a
mechanism which is different from other AMPK activators including metformin, TZD
and berberine. Furthermore, we have demonstrated that one triperpenoid (oleanolic
acid) exerts sustained effect in maintaining reduced hyperglycemia far beyond the
treatment period by suppressing hepatic gluconeogenesis. This exciting finding may
provide a clue to develop strategies to overcome the current problem of the loss of the
therapeutic effects for most anti-diabetic drugs. Finally, we also found that treatment
with a triterpenoid can protect against the morphological damage in kidney associated
with diabetes.
This project has enabled us to consolidate our strategic collaboration with the
Shanghai Institute of Materia Medica, one of top research institute in the world in
drug discovery research. During the period of this grant, we have held three joint
symposia to promote the exchange of researchers from RMIT, Shanghai Institute of
Materia Medica and Garvan Institute. This collaboration is part of our ongoing study
on the new triterpenoids discovered from bitter melon which is listed as one of the
most successful scientific collaborations between Australia and China in the past 30
years.
Expected future outcomes:
Continuing collaboration with Shanghai Institute of Materia Medica for the research
in Shanghai to optimize the triterpenoid lead as possible drug candidate doe the
treatment of type 2 diabetes. Follow-up study on the mechanism of the sustained the
anti-hyperglycemia effects of triterpenoids. These studies are likely to generate
additional publications.
NHMRC Research Achievements - SUMMARY
Name of contact: Jiming Ye
Email of contact: jiming.ye@rmit.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 345439
CIA Name: Dr Andrew Carey
Main RFCD: Protein Targeting and Signal Transduction
Admin Inst: Royal Melbourne Institute of Technology
Start Year: 2005
End Year: 2008
Total funding: $279,906.00
Grant Type: Early Career
Fellowships (Australia)
Title of research award:
Transcriptional targets for the AMP-activated protein kinase
Lay Description (from application):
Not Available
Research achievements (from final report):
The studies conducted under this award revealed mechanisms that are pertinent to the
actions of novel molecules that are important in the eitiology and potential therapy for
obesity and type 2 diabetes. Knowledge gained from these studies paves the way for
further investigation into these molecular mechanisms, that might eventually lead to
effective treatments for obesity related diseases.
Expected future outcomes:
Additional experiments are currently in progress that will further our knowledge in
this area, and results will be published in coming months.
Name of contact: Andrew Carey
Email of contact: andrew.carey@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 456049
CIA Name: Prof Philip Poronnik
Main RFCD: Nephrology and Urology
Admin Inst: Royal Melbourne Institute of Technology
Start Year: 2007
End Year: 2009
Total funding: $346,603.00
Grant Type: NHMRC Project
Grants
Title of research award:
Two-photon microscopy of albumin handling by the intact kidney
Lay Description (from application):
The clinical association between protein loss in the urine and retention of salt,
resulting in high blood pressure and progressive decline in kidney function, is well
known. Under normal conditions, the kidneys filter 180 litres of water and reabsorb
1.7 kg of salt per day, a function which is principally performed by the kidney tubules
in the kidney. Similarly the kidney tubule cells reabsorb and break down up to 3
grams of albumin per day. In the past, it has been considered that excessive protein
loss in the urine is primarily due to problems in the filtering units of the kidneys,
rather than due to abnormalities in the reabsorption of protein in the kidney tubules.
However, we consider that common abnormalities in the processes within the kidney
tubules that regulate both the reabsorption of salt and the excretion of acid may result
in concomitant high blood pressure and increased protein loss in the kidney. Thus the
overall aim of the project is to investigate the mechanisms by which the complex
responsible for protein uptake determines the interrelationship between protein
reabsorption and catabolism and the ion transporting proteins in the membrane of the
proximal tubule. This project will use cutting-edge microscopic imaging technology
to investigate the mechanisms of protein uptake in the intact kidney. This information
will be integrated with data obtained from our molecular physiology experiments to
define how the kidney handles protein. As persistent proteinuria is the most important
predictor of tubulointerstitial pathology and progressive decline in renal function in
almost all renal disease, the understanding of the precise mechanism by which this
occurs is essential in the design of renoprotective therapies.
Research achievements (from final report):
This project developed new methods for visualising how the intact kidney handles
protein and undertsanding how these pathways are disrupted in disease. In addition to
the imaging work we have identified some new protein-protein interactions that shed
further light on the molecular basis for albumin uptake. This work represents
advances in basic science and our fundamental understanding of kidney function that
may in time lead to new diagnostic or therapeutic strategies for renal disease.
Expected future outcomes:
This work underpins further studies that will develop new methods for examining
how the increased urinary protein relates to renal and cardiovascular disease.
Name of contact: Philip Poronnik
Email of contact: philip.poronnik@rmit.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 499321
CIA Name: A/Pr Arnan Mitchell
Main RFCD: Instruments and Techniques
Admin Inst: Royal Melbourne Institute of Technology
Start Year: 2008
End Year: 2009
Total funding: $191,599.00
Grant Type: NHMRC
Development Grants
Title of research award:
Development of a Prototype Production System for Optical Fibre Diagnostic Probes
Lay Description (from application):
Advances in nanotechnology have led to new techniques for the precise fabrication of
nanometre scale structures. A recent breakthrough by the applicants now allows highquality nanostructures to be "stamped" onto the tip of low-cost optical fibre probes.
When coated with silver, these sensitive probes can be used for continuous
monitoring of blood glucose in diabetics and in critical care situations. This project
aims to develop a prototype manufacturing system for optical fibre glucose probes.
Research achievements (from final report):
This project has demonstrated a capability for industrial scale manufacturing of nanoimprinted optical fibre diagnostic probes. At the project onset, our proof of concept
device took 40 minutes to fabricate. At the conclusion of this project we have
developed technology that allows a single operator to repeatably fabricate over 1000
fibre probes a day.
To achieve this outcome we separated the fabrication process into a sequence of
modular 'production line' steps and parallelized the fabrication process allowing fibre
probes to be processed in batches of 40. We have automated many of the steps such
that all of the fabrication steps could be managed in parallel by a single operator.
This refined process has significantly improved both quality and repeatability of the
fibre probes. We have successfully replicated nano-textures with features on the scale
of 15nm and demonstrated fabrication of samples of 50 fibre probes which are
functionally identical.
The outcomes of this project have paved the way for the development of optical fibre
probes which use nano-photonic elements to detect trace chemicals. These sensors,
realized entirely on the tips of fibres, are compact enough that they can be integrated
within hypodermic needles to monitor chemicals within the blood stream in-vivo.
The findings of this project have been featured on the cover of the prestegious
technology journal 'Advanced Materials' [1].
Expected future outcomes:
Having demonstrated fabrication of fibre probes on an industrial scale, we are now
designing 'smart' textures for selective and sensitive detection of specific chemicals.
Continuous monitoring of glucose within blood is a major objective. Application of
this technology in other contexts, such as monitoring water contaminants, is also
under investigation.
Name of contact: Professor Arnan Mitchell
Email of contact: arnan.mitchell@rmit.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 445314
CIA Name: Prof Emilio Badoer
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Admin Inst: Royal Melbourne Institute of Technology
Start Year: 2007
End Year: 2009
Total funding: $454,692.00
Grant Type: NHMRC Project
Grants
Title of research award:
Contribution of the central nervous system to peripheral neural control in obesity and
diabetes.
Lay Description (from application):
Obesity and diabetes are becoming major worldwide public health problems. A
characteristic of human obese diabetes is a marked increase in sympathetic nerve
activity to the kidneys and to the muscle. The cause of this overactivity is unknown,
but undoubtedly involves the central nervous system. Within the brain are a select
group of regions that are able to directly influence the activation of the sympathetic
nervous system. We suspect these areas to play a critical role in the overactivity of
the sympathetic nerve activity in obese diabetics. Indeed, we believe that there are
specific chemical messengers in these select brain areas that are normally finely
balanced. In obesity / diabetes, this balance is disturbed. Finally, we hypothesise that
exercise, which is known to have beneficial effects for obesity / diabetes, restores the
balance of the neurochemicals and this contributes to the positive outcomes of
exercise.
Research achievements (from final report):
The aim of the work was to identify the role of specific brain regions (hypothalamic
PVN and RVLM) in the abnormally elevated sympathetic nerve activity to the muscle
vasculature in obesity. This project required considerable preparation work involving
a high fat feeding regime for over three months. We compared normal rats with a
group of high fat (ie 30% by weight high fat) fed rats. The high fat fed rats increased
body weight and had increased fat deposits. We found that inhibiting neuronal
function in the PVN dramatically reduced sympathetic nerve activity in both high fat
fed rats and rats fed a normal chow diet. The reduction, however, was significantly
greater in the high fat fed rats. This suggested that the PVN, a key integrative region
in the brain, was over activated in obesity. We subsequently investigated whether the
overactivity of the PVN was due to a change in the balance between the inhibitory
and excitatory influences in the PVN. We found that blocking the actions of GABA,
the major inhibitory neurotransmitter in the brain, resulted in increased sympathetic
nerve activity in high fat fed rats. Interestingly, the response in the normal chow fed
rats was not significantly different from that observed in the high fat fed group. Thus,
the results suggest that in obesity there is a tonic inhibitory input into the PVN that
influences sympathetic nerve activity of the muscle, however, the contribution this
inhibitory input makes to sympathetic nere activity is not altered by obesity.
Expected future outcomes:
Our data suggests that in obesity there is a shift in the role of specific premotor
regions in the regulation of sympathetic nerve activity. The mechanisms that underlie
these changes require investigation. Future work will highlight the mechanisms.
NHMRC Research Achievements - SUMMARY
Name of contact: Professor Emilio Badoer
Email of contact: emilio.badoer@rmit.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 251558
CIA Name: Prof Mark Febbraio
Main RFCD: Cell Physiology
Admin Inst: Royal Melbourne Institute of Technology
Start Year: 2003
End Year: 2005
Total funding: $330,375.00
Grant Type: NHMRC Project
Grants
Title of research award:
Muscle derived interleukin-6: signalling pathways and biological roles
Lay Description (from application):
Over the past few years work from our research group has identified that the cytokine
interleukin-6 (IL-6) is produced by skeletal muscle during contractions. Moreover, we
have demonstrated that IL-6 performs entirely novel functions that have major
ramifications for diseases such as type 2 diabetes and obesity. We have demonstrated
that IL-6 is a potent factor in increasing the breakdown of fatty acids in the human
body. We have also demonstrated that IL-6 down-regulates the cytokine tumour
necrosis factor alpha (TNF-a), which impairs glucose uptake and promotes insulin
resistance. The proposed work will extend upon these findings. Discovering that IL-6
produced during exercise contributes to fatty acid utilisation will have profound
ramifications for what we know about energy breakdown. If we find that the function
of IL-6 produced by muscle is to down-regulate TNF-a and lead to enhanced glucose
uptake in type 2 diabetics, it may lead to IL-6 being used as a possible therapeutic aid
in the treatment of type 2 diabetes. In summary, this project will have major
significance for not only our fundamental knowledge of the processes involved in
maintaining metabolic homeostasis, but also for our understanding of the major health
problem of obesity related diseases.
Research achievements (from final report):
Firstly, we have identified that the cytokine interleukin (IL-6) is one of only two
cytokines produced by skeletal muscle during contraction. Moreover, we have
demonstrated using in situ hybridization and immunohistochemistry that the myocytes
themselves, not other cells within the muscle (eg fibroblasts, macrophages etc), are
responsible for the increase in IL-6 within muscle seen with contraction. In addition,
we have demonstrated that p38 MAPK is phosphorylated at the nucleus of muscle
cells and acts on a downstream transcription factor to induce IL-6 transcription. We
have also demonstrated that the upstream signal appears to be calcium since it is the
calcium ionophore ionomycin that activates IL-6 in muscle. In exciting final
experiments, we have identified a novel signalling pathway for the gene transcription
of IL-6 in skeletal muscle cells.
We have identified IL-6 as a mediator of endogenous glucose production during
exercise showing that skeletal muscle is an endocrine organ capable of releasing
biologically active compounds. We have demonstrated that contrary to dogma, IL-6 is
not associated with insulin resistance and in fact increases fatty acid turnover while
enhancing insulin sensitivity as measured by the homeostatic model assessment
(HOMA-IR). This has led us to determine if IL-6 actually increases insulin sensitivity.
We have performed studies in cells to show that IL-6 increases insulin stimulated
glucose transport via activation AMP kinase and by increasing the translocation of
glucose transporter 4. We then performed experiments in humans to show that IL-6
increases glucose infusion rate during a maximal insulin clamp. We have also
NHMRC Research Achievements - SUMMARY
performed a chronic experiment in rats demonstrating that IL-6 improves glucose
tolerance. These data demonstrate that targeting the receptor for the IL-6 family of
cytokines provides a realistic therapeutic target for the treatment of obesity related
disorders such as type 2 diabetes
Expected future outcomes:
We are currently working on designing ligands that bind to the IL-6 receptor complex
to activate the metabolic master switch AMP kinase and to increase fat oxidation. It is
anticipated that these ligands will act to mimic the effects of exercise and ultimately
therapies will be developed from this work
Name of contact: Mark A Febbraio Phd
Email of contact: mark.febbraio@rmit.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 446201
CIA Name: Prof Annemarie Hennessy
Main RFCD: Medical Physiology not elsewhere classified
Admin Inst: Royal Prince Alfred Hospital
Start Year: 2007
End Year: 2012
Total funding: $632,700.00
Grant Type: NHMRC
Enabling Grants
Title of research award:
The National NHMRC Baboon Colony
Lay Description (from application):
The National NH&MRC Baboon colony provides access to large non-human primates
to support Australia’s research efforts in diverse scientific areas around the country.
These include diabetes research (kidney involvement and prevention of kidney
damage, nerve damage and eye damage); treatment options inlcuding gene therapy of
blood/bone-marrow cancers; understandng pregnancy changes in blood pressure and
the causes of hypertension (high blood pressure) in pregnancy; identification of new
techniques for analyis of brain function; the effects of aging on liver function
especially with regards to drug metabolism; new therapies for transplantation which
would allow more rational and lower/safer drug use for transplant patients; breaking
down the barriers to animal-to-human transplantation through assessment of safety
and development of new techniques; behavioural aspects of fertility management;
vaccine development; development of oral vaccination; the nature of wound healing.
There is diverse and wide access to the National NHMRC Baboon colony from
research interests around Australia. The use of the animals is at all times approved by
the Animal welfare Committee governing the colony, as well as that which governs
the researchers involved. All approved projects have been given access to the animals
required. The need for non-human primate use as opposed to other animals or other
techniques not involving animals is justified to the relvant committees before any
project proceeds. The use of the animals therefore adds a dimension to Australian
research due to animal similarity to humans physiology or size comparisons.
Contributions made by the colony in the last 20 years are listed in the attached
references, but understanding physiology at a depth not possible with other animals
has changed our thinking about the human condition as a result of primate -based
research.
Research achievements (from final report):
The provision of a colony of healthy, higher-order, non-human primates to the
Australian biomedical research community has allowed highly relevant research to be
carried out in multiple national health priority areas. Research into cardiovascular
disease, diabetes, transplantation, pregnancy complications and other areas has been
facilitated by the provision of NHMRC funding. Research groups from 18 different
institutions have been supported by access to the NBC.
Expected future outcomes:
The ANBC will continue to meet its objectives of providing a healthy colony of nonhuman primates for scientifically and ethically justified biomedical research in
Australia. The maintenance of the highest standard of animal welfare is a key priority.
Name of contact: The Director
NHMRC Research Achievements - SUMMARY
Email of contact: RPAH.NBC@sswahs.nsw.gov.au
NHMRC Research Achievements - SUMMARY
Grant ID: 292917
CIA Name: A/Pr Matthew Watt
Main RFCD: Endocrinology
Admin Inst: St Vincent's Institute of Medical Research
Start Year: 2004
End Year: 2007
Total funding: $216,494.00
Grant Type: Early Career
Fellowships (Australia)
Title of research award:
Cellular basis of cytokine-mediated fat metabolism and insulin resistance
Lay Description (from application):
Not Available
Research achievements (from final report):
Work from this grant identified the protein ciliary neurotrophic factor (CNTF) as a
potential anti-obesity factor. Mice treated with CNTF lost weight due to a decrease in
food intake and an increase in fat metabolism. Importantly, this effect was maintained
in obese mice and also partially reversed diabetes in these mice. This work was
published in the prestigious journal Nature Medicine.
Expected future outcomes:
Compounds that activate the CNTF receptor but do not cause the production of
inhibitory antibodies are being tested for their anti-obesity effects.
Name of contact: Matthew Watt
Email of contact: matthew.watt@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 502602
Start Year: 2008
CIA Name: Prof Michael Parker
End Year: 2010
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding:
$526,703.00
Admin Inst: St Vincent's Institute of Medical Research
Grant Type: NHMRC Project
Grants
Title of research award:
Structure-function studies of insulin-regulated membrane aminopeptidase
Lay Description (from application):
Memory loss can occur as a result of injuries or disease such as Alzheimer's disease,
the fourth biggest killer in developed countries. Currently there is no effective
treatment for memory loss. This proposal concerns the biochemical investigation of a
protein involved in memory and possibly diabetes. This work is expected to provide
an understanding of how this protein functions in the body and will form the basis for
the design of drugs for the treatment of memory loss.
Research achievements (from final report):
We constructed a three-dimensional model of a brain protein called insulin-regulated
aminopeptidase and then computationally screened the model against a database of 2
million potential drug-like molecules. The most promising molecule was tested in
animals and shown to enhance memory. We plan to develop these molecules into
drugs that could be used to treat a range of cognitive impairments such as Alzheimer's
disease.
Expected future outcomes:
To maximise the drug development opportunities both Institutes involved in the
discovery have enlisted a commercial partner, Bio-Link, to seek out international
biopharmaceutical companies to help develop our molecules into drugs that can used
to treat cognitive impairment such as Alzheimer's disease
Name of contact: Professor Michael W Parker
Email of contact: mparker@svi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 156713
Start Year: 2001
CIA Name: Prof Bruce Kemp
End Year: 2003
Main RFCD: Genetic Technologies: Transformation, Site-directed Mutagenesis, etc.
Total
funding: $351,110.00
Admin Inst: St Vincent's Institute of Medical Research
Grant Type: NHMRC Project
Grants
Title of research award:
Physiological effects of manipulating AMP-activated kinase genes
Lay Description (from application):
The AMP-activated protein kinase is a metabolic stress sensing protein kinase
responsible for matching the supply of energy to the body's functions. During
vigorous exercise it senses metabolic stress (reduction in energy) caused by muscle
contraction and stimulates glucose uptake and burning of fat to provide energy. The
AMP-activated protein kinase also regulates the production of nitric oxide that is
important in controlling blood pressure and blood clotting. Reduced caloric intake
activates the AMP-activated protein kinase to suppress energy consuming activities
and modify the expression of genes. Many of the conditions that activate the AMPactivated protein kinase (exercise, reduced caloric intake) are associated with a
healthy life style, increased longevity and resistance to age onset diseases including
cardiovascular disease (atherosclerosis, hypertension), obesity, neurodegeneration and
diabetes. By manipulating the gene for the AMP-activated protein kinase in mice we
expect to learn more about its key physiological roles and give new insight into the
control of age onset diseases.
Research achievements (from final report):
The AMPK is a key enzyme in the control of metabolism in response to exercise that
is involved in regulating many physiological events. Our overall goal is to track
down how exercise prevents development of many age onset diseases. AMPK
appears to be a key enzyme in these protective molecular mechanisms. The
development of drugs that activate AMPK may have benefits people with sedentary
life styles or otherwise incapable of getting adequate exercise. Since out knowledge
of AMPK is incomplete we have modified two of the genes involved in AMPK in
mice in order to determine how they are affected. In yeast removal of a
corresponding gene called sip2 causes the yeast to rapidly age.
Expected future outcomes:
N/A
Name of contact: N/A
Email of contact: N/A
NHMRC Research Achievements - SUMMARY
Grant ID: 345402
CIA Name: Prof Bruce Kemp
Main RFCD: Protein Targeting and Signal Transduction
Admin Inst: St Vincent's Institute of Medical Research
Start Year: 2005
End Year: 2007
Total funding: $582,000.00
Grant Type: NHMRC Project
Grants
Title of research award:
Regulation of Protein Kinases and their Substrates
Lay Description (from application):
Western communities are experiencing an obesity epidemic with up to half the
population being overweight. Sedentary life styles and high caloric intake are the
cause and will contribute to the development of age onset diseases including obesity,
diabetes, cardiovascular disease, stroke and neurodegeneration. This project is
investigating an enzyme that plays a pivotal role in controlling the body s response to
exercise and diet. The key enzyme involved in this process is called the AMPactivated protein kinase. This work will increase our understanding of the health
benefits of diet and exercise. This new knowledge will play a vital role in developing
new therapies for promoting exercise and mitigating the effects of diet that will
improve health during the ageing process.
Research achievements (from final report):
This research is concerned with an enzyme called AMPK that may mediate the health
benefits of diet and exercise. AMPK is also important in the control of appetite and
whole body energy metabolism. We have obtained structural information on AMPK
that may contribute to the development of activating drugs. We have identified
components of the mechanisms that control the activity of AMPK and several new
substrates which contributes to our knowledge on how AMPK controls genes
important for glucose uptake. We have also shown that activation of AMPK in mice
by genetic changes can increase exercise capacity. This research is relevant to
cardiovascular disease, obesity, type 2 diabetes and maintaining health during ageing.
Expected future outcomes:
Research on AMPK will contribute to our understanding of the underlying
mechanisms that mediate the health benefits of diet and exercise. It may be possible
to develop drugs that activate AMPK and improve metabolism to facilitate exercise
and protect against obesity and age onset diseases
Name of contact: Bruce E. Kemp
Email of contact: bkemp@svi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 219168
CIA Name: Prof Thomas Kay
Main RFCD: Not Allocated
Admin Inst: St Vincent's Institute of Medical Research
Start Year: 2001
End Year: 2006
Total funding: $3,095,000.00
Grant Type: International
Collaborations
Title of research award:
T-cell mechanisms of B-cell destruction
Lay Description (from application):
In type 1 diabetes the body becomes deficient in insulin production from pancreatic b
cells because the immune system mistakenly attacks and destroys b cells as if they
were an invading infection. Recurrence of autoimmune destruction of b cells also
occurs following transplantation of whole pancreas or islet cells and may occur in the
future when other engineered insulin producing cells are transplanted. The focus of
this program is to better understand how b cells are killed by the immune system and
to test ways of protecting beta cells from these mechanisms. Because of the
inaccessibility of the pancreas to study (particularly biopsy) in humans with diabetes,
much of the proposed work will be carried out in b cells derived from non-obese
diabetic (NOD) mice, the best available mouse model of type 1 diabetes. It is clear
from the literature that a molecule called perforin found in cytoxic T lymphocytes
(CTL) is a major, if not the major, mechanism the immune system uses against b
cells. For this reason we will try to better understand the interaction between b cells
and perforin and ultimately design ways of them from perforin-mediated cell death. It
is equally clear that there are other mechanisms besides perforin that can cause b cell
death and the program will also address discovery of these mechanisms and new ways
to block them. Beta cells in NOD mice will be protected from perforin or other
mechanisms by the addition of protective genes or removal of harmful genes using
transgenic knockout technology. Addition or removal of genes involved in cell death
can be done systematically and each protocol tested using NOD mouse model. The
process of cell death that b cell undergo in type 1 diabetes is called apoptosis.
Apoptosis is a general mechanism by which cells of all types die. Experts in the
biology of apoptosis and perforin are important members of the program, providing
the opportunity to translate the latest advances in cell death research to diabetes. This
research addresses several of the specific research areas of interest to JDRF. It
focuses on the prevention of b cell death in individuals with type 1 diabetes receiving
islet transplants. It may be applicable in the future to protection of stem or precursor
cells that have been differentiated into b cells or even to devising strategies to prevent
the development of diabetes.
Research achievements (from final report):
Our group has made significant contributions to understanding mechanisms of betacell destruction. We have clarified the mechanisms of beta-cell killing by CD8+ T
cells (CTL) showing that the perforin-granzyme pathway is the main mechanism used
in several different models of type 1 diabetes and allogeneic beta-cell transplant
rejection. Further, the susceptibility of beta cells to perforin and granzymes was
studied in detail.
Major achievements of the Program include:
NHMRC Research Achievements - SUMMARY
- Demonstrating the effect of blocking the Fas, TRAIL and TNFR1 pathway by
dominant negative FADD on progression of diabetes.
- Identifying that suppressor of cytokine signalling 1 blocks both perforin and Fasdependent beta cell death.
- Using a high-throughput screen to identify small-molecule perforin inhibitors and
development of in vitro systems to measure perforin-dependent killing of β cells.
- Identifying the role of Bim in abnormal thymic deletion in NOD mice
Expected future outcomes:
Beta-cell apoptosis is one of the major pathologic steps in progression to type 1
diabetes. Understanding the mechanisms of this and developing inhibitors that may
be clinically applicable is highly significant to future treatment of type 1 diabetes or
islet transplant rejection.
Name of contact: Professor Tom Kay
Email of contact: tkay@svi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 345433
CIA Name: Dr Helen Thomas
Main RFCD: Cellular Immunology
Admin Inst: St Vincent's Institute of Medical Research
Start Year: 2005
End Year: 2009
Total funding: $453,500.00
Grant Type: Career
Development Fellowships
Title of research award:
Mechansims of T cell-dependent pancreatic ¿ cell destruction
Lay Description (from application):
Not Available
Research achievements (from final report):
The major aim of this project was to discover a strategy for preventing loss of insulinproducing cells in the pancreas (called beta cells) from being destroyed by cells of the
immune system. To do this, it was necessary to understand the death signals that the
immune cells use to kill beta cells, and the pathways inside the beta cell that are
switched on in response to these cell death signals. We identified the pathways
activated in beta cells in response to immune cells and their toxic products. We also
determined that immune cells are capable of delivering several different death signals
in type 1 diabetes, and that all of these need to be inhibited to prevent diabetes.
Knowledge of cell death pathways in beta cells will allow us to identify how we can
prevent them from being killed in type 1 diabetes or after islet transplantation. In
addition, we successfully began transplanting human islets isolated from cadaveric
organ donors into patients with type 1 diabetes. At the completion of this grant, we
had performed 10 transplants into 6 recipients in Victoria and South Australia
Expected future outcomes:
It is expected that some of this research will be translated to human islets by
preventing their death in type 1 diabetes and after islet transplantation. The Tom
Mandel Islet Transplant program is a platform on which to apply knowledge gained
from this research.
Name of contact: Dr Helen Thomas
Email of contact: hthomas@svi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 395522
CIA Name: Prof Bruce Kemp
Main RFCD: Genome Structure
Admin Inst: St Vincent's Institute of Medical Research
Start Year: 2006
End Year: 2010
Total funding: $1,222,500.00
Grant Type: NHMRC
Strategic Awards
Title of research award:
Phosphoproteomics: Metabolic and Exercise Signalling Markers for Sedentary and
Trained Individuals
Lay Description (from application):
It is widely recognized that diet and exercise have a major influence on the health and
fitness. Sedentary lifestyles predispose people to obesity and the early development of
age onset diseases. In the past decade we have gained considerable insight into the
regulatory links between exercise and metabolism particularly involving the AMPK
signalling pathway. This project is concerned with the "phosphoproteome" of trained
and untrained skeletal muscle, fat and erythrocytes as a marker of fitness.
Research achievements (from final report):
This Medical Bioinformatics Genomics Proteomics Program was concerned with
developing technology for studying protein phosphorylation which is an important
regulatory mechanism for controlling protein function. The bioinformatics aspects of
the program were run by Professor Bostjan Kobe at the University of Queensland and
the experimental work in mass spectrometry by Professor Bruce Kemp at the St
Vincent's Institute University of Melbourne. Two of the great challenges in
understanding regulation by protein phosphorylation is being able to assign which
protein kinases are responsible for the phosphorylation of specific residues on target
proteins and the identification of changes in protein phosphorylation at specific under
physiological conditions. The key achievements in the program were the
development of the Predikin system at the University of Queensland for predicting
substrate specificity of protein kinases and the establishment of a mass spectrometry
facility at St Vincent's Institute for the analysis of phosphorylation sites. Both of
these developments will have eduring benefits to medical research in Australia
Expected future outcomes:
In bioinformatics the Predikin system is contributing to understanding the function of
over 500 protein kinases identified in the human genome. The mass spectrometry
facility will contribute to the identification of physiologically important
phosphorylation sites and the mapping of cellular signalling processes
Name of contact: Bruce E Kemp
Email of contact: bkemp@svi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 502605
CIA Name: A/Pr Helen Thomas
Main RFCD: Autoimmunity
Admin Inst: St Vincent's Institute of Medical Research
Start Year: 2008
End Year: 2010
Total funding: $535,333.00
Grant Type: NHMRC Project
Grants
Title of research award:
Apoptotic pathways in pancreatic beta cells leading to type 1 diabetes and transplant
rejection
Lay Description (from application):
The destruction of insulin-producing beta cells in the pancreas by immune cells leads
to the need for daily insulin injections in patients with type 1 diabetes. This project
aims to understand how beta cells are destroyed. A knowledge of the process by
which this occurs will indicate ways we can protect these cells. Our previous work
has suggested strategies that may protect beta cells, and we aim to test these. Such
protection may eventually allow beta cell replacement by transplantation.
Research achievements (from final report):
We demonstrated that a molecule called Bid is required for killing of insulinproducing beta cells in the pancreas by one particular pathway thought to be used by
immune cells in type 1 diabetes. When we assessed the contribution of this molecule
to development of type 1 diabetes in a mouse model, we showed that it is dispensable,
indicating that this pathway of killing is not important. We also tested the importance
of another killing pathway used by the immune system, called granzymes. We made
mice that spontaneously develop diabetes that lack important granzymes, granzyme A
and granzyme B. We discovered interesting changes in development of diabetes in
both these mouse models. Mice lacking granzyme B had a delay in the onset of the
immune process leading to diabetes, while mice lacking granzyme A developed faster
diabetes. We used cells from these mice to study how killer cells of the immune
system develop, and determined that these cells become killer cells only after they
have entered the pancreas, even though they have already begun to expand in number
while they are still in the lymph node next to the pancreas. These findings are
significant discoveries about how insulin-producing cells are killed in type 1 diabetes,
which we anticipate will lead to prevention of human beta cell killing in
transplantation or type 1 diabetes.
Expected future outcomes:
Our work remains to be tested in human systems, and that is a future aim of our work.
We have identified ways to inhibit these pathways in human islets, and have human
immune cells to test killing of islets with these pathways disabled.
Name of contact: Helen Thomas
Email of contact: hthomas@svi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 559013
CIA Name: Prof Bruce Kemp
Main RFCD: Exercise Physiology
Admin Inst: St Vincent's Institute of Medical Research
Start Year: 2009
End Year: 2011
Total funding: $540,973.00
Grant Type: NHMRC Project
Grants
Title of research award:
The Role of the AMPK-ACC2 Signaling Axis in Metabolic Control During Exercise
and Obesity
Lay Description (from application):
Australian society is experiencing an epidemic of obesity that is contributing to
diabetes, cardiovascular disease and premature death. This project is investigating
how exercise might prevent obesity and type 2 diabetes by examining the major
pathways that regulate fat metabolism.
Research achievements (from final report):
The goal of this project is to study the role of AMPK signaling in the regulation of
fatty acid metabolism and insulin sensitivity in response to muscle contractions and
exercise utilizing two unique mouse genetic models deficient in different aspects of
AMPK signalling. These models will assess whether AMPK signalling is required for
the stimulation of fatty acid oxidation during exercise but will not delineate the
pathways involved. β2 KO mice have reduced AICAR stimulated muscle glucose
uptake but contraction stimulated glucose uptake and fatty acid oxidation and ACC
phosphorylation are not impaired. During treadmill running β2 KO mice have
reduced maximal and endurance exercise capacity, which is associated with lower
starting levels of muscle and liver glycogen. When challenged with a high-fat diet, β2
KO mice are more susceptible to the development of insulin resistance. Overall these
data show that deletion of AMPK β2 reduces AMPK activity in skeletal muscle
resulting in impaired exercise capacity and exacerbation of obesity induced insulin
resistance. AMPKβ1β2 null mice mice have a profound reduction in both spontaneous
exercise and treadmill running exercise capacity. They exhibit muscle fatigue and
reductions in exercise dependent glucose uptake. These results show that AMPK is
extremely important for maintaining exercise capacity.
Expected future outcomes:
This work has contributed to our understanding of the physiological roles of AMPK
in maintaining energy balance and exercise capacity. At present we consider AMPK
a potentially important target for the therapeutic treatment of Type 2 diabetes, obesity
and cardiovascular disease.
Name of contact: Bruce E. Kemp
Email of contact: bkemp@svi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 345426
CIA Name: Prof Bruce Kemp
Main RFCD: Protein Targeting and Signal Transduction
Admin Inst: St Vincent's Institute of Medical Research
Start Year: 2009
End Year: 2009
Total funding: $153,250.00
Grant Type: Established
Career Fellowships
Title of research award:
Uncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
In terms of potential significance to Australia's Health Care system the study of the
metabolic stress sensing enzyme, AMPK provides a path to understanding the
molecular basis of the health benefits of diet and exercise. The indications are that
activation of AMPK by diet and exercise plays an important part in prevention of age
onset diseases that include, obesity, diabetes, hypertension, stroke, neurodegeneration,
cancer and cardiovascular disease. These areas of disease are the major cost items
for the Australian Health budget. The study of the AMPK family of enzymes is of
enormous fundamental and commercial importance. It has been found that several
drugs used to treat age onset diabetes (metformin, rosiglitazone) activate the AMPK
as well as the adipocyte hormones, adiponectin and leptin. Since exercise and weight
control prevent the development of diabetes it seems likely that AMPK is a critical
regulator in the health benefits of diet and exercise. Our work has opened up a very
large vista of opportunities. For example, AMPK controls both triglyceride and
cholesterol synthesis as well as the oxidation of fatty acids, drugs that activate AMPK
may have major therapeutic potential for treating obesity and cardiovascular disease
in addition to type II diabetes. The rest of the world has recognized this potential and
there are now an average of three publications per day on AMPK.
Expected future outcomes:
Our key major goals are to develop activating drugs for AMPK that will mimic the
health benefits of diet and exercise. We are studying the natural mechanisms of
activation of AMPK and the physiological roles of this signaling pathway.
Name of contact: Bruce E. Kemp
Email of contact: bkemp@svi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 575552
CIA Name: Dr Thomas Brodnicki
Main RFCD: Medical Genetics
Admin Inst: St Vincent's Institute of Medical Research
Start Year: 2009
End Year: 2011
Total funding: $732,439.00
Grant Type: NHMRC Project
Grants
Title of research award:
Genomic and functional analyses of a novel gene implicated in type 1 diabetes
Lay Description (from application):
We have recently discovered a novel gene that contributes to the development of
juvenile diabetes. Unfortunately, very little is known about the function of this gene.
To better understand how this gene affects the immune system and contributes to
disease, we have generated a unique mouse strain that has a dysfunctional copy of this
gene. These mice will enable us to characterise this gene and potentially establish a
new area of research in diabetes prevention.
Research achievements (from final report):
Autoimmune diseases are a major cause of morbidity and mortality in developed
countries. In this project we focused on type 1 diabetes, an autoimmune disease that
results in the destruction of insulin-producing beta cells found in the pancreas. More
than 120,000 Australians have type 1 diabetes, and ~6 new cases are diagnosed every
day. While the cause of T1D is still not known, genetic analyses of families and
animal models for this disease have provided important insights about the genes that
increase one's risk for developing this disease. In particular, we performed genetic
studies using the NOD mouse strain, which develops type 1 diabetes similar to
children, and discovered a novel gene that contributes to the development of this
disease. Unfortunately, very little was known about the function of this gene. To
better understand how this gene affects the immune system and contributes to disease,
we determined that this gene is expressed in certain cells of the immune system that
participate in the destruction of the pancreatic beta cells. We next generated a unique
mouse strain that has a dysfunctional copy of this gene and discovered that this gene
is important for regulating certain immune responses associated with infection and
autoimmune diseases. Thus this gene appears to act as a molecular switch to help turn
off immune cells once an infection has been clear and prevent them from initiating
autoimmune diseases, such as type 1 diabetes.
Expected future outcomes:
We anticipate that we will identify the human version of the mouse diabetes
susceptibility gene that we have discovered. Further characterization of the mouse
and human gene will help identify cellular mechanisms that may be targeted by drugs
to increase protection against the development of autoimmune disease.
Name of contact: Thomas Brodnicki
Email of contact: tbrodnicki@svi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 502610
CIA Name: Prof Bruce Kemp
Main RFCD: Cell Metabolism
Admin Inst: St Vincent's Institute of Medical Research
Start Year: 2008
End Year: 2010
Total funding: $553,197.00
Grant Type: NHMRC Project
Grants
Title of research award:
Regulation of protein kinases and their substrates
Lay Description (from application):
Our research is concerned with the control of the body's energy metabolism via an
enzyme called AMPK. This enzyme is at the hub of metabolic control in response to
diet and exercise. AMPK controls energy expenditure in response to demand as well
as appetite. It is well recognized that diet and sedentary life-styles are major
contributors to obesity and cardiovascular disease. We are testing how a new drug
activates AMPKand how energy expenditure can be increased.
Research achievements (from final report):
Phosphorylation of AMPK α subunit on Thr172 is essential for activity and this is
catalyzed by either upstream kinase LKB1 or CaMKKβ. During metabolic stress the
reduction in ATP levels and increase in ADP and AMP levels is accompanied by
increased phosphorylation of AMPK α Thr172. Up until 2010 the consensus in the
field was that AMP binding to the γ subunit inhibited dephosphorylation of AMPK
and allowed for the accumulation of pThr172 and that there was no AMP regulation
of the phosphorylation step by the upstream kinases. We found that AMP did
stimulate α Thr172 phosphorylation but this form of regulation depended entirely on
the β subunit being myristoylated. Importantly once AMPK is phosphorylated on
Thr172 the AMP allosteric activation of the enzyme and protection against
dephosphorylation does not depend on β-subunit myristoylation. Our view of the
regulation now is that the β subunit myristoyl group anchors the kinase in a
conformation protecting it against phosphorylation and activation by the upstream
kinases unless AMP is present. In addition to solving a 15-year problem in the field
our study also raises the possibility that AMP triggers a β subunit myristoyl switch
and that this serves in subcellular targeting of AMPK to membrane anchored
substrates.
The second important discovery involving the β subunit was that the thienopyridone
AMPK activating drug A769662 developed by the Abbott Laboratories was specific
for AMPK αβγ heterotrimers containing the β1 isoform and that it did not act on β2
containing heterotrimers.
Expected future outcomes:
The discovery that β-subunit myristoylation was essential for AMP regulation of
AMPK activation by phosphorylation paved the way for us to show that ADP also
activated AMPK in a similar manner. The drug screening protocols in the
Pharmaceutical Industry have been modified by our work.
Name of contact: Bruce E Kemp
Email of contact: bkemp@svi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 395507
CIA Name: Prof Bruce Kemp
Main RFCD: Protein Targeting and Signal Transduction
Admin Inst: St Vincent's Institute of Medical Research
Start Year: 2006
End Year: 2008
Total funding: $478,776.00
Grant Type: NHMRC Project
Grants
Title of research award:
Regulation of Lipid Metabolism by AMP Activated Protein Kinase
Lay Description (from application):
Western communities are experiencing an epidemic of overweight and obesity that is
contributing to diabetes, heart disease, and premature death. This project is
investigating an enzyme, called AMP-activated protein kinase, that plays a pivotal
role in controlling how our bodies control energy metabolism in response to exercise.
Improved understanding about how this enzyme regulates the body's storage and
breakdown of fat and responsiveness to insulin will enable the development of new
medicines for the treatment of obesity and the prevention of diabetes.
Research achievements (from final report):
This project is concerned the regulation of fat (triglyceride) synthesis in the body.
The first step in fatty acid synthesis is catalysed by an enzyme acetyl CoAcarboxylase (ACC), which is regulated in multiple ways and can be inhibited by
exercise. Triglycerides contain three fatty acid linked to glycerol and provide the
major form of fat storage in the body. An enzyme called glycerophosphate acyl
transferase or abbreviated GPAT is responsible for the first step of adding a single
fatty acid to glycerol in the synthesis of triglycerides. Understanding the regulation
of lipid metabolism has important implications for several diseases. Dysregulation of
fatty acid metabolism in obesity results in the accumulation of intramuscular lipid that
is central to the development of insulin resistance, which in turn may lead to age onset
diabetes. In the present study we set out to examine whether the regulation GPAT
involves direct control by another enzyme AMPK, which is activated by exercise and
is responsible for phosphorylating ACC and GPAT. By studying how exercise is able
to suppress fatty acid and triglyceride synthesis we may gain greater insight into the
health benefits of exercise. We found that AMPK phosphorylated GPAT at multiple
sites and inhibited the enzyme. In ongoing work we are attempting to determine
which phosphorylation site is responsible for this inhibition. In the case of ACC we
prepared a genetically engineered mouse that contained a mutation in the site
phosphorylated by AMPK and are continuing to evaluate the impact of this on lipid
metabolism and insulin sensitivity.
Expected future outcomes:
It is hoped our ongoing research will identify how AMPK regulates GPAT and
controls the synthesis of triglycerides. Our study of the ACC genetically modified
mice will indicate how important AMPK regulation of this enzyme is and whether
blocking this regulation leads to increase fat deposition and or alterations in appertite.
Name of contact: Bruce Kemp
Email of contact: bkemp@svi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 559007
CIA Name: Dr Stuart Mannering
Main RFCD: Autoimmunity
Admin Inst: St Vincent's Institute of Medical Research
Start Year: 2009
End Year: 2011
Total funding: $404,400.00
Grant Type: NHMRC Project
Grants
Title of research award:
A T-cell based approach to identifying islet antigens in human type 1 diabetes
Lay Description (from application):
Autoimmune diseases arise when the immune system, which protects us from
infections and cancer, attacks healthy tissues. Nobody knows why the immune system
mistakes healthy for unhealthy tissue. The immune system's T cells are prime suspects
because they play a central role in controlling the immune response. Hence, the aim of
this work is to understand what human T cells see in healthy tissues that may lead
them to cause autoimmune diseases like type 1 diabetes.
Research achievements (from final report):
Our original aim was to use an 'array' of islet proteins associated with nitrocellulose
particles. Further work with this approach confirmed that T cell responses to islet
proteins prepared in this manner were found in the blood of people with T1D, but not
those without T1D. However, we found that T cells from people with T1D also
responded to spleen proteins prepared in a similar manner. These data indicated that
the responses were not specific for islet proteins and may be directed against proteins
that are modified during electrophoresis and transfer to nitrocellulose. For this reason
we developed a new method for extracting proteins from human tissues in a format
that is compatible with T cell proliferation assays. We published a paper describing
this approach (Moon et al, 2010). Our new protein extraction protocol avoids the use
of detergents which are toxic to the cells in proliferation assays. Using this protocol
we have prepared extracts from human islets, spleen, and acinar tissues. These
extracts have been used to stimulate T-cell responses from the blood of T1D patients
and HLA matched controls. Surprisingly we found that extracts from human spleen
suppressed T-cell responses in vitro. Upon further investigation we found that the
suppression was due to residual prednisolone (prednisolone is given to the organ
donors prior to organ collection). Islet and acinar tissue extracts are also being used to
develop an assay to measure human T cell responses against beta cells and to examine
the specificity of human islet-infiltrating T-cell clones that we have isolated.
In light of these results we changed strategy and developed methods for isolating T
cells from within the residual pancreatic islets of deceaed organ donors who suffered
from type 1 diabetes. We are the first group in the world to isolate human T cells from
the islets of people who had type 1 diabetes. To date we have over 380 CD4+ T-cell
clones and >260 CD8+ T cell clones from five donors.
Expected future outcomes:
The analysis of T cells that infiltrate the islets of people with type 1 diabetes is
powerful new approach to study the autoimmune response that causes type 1 diabetes
in humans. Our future work will identify the antigens 'seen' by these T cells and
support the development of new therapies for type 1 diabetes.
NHMRC Research Achievements - SUMMARY
Name of contact: Stuart Mannering
Email of contact: smannering@svi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 448610
CIA Name: Dr Paul Stoddart
Main RFCD: Instruments and Techniques
Admin Inst: Swinburne University of Technology
Start Year: 2008
End Year: 2008
Total funding: $385,151.00
Grant Type: NHMRC
Development Grants
Title of research award:
Spectrometer Module for Surface Enhanced Raman Scattering Spectroscopy in
Glucose Analysis
Lay Description (from application):
Scientists have developed a number of incredibly powerful and sophisticated
techniques to identify chemicals and measure their concentrations in the laboratory.
However, it remains a major challenge to perform these measurements under
everyday circumstances. For example, surface-enhanced Raman scattering (SERS)
has gained widespread recognition as a technique for trace chemical detection, but it
remains confined to a small number of specialist laboratories. For this reason, Dr Paul
Stoddart at Swinburne University of Technology recognised a need for more practical
SERS probes for field applications. His team has now developed a proprietary SERS
probe, based on an optical fibre that is little thicker than a hair. These optical fibres
can form the core element of field-portable SERS spectrometers. This work has
recently been boosted by the discovery in the United States that SERS can be used to
monitor glucose in blood. The development of a continuous glucose monitor has long
been a "holy grail" of sensor research, because of the millions of diabetes sufferers
who regularly perform the painful "finger prick" test. For SERS to provide a practical
solution to glucose monitoring, it is recognised that SERS optical fibres are needed
for minimally invasive probes. With support from Biopharmica and the Diabetes
Australia Research Trust, Dr Stoddart's team has now demonstrated that sensitive
SERS probes can be produced in large quantities. The next objective is to develop a
prototype low-cost SERS spectrometer for use as part of a continuous glucose
monitoring system. This will require the development of a laser source and
spectroscopic system that can interface to the SERS probes. It is proposed to use an
Australian designed and manufactured laser system based on a low-power narrowlinewidth laser diode. The project plans to bring together Swinburne University,
OptoTech and Grey Innovation in order to develop a commercially scaleable and
robust device.
Research achievements (from final report):
Following a technology demonstration phase, prototype spectroscopic glucose
monitoring devices have been developed. These include compact optics modules for
interfacing the optical fibre glucose sensors with four different laser light sources and
a spectrometer module. A technique for mounting the optical fibre probes in a narrow
guage hypodermic needle was also developed. In parallel with this, significant
improvements to the optical fibre probes were undertaken, as the initial fabrication
method could not be scaled up to commercial levels. This process led to the
development of an innovative molding technique and a very robust vapour deposition
technique for sensor fabrication. Each of these methods offers advantages under
certain circumstances and the sensors are expected to support a great deal of further
research and application development. Efforts to integrate the system for glucose
NHMRC Research Achievements - SUMMARY
measurements were unsuccesful, pointing to the need for systematic improvement of
the sensor surface chemistry. Initial efforts to improve the surface chemistry have met
with some success. The optoelectronic technologies developed for the demonstrator
units are expected to assist in the development of other new devices, including an
advanced pulse oximeter for use with critically ill patients.
Expected future outcomes:
The prototype devices developed and knowledge achieved in this project will
underpin future work to develop a more effective surface chemistry for the sensor.
This technique remains one of the most promising candidates for continuous in vivo
glucose monitoring, which would help to improve the management of diabetes.
Name of contact: Dr Paul Stoddart
Email of contact: pstoddart@swin.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 219128
CIA Name: Prof Steven Boyages
Main RFCD: Not Allocated
Admin Inst: Sydney West Area Health Service
Start Year: 2002
End Year: 2003
Total funding: $92,375.00
Grant Type: SRDC - Research
Title of research award:
An evidence based capacity building approach to improving vascular health in an
Aboriginal Community
Lay Description (from application):
Not Available
Research achievements (from final report):
A primary health care team approach and a community development approach were
taken to making changes needed to improve the prevention, detection and
management of diabetes related illness in the local Indigenous community.
An important achievement was the development of community members' and staff
members' knowledge, attitudes and behaviours conducive to achieving the above
aims.
The insights gained into client and family members' experience living with diabetes
were of particular value in planning support and interventions. The insights gained
into community members' information needs has informed the development of health
education and promotion resources and activities.
Management systems were improved for detecting, monitoring and managing existing
diabetic illness. These included the development of policies, procedures and
protocols; improvements to computerised diabetes registers, records and recall
systems; the introduction of point of care testing for HbA1c (a key indicator of blood
glucose control) and ACR (a key indicator of kidney damage) which enabled
immediate feedback to clients from the treating medical practitioner; and the
introduction of the Aboriginal adult health check for detection of diabetes risk or
illness.
There has been improved client access to some relevant allied health services
(podiatry, optometry, dietetics, diabetes education) through improved advocacy and
collaboration with other organisations.
Staff received relevant education, training and resources to assist the team to
effectively engage in assisting clients to manage their diabetes and in educating
family and community members about diabetes.
There is enhanced competence and confidence (within the organisation as a whole) in
relation to health education and promotion and in relation to participating in primary
health care research.
Expected future outcomes:
A booklet detailing the outcomes of interviews and focus groups with clients, family
members and staff will be used in community health education and promotion.
The service strives to fully implement early detection in the face of competing acute
care priorities.
An article is to be prepared for publication.
NHMRC Research Achievements - SUMMARY
Name of contact: Maree Keogh
Email of contact: project@rivmed.org
NHMRC Research Achievements - SUMMARY
Grant ID: 219109
CIA Name: Prof Robyn McDermott
Main RFCD: Indigenous Health
Admin Inst: The Dr Edward Koch Foundation Limited
Start Year: 2002
End Year: 2003
Total funding: $414,600.00
Grant Type: SRDC - Research
Title of research award:
Sustainability & Transferability of an effective community based management system
for diabetes in remote indigenous com
Lay Description (from application):
This project aims to improve systems for secondary prevention of CVD among
Indigenous adults in remote communities in NW Queensland and ultimately to
improve patient outcomes in this high risk group. The intervention is aimed at the
three domains of health systems: the community and client group, clinical services
and health management systems. The intervention is centred around increasing the
capacity of Indigenous health Workers (IHW's) to manage recall and reminder
systems for CHD in communities, supported by appropriate training and systems
changes. The project will liaise closely with the client and community groups and aim
to improve capacity for effective self-management of cardiovascular disease among
clients. The study will evaluate the effectiveness of this complex intervention in 3
sites over two years, with 2 control communities
Research achievements (from final report):
This work built upon a successful collaboration between the University and the Health
Service in the Torres Strait (north Queensland) which proved, in a randomised cluster
trial, that a community-based system of managing basic diabetes care in remote
communities, led by properly supported local Indigenous Health Workers, improved
diabetes care processes and significantly reduced preventable hospitalisations from
complications of diabetes. The current project evaluated the sustainability of the
chronic care model over 4 years, looking at 3 domains of policy and resources,
clinical systems (including registers, recall and reminder systems) and community and
patient perceptions of quality of care. The project showed that, given a supportive
policy environment and clinical systems (including workforce development), a
sustained improvement in diabetes care processes and outcomes could be achieved
across the whole health service (population approximately 10,000) ina high risk
remote Indigenous population.
Expected future outcomes:
This work has contributed to the evidence base supporting the chronic disease strategy
in north Queensland. It has been used in developing an Evaluation Framework for the
Chronic Disease Strategies in NQ and the NT.
Name of contact: Robyn Mcdermott
Email of contact: robyn.mcdermott@unisa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 519245
CIA Name: Prof Jennifer Couper
Main RFCD: Endocrinology
Admin Inst: University of Adelaide
Start Year: 2008
End Year: 2011
Total funding: $368,062.00
Grant Type: NHMRC Project
Grants
Title of research award:
Defining vascular health and modifiable risk factors over time in childhood.
Lay Description (from application):
Adult heart disease and strokes have their origin in childhood. We will follow healthy
children and children with diabetes or obesity over 2 years during puberty when
blood vessel disease is detectable. We will define which are the most sensitive
markers of blood vessel disease and the continuum of risk factors. This is essential
knowledge to best define children at risk and to test clinical and public health
interventions.
Research achievements (from final report):
Not Available
Expected future outcomes:
N/A
Name of contact: Professor Jennifer Couper
Email of contact: jennifer.couper@adelaide.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 158007
CIA Name: A/Pr Michael DAVIES
Main RFCD: Obstetrics and Gynaecology
Admin Inst: University of Adelaide
Start Year: 2001
End Year: 2003
Total funding: $449,073.00
Grant Type: NHMRC Project
Grants
Title of research award:
Fetal and genetic origins of Polycystic Ovary Syndrome (PCOS) in young women
Lay Description (from application):
Polycystic ovary syndrome (PCOS) is a common hormonal condition which emerges
at puberty and afflicts up to 10% of women. The cause of PCOS is uncertain.
Symptoms include menstrual disorders, acne, obesity, and excess body hair. PCOS is
of great significance for women because of the high incidence of infertility and the
high risk of other serious diseases, including diabetes mellitus and endometrial
cancer. PCOS is probably the most common hormonal condition among young
women. The cause of PCOS is unknown and the relationship between PCOS and
the more common condition of polycystic ovaries, which often features in PCOS, is
uncertain. There is evidence that genetic factors contribute to PCOS, but cannot
explain certain aspects. There is also striking new evidence that abnormal growth in
the womb can alter the metabolism of the baby for life, resulting in increased risks of
adult disease, including diabetes and cardiovascular disease. PCOS may be another
consequence of abnormal fetal growth, a suggestion that is supported by two recent
studies of closely related conditions.
To investigate the origins of PCOS, we
propose to establish the first international study of the relationships between fetal
growth, genetic factors and the presence of PCOS. In this study, we shall trace
3,260 women born in one maternity ward during 1973-75. These women, now young
adults, will be invited into our study for an interview, physical examination, and a
blood test. We expect 2,200 women will participate. Of this group, some 220
women with PCOS will receive further tests to investigate a range of metabolic
problems. The study has the potential to illuminate the path from genetic
predisposition and fetal growth, to the emergence of an important reproductive
disorder with serious associated diseases in a woman s later life.
Research achievements (from final report):
N/A
Expected future outcomes:
N/A
Name of contact: Dr Michael Davies
Email of contact: michael.davies@adelaide.ed.au
NHMRC Research Achievements - SUMMARY
Grant ID: 250403
CIA Name: A/Pr William Hague
Main RFCD: Obstetrics and Gynaecology
Admin Inst: University of Adelaide
Start Year: 2003
End Year: 2005
Total funding: $257,400.00
Grant Type: NHMRC Project
Grants
Title of research award:
Gestational diabetes: treatment with metformin compared to insulin
Lay Description (from application):
Gestational diabetes (GDM) is diagnosed when women have elevated blood sugar
levels detected in pregnancy. Treatment aims to keep the mother's blood sugar normal
and to prevent extra sugar transferring to the baby, as this can lead to elevated insulin
levels, and subsequent complications, in the baby. Initial treatment is by diet, but
more than 30% of women need further treatment with insulin injections. Metformin,
which can be taken by as a tablet, is an alternative to insulin that is used widely
outside pregnancy for people with diabetes. There are good data to support the safety
of metformin in pregnancy. We plan to test that metformin is not only safe but also an
effective alternative to insulin for women with GDM. Metformin works by reducing
resistance to insulin, which is a key factor for the development of GDM and also for
high blood pressure complications. We hope to demonstrate a reduction in these
complications with metformin treatment. Metformin is associated with less weight
gain than insulin and we hope to demonstrate an associated reduction in the risk of
diabetes following pregnancy in women with GDM treated with metformin. It is
likely that metformin crosses the placenta, and if so, it may reduce elevated insulin
levels in the baby. The study will measure insulin levels in the cord blood, hoping to
demonstrate that more babies have normal insulin levels in pregnancies treated with
metformin
Research achievements (from final report):
We have demonstrated in an adequately powered randomised clinical trial that, in
women with gestational diabetes who require more than lifestyle adjustment to
control hyperglycaemia, an oral medication metformin is safe and effective with
similar perinatal outcomes when compared with insulin which needs to be given by
injection. Women prefer metformin to insulin. Longer term outcomes for the
offspring need to be established.
Expected future outcomes:
With funded long-term follow-up studies, we expect to be able to establish whether
there is any benefit , such as a reduction in the rate of childhood obesity and the
degree of resistance to insulin, for the offspring of mothers with gestational diabetes,
who have been exposed to metformin in utero, given the potential of metformin to
affect fetal insulin action.
Name of contact: Dr Bill Hague
Email of contact: bill.hague@adelaide.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 453647
CIA Name: Prof Michael Horowitz
Main RFCD: Gastroenterology
Admin Inst: University of Adelaide
Start Year: 2007
End Year: 2009
Total funding: $543,302.00
Grant Type: NHMRC Project
Grants
Title of research award:
Upper gastrointestinal motility and glycaemic control in diabetes mellitus
Lay Description (from application):
The application of novel techniques to evaluate gastrointestinal motor function has
established that the rate at which the stomach empties is abnormally slow in ~50% of
people who have insulin-dependent (type 1) or non-insulin dependent (type 2)
diabetes. Delayed stomach emptying, which was thought to be an infrequent
complication of diabetes, may contribute to a number of problems including
symptoms such as nausea and bloating, and poor control of blood glucose
concentrations. The blood glucose level itself also has a reversible effect on both
stomach contractions and symptoms; when the blood glucose is abnormally high, the
rate at which the stomach empties is slower, and symptoms, such as fullness, are
greater. The rate of stomach emptying and the absorption of sugar from the intestine
have a major influence on the rise in the blood glucose level after a meal. This is
important because in people with diabetes it is desirable to maintain blood glucose
levels as close as possible to normal to minimise the risk of complications such as eye
and nerve damage. Specific modifications in diet and recently developed drugs which
have actions similar to that of the hormone, glucagon-like peptide-1, may improve
blood glucose control in type 2 diabetes by slowing the rate of gastric emptying.
People with cystic fibrosis frequently develop diabetes which is often difficult to
manage; this may result from abnormally rapid gastric emptying and impaired release
of hormones. If so, pancreatic enzyme replacement, in the form of tablets, should
prove effective. Our group has conducted research in this area for about 24 years and
have performed the most comprehensive studies to date resulting in international
recognition. The studies proposed in the current application represent a logical
development from our previous work and have important implications for the
management of diabetes.
Research achievements (from final report):
This research has highlighted the central role of the gut in diabetes management.
Stomach and intestinal function is frequently abnormal in people with diabetes, while
conversely, gut function is a key determinant of blood glucose control after meals.
The work has employed novel research tools to gain insights into physiological
mechanisms that can be translated into effective dietary and pharmacological
strategies for better control of blood glucose.
Expected future outcomes:
A better understanding of the long term prognosis of disordered gut function in
diabetes will emerge with ongoing study, and more specific therapies will be
developed. Dietary interventions that aim to stimulate gut peptide release for the
treatment of type 2 diabetes will be evaluated on a broader scale.
NHMRC Research Achievements - SUMMARY
Name of contact: A/Prof Chris Rayner
Email of contact: chris.rayner@adelaide.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 349443
CIA Name: A/Pr Mark Nottle
Main RFCD: Biotechnology not elsewhere classified
Admin Inst: University of Adelaide
Start Year: 2005
End Year: 2010
Total funding: $721,601.00
Grant Type: Established
Career Fellowships
Title of research award:
Uncoupled Research Fellowship
Lay Description (from application):
I am a reproductive physiologist who collaborates with a number of leading Hospital,
University and Institute Research Groups nationally and internationally examining the
potential of genetically modified pigs as organ, tissue and cell donors for humans.
Research achievements (from final report):
The aim of the fellowship request was to isolate porcine embryonic stem cells (ESCs)
to facilitate the production of transgenic pigs expressing multiple transgenes for pig to
human transplantation research. As a result of this research we developed a new
method for isolating stem cells and used this to have isolate several porcine ESC
lines. These have have been extensively characterised to confirm their ability to giv
rise to all the cell type sinth ebody incluidng th eprodcution of chimaeric pigs We
have also used this method to isolate porcine ESCs from cloned embryos and also
demonstrated that our method can be used to isolate ESCs from several strains of
mice as well as cattle.
Expected future outcomes:
Future work will examine capacity of these cells to undergo multiple rounds of
gnentic modifcation to produce animals expressing multiple transgenses in the space
of one generation for xenotransplantation research. Something which cannot be done
using current technology. We will also use these cells to develop the pig as a large
animal model for human stem cell research.
Name of contact: Mark Nottle
Email of contact: mark.nottle@adelaide.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 158012
CIA Name: Prof Gary Wittert
Main RFCD: Nutrition and Dietetics
Admin Inst: University of Adelaide
Start Year: 2001
End Year: 2003
Total funding: $208,055.00
Grant Type: NHMRC Project
Grants
Title of research award:
The role of dietary protein on weight loss and body composition in men and women
with insulin resistance
Lay Description (from application):
Obesity is an increasing problem in the community and is associated with an
increased incidence of high blood pressure, high cholesterol and triglycerides,
diabetes, heart disease and cancer. Although conventional dietary advice for weight
loss is a low fat high carbohydrate and high fibre diet there is a very strong interest in
the media and the general population in alternative diets that feature reduced
carbohydrate with the remainder of the diet either protein or a mixture of protein and
fat. Unfortunately there is very little published data to guide the decisions of health
professionals in this area and there is a strong demand for such information. We plan
to perform 2 large weight loss studies which focus on high protein diets with one
exchanging protein for carbohydrate and keeping fat constant and the second
exchanging protein for fat keeping carbohydrate constant. We will assess whether the
high protein diets blunt the decrease in metabolic rate that occurs with weight loss,
and whether it spares some of the inevitable loss of muscle mass. We will also
measure whether high protein diets improve glucose metabolism in people already at
risk of diabetes and heart disease because of their obesity and high insulin levels.
Research achievements (from final report):
The outcomes of this research provided a better understanding of the role of protein in
a healthly, nutritionally balanced diet for weight loss, weight maintenance and the
improvement of risk factors associated with the metabolic syndrome. Although we
found that without active ongoing dietary advice, long-term adherence to the dietary
patterns invetsigated is poor, they all resulted in net weight loss and improvements in
cardiovascular risk factors. That the increased protein diets confered several benefical
effects over the standard protein (control) diets without causing detrimental effects,
warrants that they be given consideration by health professionals as an effective
dietary choice for treating obesity and the metabolic syndrome.
Expected future outcomes:
All work is complete and published
Name of contact: Professor Gary Wittert
Email of contact: gary.wittert@adelaide.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 453655
CIA Name: Dr Vivienne Moore
Main RFCD: Foetal Development and Medicine
Admin Inst: University of Adelaide
Start Year: 2007
End Year: 2009
Total funding: $255,753.00
Grant Type: NHMRC Project
Grants
Title of research award:
Does women's nutrition during pregnancy influence metabolic health of their
children?
Lay Description (from application):
The occurrence of type 2 diabetes is increasing around the world, with the rising
incidence among children and adolescents especially worrying. Widespread obesity
has clearly contributed to this "epidemic", but does not fully explain it. Diabetes
develops over many years and obesity appears to exacerbate a pre-existing
susceptibility. Our work focuses on understanding and preventing this initial
susceptibility. Metabolic changes in the way the body produces and disposes of
insulin, and responds to glucose, are seen much earlier in individuals who become
diabetic. These metabolic defects are thought to be due, in part, to sub-optimal
growth and development before birth (affecting the way the pancreas and liver
function, for example). Poor nutrition before birth may be an important underlying
cause. Animal studies reliably demonstrate that a poor quality diet of the pregnant
mother can result in offspring that have impaired glucose tolerance and related
metabolic problems. We now need to determine whether this occurs in humans. A
limited amount of community-based research suggests this is possible. The balance
between carbohydrate and protein in the mother's diet may be a key factor, and
possibly the type of carbohydrate (high or low glycaemic). Weight before and during
pregnancy could also be influential. We have been following a cohort of 500 children
from before birth, through childhood. We collected detailed information on the
mothers' diets during pregnancy. In this project, we plan to assess the glucose-insulin
metabolism of the children at 8 years of age. We will then investigate whether diet of
the mothers during pregnancy affects the metabolism of the children later on.
Improving nutrition of pregnant women could lead to life-long improvement in
metabolic health of the children. This study will contribute to the evidence-base
about whether maternal diet is important, and give specific details about what kinds of
changes are needed.
Research achievements (from final report):
In this project, we followed up a cohort of children whose mothers had joined a
research study when they were pregnant. We investigated relationships between
maternal diet, body size and weight gain during pregnancy, and insulin resistance (IR)
in offspring at 9 years. Preliminary results of this project do not support arguments
that maternal diet, in isolation, has important consequences for child's metabolism.
Rather, the important predictive factor is high body weight of the mother before
pregnancy. Overweight and obesity in women needs to be addressed through public
health intiatives, whether or not the effects we have identified are a direct
consequence of the intrauterine environment or reflect a common family/social
environment.
NHMRC Research Achievements - SUMMARY
Expected future outcomes:
Additional research hypotheses developed while the project was being undertaken
concern a role for maternal impaired glucose tolerance during pregnancy. These
findings, and those of linked research about the family environment and child obesity,
will be completed in 2011.
Name of contact: Vivienne Moore
Email of contact: vivienne.moore@adelaide.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 406700
CIA Name: Prof Hamish Scott
Main RFCD: Autoimmunity
Admin Inst: University of Adelaide
Start Year: 2007
End Year: 2008
Total funding: $300,492.00
Grant Type: International
Collaborations
Title of research award:
Autoimmune polyendocrine syndrome type I
Lay Description (from application):
Our work package looks at Control of pathogenic autoimmunity through regulation by
the autoimmune regulator gene (AIRE) in thymic epithelial cells” and has a major
influence on work package no 1). –“ Design of specific tolerogenic peptide therapies
based on the identification of tissue-restricted self-antigen epitopes escaping
tolerance”, but interacts either directly or indirectly with all other packages
Research achievements (from final report):
This project was conceived as an important initiative to bring together the leading
scientists working on the best available biological model for autoimmunity,
Autoimmune Polyendocrine Syndrome Type I (APS I). The groundbreaking research
on this rare disease has provided new insights into mechanisms of tolerance induction
as well as providing tools for improved diagnostic tests and better care of patients.
The results of this research provide an example of an integrated effort to characterize
the molecular details of autoimmunity creating the basis for novel treatment and
intervention strategies for autoimmune diseases. Equally important, the effort will
provide well structured information of the details of the clinical course, accessible on
the internet by clinicians worldwide and providing the basis for the improvement in
patient care..
Expected future outcomes:
Additional publications. Better patient care. Potential novel therapies.
Name of contact: Professor Hamish S. Scott
Email of contact: hamish.scott@health.sa.gov.au
NHMRC Research Achievements - SUMMARY
Grant ID: 399123
CIA Name: A/Pr Simon Barry
Main RFCD: Cellular Immunology
Admin Inst: University of Adelaide
Start Year: 2006
End Year: 2008
Total funding: $483,273.00
Grant Type: NHMRC Project
Grants
Title of research award:
The molecular identification of FoxP3 +ve regulatory T cells
Lay Description (from application):
The immune system has a series of checks and balances in place to distinguish foreign
bodies from normal, or self-antigens. In healthy individuals this prevents the immune
system from attacking the cells and tissues of the body, food proteins, and the
beneficial bacteria of the gut. However in autoimmune disease the system becomes
imbalanced, allowing reactions to benign antigens, causing diseases such as diabetes,
asthma and rheumatoid arthritis. One of the key players in the maintenance of a
healthy immune system is a specialized set of T cells known as T Regulatory cells.
These cells are rare, at 1-4% of all T cells, yet are potent modulators of other T cells,
and can prevent the activation of a T cell if it is reacting to a self-antigen. If they can
control the cause of autoimmune disease, and patient Treg cells can be manipulated, it
may be possible to use them therapeutically. Recently the switch that is required to
generate regulatory cells was identified from patients with a rare autoimmune disease
called Immunodysregulation, polyendocrynopathy, enteropathy, X-linked syndrome
or IPEX. A mouse disease, Scurfy, with similar symptoms, is caused by the same
mutations. The mutated gene encodes a protein, FoxP3, and this protein is able to bind
to other genes in T cells and regulate their function. Without this protein, there are no
T regulatory cells, resulting in autoimmune disorders. At this time there is very little
known about how the FoxP3 gene is able to make a T cell become a regulatory T cell,
and nothing is known about the genes that are turned off and on to facilitate this. If we
can understand better the role of this protein, FoxP3, in the generation and
maintenance of T cells with regulatory function, we may better be able to diagnose
and treat autoimmune diseases, and this knowledge will have broad application to
many autoimmune disorders.
Research achievements (from final report):
The major aims of the grant have been achieved as we have now performed 4
chromatin immunoprecipitation-arrays (chIP-chip) from biological replicate nTreg
cells with our foxp3 immunoprecipitation protocol. We have performed duplicate
promoter arrays and duplicate whole genome arrays, and find over 90% agreement
between the promoter arrays and the whole genome arrays. We are among the first in
Australia to perform human chip-chip for a transcription factor and currently there are
no published data for the targets of human FoxP3, giving us a world first human
foxP3 target gene set. The final goal of this grant was confirming by quantitative-PCR
that the ChIP material is enriched for these key target genes, and validation of the
regulation of these genes at the mRNA level. This is now complete, and in preparation
for publication. We are now in the process of testing these genes to define their role
in Treg function using lentiviral overexpression or shRNAi.
Expected future outcomes:
NHMRC Research Achievements - SUMMARY
We have developed a world first profile of the genes regulated by human foxp3, have
discovered a novel Treg biomarker, and have started to analyse Treg genes in
fuctional assays. This may lead to novel therapeutic targets, and modulation of Treg
function will be applicable in autoimmune diseases and transplant tolerisation.
Name of contact: Dr Simon C Aarry
Email of contact: simon.barry@adelaide.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 453640
CIA Name: Prof Julie Owens
Main RFCD: Foetal Development and Medicine
Admin Inst: University of Adelaide
Start Year: 2007
End Year: 2009
Total funding: $545,183.00
Grant Type: NHMRC Project
Grants
Title of research award:
Functional and epigenetic consequences of maternal folate deficiency,
supplementation and fetal growth restriction
Lay Description (from application):
Growing slowly before birth or being born early and premature are very common.
Both conditions greatly increase the risk of illness or death around birth and of the
infant developing major conditions such as diabetes and cardiovascular disease in
later life. Despite their importance, we understand little of what causes fetal growth
failure or prematurity or why they influence an individual's health throughout life.
Recent findings suggest that low levels of folate in the mother, due to either dietary or
genetic factors, may be involved in their origins and their long-term outcomes. Folate
is a nutrient required regularly in small amounts for growth and maintenance of
health. Folate supplementation in women is currently recommended before and in
early pregnancy, but may have a role throughout the whole of pregnancy in promoting
growth and health of the infant. Using experimental models, this project will
determine if too little or too much maternal folate modifies the genetic code of the
infant (called epigenetic changes), which leads to later metabolic disease and high
blood pressure. These epigenetic changes are mild and subtle chemical modifications
of DNA that persist in the cells of the infant altering their function. The efficacy of
maternal folate supplementation in improving these outcomes for the small baby will
also be tested in the models. Finally, the effect of folate status in the normal and small
human infant on the epigenetic state of their placenta, cord blood white blood cells
and mucous cells of the mouth will be tested. These outcomes will enable the design
and testing of interventions with folate and related nutrients in the mother to improve
the health of their babies before birth and subsequently throughout their lives.
Because these pregnancy complications of being born small or early are common and
account for much of the diabetes that occurs in later life, the health benefits from
development of effective interventions may be large.
Research achievements (from final report):
The outcomes of this project include the demonstration that maternal methyl nutrient
deficiency or excess causes altered insulin action and glucose control in offspring. In
addition, the mechanistic pathways were shown to include epigenetic modifications to
both functional and regulatory genes affecting growth and glucose and lipid
metabolism in key effector and regulatory tissues. Novel non-coding RNAs,
microRNAs were shown to be major targets of maternal methyl nutrient modulation
in affecting the metabolic phenotype of offspring. Another key finding was that
maternal folic acid supplementation from before and throughout pregnancy, at a level
mimicking that recommended for pregnant women, adversely affects insulin control
of metabolism in offspring. This highlights the need for further investigation of the
long term consequences of maternal folic acid supplementation in humans,
particularly since the introduction of food fortification in Australia and elsewhere.
NHMRC Research Achievements - SUMMARY
Expected future outcomes:
The findings of these studies will inform the design and conduct of future studies to
assess the impact of increased folic acid intake during pregnancy on health of
offspring.
Name of contact: Julie Owens
Email of contact: julie.owens@adelaide.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 250483
CIA Name: Prof Antonio Ferrante
Main RFCD: Medical Biotechnology
Admin Inst: University of Adelaide
Start Year: 2003
End Year: 2004
Total funding: $150,000.00
Grant Type: NHMRC
Development Grants
Title of research award:
Targeting protein kinase C in diabetes management using novel polyunsaturated fatty
acids
Lay Description (from application):
PKC regulates a diverse range of cellular processes in an isozyme-specific manner.
There is strong recent evidence to implicate PKC, especially PKC _, in mediating the
actions of glucose in diabetes. This includes the action of glucose in renal glomeruli,
retina, aorta and heart of diabetic animals and in cultured cells from these organs.
More importantly, inhibition of PKC_ with the PKC_-specific inhibitor, LY333531,
blocks the actions of glucose. Recently, our research group designed and synthesised
a family of novel polyunsaturated fatty acids. One of these, MP5 (_-oxa- 21:3n-3),
inhibited high glucose-induced activation of PKCβ in cultured mesangial cells as well
as in glomeruli of diabetic rats in a relatively selective manner. The overall aim of
this proposal is to evaluate the potential for a chemically engineered novel
polyunsaturated fatty acid, MP5 (_-oxa-21:3n-3), to treat pathogenesis associated with
diabetes by targeting the PKC system. The specific aims are to: 1. Characterise the
effects of MP5 on glucose- or advanced glycosylation end product-stimulated
activation of protein kinase C (PKC). 2. Determine whether esterification of MP5 into
diacylglycerol is essential for the action of MP5 3. Investigate whether MP5 is
efficacious at preventing the actions of glucose in vitro e.g. glucose stimulated TGF_
production in mesangial cells, and in vivo in streptozotocin-diabetic r
Research achievements (from final report):
Our group has generated a family of designer fats based on fish oils and one of these
has demonstrated great potential as an agent to fight against the development of
complications caused by diabetes, such as kidney failure. Funds provided by the
NH&MRC have enabled our group to discover that this designer fat, called MP5, is
able to suppress the ability of high glucose concentrations to bring about biochemical
changes which damage the kidneys. In studies with animal models of experimental
diabetes, our results have demonstrated that MP5 made the diabetic animals less
thirsty, reduced the amount of urine produced and greatly reduced the severity of
kidney damage. Important features of this fat are that the effects on thirst and urine
output were seen within 72 hours after the commencement of treatment and lasted for
around two weeks after the treatments had ended. These results demonstrate that MP5
and similar designer fats have the hallmarks of novel drugs to fight against the
development of diabetic complications.
Expected future outcomes:
This technology is now signed over to Peplin Biotech, an Australian company. It is
currently under product stability and toxicology studies. It expected that within the
next 6 months, a commercial package will be precipitated for licensing to a large
NHMRC Research Achievements - SUMMARY
international pharmaceutical company to produce a successful drug for managing
diabetes.
Name of contact: Prof Antonio Ferrante
Email of contact: antonio.ferrante@adelaide.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 375170
CIA Name: Dr Claire Jessup
Main RFCD: Cellular Immunology
Admin Inst: University of Adelaide
Start Year: 2006
End Year: 2010
Total funding: $372,010.00
Grant Type: Early Career
Fellowships (Overseas)
Title of research award:
Modulation of T cell surface receptors that are dependent on extrinsic tyrosine
kinases.
Lay Description (from application):
Not Available
Research achievements (from final report):
This training award allowed me to undertake 2 years of laboratory-based research at
the University of Oxford in the UK - one of the top three research universities in the
world. In addition to learning cutting-edge techniques, I was able to make valuable
connections with high calibre scientists. During my time in Oxford, we were able to
describe some of the protein structures that control signalling through a molecule
called PD-1 that is responsible for controlling immune cells (T cells). Upon my return
to Adelaide, I was able to apply some of my new techniques, including the use of a
particular engineered immune cell line, to the research work being undertaken at the
University of Adelaide. This includes investigating approaches to improve the success
of a new potential cure for Type I Diabetes, pancreatic islet transplantation, which is
currently at the clinical trial stage in Australia. Potentially, my current research will
one day be used to prevent the onset of Type I diabetes, treat ongoing Type 2 diabetes
and improve outcomes for pancreatic islet transplantation.
Expected future outcomes:
The confidence and experience gained during my training award is expected to result
in the publication of 10 scientific papers in the next 12 months and the establishment
of my own Diabetes research group in the next 2-3 years.
Name of contact: Claire Jessup
Email of contact: claire.jessup@flinders.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 250335
CIA Name: Prof Michael Horowitz
Main RFCD: Gastroenterology
Admin Inst: University of Adelaide
Start Year: 2003
End Year: 2005
Total funding: $393,750.00
Grant Type: NHMRC Project
Grants
Title of research award:
Gastroduodenal motility and glycaemic control in diabetes mellitus
Lay Description (from application):
The recent application of novel techniques to evaluate gastrointestinal motor function
has established that the rate which the stomach empties food is abnormally slow in
~50% of people who have insulin-dependent (type 1) or non-insulin dependent (type
2) diabetes. Delayed stomach emptying was thought to be an infrequent complication
in diabetes; much less common than damage to the eyes, kidneys or nerves.
Abnormal stomach emptying may contribute to a number of problems in diabetes,
including symptoms such as nausea and bloating, and poor control of blood glucose
concentrations. It is now recognised that the blood glucose level itself has a
reversible effect on both stomach contractions and symptoms. For example, when the
blood glucose is abnormally high (hyperglycaemia), the rate at which the stomach
empties food into the intestine is slower and symptoms, such as fullness, are greater.
The rate of stomach emptying and the absorption of glucose from the intestine affect
the rise in the blood glucose level after a meal; this is an important issue because it is
desirable to maintain blood glucose levels within the normal range to minimise the
risk of both the development and progression of the complications of diabetes. In
many people with diabetes eating a meal results in a substantial fall in blood pressure,
which may cause fainting and falls. By slowing gastric emptying the magnitude of
the fall in blood pressure is minimised. Our group has been the recipient of ongoing
support from the NH&MRC for approximately 18 years to conduct research in this
area. As a result we have performed the most comprehensive studies to date and
developed new methods to evaluate stomach and intestinal function in people with
diabetes, resulting in international recognition. The studies proposed in the current
application represent a logical development from our previous work and have
important implications for the management of diabetes.
Research achievements (from final report):
Our group has conducted research in this area for some 20 years and have performed
the most comprehensive studies to date, resulting in international recognitiion. The
studies that were performed represented a logical development from our previous
work and have important implications for the management of diabetes. This research
capitalised on novel techniques (eg scintigraphy, ultrasound and manometry)
developed in many cases by members of our group to study gastric emptying and its
mechanics, gastrointestinal symptoms, intestinal carbohydrate absorption, hormonal
responses to nutrient delivery and the impact of the blood glucose concentration on
gastrointestinal motor and sensory function. The central role of gastric emptying, and
probably small intestinal motility, to blood glucose homeostasis has only recently
been widely appreciated and is of major importance to the effective management of
diabetes. The grant was highly productive (as attested to by the publication record)
NHMRC Research Achievements - SUMMARY
and the outcome of this work will have a substantial impact on patient management.
It has also consolidated our position as arguably the world leaders in this area.
Expected future outcomes:
We propose to continue our research programme in this area with an increasing focus
on the capacity to modulate gastric and small intestinal motility, by dietary and
pharmacological means, to optimise glycaemic control in diabetes mellitus
Name of contact: Prof Michael Horowitz
Email of contact: michael.horowitz@adelaide.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 453464
CIA Name: Prof Antonio Ferrante
Main RFCD: Endocrinology
Admin Inst: University of Adelaide
Start Year: 2007
End Year: 2009
Total funding: $418,447.00
Grant Type: NHMRC Project
Grants
Title of research award:
Omega 3 polyunsaturated fatty acid analogues in the treatment of diabetic
complications
Lay Description (from application):
Treatment of diabetes has become an even greater challenge to our community today.
The ill health from diabetes arises from the high blood sugar levels. Treatment of
diabetic complications such as kidney damage has now become a major goal. This
research addresses this problem by trying to find out if a group of novel
polyunsaturated fatty acids can target the process initiated by high blood sugar
responsible for kidney damage.
Research achievements (from final report):
Our attempts to establish the protective effects of novel polyunsaturated fatty acids in
an experimental rat model of diabetes against the development of diabetic
nephropathy and associated complications have been completed and objectives
achieved, including the gaining of an understanding of the basis of their protective
effects. Taking into consideration all our other knowledge available on these novel
fats and the classical omega 3 polyunsaturated fatty acids, it is evident that the
limitations experienced in using omega3 fatty acid supplementation to treat chronic
diseases such as diabetes could be overcome by using the novel fats. The advantages
of the novel fats are with respect to an increase in potency, tissue stability and target
selectivity. We have been able to show that these have the ability to selectively target
cellular enzymes stimulated by high blood glucose which give rise to complications
such as kidney damage. The work suggests that fats of this type prevent or reduce the
activation of these enzymes by high glucose. Animals treated with the novel fats
showed also protection against damage experienced by other organs such as the liver.
Expected future outcomes:
Further research on the novel fats would yield important information to make
decisions on the therapeutic potential of these fats over the natural omega3 fats and
other diabetic medications. Studies should extend proof to other diabetic models and
gaining a better understanding of the structure responsible for the protection.
Name of contact: Professor Tony Ferrante
Email of contact: antonio.ferrante@health.sa.gov.au
NHMRC Research Achievements - SUMMARY
Grant ID: 565319
CIA Name: Dr Elizabeth Beckett
Main RFCD: Gastroenterology
Admin Inst: University of Adelaide
Start Year: 2009
End Year: 2012
Total funding: $386,104.00
Grant Type: NHMRC Project
Grants
Title of research award:
Involvement of interstitial cells of Cajal in the pathogenesis of diabetic gastroparesis
Lay Description (from application):
Diabetics commonly suffer from gastrointestinal symptoms such as bloating and
nausea. We have preliminary evidence that interstitial cells of Cajal (ICC), which are
essential for normal gut motility, are particularly vunerable to damage in diabetes.
The goal of this study is to determine how the loss of ICC in diabetes leads to delayed
gastric emptying. Our overall aim is to identify potential therapeutic targets for
improved treatment of diabetes-related gastrointestinal motility disorders.
Research achievements (from final report):
This research award from the NHMRC has enabled a thorough and detailed
investigation into the pathophysiological basis for the disordered gastrointestinal
function that commonly accompanies longstanding diabetes mellitus. A murine
model exhibiting obesity and chronically elevated blood sugar levels was utilised to
determine which regions of the gastrointestinal tract are most severely affected by this
condition, and the nature of the deficits present. Our experiments examined
differences between non-diabetic and normal control animals at the level of the whole
animal, isolated gastrintestinal tissues, through to a detailed examination of changes at
the cellular and molecular level. In contrast to previously published findings from
other research groups using similar strains of mice, the deficits in pacemaking
activity, motor neurotransmission and cellular deficits were found to be subtle and the
variability between animals in the diabetic population considerable, with some
animals exhibited irratic motility patterns and disrupted neural and ICC populations,
whilst the agstrointestinal tracts of others were not significantly altered by the diabetic
condition.
Expected future outcomes:
These studies have been presented at international conferences and are currently being
prepared for publication as journal articles. Information attained from these studies
will add to the body of knowledge in this field and likely assist with the development
of new targeted therapies for the gastrointestinal motility disorders that commonly
accompany longstanding diabetes mellitus.
Name of contact: Elizabeth Beckett
Email of contact: elizabeth.beckett@adelaide.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 481354
CIA Name: A/Pr Leonie Heilbronn
Main RFCD: Endocrinology
Admin Inst: University of Adelaide
Start Year: 2008
End Year: 2011
Total funding: $380,559.00
Grant Type: Career
Development Fellowships
Title of research award:
Short term effects of overfeeding on metabolic risk in humans
Lay Description (from application):
Obesity is associated with increased risk of diabetes, heart disease and cancer. Obesity
prevalence is rapidly increasing and consitutes one of the greatest threats to human
health. The aim of this study is to determine mechanism/s underlying the close
relationship between obesity and insulin resistance by inducing experimental weight
gain in humans with and without a genetic predisposition to diabetes. This project will
help identify new candidates for anti-diabetes drugs.
Research achievements (from final report):
The overall goal of my research during my CDA was to examine the physiological
and molecular basis of over and under nutrition in obesity, with a focus on identifying
early mechanisms of insulin resistance. During my CDA, we performed studies
investigating effects of overfeeding on various outcomes in humans, including on
macrophage accumulation in adipose tissue and mitochondrial function in skeletal
muscle. We also iniated studies examining the effects of hyperbaric oxygen therapy
on insulin sensitivity in type 2 diabetes, and begun studies to phenotype individuals
and mice born following IVF for diabetes and cardiovascular risk factors. This CDA
award enabled me to focus solely on research during this time. During my CDA, I
completed my first NHMRC project grant as CIA to examine the effects of high fat
overfeeding and insulin resistance in sex and BMI matched individuals with and
without a family history of type 2 diabetes where I was directly responsible for the
budget, 2 staff members and a PhD candidate and had excellent research productivity
with 27 publications. In Jan 2010, I transferred my research from Garvan Institute to
the University of Adelaide where I was appointed at Level D. The beginning of 2010
was spent setting up my research program and applying for grants, of which I was
succesful in obtaining a 2011 Royal Adelaide Hospital award, a 2012 NHMRC
project grant as CIA, as well as a 2012 DART and 2012 Channel 7 award.
Expected future outcomes:
My next NHMRC project award is due to start in October 2012. This study will
compare the effects of periodic fasting with and without energy restriction with
continous energy restriction in humans, and am continuing my work in hyperbaric
oxygen therapy and characterising IVF born individuals.
Name of contact: Leonie Heilbronn
Email of contact: leonie.heilbronn@adelaide.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 278806
CIA Name: Dr Claudine Bonder
Main RFCD: Autoimmunity
Admin Inst: University of Adelaide
Start Year: 2005
End Year: 2008
Total funding: $308,579.00
Grant Type: Early Career
Fellowships (Australia)
Title of research award:
The role of sphingosine kinase and endothelial cell activation in autoimmun diseases
Lay Description (from application):
Not Available
Research achievements (from final report):
Aberrant blood vessel formation underpins the mortality associated with cancer,
cardiovascular complications, transplantation rejection, diabetes and rheumatoid
arthritis. Endothelial progenitor cells (EPCs) are key contributors to this vasculogenic
process although their exact contribution is still under intense debate. EPCs are the
target of over 100 clinical trials and initial results have not been promising. Their lack
of success is likely due to our inability to distinguish them from the closely related
mature endothelial cells and haematopoietic progenitor cells as well as insufficient
EPC survival and retention. We recently made the key discovery that the lipid
enzyme sphingosine kinase (SK)-1 regulates the rate of EPC differentiation without
effect on the haematopoietic compartment and controls EPC survival and trafficking
via hitherto unknown pathways. These observations open the door, for the first time,
for the full characterisation of EPCs for diagnostic and therapeutic purposes for the
two major killers in the Western world, cardiovascular disease and cancer.
Dr Bonder has obtained multiple peer reviewed competitive funding and has
developed a significant program into the characterization of endothelial progenitor
cells (EPCs) through a combination of in vitro and in vivo approaches. The clinical
value of this program has now been validated by Dr Bonder's publication of EPCs dedifferentiating from mature endothelial cells by regulating sphingosine kinase levels
(Bonder et al, Blood (IF = 10.4)). This seminal work opens the door for the
exploitation of EPCs in the clinical arena.
Expected future outcomes:
This is an emerging and important area in clinical research which seeks to identify
and ultimately control EPCs and thereby blood vasculature in diseases (eg cancer).
The importance of Dr Bonder's program on EPCs is both scientific and commercial,
and is already bringing SA significant returns in scientific reputation, research dollars
and equity gains.
Name of contact: Dr Claudine Bonder
Email of contact: claudine.bonder@health.sa.gov.au
NHMRC Research Achievements - SUMMARY
Grant ID: 627227
CIA Name: Prof Gary Wittert
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Admin Inst: University of Adelaide
Start Year: 2010
End Year: 2012
Total funding: $1,817,271.00
Grant Type: NHMRC Project
Grants
Title of research award:
Effect of sex steroids, inflammation, environmental and biopsychosocial factors on
cardiometabolic disease risk in men
Lay Description (from application):
Heart disease is more frequent and occurs at an earlier age in men than women. The
reason is unknown. Apart from obesity and associated disturbances of metabolism,
changes in sex hormones such as testosterone, together with the effects of
inflammation may be important, and may in turn be affected by environment, lifestyle
behaviours, and stress. To untangle these relationships, we will use cutting edge
technology, in a large sample of men, in partnership with other international
scientists.
Research achievements (from final report):
1.A decreased levels of the male hormone testosterone with increasing age is not due
to ageing as such but rather reflects the burden of disease, particularly obesity. When
fat mass decreases testosterone levels increase. Significance: A low testosterone level
should not be attributed to age and reflexively treated with testosterone. Rather detect
and treat obesity and associated chronic disease with a lifestyle modification program.
2. Sex hormone binding globulin (SHBG), a protein, made in the liver, carries
testosterone in the blood. A low level is associated with obesity and insulin resistance
but it is not a risk factor for type 2 diabetes whereas low testosterone is an
independent risk factor. Significance: NHMRC funded clinical trial to determine in
men aged 50+ with prediabetes, whether testosterone together with a lifestyle
program prevents the progression to diabetes over and above lifestyle program alone.
3. Lower urinary tract symptoms (LUTS) (waking to pass urine, frequency, and
urgency) are common but not an inevitable part of ageing. They share risk factors
with diabetes and cardiovascular disease in particular obesity, obstructive sleep
apnoea, high blood pressure, depression and lack of physical activity. These
symptoms improve or even resolve with correction of risk factors. Significance: when
LUTS are present don't just assume it is due to ageing or the prostate; think beyond
the prostate.
4. Obstructive sleep apnoea is common affecting 52% of men aged 40+ and is
moderately severe or severe in 25%. The associated comorbidities occur independent
of the presence of sleepiness.
Expected future outcomes:
1. Relative contributions of sleep disorders, stress, obesity, lifestyle, low testosterone
and inflammation to incident diabetes and cardiovascular disease
2. Sleep disorders: (i) relationship to sex hormones, disease risk; (ii) improved clinical
algorithms for screening
NHMRC Research Achievements - SUMMARY
3. Relationships between urinary BPA and or phthalate levels, endocrine status and
disease risk.
Name of contact: Prof Gary Wittert
Email of contact: gary.wittert@adelaide.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 490975
CIA Name: Dr Lisa Moran
Main RFCD: Endocrinology
Admin Inst: University of Adelaide
Start Year: 2008
End Year: 2012
Total funding: $304,047.00
Grant Type: Early Career
Fellowships (Australia)
Title of research award:
The assessment and treatment of cardiovascular risk factors,diabetes and insulin
resistance in Polycystic Ovary Syndrome
Lay Description (from application):
Cardiovascular disease (CVD) and Type II Diabetes Mellitus (T2DM) are major
health burdens in Australia. T2DM is increased and CVD may be increased in
polycystic ovary syndrome (PCOS), a condition present in 10% of women and 30% of
obese reproductive aged women. We aim to explore risk factors for CVD and T2DM
in women with PCOS and to assess the effect of treatment strategies on metabolic and
reproductive features in PCOS. This is crucial for reducing disease risk in this
common condition.
Research achievements (from final report):
The aim of this fellowship was the assessment and treatment of risk factors for
cardiovascular disease (CVD) and diabetes (DM2) in polycystic ovary syndrome
(PCOS). PCOS is a very common condition affecting up to 1 in 5 women of
reproductive age in Australia. It is associated with infertility, obesity, an increased
risk of DM2 and CVD and worsened psychological health. During my fellowship, I
reported elevated levels in a variety of novel markers for CVD in PCOS, namely
asymmetric dimethylarginine (ADMA) and plasminogen activator inhibitor-1 (PAI1). I also reported that women with a newer 'milder' diagnosis of PCOS still present
with worsened blood vessel health, DM2 risk and anxiety. I additionally examined the
effect of different treatments on CVD and DM2 risk in PCOS. I reported that weight
loss improved inflammation and blood vessel function. Insulin sensitising drugs (such
as metformin) or the oral contraceptive pill both improved CVD and DM2 risk factors
including PAI-1 and ADMA. However, the oral contraceptive pill was associated with
some deleterious effects on DM2 and CVD risk factors including worsened insulin
resistance, inflammation and glucose tolerance. I conducted evidence-based medicine
including the first systematic literature review examining the effectiveness of lifestyle
treatments including diet and exercise on PCOS. This found lifestyle treatment
improved weight, reproductive hormones, excess hair growth and DM2 and CVD risk
factors. I led the development of NHMRC-approved evidence-based guidelines for
the treatment of PCOS which reported the importance of lifestyle treatment in
conjunction with pharmacological and medical therapy for PCOS.
Expected future outcomes:
This research will contribute to the development of optimal screening and treatment
strategies for DM2, CVD and psychological dysfunction in PCOS. This research has
already been incorporated in national NHMRC-approved evidence-based guidelines
and will guide clinical practice.
Name of contact: Lisa Moran
NHMRC Research Achievements - SUMMARY
Email of contact: lisa.moran@adelaide.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 399131
CIA Name: A/Pr David Kennaway
Main RFCD: Endocrinology
Admin Inst: University of Adelaide
Start Year: 2006
End Year: 2008
Total funding: $631,782.00
Grant Type: NHMRC Project
Grants
Title of research award:
How does disruption of circadian rhythms induce diabetes?
Lay Description (from application):
Increasing evidence suggests that disturbed circadian rhythms initiate and amplify
metabolic and cardiovascular disease. The increasing and already high proportion of
workers engaged in shiftwork, and increased frequency of disruption of these rhythms
in the population more generally, implicate this body system as contributing to the
growing epidemic of obesity and diabetes and related disorders in our community and
world-wide. While we are now beginning to understand how our rhythms are
synchronised to night and day, how this rhythmicity is linked to our organs in the
normal and common disease states such as diabetes is poorly understood. The
discovery of a special set of genes, called clock genes that function in all of the cells
in our bodies and strongly influence the function of our organs such as the liver,
pancreas and heart has been particularly important. We hypothesise that both
environmentally (exogenous) and genetically (endogenous) induced disruption of
circadian rhythms causes metabolic dysfunction. This is due to altered central and
peripheral clock gene expression rhythms, which in turn alter metabolic rhythms and
impair glucose homeostasis. This project aims to determine the impact of disrupted
rhythmicity on metabolism with a particular emphasis on the possibility that the
disrupted rhythmicity may be a predisposing factor for the development of diabetes.
Research achievements (from final report):
We have established a new animal model that mimics a shiftwork schedule. We have
shown that exposure of mice and rats to repeated changes of the light/dark cycle
altered sleep/wake behaviour. Thus the animals were active in the dark phase and
inactive in the light phase from the commencement of the schedule, validating its use
as a true shiftwork simulation. After 4 weeks of shiftwork simulation, liver function
was enhanced when the mice were preparing for rest instead of active. The
consequences were elevated plasma insulin levels, a risk factor for diabetes, in mice
subjected to shiftwork simulation, which was exacerbated by a high fat diet. When
rats were subjected to shiftwork simulation, insulin secretion and insulin sensitivity
were both impaired and glucose tolerance reduced, all signs of prediabetes and this
persisted for up to a week or more post shiftwork.
Mice with mutations in genes responsible for generating biological rhythms in cells
also had impaired insulin secretion, but compensated with increased production of
hormones that protected against the insulin sensitivity. When these mice were fed a
high fat diet they also appeared to be protected from the deleterious impact of the diet
despite increased body fat.
In summary we have confirmed and further delineated the major role of cellular
rhythms in metabolic homeostasis and provided compelling and direct evidence that
disruption of circadian rhythmicity alters the adipo-insulin axis and impairs glucoe
tolerance, acting in a tissue specific fashion. Understanding how disruption to cellular
NHMRC Research Achievements - SUMMARY
rhythms leads to diabetes, but can also enhance the metabolic state of adipocytes with
the potential to preserve metabolic homeostasis, may lead to novel ways to improve
the health of shiftworkers.
Expected future outcomes:
This research has provided important new information on how daily rhythms impact
on metabolic health. Using this knowledge we expect to design and test strategies for
minimising the negative impact of shiftwork on health.
Name of contact: Assoc. Prof. David Kennaway
Email of contact: david.kennaway@adelaide.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 502628
CIA Name: Dr Sheena Wee
Main RFCD: Medical Biochemistry: Proteins and Peptides
Admin Inst: University of Melbourne
Start Year: 2008
End Year: 2011
Total funding: $141,000.00
Grant Type: Early Career
Fellowships (Australia)
Title of research award:
Chemical aided phospoproteome sequencing with mass spectrometry
Lay Description (from application):
Essentially all of the body's functions from muscle contraction, energy expenditure
through to appetite are controlled by a complex molecular communications system.
One of the key elements involves the modification of proteins to alter their properties
by adding and removing phosphate. By analysing this process in response to diet and
exercise we will obtain a greater understanding of their health benefits and understand
how type 2 diabetes and obesity develop at the molecular level.
Research achievements (from final report):
The sucess of an islet transplant may be more easily monitored now.
Expected future outcomes:
This may lead to higher survival rate for patients who receive this treatment.
Name of contact: Sheena Wee
Email of contact: swee@imcb.a-star.edu.sg
NHMRC Research Achievements - SUMMARY
Grant ID: 299800
CIA Name: A/Pr Ulrike Grunert
Main RFCD: Sensory Systems
Admin Inst: University of Melbourne
Start Year: 2004
End Year: 2006
Total funding: $367,500.00
Grant Type: NHMRC Project
Grants
Title of research award:
Synaptic connectivity of colour pathways in primate retina
Lay Description (from application):
The first step in the visual process occurs when light enters the eye and activates
specialised nerve cells called photoreceptors. The photoreceptors for daytime vision
(called cones for their cone-like shape) comprise three types, which are sensitive to
the long- ("red"), medium- ("green") or short-wavelength ("blue") regions of the
visible spectrum. Although the properties of the cones are well known, the way in
which they are functionally connected to nerve pathways for vision is not clearly
understood. Clinical research has shown that reduced sensitivity to blue light is a
feature of the early stages of certain visual diseases (for example, glaucoma), so it is
important to know how the short-wavelength ("blue") cones contribute to visual
functions such as form, motion and colour perception. Such knowledge can help to
design better tests for diagnosis of visual disorders, and will improve our
understanding of the normal function of the visual system in the human brain. In this
project the connections of neurones in the primate retina (the nerve cells which line
the back of the eye) will be analysed. The blue cones and other nerve cells will be
identified using contemporary anatomical methods (double- and triple-label
immunocytochemistry) combined with a new method for high-resolution light
microscopy, called deconvolution microscopy. Immunocytochemistry is a method
borrowed from the field of immunology, where specific antibodies are raised which
bind selectively to "label" specific populations of neurones. Deconvolution
microscopy allows rapid and simultaneous visualisation of multiple labelled cell
classes, at a resolution close to the limit of the light microscope. Together, these
techniques allow the "wiring diagram" of the blue cones within the retina to be
analysed to a higher level of accuracy than previously achieved. The results will
improve our understanding of the role of blue-cone circuits in normal vision and
visual disorders.
Research achievements (from final report):
We used high-resolution microscopy and new labelling methods to reveal the
connection patterns of nerve pathways for red-green and blue-yellow colour vision in
the primate eye.
These findings have helped us to understand the basis of colour vision and the causes
of colour blindness.
Expected future outcomes:
N/A
Name of contact: Ulrike Grunert
Email of contact: uhg@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 566804
Start Year: 2009
CIA Name: A/Pr Marie Bogoyevitch
End Year: 2011
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding:
$480,127.00
Admin Inst: University of Melbourne
Grant Type: NHMRC Project
Grants
Title of research award:
c-Jun N-terminal Kinase Actions in the Response to Stress
Lay Description (from application):
All cells in our body sense and respond to stressful changes in our environment. We
are focused on enzymes called JNKs that relay this information, and so form part of
the key response pathways. JNKs are now being evaluated as new drug targets for the
treatment of diseases including diabetes and stroke, but we know very little about how
JNKs work in stressed cells. We will define new partners for the JNKs and in so
doing reveal new information on the stress-activated events they regulate.
Research achievements (from final report):
We have defined novel substrates for the stress-activated kinases known as the JNKs
using combined molecular biology and biochemistry approaches. These substrates
have now provided new insights into the functions that JNKs play, both in response to
stress, but in addition have revealed exciting new roles beyond the stress response.
Expected future outcomes:
Our results, showing novel JNK partners involved in critical aspects of cell biology,
will impact on current events to develop JNK inhibitors for therapeutic applications
such as diabetes, stroke and inflammatory bowel disorders.
Name of contact: Marie A Bogoyevitch
Email of contact: marieb@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 208940
CIA Name: Prof Mark Cooper
Main RFCD: Endocrinology
Admin Inst: University of Melbourne
Start Year: 2002
End Year: 2004
Total funding: $210,990.00
Grant Type: NHMRC Project
Grants
Title of research award:
Characterisation of Novel AGE Binding Proteins: Implications for Diabetic Vascular
Complications.
Lay Description (from application):
This project will explore a process known as advanced glycation and in particular
how this may lead to organ injury in diabetes. Diabetes is characterised by sustained
elevation of blood glucose levels which interact with proteins to generate products
known as advanced glycation end-products (AGEs). These AGEs bind to other
proteins some of which have been isolated and are considered receptors. Our own
group has identified a new family of proteins known as ERM proteins which bind to
AGEs. This is a highly novel finding which now needs to be examined in more detail.
The ERM proteins which include ezrin, radixin and moiesin are found at many sites
of diabetic complications including the kidney, retina and blood vessel wall. They
have a number of functions including effects on cell adhesion and cell structure. This
is important in diabetes where changes in cells including altered structure have been
observed. This grant will characterise the interactions between AGEs and ERM
proteins at the molecular and cellular level. It will define how AGEs influence cells
via interactions with ERM proteins. These studies have the potential to lead to
treatments that may modulate the AGE/ERM interactions, thereby retarding or
preventing diabetic vascular complications. These complications are of important
clinical significance since they are the major cause of morbidity and mortality in the
diabetic population. Furthermore, diabetes is a major cause of premature
atherosclerosis in our community, diabetic kidney disease is the leading cause of endstage renal failure in the Western world and diabetic retinopathy (eye disease) is the
main cause of blindness in the working age population.
Research achievements (from final report):
We have identified a novel interaction between proteins which have been chronically
modified by glucose and specific proteins known as the ERM proteins. Studies have
demonstrated that these ERM proteins may be excellent targets for developing drugs
that reduce diabetic complications. The experiments provide further evidence for this
possibility and strengthen the rationale for the strategy being developed as part of this
project.
Expected future outcomes:
Generation of novel inhibitors of the glycated protein/ERM interaction can now be
developed since the molecular basis for this interaction has been further clarified in
these experimental studies.
Name of contact: Leon Bach
Email of contact: leon.bach@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 400004
CIA Name: A/Pr Mary Wlodek
Main RFCD: Foetal Development and Medicine
Admin Inst: University of Melbourne
Start Year: 2006
End Year: 2008
Total funding: $438,521.00
Grant Type: NHMRC Project
Grants
Title of research award:
Perinatal and intergenerational influences on adult diabetes
Lay Description (from application):
The aim of this project is to determine the effects of restriction of nutrient supply
before and after birth on growth and the development of adult onset diabetes. Being
born small and its associated neonatal catch-up growth independently predict adult
diabetes. Placental restriction is a major cause of reduced nutrition and growth before
birth and is implicated in this "programming" of disease. Our novel findings suggest
that placental compromise increases appetite but also impairs milk quality and supply
which limits overfeeding and catch-up growth initially, but on weaning, may
independently lead to diabetes. We will determine if this is a direct result of poor
nutrition and made worse by overfeeding in response to restored nutrition. We
hypothesize that placental compromise permanently reduces an individual's metabolic
capacity and that the extent of availability of nutrition after birth determines the
consequences for insulin action and increased body fat. Manipulations of postnatal
nutrition (by cross-fostering) and fat oxidation will be performed, which are pivotal to
understanding the roles of catch-up growth and increased food intake in disease onset.
We have found that cross-fostering small rat pups at birth onto mothers with normal
lactation improves growth during lactation. The proposed studies will establish the
cross-fostering effect on the development of diabetes and identify a developmental
stage during which nutritional or other manipulations may have beneficial
consequences for the health of the breastfeeding small infant. We propose to
determine whether adult females, exposed to placental restriction as a fetus, produce
offspring that develop diabetes, and establish whether this effect is caused by
programming before conception and/or an altered fetal environment. Identification of
critical periods after birth, rather than before, would offer a greater likelihood that
practical public health interventions can be developed to improve adult health.
Research achievements (from final report):
We have demonstrated that being born small programs gender specific metabolic
dysfunction. Male rats are more adversely affected. We have characterised the
response to a glucose tolerance test, measured muscle mitochondiral biogenesis and
pancreatic Bcell mass and deficits in bone bending strength. Importantly we have
demonstrated that improved postnatal nutrition can prevent these programmed deficits
ameloriating disease outcomes.
Expected future outcomes:
We aim to characterise the effects of metabolic dysfunction in females on their
adaptation to pregnancy and the impact on intergenerational metabolic disease
transmission.
Name of contact: Assoc Prof Mary Wlodek
NHMRC Research Achievements - SUMMARY
Email of contact: m.wlodek@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 509008
CIA Name: A/Pr Barbara Coulson
Main RFCD: Medical Virology
Admin Inst: University of Melbourne
Start Year: 2008
End Year: 2010
Total funding: $413,775.00
Grant Type: NHMRC Project
Grants
Title of research award:
Modulation of type 1 diabetes development by rotavirus infection
Lay Description (from application):
Rotavirus is the main cause of severe diarrhoea in children, and may contribute to
progression to type 1 diabetes. We have now shown that rotavirus also modulates
diabetes in mice, by a novel mechanism. In this project, the mechanism of this process
will be elucidated and the capacity of human rotavirus to affect diabetes will be
determined. This study will help determine the design of further human studies, and
whether rotavirus vaccines also are possible modulators of diabetes development.
Research achievements (from final report):
In this project, extensive studies addressing the likely mechanisms behind rotavirus
modulation of type 1 diabetes were undertaken. Both rotavirus genes and host factors
were shown to be important. The data obtained have led to a much greater
understanding of how rotavirus infection in diabetes-prone mice can either delay or
accelerate diabetes onset, depending on the degree of pancreatic inflammation at the
time of rotavirus infection.
Expected future outcomes:
The improved understanding of the mechanisms involved in rotavirus modulation of
type 1 diabetes in mice will allow us to identify the particular rotavirus genes
involved, and the roles of regulatory T cells and B cells. These results will inform
future studies in children.
Name of contact: Barbara Coulson
Email of contact: barbarac@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 350485
CIA Name: Prof George Jerums
Main RFCD: Endocrinology
Admin Inst: University of Melbourne
Start Year: 2005
End Year: 2007
Total funding: $465,000.00
Grant Type: NHMRC Project
Grants
Title of research award:
Role of circulating advanced glycation end products (AGEs) in diabetic nephropathy:
Effect of benfotiamine intervention
Lay Description (from application):
Advanced glycation products (AGEs) are compounds formed by the addition of
sugars to amino acids (the building blocks of proteins). The addition of sugars to
proteins induces biological changes that have been implicated in the development of
diabetic complications, especially diabetic kidney disease. AGEs are a diverse group
of compounds and to date the exact role that specific AGEs play in the causation of
diabetic kidney disease is still unclear. However, new methods are now available that
allow the comprehensive quantification of individual AGE levels in blood. Our study
involves the comparison of AGE blood levels, as a group or as specific AGEs with
markers of diabetic kidney disease such as albumin (protein) excretion in the urine
and the rate that the kidney filters the blood to form urine (glomerular filtration rate).
Benfotiamine is a thiamine (vitamin B1) derivative that has been shown to decrease
the formation of AGEs and to prevent kidney disease in diabetic animals. The present
clinical study will assess whether benfotiamine has similar effects on AGEs and
kidney disease in patients with type 2 diabetes. If successful, this study has the
potential to provide a new treatment strategy for diabetic kidney disease in humans.
Research achievements (from final report):
The main focus of the grant was to examine the effects of a lipid soluble derivative of
thiamine (benfotiamine) on kidney function in people with type 2 diabetes and early
kidney disease. This was a multicentre study involving Austin Health, Royal Prince
Alfred Hospital and Royal North Shore Hospital. The study involved 86 participants
who were studied for 7 months. Due to slow recruitment, the study has just been
completed and the results are being analysed.
Expected future outcomes:
This is the first randomised, prospective, placebo controlled trial of the effects of
benfotiamine on early renal disease in patients with type 2 diabetes. It is expected
that effects of benfotiamine on albuminuria and glomerular filtration rate, as well as
on circulating markers of protein damage will be ready for publication in 2009.
Name of contact: Professor G Jerums
Email of contact: ah-endo@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 350424
Start Year: 2005
CIA Name: Dr Suzanne Rogers
End Year: 2007
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding:
$499,000.00
Admin Inst: University of Melbourne
Grant Type: NHMRC Project
Grants
Title of research award:
Cellular Mechanisms and Physiological Roles of GLUT12 Mediated Glucose
Transport in Glucose Homeostasis
Lay Description (from application):
Diabetes affects almost one million Australians, although only 50% are aware they
have the disease. Type 2 diabetes accounts for about 90% of diabetes and usually
occurs after the age of 40. As a leading cause of death, adult blindness, lower limb
amputation, kidney failure, stroke and heart attack, diabetes has huge economic and
social consequences and has been designated an Australian National Health priority.
A clinical feature of Type 2 diabetes is high blood glucose levels. This occurs
because insulin does not effectively stimulate the transfer of glucose from the blood
into muscle and fat. The reasons for this are not fully understood. Insulin normally
works to move glucose transporter (GLUT) proteins to the surface of muscle and fat
cells. One GLUT that has been studied extensively in muscle and fat is GLUT4.
GLUT4 moves to the cell surface in response to insulin and this response is one of the
defects that is known to occur in Type 2 diabetes. Glucose then accumulates in the
blood, leading to many of the complications of diabetes. We have discovered a novel
glucose transporter, GLUT12, that is also present in muscle and fat. We have shown
that GLUT12, like GLUT4, responds to insulin. GLUT12 could therefore be a critical
backup for GLUT4. We have also found that GLUT12 responds to glucose itself,
suggesting a unique role in controlling blood glucose levels. We will explore how
GLUT12 acts in muscle and fat cells to find whether GLUT12 can act as a backup for
GLUT4. We will also study GLUT12 in tissue from normal animals and in animals
with features of Type 2 diabetes. To determine the role of GLUT12 in maintaining
normal blood glucose levels, we will produce mice with an inactive GLUT12 gene.
Our research could identify novel ways of increasing GLUT12 activity. The eventual
goal will be to find a pharmaceutical compound that can improve glucose transport
into muscle, reduce high blood glucose levels and thus the complications of Type 2
diabetes.
Research achievements (from final report):
Diet related obesity is prevalent in modern society and is linked to increased
incidence of Type 2 diabetes. More than one million Australians have diabetes with
economic and social burden. A feature of the disease is high blood glucose levels.
We have discovered a novel protein that may provide the missing link between
nutrient overload, high blood glucose and development of Type 2 diabetes.
Understanding this link may provide novel strategies for prevention and treatment of
diabetes.
Expected future outcomes:
NHMRC Research Achievements - SUMMARY
Future investigations will aim to delineate a mechanism for insulin resistance that
may be a novel target for diabetic therapy .
Name of contact: Suzanne Rogers
Email of contact: s.rogers@medicine.unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 188826
CIA Name: Dr Adamandia Kriketos
Main RFCD: Endocrinology
Admin Inst: University of Melbourne
Start Year: 2002
End Year: 2009
Total funding: $425,000.00
Grant Type: Career
Development Fellowships
Title of research award:
Understanding the molecular mechanisms of the development of the Insulin
Resistance Syndrome - from the laboratory to th
Lay Description (from application):
Not Available
Research achievements (from final report):
This Career Development Award was beneficial to the postdoctoral career of Dr
Adamandia Kriketos. She was able to conduct clinical research in the area of type 2
diabetes. In particular, her work investigated the role of family history on the
development of insulin resistance and the risk of developing type 2 diabetes.
Following a relocation to Melbourne, Dr Kriketos was able to conduct clinical
research in the area of obesity (weight loss and weight regain) using the clinical
research skills she had acquired in the earlier stages of the CDA at the Garvan
Institute in Sydney.
Expected future outcomes:
Findings from this research are currently being further investigated in a NHMRC
Project Grant examining the roles of cytokines and hormones in weight regain
following weight loss.
Name of contact: Dr Adamandia Kriketos
Email of contact: a.kriketos@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 209026
CIA Name: Prof Mark Cooper
Main RFCD: Nephrology and Urology
Admin Inst: University of Melbourne
Start Year: 2002
End Year: 2004
Total funding: $361,650.00
Grant Type: NHMRC Project
Grants
Title of research award:
Role of vasoactive hormones and cytokines in diabetic nephropathy
Lay Description (from application):
Kidney disease is a major cause of disability and premature death in the Australian
population. In diabetic kidney disease a major factor which accelerates the
progression of this disorder is the presence of hypertension. Indeed international and
national organisations now recommend aggressive blood pressure treatment in the
diabetic patient. This proposal aims to optimise blood pressure treatment in diabetes
and evaluate novel more potent blood pressure lowering agents which block within
the kidney important hormonal pathways implicated in diabetic kidney disease. This
approach will assist in determining key factors which mediate the damage to the
kidney induced by elevated blood pressure. It is anticipated that these studies will
lead to more rational, targeted and powerful antihypertensive agents which will retard
or prevent the development of diabetic nephropathy.
Research achievements (from final report):
This study has identified new strategies to reduce diabetic complications, specifically
renal disease. We used various combination drugs which influence multiple hormone
systems within the kidney and showed that these newre agents were more effective
than conventional treatments which block only one hormone pathway. Furthermore,
we identified new hormone pathways which appeared to be altered in the diabetic
kidney and provide new targets for better treatments to prevent, reverse and rertard
diabetic kidney disease which is now the leading cause of kidney failure in the
Western world.
Expected future outcomes:
These new treatments will be tested in the clinic. Furthermore, the new targets
identified such as ACE2 will be further explored and potentially this could lead to
new drugs for diabetic kidney disease.
Name of contact: Prof Mark Cooper
Email of contact: mark.cooper@baker.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 400458
CIA Name: Dr Sumone Chakravarti
Main RFCD: Autoimmunity
Admin Inst: University of Melbourne
Start Year: 2007
End Year: 2009
Total funding: $190,537.00
Grant Type: Early Career
Fellowships (Australia)
Title of research award:
Differential regulation of autoimmunity by NKT cell subsets.
Lay Description (from application):
Not Available
Research achievements (from final report):
Natural Killer T cells are cells capable of modulating the immune response in various
disease states including autoimmunity. We have shown that these cells can be
separated into groups that produce a specific array of soluble mediators, such that
some of these cells are beneficial is ameliorating disease while others could
exacerbate disease. This work suggests that harnassing the potential of particular subgroups of natural killer cells will be of greatest value in addressing therapeutic
options. Additionally, we demonstrated the the cytokine IL-21 was not essential in the
pathogenesis of EAE, the mouse model for Multiple Sclerosis.
Expected future outcomes:
In the near future we expect to have greater understanding of the role of individual
subsets in disease. We also will have a greater understanding of the role of IL-21 from
natural killer T cells in autimmunity, including EAE.
Name of contact: Sumone Chakravarti
Email of contact: sumonec@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 251657
CIA Name: Prof Paul Gleeson
Main RFCD: Autoimmunity
Admin Inst: University of Melbourne
Start Year: 2003
End Year: 2005
Total funding: $441,000.00
Grant Type: NHMRC Project
Grants
Title of research award:
Investigating T cell tolerance and organ-specific auotimmunity using autoantigen
deficient mice
Lay Description (from application):
The immune system normally protects against invasion by pathogens such as harmful
viruses and bacteria. In autoimmune diseases the same mechanisms that are used to
protect us are erroneously targeted to our own tissues. Our studies will employ
technologies to genetically manipulate mice to further our knowledge of this class of
disease and to uncover the normal mechanisms that allow the immune system to
prevent autoimmune attack. In particular we will gain information on the way that a
new class of lymphocytes, known as regulatory lymphocytes, are able to protect
against autoimmune disease. Such regulatory lymphocytes have been identified in
humans and are attractive therapeutic agents to prevent a variety of immune-mediated
diseases, including autoimmune diseases, allergy and transplantation rejection.
Research achievements (from final report):
The immune system normally protects against invasion by pathogens such as harmful
viruses and bacteria. In autoimmune diseases the same mechanisms that are used to
protect us are erroneously targeted to our own tissues. We have used a highly defined
mouse model of an autoimmune disease of the stomach to understand the normal
mechanisms that protect us from autoimmune disease and the conditions that allow
the immune cells to cause tissue destruction. Our work has demonstrated that
potentially pathogenic lymphocytes exist in the body of healthy individuals and
factors such as infection can turn-on these otherwise silent pathogenic lymphocytes.
Expected future outcomes:
Our future work is now aimed at selectively silencing the disease causing
lymphocytes. The outcome of these studies will provide strategies to "turn-off"
harmful lymphocytes and reverse the disease process in a range of autoimmune
diseases, such as diabetes and pernicious anaemia.
Name of contact: Paul Gleeson
Email of contact: pgleeson@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 219170
CIA Name: Prof Richard Gilbert
Main RFCD: Cellular Immunology
Admin Inst: University of Melbourne
Start Year: 2002
End Year: 2006
Total funding: $4,715,000.00
Grant Type: International
Collaborations
Title of research award:
Novel strategies for the early identification provention and treatment of the
microvascular complications of diabetes
Lay Description (from application):
Despite recent advances, approximately one third of subjects with type 1 diabetes
develop kidney disease and similar proportion develop vision-threatening eye disease.
Indeed, in many instances eye and kidney disease occur in the same individual. The
central aim of this proposed Special Program is the exploration of mechanisms that
lead to the development and progression of these devastating complications of type 1
diabetes with a particular focus on novel strategies, directly applicable to man, for
their prevention and treatment. Participants in Special Program include both
established diabetes researchers and investigators from other areas of academia (blood
vessel biology and applied genetics). Strong interrelationships between the various
investigators and their departments already exist and will be further consolidated with
continued collaboration, sharing a combination of models, novel interventions and
complex genetic techniques that would not be possible outside of a large collaborative
framework. In addition to academic collaboration, interactions with industry-based
drug discovery programs is also an important component in developing new treatment
strategies for diabetic kidney and eye disease. The Special Program will thus consist
of a range of studies of direct relevance to diabetic kidney and diabetic eye disease in
humans. It is expected that these studies will lead to new strategies for the
prevention, treatment and even the reversal of long term complications of diabetes.
Research achievements (from final report):
We have been exploring new approaches to the treatment of the longterm
complications of diabetes. To do this we needed an animal model that closely
resembles humans with regard to the development of diabetes complications. Having
established such a model, then set about developing new therapies for their treatment.
During the period of this grant we have had some major successes with new drug and
stem cell-based treatments that we have shown reduce the development and
progression of the complications of diabetes. A small human trial exploring the
effects of stem cell treatment has been completed and we are well undreway to test
our new drug treatments also.
Expected future outcomes:
We have continued to develop our discoveries and anticipate having a new therapy
ready to be tested for the treatment of diabetic kidney disease in humans sometime in
the next 2-3 years.
Name of contact: Prof. Richard Gilbert
Email of contact: richard.gilbert@utoronto.ca
NHMRC Research Achievements - SUMMARY
Grant ID: 300004
CIA Name: Prof Judy Savige
Main RFCD: Nephrology and Urology
Admin Inst: University of Melbourne
Start Year: 2004
End Year: 2006
Total funding: $253,500.00
Grant Type: NHMRC Project
Grants
Title of research award:
The risks of Thin basement membrane nephropathy (TBMN)
Lay Description (from application):
Our aims are to save the $10 million spent on inappropriate investigations in TBMN
each year by the Australian community; to identify and treat individuals with TBMN
at risk of renal impairment in order to delay the onset of kidney failure; to understand
the underlying disease mechanisms in order to develop specific treatments; and to
contribute to the development of a diagnostic assay for TBMN that flags mutations
associated with renal impairment and includes a screening test for modifying genes.
The proposed project will: 1. change the practice of clinicians by providing
evidence for our clinical definition of TBMN and reduce the need for renal biopsies
and other investigations thus saving the Australian community up to $10 million
annually; 2. demonstrate that a peripheral retinopathy distinguishes between TBMN
and X-linked Alport syndrome. This will be a major advance in the diagnosis of
Alport syndrome too determine how often individuals with persistent haematuria who
have proteinuria >500 mg/day or renal impairment actually have TBMN. Identify the
genetic risk factors for renal impairment in TBMN in both the genes directly
responsible for TBMN as well as in the modifying genes. 3. determine the
mechanisms by which genetic mutations and modifying genes in TBMN cause
disease and predispose to renal impairment. Understanding these mechanisms is the
first step in the development of specific treatments.
Research achievements (from final report):
At least 1% of the population has persistent haematuria, and this is due to Thin
basement membrane nephropathy (TBMN) and less often to X-linked Alport
syndrome. TBMN is usually a benign condition but 7% hospital-based patients go on
to develop renal failure. These studies investigated why some patients develop renal
impairment. They helped develop a novel diagnostic assay for TBMN (and for Xlinked Alport syndrome), confirmed a simple eye test distinguished between these
conditions, demonstrated further novel causative mutations in TBMN, identified an
independent genetic mutation that contributed to renal impairment, and described a
novel canine model for TBMN.
Expected future outcomes:
We will make our diagnostic assays for TBMN and Alport syndrome generally
available, and will examine how the underlying mutations result in disease at the
molecular level. Understading how mutations cause disease is the first step in
developing specific treatments.
Name of contact: Prof Judy Savige
Email of contact: jasavige@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 350448
CIA Name: Prof Tien Wong
Main RFCD: Endocrinology
Admin Inst: University of Melbourne
Start Year: 2005
End Year: 2007
Total funding: $212,500.00
Grant Type: NHMRC Project
Grants
Title of research award:
Early Retinal Vessel Changes In Diabetes and the Metabolic Syndrome
Lay Description (from application):
Diabetes mellitus affects a large proportion of adult Australians. Furthermore, many
non-diabetic Australians are at high risk of developing diabetes (e.g., people with
lesser glucose abnormalities, and those who are obese, have high blood pressure, or
have high lipid levels). It has been suggested that diseases affecting small blood
vessels (microvascular disease) in the body is closely related to the development of
both diabetes and the "pre-diabetes" state. The current study will examine the
relationship of microvascular disease in the retina (at the back of the eye) to diabetes,
pre-diabetes status and diabetes complications. We will use a computer-imaging
technique to measure the diameters of retinal blood vessel from digital photographs
taken in 2,177 participants of the 1999-2000 Australian Diabetes, Obesity and
Lifestyle (AusDiab) Study, a community-based survey of people aged 25 years and
older examining risk factors and complications of diabetes. In the proposed study, we
aim to answer the following questions: 1) Are changes in the retinal blood vessel
diameter (e.g., narrowed or dilated vessels) associated with diabetes and pre-diabetes?
2) Are these retinal vessel changes related to obesity, high blood pressure and high
lipid levels? 3) Are retinal vessel changes related to diabetes complications, such as
heart disease, kidney disease, nerve problems and foot ulcers? 4) Do retinal vessel
diameter changes predict people who will subsequently develop diabetes, irrespective
of their risk factor profile? Using this well-characterized population, and existing
digital retinal photographs, the proposed study will offer a unique and cost-effective
opportunity to address important gaps in our understanding of how diabetes and "prediabetes" develop, and whether they are related to microvascular diseases. This may
ultimately lead to new treatment and preventive approaches targeted at the small
blood vessels in the body.
Research achievements (from final report):
We have shown that retinal arterioles are wider in those persons with diabetes than
those without, while retinal venules are wider in those persons with diabetes and
retinopathy than those with diabetes but without retinopathy. Persons with diabetes
who have wider retinal arterioles also have a higher risk of developing diabetic
retinopathy, suggesting retinal arteriolar dilation is a specific sign of diabetic
microvascular dysfunction and may be a preclinical marker of diabetic retinopathy.
Persons who do not have diabetes, but have narrower retinal arterioles have a higher
risk of diabetes, providing further evidence that microvascular changes may
contribute to the pathogenesis of diabetes.
Expected future outcomes:
NHMRC Research Achievements - SUMMARY
Retinal vascular imaging may be used to stratify a persons risk for diabetes (in those
without diabetes), and diabetic complications, in particular diabetic retinopathy, in
those with diabetes.
Name of contact: Tien Wong
Email of contact: twong@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 454363
CIA Name: Dr Stuart Berzins
Main RFCD: Cellular Immunology
Admin Inst: University of Melbourne
Start Year: 2007
End Year: 2009
Total funding: $533,828.00
Grant Type: NHMRC Project
Grants
Title of research award:
Development and function of NKT cell subsets in humans
Lay Description (from application):
NKT cells are a type of white blood cell that help to control the function of the
immune system. Many studies have reported an association between low NKT cell
levels and increased rates of cancer and autoimmune diseases such as type 1 diabetes
(T1D). Unfortunately, NKT cells are a relatively recent discovery and their function is
not well understood, especially in humans. For example, it has only recently been
discovered that there are different types of NKT cells with different functions. This
lack of knowledge has prevented us from understanding how NKT cells normally
prevent disease, and how we should treat diseases associated with low NKT cell
numbers. In this project, we will study human NKT cells to determine how many
different subsets exist, how they develop, and what role they play in the immune
system. Importantly, we will use our knowledge to compare NKT cells from healthy
donors and patient groups with T1D and cancer to determine exactly what is wrong
with the NKT cells in these people. While both diseases are already linked to low
NKT cell numbers, we do not know how these problems arise, or if some types of
NKT cells are more important than others. Our study will determine how different
types of NKT cells develop and function in humans and therefore allow a much more
detailed understandng of how to diagnose and treat NKT cell deficiencies associated
with different diseases.
Research achievements (from final report):
This grant was used to investigate the development and function of specialised
immune cells that are belvied to be important for regulating immune responses in
humans. We sucessfully investigated these cells in the context of health and diseases,
including in patient groups with different forms of cancer or autoimmunity. We
published a number of important primary research articles from our research,
including papers examing the heterogeneity of NKT cells in healthy individuals and
an investigation of NKT cells in the human diease myleodysplasitc syndromes
(MDS). The significacne of our work is evidenced by the invitations I recived to write
review articles and ad commentaries for leading journals.
Expected future outcomes:
Collaborations that were establishedin support of this research re still intact and we
expect to publish more papers from this work..
Name of contact: Stuart Berzins
Email of contact: sberzins@ballarat.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 520695
CIA Name: Dr Siew Yeen Chai
Main RFCD: Clinical Pharmacology and Therapeutics
Admin Inst: University of Melbourne
Start Year: 2008
End Year: 2010
Total funding: $369,899.00
Grant Type: NHMRC
Development Grants
Title of research award:
Development of small molecule IRAP inhibitors for treating memory deficits
Lay Description (from application):
We have identified a series of small molecule compounds based on their ability to
inhibit the catalytic activity of a protein, IRAP using a computer model of IRAP to
screen chemical libraries. This research proposal aims to investigate the properties of
these compounds and their ability to treat Alzheimer's dementia. At the conclusion of
this project, we will have 2 families of "lead" compounds suitable for development
into a new class of therapeutic agents for treating Alzheimer's disease.
Research achievements (from final report):
IRAP inhibitors were initially developed for the symptomatic treatment of
Alzheimer's disease (AD) based on earlier reports that peptides that inhibit IRAP
activity significantly facilitate memory in rat deficit models. However, we have
recent exciting data that chronic delivery of HFI419 markedly decreased amyloid
plaque accumulation, a pathological hallmark of AD, in a mouse model of the disease.
This early data is consistent with a role for IRAP inhibitors in AD modification,
alleviating and/or preventing disease progression as well as treating the cognitive
symptoms. We are currently investigating the disease-modifying effects of HFI419 in
two mouse models (familial and late onset) of the disease.
Expected future outcomes:
We hope to obtain important proof-of-concept that IRAP inhibitors are strong
candidates to be developed into a clinically effective treatment for AD based on their
effects in treating the memory symptoms as well as arresting the progression of the
disease.
Name of contact: Siew Yeen Chai
Email of contact: sychai@florey.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 566960
CIA Name: Prof Joseph Proietto
Main RFCD: Endocrinology
Admin Inst: University of Melbourne
Start Year: 2009
End Year: 2011
Total funding: $332,798.00
Grant Type: NHMRC Project
Grants
Title of research award:
Investigating the origin of obesity-induced dyslipidaemia
Lay Description (from application):
This project will investigate a possible mechanism to explain why it is that obese and
diabetic individuals often have a typical type of abnormal fats in the blood
particularly elevated triglycerides. If this theory is confirmed it may lead to new
targets for improving abnormal lipids in these conditions.
Research achievements (from final report):
Ischaemic heart disease, stroke and peripheral vascular disease continue to be major
causes of morbidity and mortality. There are multiple risk factors for the development
of vascular disease. Of these, obesity, insulin resistance and abnormal lipids are three
powerful and potentially modifiable risk factors. All three are common and evidence
suggests that they are interrelated. This study investigated a possible mechanism to
explain how these cardiovascular risk factors are interrelated. First we showed that
weight loss corrected the abnormal lipid profile in our model. We demonstrated that a
possible link between obesity and abnormal lipids is the presence of a low grade
inflammatory state caused by insulin resistance.
Expected future outcomes:
The confirmation that a selective defect in insulin signalling can cause a key feature
of the metabolic syndrome, (dyslipidaemia) may lead to the development of possible
new therapeutics followed by intervention studies to improve lipid profile in those in
whom weight loss is not possible or fails.
Name of contact: Prof Joe Proietto
Email of contact: j.proietto@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 299862
CIA Name: A/Pr Barbara Coulson
Main RFCD: Medical Virology
Admin Inst: University of Melbourne
Start Year: 2004
End Year: 2006
Total funding: $348,875.00
Grant Type: NHMRC Project
Grants
Title of research award:
Analysis of the role of rotavirus infection in development of type 1 diabetes
Lay Description (from application):
Our earlier studies in children with a family history of type 1 diabetes have shown
that infection with a common virus, rotavirus, may be one factor contributing to their
progression to diabetes. Rotavirus is the most common cause of diarrhoea, vomiting
and dehydration in young children, and it was thought that rotavirus infection is
usually confined to the intestine. To understand how rotavirus infection might
promote diabetes, my group has developed a mouse model. Using mice for these
studies allows us to control infection and completely analyse the results of infection,
which we cannot do in humans. A type of mouse that is very likely to develop type 1
diabetes in its first 6 months of life is infected by mouth with rotavirus. We have
shown that these mice develop diabetes 7 weeks faster than the same type of mice that
are not given virus. In this project, we will determine the effects of mouse age, virus
strain, the number of times infection occurs, and levels of virus growth in the intestine
or pancreas on virus-induced diabetes acceleration. The ability of treatments for
rotavirus infection, and vaccination against rotavirus, to block this accelerated
diabetes also will be tested. We expect that rotavirus will be found growing in the
pancreas, that virus growth is necessary for diabetes acceleration, and that prevention
of rotavirus infection will also prevent the rapid diabetes onset. This model could
prove to be suitable for testing the effectiveness and safety of new drugs and vaccines
against both rotavirus and type 1 diabetes. Our studies will be crucial in determining
the importance of rotavirus infection in the development of type 1 diabetes.
Research achievements (from final report):
Rotaviruses are the main case of severe diarrhoea in infants and young children. Live
rotavirus vaccines have been introduced into Australia in 2007. This research award
led to the discovery that rotavirus infection modulates type 1 diabetes in mice. These
mice are the best available models for human disease. Rotavirus infection of infant or
young adult mice was protective against diabetes development. However, infection of
older adult mice with pre-existing pancreatic damage produced diabetes acceleration.
This latter result is in line with previous studies in genetically at-risk children. These
mouse studies suggest that any effect of rotavirus infection on diabetes development
in at-risk children might depend on the timing of the infection.
Expected future outcomes:
Further use of the mouse models developed using this research award will facilitate
elucidation of the mechanisms behind rotavirus modulation of type 1 diabetes. The
ability of human rotaviruses and vaccine viruses to modulate diabetes also can now be
tested.
Name of contact: Barbara Coulson
NHMRC Research Achievements - SUMMARY
Email of contact: barbarac@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 566911
CIA Name: Prof Gregory Dusting
Main RFCD: Basic Pharmacology
Admin Inst: University of Melbourne
Start Year: 2009
End Year: 2011
Total funding: $581,989.00
Grant Type: NHMRC Project
Grants
Title of research award:
NADPH oxidase in pathological angiogenesis in solid tumours and retina
Lay Description (from application):
Understanding blood vessel growth has profound clinical implications for many
diseases. Blocking vessel growth is a promising strategy for treatment of cancer and
eye complications accompanying diabetes, whereas treatments to stimulate new vessel
growth will treat ischemic disorders ie. heart attack and stroke. Here we investigate
whether targeting an enzyme that grows blood vessels has potential for making drugs
to stop tumor growth or eye damage that occurs with diabetes and premature births.
Research achievements (from final report):
The excessive and erratic growth of blood vessels in the retina of the eye can become
leaky, and this severely compromises vision. Because of this, diabetes and macula
degeneration are two of the major and growing causes of blindness in the community,
especially in the elderly. In addition, the growth of solid tumours is critically
dependent upon the development of new blood vessels to feed the cancer tissue. We
sought to understand some of the important genes involved in how cells reproduce to
grow new blood vessels in these diseases. We found a critical gene known as Nox4 is
involved in this cell signaling. We also showed that blocking this gene with new
drugs or gene therapy could slow the growth of tumours and stop excessive blood
vessel proliferation in the eye, which otherwise leads to loss of vision.
Expected future outcomes:
Developing new drugs targeting this Nox enzyme might provide better treatments for
these growing causes of blindness associated with ageing and diabetes, and also
become useful teatments for some cancers, together with cytotoxic drugs.
Name of contact: Prof. Gregory J. Dusting
Email of contact: g.dusting@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 454708
CIA Name: Dr Sofianos Andrikopoulos
Main RFCD: Endocrinology
Admin Inst: University of Melbourne
Start Year: 2007
End Year: 2009
Total funding: $350,060.00
Grant Type: NHMRC Project
Grants
Title of research award:
The role of FBPase in beta cell dysfunction
Lay Description (from application):
Type 2 diabetes is caused by multiple genetic defects, resulting in high blood sugar
levels. These high sugar levels are primarily due to a decrease in the concentration of
insulin, a hormone produced by the pancreas. A number of recent studies have aimed
to identify which genes are regulated under conditions that mimic diabetes. One gene
shown to have altered expression levels under these conditions is an enzyme called
fructose-1,6-bisphosphatase (or FBPase). This enzyme is involved in the metabolism
of sugar and is usually expressed at undetectable levels in the pancreas, but when
blood sugar levels are high, the amount of FBPase in the pancreas increases
considerably. We hypothesise that this increase in FBPase may contribute to the
decrease in insulin secretion by the pancreas, seen in the diabetic state. The aim of
this proposal therefore is to study mice that we have modified to express increased
FBPase specifically in the pancreas, in order to determine whether this will lead to a
decrease in insulin release and to diabetes. If this is the case, then FBPase could be
targeted for the development of drugs that would improve the control of blood sugar
levels in diabetes.
Research achievements (from final report):
Type 2 diabetes is characterised by high blood sugar levels because the pancreas fails
to make and release enough of the hormone insulin. So that we can understand what
causes this reduction in insulin release we and others have investigated the genes that
are altered in Type 2 diabetes. One of these genes is called fructose-1,6bisphosphatase or FBPase. By using technology that manipulates the levels of
FBPase specifically in the pancreas we were able to show that this gene significantly
impacts on rate of insulin secretion. Importantly we have found that under conditions
that mimic the diabetic state, FBPase was able to protect the pancreatic cells such that
the amount of insulin released was enhanced and the control of blood sugar was
enhanced. Our data have identified FBPase as a possible target for better therapeutic
treatment for the treatment of diabetes.
Expected future outcomes:
We have shown that the gene FBPase may be a target to improve insulin secretion in
Type 2 diabetes which will lead to lower blood sugar levels and therefore a decrease
in the incidence of heart attacks and stroke.
Name of contact: Sof Andrikopoulos
Email of contact: sof@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 208950
CIA Name: Dr Erica Fletcher
Main RFCD: Sensory Systems
Admin Inst: University of Melbourne
Start Year: 2002
End Year: 2004
Total funding: $211,320.00
Grant Type: NHMRC Project
Grants
Title of research award:
TRAFFICKING OF METABOLITES BETWEEN M LLER CELLS AND
NEURONS IN DIABETIC RETINOPATHY.
Lay Description (from application):
Diabetes is the leading cause of blindness in the working population. In some
diabetics, blood vessels within the retina proliferate, haemorrhage or cause retinal
detachment. The underlying changes within the retina that lead to the proliferation of
blood vessels are not well understood. One of the factors that leads to changes in
retinal blood vessels is an incease in growth factors from cells in the retina called
Muller cells. Muller cells are vital for the normal function of the retina, and are
known to be abnromal late in diabetes. They may also be dysfunctional early in
diabetes and could play a significant role in the early chnages seen in diabetes.
Therefore a good understanding of how Muller cells change and the time at which
they change is vitally important to gain a better undetrstanding of the defects that are
associated with diabetes. Furthermore, an understanding of the basic underlying
cellular changes that occur in diabetes will aid the development of more specific
therapeutic agents in the future.
Research achievements (from final report):
The aim of this study was to characterize the role that supporting cells within the
retina, called Muller cells, play in diabetic retinopathy. We examined the changes in
retinal function, turnover of neurotransmitter within Muller cells and their metabolic
coupling in an animal model of Type I diabetes. We found that the neurons within the
retina become abnormal before the first sign of vascular change and that the turnover
of the neurotransmitter, glutamate, by Muller cells is abnormal. Abnormalities in
metabolic coupling, tested by examining the trafficking of lactate between Muller
cells and neurons was not seen. These findings are important because they suggest
that there are changes within the retina well b efore the onset of vascular disease. If
these are explored further, this may lead to better ways of detecting those at risk of
developing diabetic retinopathy.
Expected future outcomes:
We are continuing to explore the role of Muller cells in animal models of Type I
diabetes. In particular we will continue to explore why neurons and Muller cells are
abnormal before the first vascular abnormalities develop.
Name of contact: Erica Fletcher
Email of contact: elf@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 566815
CIA Name: A/Pr Erica Fletcher
Main RFCD: Sensory Systems
Admin Inst: University of Melbourne
Start Year: 2009
End Year: 2011
Total funding: $311,568.00
Grant Type: NHMRC Project
Grants
Title of research award:
The significance of glial dysfunction in retinopathy of prematurity
Lay Description (from application):
Abnormalities in cells at the back of the eye called photoreceptors are associated with
at least 50% of all cases of blindness in this country.This project will determine
whether substances released from dying photoreceptors cause the death of
neighbouring cells. In addition we will examine whether treatments that block the
actions of these released substances can prevent the death of photoreceptors, thereby
providing a novel therapeutic agent for the treatment of devastating eye diseases.
Research achievements (from final report):
Retinopathy of Prematurity is a leading cause of childhood blindness in those born
prematurely. This project aimed to (1) examine the role that supporting cells called
glia play in causing abnormal blood vessel growth in the retin and (2) evaluate
whether a class of drugs known as angiotensin receptor blockers (ARB) could
prevent glial, vascular and neuronal changes in the retina. We found that glial cells
and particular classes of neurons are lost in an animal model of ROP. In addition we
found that ARBs prevented the abnormal growth of blood vessels, but did not prevent
neuronal or glial loss. These results are important for two reasons. First the
information has helped us understand how vision loss occurs in ROP. Secondly, for
improved treatment of those with ROP we need to develop a drug that prevents the
pathological growth of blood vessels, but at the same time promotes normal
development of the retina.
Expected future outcomes:
We will continue to evaluate the role that glia play in retinal vascular diseases like
ROP and diabetic retinopathy.
Name of contact: Erica Fletcher
Email of contact: elf@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 400238
CIA Name: Dr Kenneth Knight
Main RFCD: Surgery
Admin Inst: University of Melbourne
Start Year: 2006
End Year: 2008
Total funding: $451,651.00
Grant Type: NHMRC Project
Grants
Title of research award:
Optimising islet transplantation with vascularized tissue engineering chambers
Lay Description (from application):
Diabetics have high blood sugar levels because cells in the pancreas known as "islets"
produce too little of the hormone insulin. Most diabetics need daily insulin injections
to maintain normal blood sugar levels. Transplanting islets is the most promising way
to treat type 1 diabetes, but, apart from the obvious difficulty of rejection of "foreign"
islets, several major problems remain: (1) there are insufficient pancreata (and
therefore islets) for transplantation; and (2) the efficiency of delivery of surviving islet
transplants is too low. In pilot studies we have grown a new living "pancreatic organ"
in mice by inserting islets from genetically-related mice together with a structural
protein matrix, growth factors and blood vessels inside a plastic chamber. The blood
vessels maintain nutrition to the islet cells and simultaneously allow insulin to be
released into the bloodstream, thus normalising the high blood sugar in diabetics. In
Aim 1 of these experiments we will find the optimal way to grow mature islets in
blood vessel-containing chambers in diabetic mice, focusing on (a) the best time to
add islets to the chamber - 0, 1 or 2 weeks after establishment, (b) the minimum
number of islets to effectively normalise blood sugar and (c) how long we can keep
islets alive and functional in chambers, examining periods up to 12 months. In Aim 2
we will test the ability of islet "stem cells" (provided by our co-investigators at Walter
& Eliza Hall Institute, Melbourne) to survive in the chambers and to produce
sufficient insulin to effectively lower blood sugar levels to normal in diabetic mice. In
Aim 3 we will grow human islets in chambers in special diabetic mice that do not
reject "foreign" tissue, in order to confirm similar behaviour of human islets in this
controlled environment. Using this data, we hope to create a research model of
functioning islets, that is accessible, retrievable and manipulable, for the further study
of diabetes and transplantation.
Research achievements (from final report):
Our research has led to the development of potentially new methods for islet
transplantation for the control of diabetes:
1. We have shown that a 21 day period of blood vessel growth in our chamber model
prior to the transplantation of islets results in an improved islet graft survival and
function in diabetic mice for up to 9 months.
2. We have also shown by using a modified version of the chamber model that is
based on the femoral artery and vein, that transplanted islets seeded into a gelatin
sponge and supplemented with nerve growth factor have improved survival and
function.
3. Our chamber model can be used to differentiate putative pancreatic adult precursor
cells into cells secreting insulin, glucagon and somatostatin.
NHMRC Research Achievements - SUMMARY
Our models allow for futher study into pancreatic islet/adult precursor cell
transplantation, to characterise the effect of treatments and to futher optimise these
methods as potential methods of islet transplantation in the clinic.
Expected future outcomes:
We have developed a model that can be used to further study diabetes and islet or
pancreatic stem cell transplantation. In particular this islet/stem cell model can be
retrieved to further characterize the impact of treatments.
Name of contact: Ass. Prof. Anthony Penington
Email of contact: a.penington@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 568850
CIA Name: A/Pr James Brock
Main RFCD: Autonomic Nervous System
Admin Inst: University of Melbourne
Start Year: 2009
End Year: 2011
Total funding: $390,886.00
Grant Type: NHMRC Project
Grants
Title of research award:
Do postjunctional alterations explain the effects of diabetes on neurovascular
transmission?
Lay Description (from application):
Diabetes produces disordered skin blood flow that increases risk of skin ulcers and
gangrene. The project investigates nervous control of skin blood vessels in diabetes. It
is assumed that all affects of diabetes on nerve function are explained by loss of
nerves. We hypothesize that some affects of diabetes are due to dysfunction of blood
vessels and not to nerve loss. The objective is to identify drug targets to improve
blood flow in skin and thereby reduce the risk of skin ulcers and gangrene.
Research achievements (from final report):
The primary achievement of this study is the establishment of an animal model for
investigating the effects of diabetes on the nerves (sympathetic nerves) that control
blood vessels. Specifically the project has identified that diabetes produces changes in
the structure and chemistry of sympathetic nerve terminals in a small artery that
supplies blood to skin. While it is widely believed that diabetes can damage
sympathetic nerves, to our knowledge this is the first study to directly demonstrate
that diabetes affects sympathetic nerves supplying arterial blood vessels. Importantly,
these changes were seen in an artey supplying blood to skin where diabetes is known
to impair nerve-mediated control of blood flow. The effects of diabetes on
sympathetic nerves controlling arteries that supply blood to the intestine were also
investigated but these were not affected by diabetes. The new model will provide
opportunities to test drugs that prevent or reverse diabetes-induced nerve damage.
Expected future outcomes:
The viability of this model for testing neuroprotective agents needs to be further
assessed. Ideally we would like to do this with Industry support and will investigating
this possibility in the near future.
Name of contact: James Brock
Email of contact: j.brock@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 400269
CIA Name: Dr Sofianos Andrikopoulos
Main RFCD: Endocrinology
Admin Inst: University of Melbourne
Start Year: 2006
End Year: 2008
Total funding: $430,321.00
Grant Type: NHMRC Project
Grants
Title of research award:
Identification and characterisation of a gene causing insulin hypersecretion in a mouse
model of diabetes susceptibility
Lay Description (from application):
Diabetes is a disorder primarily characterised by the inability to produce and secrete
the pancreatic hormone insulin, which regulates plasma sugar levels. This results in
increased sugar levels which cause diabetic complications such as retinopathy and
nephropathy. The inability to produce and secrete insulin is due to both defects in
function as well as a reduction in pancreatic beta cells. Paradoxically it has been
shown that some patients who are at risk of develping diabetes actually secrete more
insulin than normal. Furthermore it has been suggested that this increase in insulin
secretion actually may be associated with the decreased production and secretion of
insulin characteristic of diabetes. The DBA/2 mouse is a model of reduced insulin
production and secretion when exposed to high sugar levels or diabetes. However we
have shown that in the normal non-stressed state DBA/2 mice actually secrete more
insulin than normal and that this occurs from a very early age, suggesting that this
trait is inherited. We have subsequently performed genetic studies and have identified
a segment of DNA containing 10 genes associated with increased insulin secretion in
DBA/2 mice. The level of one of these genes we have called Hip1 is increased 5-fold
in DBA/2 mice, providing a candidate gene for increased insulin secretion in this
model of diabetes susceptibility. However, whether Hip1 is also responsible for
reduced insulin production and secretion in the DBA/2 mouse is not known.
Therefore the overall hypothesis of this project is that the gene Hip1 which is
associated with increased insulin secretion is also responsible for reduced insulin
production and secretion when DBA/2 mice are exposed to high sugar or obesity.
Determining why Hip1 is increased and whether it results in diabetes in DBA/2 mice
may provide a reasonable candidate for the development of therapeutic interventions
which may prevent the progression of diabetes in some patients.
Research achievements (from final report):
Type 2 diabetes is characterised by an increase in blood sugar levels that is
contributed to by the inability of the pancreas to secrete enough of a hormone that
clears sugar called insulin. We have found that under certain circumstances
individuals that secrete too much insulin may in fact be prone to developing diabetes.
Using mouse models with susceptibility to diabetes, we showed that an increase in
insulin secretion is associated with a defect in a gene of metabolism called
nicotinamide nucleotide transgydrogenase (Nnt). Our work showed that an increase
in levels of this gene were associated with increased insulin release in mouse models
with a higher susceptibility to developing diabetes. This work has clinical
implications as it suggests that an increase in insulin secretion may be detrimental.
The clinical implication of this work is that strategies that reduce the workload of the
NHMRC Research Achievements - SUMMARY
pancreas in obesity and diabetes may spare the insulin producing cells and delay
disease onset.
Expected future outcomes:
We expect to find the cause of the increase in Nnt expression levels and to provide
better therapeutic outcomes for patients with type 2 diabetes.
Name of contact: Sof Andrikopoulos
Email of contact: sof@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 509300
CIA Name: A/Pr Sofianos Andrikopoulos
Main RFCD: Endocrinology
Admin Inst: University of Melbourne
Start Year: 2008
End Year: 2011
Total funding: $711,224.00
Grant Type: NHMRC Project
Grants
Title of research award:
Understanding the cause and consequence of impaired insulin secretion in the NZO
mouse a model of diabetes.
Lay Description (from application):
Type 2 diabetes is a major health problem affeting over 1 million Australians. A key
feature of this disease is reduced secretion of the pancreratic hormone insulin which
results in high blood sugar levels. We are using a naturally occurring animal model of
diates called the NZO mouse to understand why the pancreas secretes less insulin and
the consequences of this defect. This project has the potential of providing better
therapeutic strategies for patients with Type 2 diabetes.
Research achievements (from final report):
The overall goal of this project was to determine the genetic and biochemical cause of
reduced insulin release in the context of Type 2 diabetes. Insulin is the main hormone
that regulates blood sugar (glucose) levels and its reduced amounts cause the high
blood sugars characteristic of diabetes. Using an appropriate aninal model of Type 2
diabetes, the New Zealand Obese (NZO) mouse, we showed that the reason for
reduced insulin secretion was a genetic defect in a molecule that regulates this process
called the sulfonylurea receptor. We confirmed this by restoring the sulfonylurea
receptor in the NZO mouse and showed improved insulin release and glucose
tolerance. Furthermore, the long-term effects of correcting the sulfonylurea receptor
mutation in the NZO mouse was sustained insulin secretory capacity and improved
glucose tolerance. This study highlights that the sulfonylurea receptor can be
involved in the pathogenesis of common Type 2 diabetes and that strategies that can
correct this defect can have long lasting effects to improve blood sugar levels.
Expected future outcomes:
Therapeutic strategies that can target the sulfonylurea receptor can be beneficial to
insulin secretion and blood sugar control in patients with Type 2 diabetes.
Name of contact: Sof Andrikopoulos
Email of contact: sof@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 454714
CIA Name: Dr Siew Yeen Chai
Main RFCD: Therapies and Therapeutic Technology
Admin Inst: University of Melbourne
Start Year: 2007
End Year: 2007
Total funding: $195,450.00
Grant Type: NHMRC
Development Grants
Title of research award:
Development of small molecule inhibitors of IRAP - potential use for the treatment of
memory disorders
Lay Description (from application):
This research project provides proof of concept that IRAP is a suitable target for use
in the development of a new class of clinically valuable cognitive-enhancing agents.
We have recently identified a family of small molecule compounds that inhibited the
catalytic activity of the enzyme using a molecule model of IRAP to screen virtual
libraries. This research proposal aims to validate that this family of compounds have
memory-enhancing properties by acting specifically on IRAP. At the conclusion of
this project, we will have elucidated important information on the specificity of the
memory effects and the structure activity relationship of this family of compounds.
We will have identified and characterised a lead compound for development into a
new class of cognitive enhancers.
Research achievements (from final report):
A family of new drug-like compounds suitable for development into drugs for treating
memory loss has been developed based on their ability to bind to and inhibit a protein
in the brain known as insulin-regulated aminopeptidase (IRAP). A computer model
of IRAP was used to screen 1.5 million compounds on different chemical databases
for their ability to fit into the active site of IRAP. These compounds were then tested
in the laboratory for their ability bind to and alter the activity of IRAP. Then their
chemical structures were then modified to improve their 'drug-like' properties and the
most effective compound was found to improve performance in normal rats in two
different memory tasks. Therefore a family of drug-like compounds that specifically
target IRAP (named HFI 142 analogues) that have memory-enhancing properties have
been identified at the conclusion of the project. We propose that these analogues will
serve as potential lead compounds that can be developed into therapeutically effective
agents that will be used to treat the cognitive decline in Alzheimer's disease.
Expected future outcomes:
The expected future outcome would be the identification of families of IRAP
inhibitors with memory-enhancing properties that will form the "lead series" for a
drug development program for a new class of cognitive-enhancing agents.
Name of contact: Siew Yeen Chai
Email of contact: sychai@florey.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 350434
CIA Name: Dr Erica Fletcher
Main RFCD: Sensory Systems
Admin Inst: University of Melbourne
Start Year: 2005
End Year: 2007
Total funding: $258,000.00
Grant Type: NHMRC Project
Grants
Title of research award:
Muller cell reactivity during diabetic retinopathy
Lay Description (from application):
Diabetes is the leading cause of blindness in the working population. In some patients
with diabetes, blood vessels within the retina proliferate, haemorrhage or cause retinal
detachment. The underlying changes within the retina that lead to the proliferation of
blood vessels are not well understood. One of the factors that leads to changes in
retinal blood vessels is an increase in growth factors from cells within the retina called
Muller cells. Muller cells are vital for the normal function of the retina and are known
to be abnormal late in diabetes. They may also be dysfunctional early in diabetes and
could play a significant role in causing the early changes seen in diabetes. Therefore a
good understanding of how Muller cells change and the time at which they change is
vitally important to gain a better understanding of the defects that are associated with
diabetes. Furthermore, an understanding of the basic underlying cellular changes that
occur in dibaetes will aid the development of more specific therapeutic agents in the
future.
Research achievements (from final report):
The central aim of this study was to evaluate the role of the supporting cells play in
causing blood vessel changes at the back of the eye during diabetes. This study
showed that diabetes doesn't just cause changes in blood vessels at the back of the eye
as previously thought. Rather, there are other supporting cells at the back of the eye
that are altered before the blood vessels change. Moreover, the cells at the back of the
eye that allow us to see, are altered from a very early stage of diabetes. We examined
the mechanism by which diabetes induced changes in the supporting cells and
identified that a new class of receptors called purines play an important role. The
results of this project are importand for two reasons. First, the information on cell
changes will enable us to develop predictive tools that determine which patients might
be at risk of progression of diabetic retinopathy. Secondly, by examining the novel
class of receptors in more detail we may be in a position in the future to develop a
new class of drugs that prevents the development of diabetic complications..
Expected future outcomes:
we will continue to understand the mechanisms by which glia and neurons change
during diabetic retinopathy
Name of contact: Erica Fletcher
Email of contact: elf@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 628698
CIA Name: Dr David Stapleton
Main RFCD: Exercise Physiology
Admin Inst: University of Melbourne
Start Year: 2010
End Year: 2012
Total funding: $561,558.00
Grant Type: NHMRC Project
Grants
Title of research award:
Regulation of skeletal muscle AMP-activated protein kinase by glycogen
Lay Description (from application):
The enzyme AMP protein kinase has three parts (subunits) and is central to
controlling the body's metabolism. We have discovered that one subunit is essential
for tightly associating the enzyme with muscle glycogen which is a source of high
energy and efficient metabolism. We will identify where the enzyme attaches to
glycogen, and how diet and exercise alter this association. Understanding this could
lead to new approaches for treating Type 2 diabetes where energy metabolism is
disrupted.
Research achievements (from final report):
The enzyme AMP-activated protein kinase (AMPK) has three parts (subunits) and is
central to controlling the body's metabolism. We have discovered that in muscle, one
AMPK subunit known as the beta-2 subunit is essential for tightly associating the
enzyme with glycogen particles - the cellular store of glucose and a source of high
energy required for muscle contractions during exercise. However, the beta-1 subunit
found in all other tissues in the body does not bind well to glycogen. During this
research funding we have developed a method to isolate glycogen particles from
animals that have done no exercise and those that have exercised and found that the
AMPK beta-2 subunit binds tightly to the exercised glycogen but the AMPK beta-1
subunit does not. Furthermore, using small parts of glycogen we have discovered that
the AMPK beta-2 subunit prefers to bind to glycogen that has been broken down
during exercise, and we have also discovered what parts of the beta-2 subunit are
essential for this interaction. These results now provide a molecular reason for the
well-documented relationship between AMPK and glycogen over he last 10 years.
Expected future outcomes:
We plan to use the information about where in the beta-2 subunit glycogen actually
binds to develop small molecules that may lead to breaking this interaction that we
predict will lead to an active AMPK. This approach could result in new ways of
treating Type 2 diabetes.
Name of contact: Dr. David Stapleton
Email of contact: dis@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 208945
CIA Name: Dr Sofianos Andrikopoulos
Main RFCD: Endocrinology
Admin Inst: University of Melbourne
Start Year: 2002
End Year: 2004
Total funding: $406,980.00
Grant Type: NHMRC Project
Grants
Title of research award:
Investigation of the genetic basis of insulin hypersecretion in a mouse model of
pancreatic islet failure
Lay Description (from application):
Type 2 diabetes is a chronic disease that is associated with blindness, kidney failure,
heart attacks and stroke and these are secondary to high blood sugar levels. Thus,
determining the cause of high blood sugar levels in type 2 diabetes will lead to better
management of the disease and ease the financial burden on the public health system.
High blood sugar in type 2 diabetes results from the inability of the body to secrete
enough insulin. Insulin is the main hormone that lowers blood sugar levels and is
produced by the pancreas. The reason for reduced insulin secretion in type 2 diabetes
is not known. Paradoxically, it has been shown that some people who are at an
increased risk of developing diabetes (eg people with obesity or a family history of
diabetes) secrete more insulin than normal. It is not clear why this is, but a few
studies have suggested that reducing insulin secretion in these circumstances can
protect the pancreas and preserve its ability to secrete the appropriate amount of
insulin. The DBA/2 is a mouse strain that like humans with type 2 diabetes, its
pancreas can also fail to secrete the appropriate amount of insulin and under these
circumstances becomes diabetic. Furthermore our laboratory has generated evidence
that shows that like people who are at risk of diabetes, DBA/2 mice in fact secrete
more insulin prior to becoming diabetic. Whether the cause of this increased insulin
secretion is linked to the eventual reduction of secretion is not known. The aim of
this study is to identify the gene that causes increased insulin secretion in the DBA/2
mouse. Furthermore, genetically manipulated animals will be produced that contain
only this gene to determine its effect on insulin secretion. Should the identification of
this gene be related to the eventual failure of the pancreas to secrete enough insulin,
then it would provide a target for drug therapy to correct insulin levels and therefore
reduce blood sugar levels.
Research achievements (from final report):
Reduced secretion of the hormone insulin from the pancreas is the cause of high blood
sugar levels in patients with Type 2 diabetes. Paradoxically there is enough evidence
to suggest that too much insulin secretion is present in at least some patients who are
at risk of developing with Type 2 diabetes and that it may contribute to the eventual
demise of the pancreas. The DBA/2 mouse is a model of reduced insulin secretion
when exposed to obesity/insulin resistance which, interestingly, secretes more insulin
in the normal "non-stressed" state. Furthermore we believe that this insulin
hypersecretion is genetically determined in DBA/2 mice. With support from this
grant we have identified a gene , we have called Hip1, that is associated with insulin
hypersecretion, and that this gene is upregulated 5-fold in DBA/2 islets.
NHMRC Research Achievements - SUMMARY
The significance of this work is that Hip1 may provide a diagnostic tool for
identifying subjects at risk of developing diabetes and also has the potential of
providing a target for the development of therapeutic agents for the prevention of
diabetes in the subsection of diabetes-prone subjects that hypersecrete insulin.
Expected future outcomes:
It is anticipated that future outcomes will be to determine the reason that Hip1 is
induced in DBA/2 islets and to determine whether subjects who are at risk of
developing Type 2 diabetes also have increased Hip1 expression.
Name of contact: Sofianos Andrikopoulos
Email of contact: sof@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 359374
CIA Name: Prof Doris Young
Main RFCD: Primary Health Care
Admin Inst: University of Melbourne
Start Year: 2006
End Year: 2008
Total funding: $499,263.00
Grant Type: NHMRC
Strategic Awards
Title of research award:
PEACH study- Patient Engagement and Coaching for Health: an intensive treatment
intervention for patients with type 2 di
Lay Description (from application):
This study uses practice nurses integrated in existing general practice structures to
implement telephone coaching for patients with type 2 diabetes (T2D) in a
disadvantaged community. This is an evidence based patient empowerment strategy
designed to increase patient self-management and engagement with the health care
system to improve health outcomes.
Research achievements (from final report):
This project has enabled us to train 30 practice nurses working in general practice to
use telephone coaching to engage with patients with poorly controlled diabetes care
using best practice guidelines. We have enabled the practice nurses in both
intervention and control practices to learn to recruit patients using practice databases,
collect clinical information, administer questionnaires and engage in primary care
research. Some Practice nurses have learnt to use telephone coaching methodology
and web based instruments. Others are aware of the rigour needed to conduct proper
clinical trials in a busy general practice.We have also estimated the costs of this
additional role by practice nurses working in general practice and the barriers and
facilitators to achieve this. If this intensive telephone coaching of diabetes patients by
practice nurses were shown to provide better diabetes, blood pressure and cholesterol
control and uptake of healthier lifestyles, then we can implement this as the new role
for practice nurses in the management of chronic diseases in the GP primary care
setting.This has future workforce implications for practice nurses working in primary
care.
Expected future outcomes:
We expect that the patients with type 2 diabetes who have received telephone
coaching from practice nurses about their diabetes management have better blood
sugar, blood pressure and cholesterol control than those who have not over an 18
month period and that this is achieved by appropriate medications and adopting
healthier lifestyles
Name of contact: Professor Doris Young
Email of contact: d.young@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 350253
CIA Name: A/Pr Barbara Coulson
Main RFCD: Medical Microbiology not elsewhere classified
Admin Inst: University of Melbourne
Start Year: 2005
End Year: 2009
Total funding: $538,250.00
Grant Type: Established
Career Fellowships
Title of research award:
Uncoupled Research Fellowship
Lay Description (from application):
I am a physiologist with expertise in endocrinology determining the roles of particular
regulatory peptides in the normal functions of the gastrointestinal tract and in the
development of gastrointestinal, renal and prostate cancers.
Research achievements (from final report):
My research program has encompassed discoveries of rotavirus cell receptor
specificities and entry mechanisms; structural determinations of rotavirus-receptor
complexes; understanding how rotavirus modulates cell signalling , interferes with
transcription and evades antiviral responses; identification of immune cells invaded
by rotavirus; determining the extent and mechanisms of rotavirus modulation of type
1 diabetes; and development of inhibitors of rotavirus-cell entry. This research will
continue to help build Australia's future capacity and intellectual rigor in virological
research through training of Post-Doctoral Fellows and students. Development of
diagnostic reagents and techniques to detect novel emerging rotavirus strains,
adaption of vaccine implementation to local conditions, monitoring vaccine effects,
developing drugs to treat the children not protected by vaccination and an
understanding of how these vaccines intersect with other conditions such as type 1
diabetes all will require this expertise. The rigor, depth and extent of rotavirus
research training I provide is not available from any other Australasian, South-East
Asian or Western Pacific laboratory.
Expected future outcomes:
This fellowship has enabled subtantial progress in understanding rotavirus disease and
pathogenesis, which will assist in development of advanced treatments and vaccines.
Name of contact: Barbara Coulson
Email of contact: barbarac@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 350229
CIA Name: A/Pr Geoffrey Howlett
Main RFCD: Medical Biochemistry: Proteins and Peptides
Admin Inst: University of Melbourne
Start Year: 2005
End Year: 2007
Total funding: $439,500.00
Grant Type: NHMRC Project
Grants
Title of research award:
Apolipoproteins and Amyloid Formation in Atheroma
Lay Description (from application):
We propose to study the poorly understood, disease-associated process of amyloid
formation, using a sensitive and reproducible model developed in our laboratory.
Amyloid deposits are a feature of several neurodegenerative and metabolic disorders
such as Alzheimer's and Parkinson's disease and are also common in atherosclerotic
plaque or atheroma. They are composed of tangled networks of fibrillar proteins
together with several non-fibrillar proteins and proteoglycans. Atherosclerotic
plaques typically consist of fibrous proteins, lipids and foam cells derived from
macrophages via receptor-mediated uptake of oxidized low density lipoproteins.
Our model system is based on the formation of amyloid fibrils from apolipoprotein
(apo) C-II which accumulates in atherosclerotic plaques where it co-localizes with
serum amyloid P component, a marker of amyloid fibrils. ApoC-II is a component of
plasma lipoproteins and an important activator of the enzyme lipoprotein lipase,
which functions in the transport and distribution of triacylglycerols to tissues. We
have shown that apoC-II (79 amino acids) readily forms amyloid fibrils under lipidfree conditions, adopting a cross-beta sheet structure that reacts with the amyloid
stains thioflavin T and Congo Red. The formation and properties of apoC-II amyloid
fibrils and the amyloid-like properties of oxidized lipoproteins are the subject of the
present proposal. We will characterize the effects of lipids and oxidation on the rate
of formation and the properties of apoC-II amyloid fibrils. We will also study the
effects of oxidation on the amyloid-like properties of lipoproteins and their
interactions with serum amyloid P component and cell surface receptors.
Research achievements (from final report):
Protein aggregation and amyloid formation accompanies numerous medical
conditions, notably Alzheimer disease and Parkinson's disease. These diseases
involve a variety of normally non-fibrillar proteins with at least 20 human proteins
identified as components of different types of amyloid. The prevalence of
apolipoproteins in atherosclerotic plaques suggests a general propensity for human
apolipoproteins to form pathogenic amyloid fibrils. In this project we identified
several factors that affect amyloid fibril formation by lipid-free human apolipoprotein
C-II (apoC-II). We discovered a new apoC-II fibril morphology promoted by lipid
bilayers and developed a reversible kinetic scheme to describe apoC-II fibril
formation. We also demonstated the accumulation of fibrillar deposits of
apolipoproteins in atherosclerotic plaques and the ability of amyloid fibrils to activate
scavenger cells, an early event in the development of atherosclerosis and heart
disease. Our studies provide new insight into the structure and mechanism of
formation of amyloid fibrils and the role of in vivo factors such as oxidation and the
binding of amyloid specific proteins in regulating amyloid growth.
NHMRC Research Achievements - SUMMARY
Expected future outcomes:
Our observations highlight the potential importance of amyloid deposits in
atherosclerosis. Our structural and mechanistic studies suggest new strategies for
reversing amyloid fibril formation and for the development of inhibitors for the
treatment of atherosclerosis and other amyloid related diseases.
Name of contact: Geoffrey Howlett
Email of contact: ghowlett@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 566826
CIA Name: A/Pr Sofianos Andrikopoulos
Main RFCD: Endocrinology
Admin Inst: University of Melbourne
Start Year: 2009
End Year: 2010
Total funding: $318,622.00
Grant Type: Career
Development Fellowships
Title of research award:
The role of insulin hypersecretion in beta cell dysfunction in Type 2 diabetes
Lay Description (from application):
The treatment of diabetes involves the use of drugs that stimulate the release of
insulin from the pancreas to reduce the high blood sugar levels. However, we believe
that while in the short term this is a good strategy, in the long-term it damages the
cells that produce insulin leading to a worsening state of diabetes. It is the aim of this
application to understand the mechanisms by which the insulin producing cells are
damaged when forced to oversecrete insulin.
Research achievements (from final report):
Type 2 diabetes is characterised by high sugar levels as a result of reduced production
and release of the hormone insulin from the pancreas. The aim of this study was to
understanding the mechanism(s) associated with reduced insulin release in Type 2
diabetes. Using state-of-the-art genetic models we showed in this research that when
the pancreas is overworked and is made to produce and secrete too much insulin in a
short time-period that it fails and shuts down. One of the mechanisms associated with
this shut down is called oxidative stress and is caused by the pancreas working too
hard and damages the cells that produce and release insulin. We also showed that
slowing down the rate with which the pancreas works in diabetes can be beneficial
and restore its normal function. The potential benefits of this research are that
therapeutic interventions that further stimulate the pancreas to produce and release
insulin cause damage and should be avoided. Instead, therapies that reduce the work
load of the pancreas should be promoted to give long term relief to the insulin
producing and secreting cells, thus providing better blood sugar control to the
individual with diabetes.
Expected future outcomes:
It is expected that with the knowledge and understanding of the cause of reduced
insulin secretion from this study that better therapeutic strategies will be developed to
reduce the workload of the pancreas and thus provide better blood sugar control for
the individual with diabetes.
Name of contact: Sof Andrikopoulos
Email of contact: sof@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 454725
CIA Name: A/Pr Alicia Jenkins
Main RFCD: Medical Biochemistry: Lipids
Admin Inst: University of Melbourne
Start Year: 2007
End Year: 2009
Total funding: $335,019.00
Grant Type: NHMRC Project
Grants
Title of research award:
HDL and vascular cells dysfunction in Type 2 Diabetes and Coronary Arteries
Disease
Lay Description (from application):
Diabetes is a common cause of renal failure, blindness and accelerated cardiovascular
disease (CVD). Hyperglycemia, hypertension and dyslipoproteinaemia, including
High Density Lipoprotein (HDL) dysfunction, may promote complications and
represent therapeutic targets. In diabetes, qualitative and quantitative changes in
lipoproteins, such as low HDL and non-enzymatic glycation and oxidation may
promote CVD. In addition to its role in reverse cholesterol transport, HDL has
antioxidant, anti-inflammatory, anti-thrombotic and vasodilatory effects, which may
be vasoprotective. The underlying hypothesis is that impaired HDL function in
diabetes promotes CVD. Lipoprotein function will be evaluated in a series of in vitro
assays to determine if HDL functions are impaired in Type 2 diabetes (and in CAD.
Angiogenesis, the formation of new blood vessels from existent blood vessels is a
multi-step process involving matrix degradation, proliferation of endothelial and
smooth muscle cells and fibroblasts. This process is increased in proliferative diabetic
retinopathy, but elsewhere in diabetes is reduced, as evidenced by delayed wound
healing and reduced collateral formation around atheroma. Dysfunctional HDL
through its impaired ability to inhibit intracellular reactive oxygen species formation
and reduced anti-inflammatory effects might contribute substantially to this process.
Thus, a better understanding of mechanisms perturbing angiogenesis in diabetes and
model systems to test angiogenesis promoters and inhibitors are highly relevant. In
vitro measures of lipoprotein dysfunction and disturbed angiogenesis in Type 2
diabetes may guide early identification of high complication risk patients and aid
development and testing of better treatment strategies.
Research achievements (from final report):
Our results demonstrate that HDL, but not LDL suppresses TNF-α induced HAEC
CAM expression, and HDL early glycation and marked oxidation reduce efficacy of
detoxification, both in vitro and in vivo. Intracellular ROS assays suggest that HDL
(but not LDL) protects aortic endothelial cells against intracellular oxidative stress,
and this function is impaired by early glycation of HDL. We have published that in
vitro HDL oxidation results in modification of ApoA1 methionine residues in HDL's
apoA1, and that these modifications occur in patients with diabetes. We have
demonstrated adverse effects of late but not early glycation of some antiinflammatory and reverse cholesterol transport related functions of HDL, and related
it to specific macrophage efflux receptors. We have also shown that there is an early
glycation related impairment of HDL function with regard to suppression of TNF-α
induced HAEC VCAM-1 and ICAM expression, which corresponds to a HbA1c level
of approximately 8%. In diabetic patients with good glycaemic control this anti-
NHMRC Research Achievements - SUMMARY
inflammatory dysfunction was not evident. However with in vivo modified HDL from
Type 2 DB subjects the anti-oxidant function of human macrophages was impaired.
Expected future outcomes:
Future research will concentrate on:
- mechanism of action of non-enzymatic processess on HDL function,
- therapeutic effects of various agents on improvement of HDL function in Diabetes.
Name of contact: A/Prof. Alicia Jenkins
Email of contact: jenkinsa@medstv.unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 566586
CIA Name: Prof Doris Young
Main RFCD: Primary Health Care
Admin Inst: University of Melbourne
Start Year: 2009
End Year: 2009
Total funding: $304,300.00
Grant Type: NHMRC Project
Grants
Title of research award:
PEACH: Patient Engagement and Coaching for Health: An intensive treatment
intervention for patients with type 2 diabetes
Lay Description (from application):
Diabetes care is a partnership between health professionals and patients, but each
faces difficulties in optimising medical care. The PEACH study exoplores how
practice nurses can work with patients to empower them to manage their own
condition and medicines better and be more active in working with their doctor to
improve their diabetes control. The study could have important implications for
patients and the way Governments fund primary care.
Research achievements (from final report):
This project has enabled us to train 30 practice nurses working in general practice to
use telephone coaching to engage with patients with poorly controlled type 2 diabetes
using best practice guidelines. We have enabled the practice nurses in both the
intervention and control practices to learn to recruit patients using practice databases,
collect clinical information, administer questionnaires and engage in primary care
research. Some practice nurses have learnt to use telephone coaching methodology
and web-based instruments. Others are aware of the rigour needed to conduct proper
clinical trials in a busy general practice environment. We have also estimated the
costs of this additional role by practice nurses in general practice and the barriers and
facilitators to achieve this. If this intensive telephone coaching of diabetes patients by
practice nurses were shown to provide better diabetes, blood pressure and cholesterol
control and uptake of healthier lifestyles, then we can implement this as the new role
for practice nurses in the management of chronic diseases in the general practice
primary care setting. This has future workforce implications for practice nurses
working in primary care.
Expected future outcomes:
We expect that the patients with type 2 diabetes who have received telephone
coaching from practice nurses about their diabetes management have better blood
sugar, blood pressure and cholesterol control than those who have not over an 18
month period and that this is achieved by appropriate medications and adoption of
healthier lifestyles.
Name of contact: Prof Doris Young
Email of contact: d.young@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 454569
CIA Name: Prof Joseph Trapani
Main RFCD: Immunology not elsewhere classified
Admin Inst: University of Melbourne
Start Year: 2007
End Year: 2011
Total funding: $11,474,346.00
Grant Type: Programs
Title of research award:
Immune Regulation, Effector Function and Human Therapy
Lay Description (from application):
The immune system plays an important role in protecting the host from viral and
bacterial infections, and inhibits cancer onset and progression. Immune processes
proceed through specialised cells in conjunction with soluble factors such as
inteferons and interleukins. These soluble factors can regulate the activities of
immune cells, and inhibit the growth and survival of aberrant (virus infected, cancer)
cells. Unfortunately, the immune system can sometimes lose specificity and attack the
host, resulting in autoimmune diseases such as diabetes. This research team has
played a vital role in characterising the specific activities of immune cells and the
associated factors. Importantly, they are deciphering the intricate communication
networks of these immune components and dissecting their modes of action. By
understanding these complex processes, the team aims to harness the unique
therapeutic properties of our own immune system and translate their findings into the
clinic. The team is developing new immune-based therapies for use, eitheralone or in
combination with existing chemotherapies to fight debilitating human diseases such as
cancer and autoimmune disease.
Research achievements (from final report):
The NHMRC Program Grant (2007-2011) extended previous findings (NHMRC
Program 2003-2006) into the translational and clinical arenas. In particular, the
inclusion of CI Prince resulted in a number of clinical studies exploring the role the
immune system in multiple myeloma. Reciprocally, the immunomodulatory effects
of certain types of cancer chemotherapy to positively influence the immune response
against cancer were explored. Considerable advances were made in characterising the
molecular mechanisms by which the immune system both protects against incipient
cancer, while later intervening through the killing of frankly cancerous cells.
Significant advances were made in our unique approach to adoptive T-cell
immunotherapy, culminating in a first in human trial of anti Lewis Y autologous T
cells administered as a vaccine for acute myeloid leukaemia. The team made major
advances in our understanding of NK T-cell biology, its realtion to the genesis of
cancer and auto-immunity as well the mechanisms through which anti-cancer drugs
activate epigenetic mechanisms for therapeutic benefits, particularly for HDACs.
Finally, the molecular basis for a number of immunodeficiency states was also
explored, particularly with respect to mutations in the perforin gene.
Expected future outcomes:
The period 2007-2011 set the scene for even greater clinical translation of our work.
Specifically, we hope the next iteration of our program will include a far greater
clinical trials component focusing on immune therapies for cancer.
Name of contact: Joseph A. Trapani
NHMRC Research Achievements - SUMMARY
Email of contact: joe.trapani@petermac.org
NHMRC Research Achievements - SUMMARY
Grant ID: 350483
CIA Name: Dr Glenn McConell
Main RFCD: Exercise Physiology
Admin Inst: University of Melbourne
Start Year: 2005
End Year: 2007
Total funding: $340,750.00
Grant Type: NHMRC Project
Grants
Title of research award:
IS NITRIC OXIDE A CENTRAL REGULATOR OF EXERCISE-INDUCED
SKELETAL MUSCLE MITOCHONDRIAL BIOGENESIS?
Lay Description (from application):
Mitochondria are the energy producing parts of the cell and are the major controllers
of metabolism. There is now good evidence that reduced muscle mitochondrial size
contributes to diabetes. Exercise is good for diabetics due partly to increasing muscle
mitochondrial production (mitochondrial biogenesis). Unfortunately, little is known
about the mechanisms involved in increased muscle mitochondrial biogenesis
following exercise. It has been shown recently that nitric oxide (NO), a gas made by
muscle during exercise, plays a role in mitochondrial biogenesis in fat cells. This
project will determine whether NO is a central regulator of exercise-induced
mitochondrial biogenesis in skeletal muscle. If we find that NO increases
mitochondrial biogenesis in muscle, drugs designed to mimic these exercise effects
may prevent or improve diabetes. We will firstly establish if specific drug treatments
that alter NO levels in muscle cells grown in culture alter mitochondrial biogenesis.
These results will help us to clarify the role of NO in mitochondrial biogenesis.
However, it is difficult to directly examine the effects of exercise in cultured cells.
Therefore, further studies will then use real life models such as rodents that have been
exercised to examine the role of NO and exercise on mitochondrial biogenesis. We
will feed a drug to decrease NO levels in normal rats; and use mice, genetically
altered to be lacking in NO to determine if these treatments decrease mitochondrial
biogenesis that is normally seen following endurance exercise. Furthermore, since
defects in mitochondrial biogenesis have such an important impact on diabetic
humans, we will use humans to examine if differences in NO levels in skeletal muscle
among type 2 diabetics or endurance-trained athletes correlate with mitochondrial
biogenesis. Finally, we will infuse a drug into type 2 diabetics that increases NO in
muscle to determine if it also increases mitochondrial biogenesis.
Research achievements (from final report):
Mitochondria are the energy procing oragns of the cell. Defective small skeletal
muscle mitochondria are now recognised as a major component of the metabolic
abnormalities of diabetes. Exercise increases mitochondrial volume and improves
mitochondrial function (mitochondrial biogenesis). Many research groups are
attempting to determine how exercise increases mitochondrial biogenesis and thereby
prevents or improves diabetes. There are large gaps in our current knowledge. Prior
to commencing our grant funding a paper presented convincing evidence that nitric
oxide (NO) regulates mitochondrial biogenesis in fat cells. As skeletal muscle NO
production increases during exercise, NO could provide an important link between
exercise and its beneficial effects on diabetes. In this project we examined whether
NO plays an important role in the increase in mitochondrial biogenesis in response to
exercise. We provided clear evidence that NO plays an important role in resting
NHMRC Research Achievements - SUMMARY
(basal) skeletal muscle mitochondrial biogenesis but not the increase in skeletal
muscle mitochondrial biogenesis in response to acute exercise or exercise training.
Based on this we have begun investigations into other potential regulators of skeletal
muscle mitochondrial biogenesis in response to exercise.
Expected future outcomes:
We have begun investigations into other potential regulators of skeletal muscle
mitochondrial biogenesis in response to exercise, in particular free radicals. We have
also obtained NHMRC funding to examine whether exercise training can correct
deficits in skeletal muscle mitochondrial biogenesis in adulthood when one is born
small.
Name of contact: Dr Glenn Mcconell
Email of contact: mcconell@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 508900
CIA Name: Prof Ian van Driel
Main RFCD: Cellular Immunology
Admin Inst: University of Melbourne
Start Year: 2008
End Year: 2011
Total funding: $488,578.00
Grant Type: NHMRC Project
Grants
Title of research award:
The generation and function of tissue-specific regulatory T cells
Lay Description (from application):
The immune system normally protects against invasion by pathogens such as harmful
viruses and bacteria. In autoimmune diseases the same mechanisms that are used to
protect us are erroneously targeted to our own tissues. We will discover how
regulatory lymphocytes, are able to protect against autoimmune disease. Such
regulatory lymphocytes are attractive therapeutic agents to prevent a variety of
immune-mediated diseases, including autoimmune diseases, allergy and
transplantation rejection.
Research achievements (from final report):
We have investigated the role of specific antigen in the generation of autoantigenspecific Treg cells both in the thymus and in extra-thymic tissue. We have shown that
functionally suppressive, Foxp3-expressing Treg cells are naturally generated in vivo.
Using a genetic approach, we have also investigated how the presence of endogenous
antigen in thymic and extra-thymic tissues influences the generation of antigenspecific TREG.
We evaluated the therapeutic potential of autoantigen-specific Treg cells in treating
autoimmune gastritis at late pathogenic stages. H+/K+ ATPase autoantigen-specific
Treg cells were generated by stimulating CD4+ T cells from TCR transgenic mice in
the presence of TGFβ and retinoic acid in vitro. iTreg cells specifically homed to the
paragastric lymph node and effectively inhibited the development of autoimmune
gastritis. We have assessed the ability of iTreg cells to reverse autoimmune gastritis
where the stomach tissue is severely depleted of gastric mucosal cells. We found that,
10 weeks after the administration of iTreg cells, there was regeneration of the gastric
mucosal cells although other characteristics of the disease such as hypertrophy of the
gastric mucosa were still observed. However, 6 months after treatment there was
substantial reversal of disease.
Expected future outcomes:
This work may lead to a better understandiong of immuological toletance and
treatments for autoimmune disease.
Name of contact: Ian Van Driel
Email of contact: i.vandriel@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 509252
CIA Name: Prof Louise Burrell
Main RFCD: Endocrinology
Admin Inst: University of Melbourne
Start Year: 2008
End Year: 2010
Total funding: $508,839.00
Grant Type: NHMRC Project
Grants
Title of research award:
Novel approaches to risk stratification in patients with type 2 diabetes
Lay Description (from application):
75% of the mortality in adults with Type 2 diabetes is due to a cardiac event. Early
detection and treatment of cardiac disease is paramount in improving health
outcomes. An echocardiogram is an accurate and non-invasive identification of
cardiac dysfunction. We will assess the prognostic value of echocardiography and
novel plasma markers in patients with diabetes. Our results may lead to new
management and screening guidelines for heart disease in diabetes.
Research achievements (from final report):
The Melbourne Diabetes Echo Cohort is one of the largest, observational registries of
type 2 diabetes (T2DM) patients with a detailed echocardiographic assessment
available (>1000 subjects). Our results show that an abnormal heart scan
(echocardiogram) is common in patients with T2DM with over 70% having an
abnormal echocardiogram.
We have also shown that an abnormal echocardiogram is associated with increased
risk of a cardiac event (death, myocardial infarction, angina, stroke, revascularization
of coronary or peripheral arterial disease, hospitalisation for heart failure) over a 5-y
follow up period. The results generated are highly relevant to "real-world" T2DM
patients as the primary referral base is from general practitioners (80% of subjects).
The cohort includes T2DM subjects with co-morbidities (often excluded from clinical
trials), and high-quality clinical data on diabetic complications (renal function,
retinopathy, neuropathy) and blood pressure (both clinic and 24h ambulatory) is
available. Information on quality indicators, i.e. use, or not, of medications known to
improve outcomes in diabetes is being collected, and is under analysis. Although an
echocardiogram is not yet included in any current diabetes guidelines, the results of
this study have the potential to change the guidelines in the future.
Expected future outcomes:
Improved CV risk stratification with an echocardiogram may lead to improved
outcomes in diabetes by providing the impetus to the physician to intensify their
management of known risk factors, and to reach appropriate lipid and blood pressure
targets. The results will also stimulate research into future interventions that
specifically target the underlying pathology in diabetic heart disease.
Name of contact: Professor Louise Burrell
Email of contact: l.burrell@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 454423
CIA Name: Dr Helen MacLean
Main RFCD: Endocrinology
Admin Inst: University of Melbourne
Start Year: 2007
End Year: 2009
Total funding: $395,422.00
Grant Type: NHMRC Project
Grants
Title of research award:
Genomic and non-genomic actions of androgens in regulation of fat mass and
metabolism
Lay Description (from application):
Men have lower amounts of body fat than women, but are more likely to deposit fat
around the stomach and abdominal region than women. This increased abdominal fat
in men significantly increases the risk of developing type 2 diabetes and heart disease.
The differences between men and women suggest that there is hormonal control of fat
development; however, little is known regarding how male sex hormones, androgens,
control these processes. We will investigate how androgens control fat formation, and
the response of fat and muscle tissue to glucose and insulin, using mutant mouse
strains. These mouse strains have a mutation in the androgen receptor, a protein
which acts as a key/lock mechanism to allow tissues to respond to androgens. This
mutation stops the androgen receptor from functioning, so these mice can be used to
determine the function of androgens acting through the androgen receptor. We will
study three strains of mutant mice: (i) in which the androgen receptor is nonfunctional in all tissues of the body; (ii) in which the androgen receptor is nonfunctional only in fat tissue, but normal in all other tissues; and (iii) in which the
androgen receptor is non-functional only in skeletal muscle, but is normal in all other
tissues. The aim of our research is to determine the effect of the mutations in these
three different mouse lines on paramateres including the amount of fat formed, the
site of fat deposition, the levels of lipids and insulin in the blood and their response to
glucose. The androgen receptor is a "master switch" that turns on or off other genes.
Therefore, we also aim to identify which genes are controlled by the androgen
receptor in fat and muscle. This research will identify how androgens control fat
development and function, and will identify genes that mediate these actions in fat
and muscle. This will provide potential molecules that could be used therapeutically
to treat obesity and prevent type 2 diabetes and heart disease.
Research achievements (from final report):
We have shown that the androgen receptor, a key-lock protein that allows the male
hormones (testosterone) to act in particular tissues, is important in controlling fat
mass in males. We demonstrated that mice with a non-functional androgen receptor
have increased subcutaneous and abdominal fat mass, and that this is associated with
abnormal fat metabolism and decreased physical activity. However, mice had normal
insulin sensitivity (no signs of insulin resistance or type 2 diabetes), despite the fact
that in some studies, low testosterone levels are more common in men with type 2
diabetes than control men. Our data demonstrate that testosterone regulates fat mass
in men, suggesting that testosterone treatment in older obese men with low
testosterone levels could be beneficial, by reducing abdominal obesity. However, our
data also suggest that insulin resistance is not directly regulated by androgens, and
therefore, that testosterone treatment may have no other benefit in reducing insulin
NHMRC Research Achievements - SUMMARY
resistance than its effect of reducing fat mass. We have also shown for the first time
that testosterone regulates physical activity, and this finding suggests that further
research is required to investigate the beneficial effects of combined exercise program
and testosterone therapy in treating men with obesity and type 2 diabetes.
Expected future outcomes:
This results from this study may be used to provide evidence in the debate on whether
men with type 2 diabetes and obesity should be treated with testosterone to reduce
their fat mass, and whether this will also potentially improve their insulin sensitivity.
Name of contact: Helen Maclean
Email of contact: hmaclean@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 251746
CIA Name: Dr Sofianos Andrikopoulos
Main RFCD: Endocrinology
Admin Inst: University of Melbourne
Start Year: 2003
End Year: 2007
Total funding: $435,500.00
Grant Type: Career
Development Fellowships
Title of research award:
Investigating Insulin Secretory Dysfunction in Type 2 Diabetes
Lay Description (from application):
Not Available
Research achievements (from final report):
Type 2 diabetes is a disease characterised by high sugar levels associated with a
reduced in the levels of the hormone insulin. The aim of this study was to determine
the mechanism for this reduced production and secretion of insulin in Type 2 diabetes.
Using appropriate models with susceptibility to developing diabetes it was found that
one of the mechanisms for reduced insulin secretion was an increase in the
detrimental compounds called reactive oxygen species or ROS. These compounds are
produced as a result of the normal function of cells, however in diabetes there is an
increase in ROS such that they reduce the amount of insulin being produced and
secreted. We showed that strategies that reduced the levels of ROS were associated
with better insulin release. Furthermore, we identified a gene associated with altered
insulin secretion, called nicotinamide nucleotide transhydrogenase (Nnt), which is
involved in the production of ROS. We found that in models that are susceptible to
diabetes the levels of Nnt were increased leading to higher insulin secretion. This
increase in the ability to secrete more insulin and therefore produce was ROS may
eventually lead to diabetes by reducing the ability to secrete insulin. Our results
suggest that therapies that stimulate secretion of insulin in diabetes should be avoided.
Expected future outcomes:
It is expected that further insights into the mechanism by which an increased ability to
secrete insulin may contribute to diabetes will be made in the future. This has
inplications for the treatment of patients with diabetes as drugs that stimulate insulin
secretion should be avoided in diabetes.
Name of contact: Sof Andrikopoulos
Email of contact: sof@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 628701
CIA Name: Prof Ego Seeman
Main RFCD: Endocrinology
Admin Inst: University of Melbourne
Start Year: 2010
End Year: 2012
Total funding: $865,474.00
Grant Type: NHMRC Project
Grants
Title of research award:
Fragility Fractures: The Neglected Role of Cortical Porosity
Lay Description (from application):
We just discovered that bone lost with age occurs mostly from pores within the cortex
(outer shell) of the bone; These pores become larger (porosity) making bones fragile.
This process is poorly detected by bone density (currently used tool) so that most
people with weak bones are missed. To address this issue, we have for the first time,
develop a technology to accurately quantify porosity in living peoples. With teams
around the world, we aim here to fill this gap in the diagnosis.
Research achievements (from final report):
Bone mineral density (BMD) the test commonly used in clinical and research settings
to identify individuals at risk for fracture. This test is neither sensitive nor specific;
most people diagnosed by BMD as at risk for fracture never sustain a sustain a
fracture, and most (~70%) of all fracture occur in people with BMD higher than the
range defining osteoorosity. To prevent fractures the important challenge is to
identify the majority of people with normal BMD who sustain a fracture.
Our first study measureing porosity of bone was published in the Lancet. This
identified porosity as a main consequence of bone loss and weakness of bone. This
now provides a test to identify people at risk for fractures missed by BMD. The grant
provided by the NHMRC helped us develop and validate a computer program that
automatically measures this porosity in clinical settings. This program called StrAx1.0
is now widely recognised and we are collaborating with many investigators in
Australia, Europe and USA applying this method. Several studies are now published
and the most recent identifies women at risk for forearm fractures not identified using
bone densitometry. this provides clinicians with useful information helping them
decide who to treat and not treat . This has been confirmed in two separates groups of
women in Australia and USA. The work is in review at a top medical journal at this
time.
Expected future outcomes:
Measuring porosity will become a rountine test helping doctors identify patients
needing therapy and will help to determine if treatment is successful by reducing
porosity.
Name of contact: Roger Zebaze
Email of contact: zebaze@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 400219
CIA Name: Prof Paul Gleeson
Main RFCD: Autoimmunity
Admin Inst: University of Melbourne
Start Year: 2006
End Year: 2008
Total funding: $579,764.00
Grant Type: NHMRC Project
Grants
Title of research award:
Organ-specific autoimmunity: The role of the thymus and periphery in shaping the
gastric-specific T cell repertoire
Lay Description (from application):
The immune system normally protects against invasion by pathogens such as harmful
viruses and bacteria. In autoimmune diseases the same mechanisms that are used to
protect us are erroneously targeted to our own tissues. White blood cells, called T
lymphocytes are responsible for attacking our own tissues in autoimmune diseases.
Our studies will employ a range of molecular, genetic and imaging technologies to
track the rare and potential harmful white blood cells. Our studies should reveal the
mechanisms by which these self destructive T lymphocytes are silenced in healthy
individuals on the one hand, and on the other hand escape to cause destruction in
individuals with autoimmune diseases. This fundamental information will allow the
development of therapeutic strategies to selectively "turn-off" these destructive T
lymphoctyes in individuals with autoimmune disease and thereby remove the
damaging immune response and cure the disease.
Research achievements (from final report):
The immune system normally protects against invasion by pathogens such as harmful
viruses and bacteria. In autoimmune diseases the same mechanisms that are used to
protect us are erroneously targeted to our own tissues.
Our studies have employed
a range of molecular, genetic and imaging technologies to track the rare and potential
harmful T lymphocytes in an organ-specific autoimmune disease known as
autoimmune gastritis. Autoimmune gastritis is due to a CD4+ T cell response to the
gastric H/K ATPase α and β subunits (H/Kα and H/Kβ). Our studies have revealed
the mechanisms by which these self destructive CD4+ lymphocytes are silenced in
healthy individuals. A set of experiments showed that prevention of autoimmune
gastritis requires the extra-thymic deletion of highly autoaggressive H/K ATPasespecific T cells to produce a T cell repertoire that is susceptible to the suppressive
activity of regulatory T cells. These studies have identified three elements of CD4+
T cell tolerance to gastric self-antigens (1) peripheral T cell deletion, (2) functional
ignorance of gastric-specific T cells and (3) suppression of potentially pathogenic T
cells by Foxp3+ Tregs This fundamental information will allow the development of
therapeutic strategies to selectively "turn-off" these destructive T lymphoctyes in
individuals with autoimmune disease and thereby remove the damaging immune
response and cure the disease.
Expected future outcomes:
Our work has identified the mechanisms of CD4+ T cell tolerance to gastric selfantigens. Given these findings, and defined H/K ATPase-specific T cell populations
it will now be possible to document the effects of inflammatory mediators on loss of
self-tolerance and the development of organ-specific autoimmunity.
NHMRC Research Achievements - SUMMARY
Name of contact: Paul Gleeson
Email of contact: pgleeson@unimelb.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 567100
CIA Name: A/Pr Darren Kelly
Main RFCD: Endocrinology
Admin Inst: University of Melbourne
Start Year: 2009
End Year: 2009
Total funding: $133,800.00
Grant Type: NHMRC
Development Grants
Title of research award:
Development of new anti-fibrotic drugs for prevention of diabetic nephropathy.
Lay Description (from application):
Diabetic kidney disease is the leading cause of kidney failure in the developed world.
Currently there is no treatment that reduces the excessive scarring that leads to kidney
failure. This project aims to test whether a series of novel compounds that have been
specifically designed to reduce scarring can prevent diabetic kidney disease
Research achievements (from final report):
Fibrosis is a pathological response to a range of tissue insults that ultimately lead to
organ dysfunction, including diabetic nephropathy. Accordingly, strategies that
reduce the pathological accumulation of extracellular matrix (ECM) have been
advocated as potential therapies for the treatment and prevention of kidney failure.
Our small molecule drugs inhibit the pathological fibrotic response and therefore have
the potential to target an unmet clinical need for treatment. In a recent series of
publications in the Journal of Clinical Investigation it was noted that 40-45% of
mortality in the developed world could be attributed to underlying fibro-proliferative
disorders Our series of novel, orally active anti-fibrotics have the potential to delay or
even the progression of renal decline, through reducing pathological fibrosis. As such
they represent potential add-on therapy for use with anti-hypertensives and ACEi. In
addition, by acting through a conserved mechanism for pathological fibrosis they have
the potential to reduce fibrosis in the myocardium and reduce the risk of
cardiovascular disease. In this study FT011 prevented the onset of albuminuria and
fibrosis in diabetic rats with kidney disease. These data will form an important part of
Fibrotech's investigational new drug application over the coming years. FT011 can
therefore be translated from a proof of concept tool in rats to proof of concept studies
in man.
Expected future outcomes:
A new patent was filed as a result of this grant. A series of new anti-fibrotic
compounds were synthesized. Furthermore, FT011 was proven to be efficacious in
late stage diabetic nephropathy. These data have now been used to design a formal
preclinical and clinical program for FT011 in late stage diabetic nephropathy.
Name of contact: A Prof Darren Kelly
Email of contact: dkelly@medstv.unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 209001
CIA Name: Prof Joseph Proietto
Main RFCD: Endocrinology
Admin Inst: University of Melbourne
Start Year: 2002
End Year: 2004
Total funding: $412,200.00
Grant Type: NHMRC Project
Grants
Title of research award:
Investigation of transgenic mouse models of Type 2 diabetes
Lay Description (from application):
Type 2 diabetes is a common condition characterised by high blood glucose, that
afflicts 700,000 Australians. It causes blindness, kidney failure and an increased risk
of heart attack and stroke. despite intensive study over many years, the reasons for the
elevated blood glucose in this condition are not fully understood. Several
abnormalities can contribute to the high glucose and different researchers have
proposed different defects as the initial cause. It has proven difficult to unravel the
sequence of events in the evolution of the syndrome because high glucose can cause
insulin resistance and a defect in insulin secretion, both of which can lead to high
blood glucose. One approach to study the consequences of specific defects is to
genetically engineer them. The aims of this project are to: 1. make a mouse with
reduced ability to store glucose in muscle. 2. test the metabolic consequences of a
defect in the manufacture of glycogen (starch) in muscle. 3. study the effects of
combining a defect in glucose storage with one that results in an oversupply of
glucose. 4. study the effects on a mouse with a genetic predisposition for failure of
beta cells (insulin making cells) of a defect in muscle glucose storage and over
production of glucose. A successful completion of this grant will greatly enhance
our understanding of how blood glucose is increased in Type 2 diabetes.
Research achievements (from final report):
The aim of this project is to investigate the impact of a defect in the action of muscle
glycogen synthase, ( the enzyme that manufactures glycogen in muscle) on glucose
metabolism. It is known that patients with type 2 diabetes have a defect in glucose
storage in muscle. To achieve this aim we will delete the glycogen synthase gene in
the muscules of mice using a technique that can selectively delete genes in specific
tissues. This is a complex technique that requires the production of two lines of
transgenic mice, one in which the wildtype (normal) glycogen synthase gene has been
replaced by a modified gene in which extra pieces of DNA have been added to allow
deletion of parts of it, and a second mouse line in which there is expressed a deleting
gene that is only active in muscle. Breeding the two mice together will make a third
mouse line in which the target gene and the cutting gene are both present. We have
made the deleting mouse and the target mouse is being made now. A second aim of
this project is to determine the impact of other known abnormalities present in
diabetes such as increased glucose production and impaired insulin secretion when
added to this defect. This will be achieved by mating the glycogen synthase knockout
mouse with mice that have the other two defects. The major benefit of this study is
that it may point to which defects are more important in the development of type 2
diabetes and thus which make the best targets for therapy.
Expected future outcomes:
NHMRC Research Achievements - SUMMARY
We will determine if the glycogen synthase defect included in adult mice will result in
insulin resistance in muscle. These mice will have little or no glycogen in muscle and
the effect of this on exercise tolerence can also be studied. The glycogen synthase
target mice can also be used to delete glycogen synthase in other tissue such as brain
and fat cells.
Name of contact: Joseph Proietto
Email of contact: j.proiteeo@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 145769
CIA Name: Dr Sofianos Andrikopoulos
Main RFCD: Endocrinology
Admin Inst: University of Melbourne
Start Year: 2002
End Year: 2003
Total funding: $212,485.00
Grant Type: NHMRC Project
Grants
Title of research award:
The role fructose-1,6-bisphosphatase on the regulation of hepatic gluconeogenesis
Lay Description (from application):
Type 2 or adult onset diabetes is a disease characterised by high blood sugar that
causes damage to the kidneys, eyes and to the circulation and many patients die from
heart attack or stroke. There is an increase in the prevalence of diabetes in Australia
and a substantial portion of the health budget is utilised by caring for people with
diabetes. Determining what exactly causes the increase in blood sugar levels is
critical in the treatment of the disease. It is known that the sugar produced and
released by the liver is an important contributor to the high blood sugar levels found
in patients with diabetes. The main biochemical pathway responsible for this is called
gluconeogenesis, a complex arrangement of enzymes, which convert amino acids and
fat into sugar. Although it is known that this pathway is overactive in patients with
diabetes, the exact reason for this is not clearly understood. The aim of this proposal
is to produce a transgenic mouse that has an increase in liver sugar production as a
result of an increase in gluconeogenesis, and to study its effects on blood sugar levels.
Furthermore, studies will be performed to understand the regulation of this pathway
by infusing the transgenic mice with insulin, the hormone that inhibits
gluconeogenesis. The mechanism of action of insulin will be determined by the
measurement of key enzymes that regulate gluconeogenesis. The significance of this
grant is to identify possible sites for the development of new drugs or gene therapy
that will lead to a decrease in the production of sugar by the liver. This will lead to
better control of blood sugar levels and slow down or even prevent the onset of
diabetes complications.
Research achievements (from final report):
Type 2 diabetes is characterised by an increase in blood sugar levels which over time
has detrimental effects on the health of the patients compromising kidney and eye
function and contributing to an increase in the risk of heart disease and stroke. Thus
understanding the reason that blood sugar levels are increased in Type 2 diabetes is
crucial in the management of this disease. Research has shown that a biochemical
pathway in the liver called gluconeogenesis, which produces sugar, is overactive and
contributes to the high sugar levels in patients with diabetes. Furthermore our group
has shown that an enzyme in gluconeogenesis called FBPase is increased in animal
models of Type diabetes and that this may be the reason for increased sugar
production. The of this project was to generate a transgenic mouse that overexpressed
the human form of FBPase in the liver, to determine whether this genetic alteration
will lead to increased gluconeogenesis and eventually diabetes. During the course of
this project we cloned the human FBPase gene, inserted it into a vector and generated
liver FBPase transgenic mice. Over the last 10 months we have been studying the
physiological outcomes of an increase in liver FBPase, with the suggestion that it
results in an increase in sugar production. If this transgenic mouse develops increased
NHMRC Research Achievements - SUMMARY
sugar production it will identify FBPase as a potential therapeutic target for the
development of drug therapy for patients with Type 2 diabetes.
Expected future outcomes:
Interventions decreasing blood sugar levels are very important in reducing the risk of
death from heart attacks and stroke in Type 2 diabetes. This project has the potential
of showing whether an enzyme, called FBPase, involved in sugar production can be a
potential therapeutic target for the development of drug compounds which would be
beneficial in patients with Type 2 diabetes.
Name of contact: Sofianos Andrikopoulos
Email of contact: sof@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 400143
CIA Name: Dr David Stapleton
Main RFCD: Protein Targeting and Signal Transduction
Admin Inst: University of Melbourne
Start Year: 2006
End Year: 2008
Total funding: $538,765.00
Grant Type: NHMRC Project
Grants
Title of research award:
Structure and function of the AMPK glycogen-binding domain
Lay Description (from application):
The AMP-activated protein kinase (AMPK) is an enzyme responsible for coordinating
metabolism in response to energy supply (diet) and energy demand (exercise).
Research into this kinase can increase our understanding of how diet and exercise are
so important for maintaining health. The kinase acts either by "sensing" when cellular
energy levels become too low for normal functioning or when the body tells it by
sending a chemical messenger (hormone) that overall energy levels are low. This
results in activation of energy-producing pathways and inhibition of energyconsuming pathways, allowing cells to match supply with demand to ensure their
survival. The AMPK comprises of three proteins that together form a functional
enzyme. I have previously found that AMPK localizes to a source of cellular energy
called glycogen (sugar stores) via one part that I have called the glycogen-binding
domain. In this application I aim to obtain a thorough understanding of the molecular
basis of how the glycogen-binding domain affects AMPK function in muscle and
heart following exercise. In addition this research may lead to the identification of
new molecules, similar to glycogen, that are important for AMPK regulation and may
lead to the development of a new class of drugs for Type 2 Diabetes. Research into
AMPK promises to dramatically increase our knowledge of how to reduce the risk of
cardiovascular and neurodegenerative diseases, diabetes and obesity and provide an
understanding of the reasons these diseases develop.
Research achievements (from final report):
The AMP-activated protein kinase (AMPK) is an enzyme responsible for coordinating
metabolism in response to energy supply (diet) and energy demand (exercise). The
AMPK acts either by "sensing" when cellular energy levels become too low for
normal functioning. This results in activation of energy-producing pathways and
inhibition of energy-consuming pathways, allowing cells to match supply with
demand to ensure their survival. The AMPK comprises of three proteins that together
form a functional enzyme. I have previously found that AMPK localizes to a source
of cellular energy called glycogen (sugar stores) via one part that I have called a
carbohydrate-binding module. During this project I have discovered that the
carbohydrate-binding module from one of the three proteins called the beta subunit,
associates with a part of glycogen that is only found when glycogen is being used.
This suggests that AMPK binds to glycogen when energy is being created and we
think leads to inhibition of AMPK because this enzyme is only activated when energy
is low. In addition, this research grant has allowed for the development of new
methodology to isolate glycogen molecules from any cell type. This has resulted in
the discovery of a new protein that binds to glycogen and new insights into how
proteins important for glycogen synthesis and breakdown actually bind to glycogen
NHMRC Research Achievements - SUMMARY
and how diet and exercise alter this association. These findings may lead to new
approaches for treating Type 2 diabetes where energy metabolism is disrupted.
Expected future outcomes:
The long-term goal of this research is to understand the regulation of skeletal muscle
AMP-activated protein kinase by glycogen that will lead to novel strategies for the
treatment of Type 2 diabetes.
Name of contact: David Stapleton
Email of contact: dis@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 365313
CIA Name: Prof Mauro Sandrin
Main RFCD: Transplantation Immunology
Admin Inst: University of Melbourne
Start Year: 2007
End Year: 2008
Total funding: $580,390.00
Grant Type: NHMRC Project
Grants
Title of research award:
Tolerance Induction to Porcine Islet Xenografts
Lay Description (from application):
The current treatment for diabetes involves diet, drugs and insulin treatment. While
these are satisfactory for some adult onset diabetes, it is clear that in juvenile diabetes,
the disease can progress in the presence of careful insulin dosage. It is apparent that
the whole islet as a functional unit is likely to give the best control of diabetes, as
when patients are transplanted with whole or segments of pancreas from human
donors, as not only is there an improvement in their diabetic status, the vessel lesions
improve. Transplantation therefore offers a new therapy to diabetic patients for
reversal of their disease and improvement in the serious side affects found in the eye,
kidney and blood vessels. However, transplantation introduces a problem in that there
is simply not sufficient human islets available for organ or islet transplantation, and in
this light, animals are being examined as a possible source of islets. This is called
xenografting or xenotransplantation. Of all the animal species, the pig is the most
suitable donor for a variety of reasons, for example similar control of blood sugar to
humans. The ultimate aims of the study are to examine possible genetic modifications
that would allow the production of transgenic pig islets for transplantation to humans
for the treatment of diabetes. The focus of the proposed studies is to elucidate the
optimal combinations using mouse models. Importantly this study will establish the
proof of principle and provide information on the genes that will be useful to finally
genetically modify pigs for clinical use.
Research achievements (from final report):
The critical shortage of donor organs represents an enormous health burden to
Australia. Thus, there is an urgent need for alternative treatments.
Xenotransplantation represents the most promising solution to this problem.
Xenotransplantation, the transplantation of organs from species other than humans, is
now seen as a viable solution to the world wide problem of lack of supply of suitable
human donors. However, the first immunological barrier to both xenotransplantation
and mismatched ABO blood group transplantation is rejection due to natural
antibodies circulating in the serum of the recipient. These antibodies recognise
antigens on the donor tissue that are absent in the recipient.
The production of pigs, with a disruption in the gene that encodes the enzyme that
makes the antigen that antibodies recognise represented a critical step towards the
clinical reality of xenotransplantation. We have now been focusing on the
development protocols and therapeutic approaches to the cellular (T cell) phase of the
xenograft response. Our hypothesis is that the expression of key immunomodulatory
molecules in modified grafts will lead to prolonged, if not indefinite, xenograft
survival. We evaluated nine candidate molecules, expressed locally as transgenes, for
their ability to extend survival of porcine cellular xenografts in mice. From these,
three key immunomodulatory molecules were identified (CTLA4Ig, ICOSIg and
NHMRC Research Achievements - SUMMARY
Indoleamine 2,3-dioxygenase (IDO)) that lead to significantly prolonged, but not
indefinite survival of xenografts.
Expected future outcomes:
This information will form the basis of therapeutic principles that will be applied to
our preclinical large diabetic animal model. This information will be essential for
potential clinical pig-to-human xenotransplantation and should identify both the
molecular and cellular mechanisms involved in xenograft prolongation.
Name of contact: Mauro Sandrin
Email of contact: m.sandrin@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 237033
CIA Name: Dr Amanda Edgley
Main RFCD: Systems Physiology
Admin Inst: University of Melbourne
Start Year: 2003
End Year: 2008
Total funding: $552,051.00
Grant Type: Early Career
Fellowships (Australia)
Title of research award:
Targeting Obesity: manipulating metabolism using genetically modified mice
Lay Description (from application):
Not Available
Research achievements (from final report):
The industry component of the fellowship was undertaken at AstraZeneca
Pharmaceuticals, Sweden, in the Dept. of Integrative Pharmacology. During this
period Dr Edgley entered into an entirely new area of research, gaining experience in
characterising metabolic disturbances in animal models of Type 2 diabetes, and
examining the properties of novel agents for correction of these metabolic
disturbances. Specifically, she developed techniques assessing fat and sugar use by
the tissues in living mice. These techniques are restricted to few groups around the
world. In January 2006, Dr Edgley returned to the Dept. of Physiology at Monash
University to continue the academic portion of the fellowship. AstraZeneca continued
to support Dr Edgleys new research program by donating a equipment to facilitate
studies of heart function in living mice. In January 2007, Dr Edgley moved to the
Department of Medicine, St. Vincent's Hospital, joining the Diabetic Complications
group headed by Assoc. Prof. Darren Kelly. The Diabetic Complications group is
actively studying cardiac complications of diabetes at clinical and basic science
levels, including in vivo studies of cardiac function in diabetic patients and animal
models, focussing on pre-clinical and early phase clinical drug development. Since
returning to Australia Dr Edgley has imported and bred a special colony of mice, that
spontaneously develop type 2 diabetes (the only colony of such mice in Australia),
and developed techniques to measure heart function in these mice and has
successfully characterised reduced heart function in these mice, similar to what is
seen in human patients with diabetes.
Expected future outcomes:
We now have a well characterised model of obesity and type 2 diabetes with reduced
heart function in our mouse model, and are commencing studies to investigate the
effect of novel agents in preventing the metabolic changes and attenuating the reduced
heart function
Name of contact: Amanda Edgley
Email of contact: aedgley@medstv.unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 400417
CIA Name: A/Pr Mathis Grossmann
Main RFCD: Endocrinology
Admin Inst: University of Melbourne
Start Year: 2006
End Year: 2010
Total funding: $214,744.00
Grant Type: Early Career
Fellowships (Australia)
Title of research award:
Androgen Deficiency in Men with Obesity-Type 2 Diabetes:Prevalence,
Characteristics, Effect of Testosterone Replacement
Lay Description (from application):
Not Available
Research achievements (from final report):
Our cross-sectional studies showed that 50% of men with type 2 diabetes had
subnormal testosterone levels, relative to healthy young men (1). Low testosterone
was associated with anaemia in such men (2), implicating biological consequences of
androgen deficiency. Moreover, low testosterone was associated with insulin
resistance and an adverse metabolic profile (1). To address whether low testosterone
was cause or consequence, we prospectively studied men with prostate cancer
receiving androgen deprivation therapy (ADT), which has become the most common
contemporary cause of severe hypogonadism (3). ADT led to increases in visceral fat
mass and insulin resistance (4), suggesting that low testosterone may promote the
development of diabetes. Conversely, weight loss increases testosterone, highlighting
the bi-directional relationship between low testosterone and diabetes (5). Given that
the risk-benefit ratio of testosterone therapy requires further rigorous study, the first
response to the aging male with diabetes and subnormal testosterone should remain
the implementation of life-style measures facilitating weight loss. In our prospective
studies using high-resolution peripheral quantitative CT imaging, ADT promoted loss
of both trabecular and cortical bone, the degree of which may be underestimated by
conventional DEXA (6). ADT also induced sarcopaenia (4), which may contribute to
fracture risk by increasing falls risk.With these adverse endocrine effects of ADT in
mind, we launched a dedicated Men's Health Clinic where all men with nonmetastatic prostate cancer receiving ADT are managed according to standardised,
evidence-based guidelines (7).
Expected future outcomes:
Men with low testosterone, whether associated with diabetes or consequent to ADT
represent high-risk populations that require dedicated management. The extent to
which low testosterone contributes to poor health outcomes, and how this can be
mitigated, requires further mechanistic and interventional studies.
Name of contact: Mathis Grossmann
Email of contact: mathisg@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 509334
Start Year: 2008
CIA Name: Prof Siaw-Teng Liaw
End Year: 2011
Main RFCD: Public Health and Health Services not elsewhere classified
Total funding:
$381,292.00
Admin Inst: University of Melbourne
Grant Type: NHMRC Project
Grants
Title of research award:
Culturally appropriate diabetes care in mainstream general practice for urban
Aboriginal and Torres Strait Islander people
Lay Description (from application):
Main study objectives are to determine the enablers & barriers for urban Indigenous
people to access mainstream primary care services, in particular diabetes chronic care
services. This knowledge of critical access and acceptability factors will guide the
development of a culturally approirate diabetes care intervention for Indigenous
patients. This adpated intervention, to be delivered in mainstream general practices,
will be pilot-tested for cultural appropriateness in Indigenous patients.
Research achievements (from final report):
We conducted an extensive literature review and consulted widely with the
Indigenous community and service providers about the success factors and barriers to
and facilitators of access to urban general practice and and primary health care
(GP&PHC) for chronic disease care. This guided the development of a cultural
respect framework and implementation toolkit called 'Ways of Thinking, Ways of
Doing'. It deconstructs urban general practice into 4 layers: the community, the
reception, the consulting room and the organisational layers. It provides guiding
principles in GP&PHC policy construction and service delivery. It incorporates care
partnerships of Indigenous and mainstream organisations at local levels and revolves
around applying practical strategies.
The Toolkit was field tested in eight general practices and four community health
centres in Melbourne. Facilitated by Indigenous research officers, care partnerships
were formed to support the pilot sites. Partners included Divisions of General Practice
and local Indigenous groups, such as Aboriginal community controlled health services
or Indigenous gathering places. A clinical re-design process was adopted to embed
activities in stages according to each site's readiness to improve cultural respect into
their professional practice.
In general, the Toolkit was acceptable and feasible in the mainstream setting. Pilot
results suggest that there were increases in identification and follow-up of Indigenous
patients, number of Indigenous health checks and other relevant MBS services
performed. There was also evidence of improved practice environment and
engagement with local Indigenous communities and organisations.
Expected future outcomes:
The care partnership and Toolkit can close the gap between thinking and doing
cultural respect in general practice and primary care. The program is congruent with
the NHMRC cultural competence and COAG cultural respect frameworks. It has the
NHMRC Research Achievements - SUMMARY
potential to be and is currently being adapted to other settings and professions. A
multicentre controlled trial of the program is being developed.
Name of contact: Dr Phyllis Lau
Email of contact: plau@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 400011
CIA Name: Dr Odilia Wijburg
Main RFCD: Immunology not elsewhere classified
Admin Inst: University of Melbourne
Start Year: 2006
End Year: 2008
Total funding: $314,773.00
Grant Type: NHMRC Project
Grants
Title of research award:
The role of secretory antibodies in mucosal homeostasis
Lay Description (from application):
This proposal will address the role of the antibodies that are present in all secretions
from the gut, the lungs, the eye and mouth in maintaining the health of the mucosal (ie
mucous covered) tissues from which they originate. It has long been presumed that
these antibodies stop bacteria and other pathogens adhering to the surface of mucosal
tissues. Our preliminary findings suggest that they have another very important role
in removing excess inflammatory material from beneath the lining of the mucosal
tissues, to prevent recognition of this material by the immune system. Such
recognition could result in serious consequences both locally (ie. in the gut) and more
distally eg. in the pnacreas leading to diabetes. As a consequence, we believe that
these antibodies are fundamental to health. The research could have important
ramifications for diseases resulting from immune responses against host tissues, socalled autoimmune diseases like diabetes.
Research achievements (from final report):
The secretory immune system is exemplified by the production of large amounts of
dimeric IgA and pentameric IgM. These antibodies are secreted across the epithelium
of the mucosal surfaces by the polymeric immunoglobulin receptor (pIgR). In this
project, we use the B6.pIgR-/- mouse as a model for deficiency of the secretory
immune system. We demonstrated that in B6.pIgR-/- mice 1) access of luminal
antigens to the systemic immune system is increased, 2) B cell populations are
dysregulated, 3) populations of regulatory-type CD4+ T cells in the mucosal tissues
are increased and 4) production of inflammatory mediators is increased. These
observations confirm our hypothesis that secretory antibodies help prevent unwanted
inflammatory responses at mucosal surfaces.
We next investigated whether increased exposure to luminal antigens results in
enhanced inflammatory and/or autoimmune responses using the diabetes-prone NonObese Diabetes mouse. The pIgR mutation was backcrossed onto NOD mice and we
observed a reduced incidence of diabetes in NOD.pIgR-/- mice. Further analysis of
NOD.pIgR-/- mice demonstrated that this reduced incidence in diabetes was not due
to altered kinetics of CD8+ T cell responses against relevant autoantigens, but, as a
result of increased exposure to luminal antigens in the absence of secretory
antibodies, the number of autoantigen specific T cells is possibly diluted in draining
lymph nodes, resulting in reduced incidence of diabetes.
Benefits: Understanding the impact of the secretory immune system on regulation of
inflammatory responses to self and/or luminal antigens is of significant importance
for our understanding of autoimmunity. The impact of mucosal vaccination strategies
on the regulatory functions of the secretory immune system should be considered.
NHMRC Research Achievements - SUMMARY
Expected future outcomes:
Detailed understanding of the regulatory functions of secretory antibodies at mucosal
surfaces and its significance for the development of inflammatory and/or autoimmune
responses.
Name of contact: Odilia Wijburg
Email of contact: odilia@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 156703
CIA Name: Prof Frank Alford
Main RFCD: Endocrinology
Admin Inst: University of Melbourne
Start Year: 2001
End Year: 2003
Total funding: $347,037.00
Grant Type: NHMRC Project
Grants
Title of research award:
Comparison between AICAR and exercise-induced stimulation of skeletal muscle
AMP-K on fat/glucose metabolism in diabetes
Lay Description (from application):
Background and Rationale: Exercise is important in the life of the diabetic. In well
controlled diabetes, the rates of whole body sugar usage and energy production in
skeletal muscle (SkM) in response to acute exercise are similar to non-diabetics.
However in diabetics, little information is available as to how SkM processes sugar
and produces energy during exercise. Insulin controls SkM sugar and energy
processing in sedentary subjects. During exercise, these processes are controlled by
non-insulin factors. The chemical catalyst AMP activated protein kinase (AMP-K),
which has been investigated only in normal exercising rats, is an important alternative
regulator of acute sugar processing and energy supply for exercising SkM. No studies
of AMP-K activity are available in diabetes. Our studies will focus on i) how
important is the stimulation of SkM AMP-K in diabetes to efficient SkM sugar
processing and energy production; ii) if the benefits of exercise can be simulated by
pharmacological stimulation of AMP-K in sedentary diabetic subjects. We aim to i)
compare the metabolic effects of exercise vs pharmacological stimulation of AMP-K
in normal and diabetic subjects; ii) define the molecular mechanisms which trigger the
AMP-K metabolic responses; iii) determine if the circulating levels of insulin, blood
sugar and/or blood fat influence the AMP-K metabolic responses. Likely Outcomes:
pharmacological stimulation of AMP-K will improve SkM sugar metabolism, but less
so in diabetes. The associated AMP-K stimulation of SkM fat metabolism may blunt
the beneficial SkM sugar responses, particularly in diabetes. This information will be
used in future drug developments for diabetics which aim to simulate the beneficial
AMP-K metabolic effects of exercise.
Research achievements (from final report):
Exercise favourably impacts on glucose and fat metabolism, promoting oxidation or
burning of glucose and fat via activation of a specialised muscle enzyme or catalyst,
AMP-activated protein kinase (AMPK). This may lead to a reduction of the patients'
medications required to achieve good control of diabetes, or even prevent emergence
of the disease. However effective long term exercise programs are difficult to
maintain in a community. Our research examined whether administration of a
chemical agent (AICAR), which substitutes for the "natural" activator of AMPK,
could mimic the metabolic benefits of exercise-induced activation of AMPK. In
normal subjects: AICAR administration increased AMPK-stimulated utilisation of
glucose (sugar) and fat by muscle, but glucose was metabolised (burnt) predominantly
via the non-oxidative low energy output pathway and tissue fat oxidation (burning)
was sourced from the bloodstream. The increased muscle utilisation of glucose was
matched by an increase in liver glucose output. When tissue fat oxidation was
blocked prior to AICAR, muscle glucose utilisation was further increased, again via
NHMRC Research Achievements - SUMMARY
the non-oxidative low energy output pathway. These metabolic responses are
different from those seen when the same subject is exercised, glucose being burnt in
muscle only via the high energy oxidative pathway and the increased fat oxidation
being derived from the body's fat stores. In contrast, in poorly controlled diabetes,
fasting muscle AMPK activity status is increased and fails to rise further with
exercise. Also AICAR alone and AICAR + fat oxidation blockade in the diabetic
caused a significant fall in blood glucose levels, not via improved muscle glucose or
fat burning, but via a reduced output of glucose from the liver. Thus, these metabolic
responses in muscle to AICAR did not mimic the positive metabolic health responses
of exercise and were different in the diabetic state compared to normals.
Expected future outcomes:
AICAR or other chemical agents that appear to mimic the exercise-induced activation
of the key physiological regulator (AMPK) of the exercise metabolic responses are
unlikely to be effective substitutes for exercise, especially in diabetics. Clearly
exercise provides multiple beneficial effects on glucose and fat metabolism, other
than those produced by activation of the AMPK pathway alone.
Name of contact: Prof Frank Alford
Email of contact: frank.alford@svhm.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 145670
CIA Name: Prof Stephen Davis
Main RFCD: Neurology and Neuromuscular Diseases
Admin Inst: University of Melbourne
Start Year: 2001
End Year: 2002
Total funding: $278,418.00
Grant Type: NHMRC Project
Grants
Title of research award:
The Adverse Effects of Diabetes on Stroke: An Echoplanar MRI Study
Lay Description (from application):
Stroke is the most common, major brain disease in Australia. It is the third most
common cause of death and the most common cause of adult disability. There is a
close link between diabetes and stroke. Firstly, diabetes is an important risk factor for
the development of stroke. Secondly, about one third of stroke patients have diabetes.
In general, their outcome is much worse than other patients. In fact little is known
about the cause of this adverse effect in stroke patients and there is uncertainty
whether intensive control of blood sugar in acute stroke improves outcome. Our pilot
work suggests that raised brain lactate, together with larger stroke size, might together
be responsible for the worse outcome in diabetic patients. We can now measure
brain lactate and stroke size with new MRI techniques called echoplanar MRI, which
can allow measurements of brain chemistry, blood flow, potentially viable and dead
tissue. A new monitoring device allows non-invasive measurement of blood sugar
every 5 minutes. Using these strategies, we are planning a comprehensive study of
the causes of the worse stroke outcome with diabetes. In addition, we are
incorporating a study to determine whether intensive control of blood sugar in the first
3 days after stroke, compared with standard treatment, reduces brain lactate and
growth of the actual stroke. An understanding of these effects will have important
implications for the acute treatment of stroke patients. If we can show that rigorous
control of blood sugar reduces brain lactate and stroke growth, our study will lay the
ground work for a large clinical trial. This could have important implications, both in
Australia, and overseas.
Research achievements (from final report):
This body of work has demonstrated that acute hyperglycemia in stroke is an
independent predictor of adverse outcome, has shed new light on the mechanisms and
duration of hyperglycemia and indicated the importance of a specific cerebral location
in its pathogenesis. We have shown that the duration of post-stroke hyperglycemia is
independently associated with infarct expansion and worse clinical outcome. Major
original contributions include the demonstration that frequent measures of tissue
glucose, every 5 minutes, over the first 72 hours after onset provide more robust
correlations with infarct volume changes, final infarct size and clinical outcome.
These serial changes are superior to single glucose estimations. This is the first report
of continuous glucose monitoring after stroke. In a separate study we have been the
first to show that a specific cerebral location, namely the insular cortex, is an
important and independent determinant of acute post-stroke "stress hyperglycemia".
We have postulated that insular ischemia produces neuroendocrine dysregulation as
part of a more generalised acute stress response. This has important implications for
future studies of post-stroke hyperglycemia. Our research has helped to elucidate the
mechanism of the adverse effect of hyperglycemia on clinical outcome, by increasing
NHMRC Research Achievements - SUMMARY
brain lactate production and factilitating conversion of critically-hypoperfused at-risk
brain tissue, in the ischemic penumbra, into frank infarction. We have also shown the
important contributions and interactions of both elevated hematocrit and elevated
glucose in stroke prognosis. Further research has been performed, analysing the
prothrombotic state in the acutely ischemic brain, incorporating measures of PAI-1
and other hematological determinants. Taken as a whole, the work on hyperglycemia
and acute stroke has been widely cited and we are acknowledged as one of the leading
international centres in this field.
Expected future outcomes:
This work indicates the importance of continuous glucose monitoring in acute stroke
patients and supports the hypothesis of normalisation of post-stroke hyperglycemia
using intravenous insulin infusions. Positive results of an on-going trial, testing
whether intensive glucose normalisation modifies lactate generation and infarct
expansion, will help change clinical practice.
Name of contact: Professor Stephen Davis
Email of contact: stephen.davis@mh.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 401112
CIA Name: Dr Shaun Sandow
Main RFCD: Cell Physiology
Admin Inst: University of New South Wales
Start Year: 2006
End Year: 2010
Total funding: $462,290.00
Grant Type: Career
Development Fellowships
Title of research award:
Understanding the relationship between arterial structure and divergent vasodilatory
function in health and disease
Lay Description (from application):
Not Available
Research achievements (from final report):
Identified various potential therapeutic targets for the control of blood flow in disease,
as per publication data.
Expected future outcomes:
Continuing to indentify potential new therpeutic targets for the control of blood flow
in disease. Several additional peer-reviewed Journal articles, as well as additional
conference/abstracts are in preparation.
Name of contact: Shaun Sandow
Email of contact: Shaun.Sandow@unsw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 401190
CIA Name: Prof Nigel Lovell
Main RFCD: Ophthalmology and Vision Science
Admin Inst: University of New South Wales
Start Year: 2008
End Year: 2008
Total funding: $404,684.00
Grant Type: NHMRC
Development Grants
Title of research award:
Development of an epiretinal neuroprosthesis based around multiple stimulation
sources and hexagonal guard electrodes
Lay Description (from application):
Not Available
Research achievements (from final report):
Engineering work was undertaken to develop and refine a retinal neurostimulator or
so called 'bionic eye'. This involved the engineering of an electronic circuit and
appropriate hermetic encapsulation as well as laser micromachining of appropriate
biostable materials to form an electrode array. A revised surgical approach was also
developed, whereby the electrode array was inserted into the eye. Bench and
experimental work was undertaken to demonstrate that in acute implantations, reliable
and reproducible indicators of visual perception could be achieved.
Expected future outcomes:
Based on the success of the work undertaken, a consortium called Bionic Vision
Australia (BVA). has been formed The consortium involves five partners including
the original collaborators on this grant. BVA has applied for continued funding from
several sources and is working towards long-term human implantations in two to three
years time.
Name of contact: Prof Nigel Lovell
Email of contact: N.Lovell@unsw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 402485
CIA Name: Prof Richard Taylor
Main RFCD: Indigenous Health
Admin Inst: University of New South Wales
Start Year: 2006
End Year: 2010
Total funding: $483,291.00
Grant Type: NHMRC Project
Grants
Title of research award:
Mortality and survival among clients of the Aboriginal Medical Service at Redfern
Lay Description (from application):
The aims of the mortality study are to: (a) document current age/sex specific and
cause-specific Indigenous mortality; (b) establish trends in age/sex specific and
cause-specific Indigenous mortality over time; (c) compare age/sex/cause specific
mortality in the AMS Redfern cohort with patterns documented in other Aboriginal
populations, and in the general Australian population. The null hypotheses for
general and cause-specific mortality (age-adjusted) are that: (a) there has been no
decline in mortality in Aboriginal people attending AMS Redfern over 30 years
covering 1972-2001; (b) survival in the AMS cohort is similar to that recorded in
Aboriginal people from NT and WA (mostly rural) for similar time periods; (c)
comparisons of the AMS cohort mortality with overall NSW mortality are similar to
previously published comparisons of NT/WA Aboriginal mortality compared to
overall Australian mortality data. Major causes of mortality will centre on endocrine
(mainly diabetes), cardio- and cerebro-vascular diseases, and on external causes,
including suicide/violence and accidental death. The mortality study will be extended
back to the inception of the AMS, and will rely on computerisation of name(s), sex,
date of birth and date of first and last AMS attendance for the whole AMS patient data
base, to provide information for matching of patient records with the National Death
Index (for deaths from 1980) and for matching with the NSW mortality data for 197179 (as there is no nationwide mortality data available from a single source prior to
1980).
Research achievements (from final report):
This research involved computerisation of demographic information on all clients
who have ever visited the AMS (approximately 35,000) and linkage with the
National Death Index to produce mortality data by age group, sex, period and cause
for an urban Aboriginal population from an eastern Australian state (NSW) for which
this information is lacking. Life tables are being prepared for this group and compared
to other Aboriginal populations and to the general Australian population . This
enables assessment of disease control priorities in urban Aboriginals in eastern
Australian states and permits overall evaluation of outcomes of services and
interventions over time.
Expected future outcomes:
This study will assist in understanding differences in Aboriginal health and mortality
in Australia, and changes over time in the level and causes of death.
Name of contact: Richard Taylor
Email of contact: r.taylor@unsw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 570762
CIA Name: Prof Peter Gunning
Main RFCD: Cell Physiology
Admin Inst: University of New South Wales
Start Year: 2009
End Year: 2011
Total funding: $545,216.00
Grant Type: NHMRC Project
Grants
Title of research award:
The actin cytoskeleton regulates glucose transport
Lay Description (from application):
A major function of skeletal muscles is the import of glucose from the blood to
provide energy for contraction. We have identified a novel structure within muscle
cells defined by the protein tropomyosin that is involved in this essential muscle
function and potentially provides new targets for treatment of diseases of altered
glucose clearance (eg diabetes and obesity).
Research achievements (from final report):
The architecture of cells is not just used to provide scaffolds to support shape and
internal organisation but is also used to move material around the cell. We have found
that one of the major architectural components of the cell is involved in regulating
glucose transport. Increased levels of this component in mice leads to increased
glucose uptake in fat, muscle and the heart. This component was found to localise in
muscle in a compartment which contains the machinery used to regulate glucose
uptake. Previous studies have hinted at the role of this scaffold in glucose transport
but this is the first demonstration of its involverment in a animal. We have also found
that this scaffold component controls the level of a motor which is involved in moving
the glucopse transport machinery into place in the cell. We think we have therefore
identified a specific scaffold which is used to control the organisation and activity of
the glucose transport machinery in the cell.
Expected future outcomes:
The identification of this scaffold and its organisation will lead to a better
understanding of the regulation of movement of the glucose uptake machinery. Drugs
we are developing against this scaffold component may be useful for regulating
glucose uptake and may also identify further drug targets.
Name of contact: Professor Peter Gunning
Email of contact: p.gunning@unsw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 568725
CIA Name: Prof Hongyuan Yang
Main RFCD: Medical Biochemistry: Lipids
Admin Inst: University of New South Wales
Start Year: 2009
End Year: 2011
Total funding: $397,750.00
Grant Type: NHMRC Project
Grants
Title of research award:
The role of seipin in lipid metabolism and adipogenesis
Lay Description (from application):
The prevalence of obesity and its related disorders has reached an alarming level in
Australia and other developed countries. Obesity is characterized by accumulation of
fully-differentiated adipocytes loaded with lipid droplets (LDs). Therefore,
understanding the cellular dynamics of LDs and the molecular mechanisms of
adipogenesis (adipocyte differentiation) is of crucial importance in our battle against
obesity. Our proposed study will help undertand the mechnisams of obesity.
Research achievements (from final report):
Adipocyte development and lipid droplet formation are two key aspects of human fat
storage and obesity. The protein, seipin, has been shown to regulate both adipocyte
development and lipid droplet formation. This project investigated the function of
seipin. We have shown that seipin may play a role in phospholipid metabolism, in
particular the metabolism of phosphotidic adic (Fei et al, PlosGenetics, 2011). We
have also demonstrated that seipin can self associate (Fei et al, J Lipid Research,
2011). Importantly, we have generated a seipin deficient knock-out mouse which
phenocopies the human lipodystrophy (Cui et al, Human Molecular Genetics, 2011).
Together, our work provided novel insights to the function of seipin at cellular and
molecular level, as well as the level of whole body metabolism. The results from this
project are highly significant because mutations in seipin gene cause the most severe
form of lipodystrophy, which is characterized by an almost complete loss of body fat,
insulin resistance, diabetes and fatty liver. A better understanding of seipin function
will not only help patients suffering from lipodystrophy, but also contribute to our
understanding of fat storage in normal human beings. More importantly, therapeutic
strategies may be developed to treat human obesity based on our improved
understanding of seipin.
Expected future outcomes:
The results from this project have formed basis of future strategies to analyze seipin
function. For instance, we have started looking for genetic variants of seipin in
normal, obese and diabetic patients. Given the critical role of seipin in adipose tissue
function, we believe that certain isoforms of seipin may contribute to the development
of human obesity.
Name of contact: Hongyuan Yang
Email of contact: h.rob.yang@unsw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 455268
CIA Name: Prof Mark Harris
Main RFCD: Primary Health Care
Admin Inst: University of New South Wales
Start Year: 2007
End Year: 2009
Total funding: $774,358.00
Grant Type: NHMRC Project
Grants
Title of research award:
A randomized controlled trial of a general practice based intervention to prevent
chronic vascular disease
Lay Description (from application):
Chronic diseases such as heart disease, stroke and diabetes contribute greatly to the
burden of disease in Australian society. Prevention of these conditions is a high
priority for the health system. There is increasing evidence for the effectiveness of
interventions to prevent chronic disease in those at high risk. However the feasibility
of intervening through general practice and other existing services has not been
demonstrated. We have previously conducted research on a structured approach to
helping patients with risk factors for chronic disease (such as smoking, poor nutrition,
hazardous alcohol consumption and physical inactivity) including both cardiovascular
disease and diabetes in general practice. This study aims to evaluate the impact of
recalling patients to general practice for a visit to assess their risk of chronic disease
and to help them to lower their risk by changes to smoking, diet, alcohol consumption
and physical activity behaviours. Practices in the intervention group will receive
training, practice visits, resources, and referral pathways to enable them to invite
eligible patients to attend the practice for an assessment and management of their risk
factors. This will include provision of education materials, support for behaviour
change, referral to diet education and physical activity program and follow up. The
feasibility of this type of vascular disease prevention intervention for high-risk
patients has not been trialled previously in Australia. The findings of this research will
help to inform Australian and State health policy especially the preventive care
initiatives recently announced by the Council of Australian Governments. It will also
inform practice leading to better guidelines for general practice preventive care, better
support for general practice to provide preventive care for patients at risk of chronic
disease and better support for patients to reduce their risk of chronic disease by
changing their behaviour.
Research achievements (from final report):
The study was a cluster randomised trial conducted in 30 general practices in urban
and rural NSW aimed to evaluate the impact of recalling patients to general practice
for a health check, breif intervention and referral to a group program to help them to
lower their risk by changes to smoking, diet, alcohol consumption and physical
activity behaviours, reduce their weight. This intervention was structured around the
5As approach.
Practices were randomised to intervention and control practices. 699 patients
completed the study - 384 in the intervention and 315 in the control goup. The
intervention had a significantly greater rate of education and increase in referral of at
risk patients. Patients in the intervention group reported greater improvement in their
readiness to change at 12m dietary fat, physical activity, alcohol and weight. There
was also significant improvement in physical activity in the intervention than the
NHMRC Research Achievements - SUMMARY
control group. Patients attending a minimum number of sessions at the group
program were also likely to report increased portions of fruit and vegetables and lost
weight (av 1kg) whereas those in the control group did not.
This study demonstrates the feasibility and most impact of a group intervention
complementing GP health checks. The study has resulted in 10 conference
presentations and 4 papers (three published and one in press). There has been
considerable interest in the intervention, findings and evaluation instruments used in
the study by Divisions of General Practice and other service providers.
Expected future outcomes:
The findings will be presented at national and international conferences. Three papers
have been published so far and 5 papers are in preparation or under reviw. The
summary results will be widely disseminated to primary care organizations,
professional bodies, national and state governments. We expect the study to influence
policies and programs including those of Divisions and government.
Name of contact: Prof. Mark Harris
Email of contact: m.f.harris@unsw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 350931
CIA Name: Prof Mark Harris
Main RFCD: Primary Health Care
Admin Inst: University of New South Wales
Start Year: 2005
End Year: 2007
Total funding: $780,625.00
Grant Type: NHMRC Project
Grants
Title of research award:
Trial of structured support to enhance the role of non-GP staff in chronic disease
management in general practice
Lay Description (from application):
Chronic disease presents a significant burden to individuals and the health care system
, contributing to both an increasing proportion of the work of primary health care
practitioners and to health expenditure. A number of interventions have been shown
to result in sustained improvement of health outcomes for people with chronic
diseases, including: more effective use of non-physician providers of care and nurse
case management; integration of self-management support programs with guideline
based treatment plans; more intensive follow up and registries that provide reminders
and feedback. While some of these approaches have been pursued within the
Coordinated Care Trials and the Enhanced Primary Care (EPC) program in Australia,
the role of non medical staff within general practice in chronic disease care has not
been systematically investigated. In 2001 the Commonwealth introduced a number of
initiatives to support better quality of care for diabetes and asthma in general practice
and $104.2 million over four years was provided for general practices in areas of high
workforce pressure to employ more Nurses. The roles of the Practice Manager and
Receptionist have received much less attention. They include faclitating access to
care, supporting the delivery of quality clinical care by the practitioners through the
provision of expert management services (primarily information technology, staff,
financial and facilities management) to the practice. With recent government
initiatives expanding the role of general practice in Australia, effective management
structures and processes within general practices are vital. Non-GP general practice
staff may be the means by which more effective chronic disease management can be
achieved at a time of increasing workforce pressure. This project aims to evaluate the
impact of a program in which non-GP staff are trained and facilitated to be involved
in the management of patients with chronic disease.
Research achievements (from final report):
This is the first Australian study to evaluate the impact of enhancing the role of nurses
and administrative staff in the care of patients with chronic disease in general
practice. The study was one of the largest of its kind, conducted in 60 general
practices in urban and rural NSW, ACT and Victoria during 2006 and 2007. It
involved 2197 patients with diabetes or cardiovascular disease. The study
demonstrated significant changes to the roles of non GP staff in the intervention
practices and an increase in the proportion of patients whose care was planned. This
was achieved without disrupting how they worked as a team and without reducing
their job satisfaction nor their willingness for further change. After 12 months
patients assessed the quality of care received to be better in the intervention practices
than the control practice. The glucose control of patients with diabetes improved
slightly in the intervention practices but not in the control practices.This study has
NHMRC Research Achievements - SUMMARY
important implications for the organisation of general practice to provide care for
patients with chronic disease suggesting that enhancing the role of practice nurses
and administrative staff in the care of general practice patients with diabetes or
cardiovascular disease may contribute to improved planning of care and patient
assessment of the quality of care. The study has resulted in 4 conference presentations
and 2 papers (one published and one in press). There has been considerable interest in
the intervention, findings and evaluation instruments used in the study from primary
care organisations and government.
Expected future outcomes:
The findings will be presented at national and international conferences and 5 papers
are currently in preparation. The summary results will be widely disseminated to
primary care organizations, professional bodies, national and state governments. We
expect the study to influence policies and programs including those of Divisions and
government.
Name of contact: Mark Harris
Email of contact: m.f.harris@unsw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 455363
CIA Name: A/Pr Maria Craig
Main RFCD: Endocrinology
Admin Inst: University of New South Wales
Start Year: 2007
End Year: 2011
Total funding: $235,529.00
Grant Type: Career
Development Fellowships
Title of research award:
Prospective evaluation of risk factors for the development of islet autoimmunity and
T1DM in children
Lay Description (from application):
Not Available
Research achievements (from final report):
The application for a NHMRC Career Development Award was to enable me to
develop independent research in my position as Senior Lecturer in the School of
Women's and Children's Health UNSW, while maintaining close collaboration with
research teams at Prince of Wales Hospital (Virology Research Group) and the
Children's Hospital at Westmead (Institute of Endocrinology and Diabetes). The
application was submitted four years after the award of my PhD at a time when I was
just starting to develop my own research group and initiate research collaborations. In
the five years of the project, I have achieved 60 peer reviewed publications, with 32
of these directly related to the CDA proposal and the remainder resulting from
collaborations and research that was enabled by dedicated research time. During this
time have mentored and supervise research students and contributed to postgraduate
education in paediatric endocrinology in Australia and internationally. I have received
more than $4 million in research funding, including four NMHRC project grants (one
as Chief Investigator A) and Juvenile Diabetes Research Foundation Grant (principal
investigator). My international profile has increased markedly, with invitations to
present at international meetings including a plenary lecture on Viruses and Diabetes
at the International Society for Paediatric and Adolescent Diabetes Meeting in 2010. I
have made significant contributions to evidence based care, as co-chair of the
National Evidence Based Clinical Care Guidelines for Type 1 diabetes (approved by
the NHMRC in 2011). I was promoted to Associate Professor in the School of
Women's and Children's Health in 2009.
Expected future outcomes:
It is my intention to continue as a productive clinician-researcher and hope to attract
NHMRC fellowship funding to support committed research time. I will continue to
have a strong emphasis on the viral aetiology of diabetes and evidence-based care in
my research, building on the achievments made during the CDA.
Name of contact: Assoc Prof Maria Craig
Email of contact: m.craig@unsw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 510258
CIA Name: A/Pr Maria Craig
Main RFCD: Paediatrics
Admin Inst: University of New South Wales
Start Year: 2008
End Year: 2011
Total funding: $475,107.00
Grant Type: NHMRC Project
Grants
Title of research award:
Viral triggers of autoimmunity and type 1 diabetes: a prospective study of at risk
children
Lay Description (from application):
We are studying the role of viruses in causing type 1 (insulin dependent) diabetes. By
following babies from birth, we can see whether early signs of damage to the body's
insulin producing cells results from infection with particular viruses. We will study
the genes and other features of these viruses to help us understand why they cause
diabetes, and how they relate to other factors such as diet and vitamin D. The results
may provide valuable information for the future prevention of diabetes.
Research achievements (from final report):
In this prospective cohort study of children followed from birth, we sought to
investigate the role of environmental triggers, in particular enteroviruses in the
development of type 1 diabetes. We recruited over 300 infants whose mother, father
or sibling has type 1 diabetes, which meant they had an increased risk of type 1
diabetes compared with the general population. We recruited their mother during the
pregnancy and followed the infant from at birth every 3-6 months. We found that
enterovirus infections were more common in children before the first signs of diabetes
developed. We also found there was a pattern of inflammation (production of
'cytokines') at the same time. We also performed a 'systematic review' and compared
our results with those of other studies around the world - this showed that enterovirus
infections were much more common both at the start of the diabetes process and at the
time of diabetes diagnosis. We also found that certain strains of enteroviruses were
involved, particularly those from the Coxsackie B group of viruses. While we found
that vitamin D deficiency in pregnancy is very common, we did not find it was a risk
factor for development of type 1 diabetes in our population. We found other common
viruses, such as cytomegalovirus and Epstein Barr Virus, were common in pregnancy,
infancy and childhood, but none were associated with type 1 diabetes. During
pregnancy, infection was associated with increased cytokine levels also.
The results of our studies have provided new information on infection and
inflammation during pregnancy and childhood, and furthered our understanding of the
timing of infection. Our parallel in vitro studies, using enterovirus isolates from the
study, have enabled us to identify specific enteroviruses that are associated with
diabetes and inflammation in the insulin producing cells of the pancreas.
Expected future outcomes:
The study has led to national collaborative study of environmental triggers of type 1
diabetes from pregnancy (NHMRC Project APP 1025083, 2012-2104, CIB - A/Prof
Craig) and collaborations with A/Prof Anand Hardikar, from the University of
NHMRC Research Achievements - SUMMARY
Sydney, investigating the role of microRNAs and enterovirus infection in type 1
dabetes.
Name of contact: Assoc Prof Maria Craig
Email of contact: m.craig@unsw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 300610
CIA Name: Dr Tertia Purves-Tyson
Main RFCD: Cellular Nervous System
Admin Inst: University of New South Wales
Start Year: 2004
End Year: 2010
Total funding: $344,855.00
Grant Type: Early Career
Fellowships (Australia)
Title of research award:
Effect of estrogen on signalling mechanisms of the pelvic autonomic nervous system
underlying bladder ...
Lay Description (from application):
Not Available
Research achievements (from final report):
The ultimate goal of this research was to provide targets for prevention or reversal of
erectile and bladder dysfunction as a result of diabetic pelvic autonomic neuropathy. I
have investigated how androgens and estrogens contribute to the molecular
mechanisms responsible for the maintenance of phenotype and function of pelvic
autonomic neurons. Androgens are converted to estrogen by aromatase and
testosterone can therefore have androgenic or estrogenic effects. The reduction of
pelvic ganglion (PG) neuron size seen following gonadectomy of adult male rats is
driven by androgens. Both androgens and estrogens act as neurotrophins and are able
to increase neurite complexity in cultured PG. The effects of androgens on axonal
growth are, at least partially, mediated by estrogen. This is important for
understanding plasticity in the pelvic autonomic nervous system and provides a target
for therapeutic agents that target sex steroid signalling. In diabetes the soma size of
pelvic ganglion neurons is decreased. Signaling molecules, ERK and JNK, have been
implicated in the aetiology of diabetic sensory neuropathy. In PG from diabetic rats
ERK activation decreased and JNK activation increased compared to controls.
Therefore changes in MAPKs in PG neurons contribute to the aetiology of pelvic
autonomic neuropathy and provide a target for intervention. A decrease in
neurotrophin production in target tissues contributes to the pathogenesis of diabetic
sensory neuropathy. Neuritin, a molecule involved in neuroplasticity, is upregulated
by testosterone in cultured neurons and linked to neurite outgrowth. Neuritin mRNA
was unchanged in PG from 12-week diabetic rats but was increased by testosterone
treatment in cultured PG. Thus, modulation of neuritin is a target for intervention to
reverse the degeneration of pelvic autonomic neurons in diabetes. This work has
provided three cellular mechanisms to target for therapeutic intervention for diabetic
autonomic neuropathy.
Expected future outcomes:
A journal manuscript is being prepared for resubmission
Name of contact: Tertia Purves-Tyson
Email of contact: t.purves-tyson@neura.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 300618
CIA Name: A/Pr Maria Craig
Main RFCD: Infectious Diseases
Admin Inst: University of New South Wales
Start Year: 2004
End Year: 2007
Total funding: $145,279.00
Grant Type: Early Career
Fellowships (Australia)
Title of research award:
Enteroviruses as triggers of autoimmunity in utero and in infancy
Lay Description (from application):
Not Available
Research achievements (from final report):
This study has been following children who have a mother, father, brother or sister
with type 1 (insulin dependent) diabetes, since birth. The children do not have 'high
risk' genes for diabetes, but they may be susceptible to factors in the environment that
can trigger the early stages of diabetes. The most important environmental factor is
infection with a particular family of viruses called 'enteroviruses'. This is a large virus
family, with more than 90 different strains. We have previously found an enterovirus
in 30% of children when they were diagnosed with type 1 diabetes, so we wanted
understand how commonly this virus is found in children before they develop
diabetes, and whether it is present at the start of the disease.
We found that the children in the study commonly experienced virus infections in
infancy; the most common virus was an enterovirus, which was found in almost half
of children before the age of 3 years. Many of the children temporarily developed
'antibodies' to the the insulin producing cells in the pancreas, suggesting that there has
been some inflammation in these cells. It was much more common for these children
to experience an enterovirus infection compared with children who did not develop
antibodies. In about half of the children, the antibodies disappeared, suggesting that
the insulin producing cells had recovered. In the remaining children, antibodies were
found more than once and they often had an enterovirus infection before developing
their first an antibody.
We then studied these viruses in more detail in the laboratory, to help us understand
how enteroviruses may cause diabetes. Insulin producing cells were infected with
different enterovirus strains in the lab: we found that only some strains damaged the
cells, while others had no effect.
The results of this study have helped us to better understand the early stages of type 1
diabetes, and shown that more research is needed into how enteroviruses are involved.
Expected future outcomes:
Recruitment of this study is ongoing and we aim to recruit approx 500 children in the
study. The larger study group will enable us to examine a large number of enterovirus
strains so we can learn more about how they infect and damage insulin producing
cells. We can also study other factors in the environment and how they contribute,
along with infection, to type 1 diabetes.
Name of contact: Maria Craig
Email of contact: m.craig@unsw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 351204
CIA Name: Dr Josephine Gwynn
Main RFCD: Indigenous Health
Admin Inst: University of Newcastle
Start Year: 2005
End Year: 2011
Total funding: $1,497,370.00
Grant Type: NHMRC
Strategic Awards
Title of research award:
A type II diabetes adn obesity prevention program for Primary school aged rural
indigenous children
Lay Description (from application):
This project aims to develop and evaluate the impact of an innovative multicomponent community and school-based program for type II diabetes and obesity
prevention program for Indigenous and non-Indigenous rural children.
Research achievements (from final report):
This project has produced the first validated measures of food intake and physical
activity for rural Aboriginal children and collected food intake, physical activity,
diabetes knowledge, BMI and waist circumference data on 2600 rural children
(around 20% of whom are Aboriginal children) with similar information gathered
from 50% of their parents. This data describes these factors in this population in both
2007/8 and 2011 and evaluates the effectiveness of the health promotion strategies
delivered over 4 years. Strategies included supporting school based programs such as
fruit and water breaks, vegetables gardens, traditional indigenous games and
delivering diabetes education lessons. Early development work geomapped all the
food outlets and physical activity venues in the Kempsey and Taree areas, leading to
a collaboration with Red Cross and Kempsey Shire Council with maps now
publically available. The project has developed a strong Aboriginal community
directed governance structure, and all permanent Aboriginal staff members have
undertaken graduate studies as follows: Bachelor of Law, a Bachelor in Applied
Science in Community Nutrition, Diploma in Community Nutrition (2 staff), and
Graduate Certificate in Diabetes Education. During data collection phases 95% of
survey workers were from the participating Aboriginal communities (around 40
casual staff). The project has resulted in 14 conference presentations and 5
publications - all of which present first time data on the food and physical activity of
Aboriginal and non- Aboriginal rural children including validation of measurement
tools, and detailed descriptions of food and nutrient intake (including Glycemic Index
and Load) and physical activity.
Expected future outcomes:
A further 2 years funding has been received from NSW health and this enables the
delivery of new community wide strategies to support healthier food intake and
increased physical activity of young people. Funding is being sought for evaluation of
this component. Additional partnerships have been formed and a number of
publications are stemming from the data collected.
Name of contact: Josephine Gwynn
Email of contact: Josephine.Gwynn@newcastle.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 409940
CIA Name: Dr James Sharman
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Admin Inst: University of Queensland
Start Year: 2006
End Year: 2009
Total funding: $276,750.00
Grant Type: Early Career
Fellowships (Australia)
Title of research award:
Clinical application of arterial pressure waveform analyses: Role of exercise central
blood pressure
Lay Description (from application):
Not Available
Research achievements (from final report):
The research award has enabled several important achievements. Important
discoveries have included understanding the potential clinical value of central blood
pressure under resting and exercise conditions. The impact of this is that central blood
pressure during light exercise, similar to that experienced during daily life, is expected
to be a new and superior method to determine an individuals 'true' risk related to
blood pressure.
Expected future outcomes:
Superior methods to determine an individuals true risk related to blood pressure is
expected to improve individual diagnosis and management of people with high blood
pressure.
Name of contact: Dr Jim Sharman
Email of contact: James.Sharman@menzies.utas.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 569741
CIA Name: Prof George Muscat
Main RFCD: Endocrinology
Admin Inst: University of Queensland
Start Year: 2009
End Year: 2012
Total funding: $581,893.00
Grant Type: NHMRC Project
Grants
Title of research award:
NR1F (ROR) nuclear hormone receptors and metabolism: insights into the control of
lipid homeostasis.
Lay Description (from application):
ROR is a member of a gene family, that regulates reproduction, endocrine physiology,
and metabolism, and are important in human health. ROR function remains illusive.
However, it is expressed in liver, fat and muscle, tissues that (i) modulate blood lipids,
insulin sensitivity and energy balance, and (ii) have an important role in diabetes and
obesity. Understanding ROR function in metabolism provides the opportunity for the
discovery of new pathways that ameliorate metabolic disease.
Research achievements (from final report):
This project was focused on RORalpha, a gene/protein belonging to the Nuclear
Hormone Receptor superfamily. This family of proteins are targeted by the top 20%
of currently utilized pharmaceuticals. We demonstrated, utilizing two mouse models
that RORalpha regulates adiposity (i.e. fat deposition), and insulin sensitivity .
Furthermore, we demonstrated that modulation of RORalpha can lead to decreased fat
deposition, resistance to diet induced obesity and improvements in insulin sensitivity
and glucose tolerance.
Expected future outcomes:
It has been recently demonstrated that RORalpha is regualted by oxygenated
sterols/hydroxy choletserols, this indicates the future potential of identifying new
compounds and potential pharamaceuticals that maybe exploited to treat obesity and
type II diabetes.
Name of contact: Bronwyn Adams
Email of contact: Bronwyn Adams <b.adams@imb.uq.edu.au>
NHMRC Research Achievements - SUMMARY
Grant ID: 511120
CIA Name: Prof Michael Waters
Main RFCD: Endocrinology
Admin Inst: University of Queensland
Start Year: 2008
End Year: 2010
Total funding: $679,501.00
Grant Type: NHMRC Project
Grants
Title of research award:
The mechanism of growth hormone receptor activation
Lay Description (from application):
Growth hormone GH excess or deficit results in considerably shortened lifespan.
While cardiovascular disease is a major element in this mortality, GH status has also
been linked to kidney disease and diabetic retinopathy. Importantly, GH produced
locally in breast cells and prostate cells transform s these cells, creating cancers. We
aim to define how GH activates its receptor, to facilitate a GH antagonist which
results from understanding how GH activates its cell surface receptor.
Research achievements (from final report):
We have elucidated a new mechanism for activation of the growth hormone receptor
by the hormone. From this we have created constitutively activated receptors (active
without hormone) which have been used to make fish grow at double the normal rate.
We have also documented the use of two kinases by the receptor in its activation
process, establishing the key role of a Src kinase in liver regeneration, which is a GHdependent process. Importantly, we have used gene arrays to identify the GHregulated gene responsible for conferring survival of mice following partial
hepatectomy.
Expected future outcomes:
Increasing aquaculture yields for farmed fish (salmon, trout), shrimp and lobster.
Candidate mutation sites in the GH receptor which may be associated with giantism
and with increased incidence of some cancers. Development of GH antagonists for
suppression of cancer and diabetes.
Name of contact: M.Waters@Uq.Edu.Au
Email of contact: m.waters@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 401504
CIA Name: Prof George Muscat
Main RFCD: Clinical Sciences not elsewhere classified
Admin Inst: University of Queensland
Start Year: 2006
End Year: 2011
Total funding: $805,133.00
Grant Type: Established
Career Fellowships
Title of research award:
Uncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
This project was focused on role of the Nuclear Hormone Receptor superfamily in the
control of lipid, carbohydrate and energy homeostasis in vitro and in vivo. This
knowledge was exploited to understand the role of these genes/protein in diabetes and
obesity. This family of proteins are targeted by the top 20% of currently utilized
pharmaceuticals. We demonstrated, utilizing several mouse models that nuclear
hormone receptors regulate adiposity (i.e. fat deposition), glucose tolerance, insulin
sensitivity, PI3K-Akt signalling etc . Furthermore, we demonstrated that modulation
of nuclear receptor expression can lead to decreased fat deposition, resistance to diet
induced obesity and improvements in insulin sensitivity and glucose tolerance.
Expected future outcomes:
We are continuing to investigate the tissue and organ specific roles of nuclear
receptors in metabolic disease. This provides the foundation for the potential
identification of novel pharamaceuticals that maybe exploited to treat obesity and type
II diabetes.
Name of contact: Bronwyn Adams
Email of contact: Bronwyn Adams <b.adams@imb.uq.edu.au>
NHMRC Research Achievements - SUMMARY
Grant ID: 519768
CIA Name: A/Pr Raymond Steptoe
Main RFCD: Cellular Immunology
Admin Inst: University of Queensland
Start Year: 2008
End Year: 2011
Total funding: $420,872.00
Grant Type: Career
Development Fellowships
Title of research award:
Tolerance induction by antigen-presenting cell-targeted antigen
Lay Description (from application):
We have found that by ‘targeting’ antigen to the cells that ‘train’ the immune system
we have been able to prevent the development of autoimmune disease. In the
research proposed here we aim to develop new ways in which antigens can be
targeted to these cells so that this approach can be applied clinically. The proposed
studies will also determine how antigens targeted in this way restore self-tolerance
and prevent autoimmune disease.
Research achievements (from final report):
This funding was used to show that memory CD4+ and memory CD8+ T cell
responses could be 'turned off'. These findings formed the basis of a possible
therapeutic approach to treatment of autoimmune diseases and inflammatory diseases
such as asthma. This is a significant discovery as it had previously been thought that
memory T cells were resistant to such efforts and had always been considered a
substantial barrier to treatment of in flammatory diseases. During this award I also
defined a role for regulatory T cells in modulation of CD8+ T cell responses and that
this uncovered a key mechanism of how these cells work to do this. The work has
uncovered important basic information that promotes understanding of how
immunotherapies ccould be applied.
Expected future outcomes:
The outcomes of the funding will form the basis for future studies that explore the
possible use of these findings as a 'therapeutic'.
Name of contact: Ray Steptoe
Email of contact: r.steptoe@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 351584
CIA Name: Prof Michael WATERS
Main RFCD: Endocrinology
Admin Inst: University of Queensland
Start Year: 2005
End Year: 2007
Total funding: $472,500.00
Grant Type: NHMRC Project
Grants
Title of research award:
Validating a new model for growth hormone receptor activation
Lay Description (from application):
Growth hormone is an important hormone therapeutic for treating dwarfism.
Recently, many new therapeutic applications for growth hormone have been
discovered, particularly in relation to its anabolic actions. These include post surgery
recovery, enhanced bone fracture healing, Crohns disease, dilated cardiomyopathy,
infertility and ageing. The hormone exerts these actions through its receptor, which is
a "class1 cytokine" receptor, similar to many receptors important in regulating
immunity, inflammation, metabolism and cancers. In principle, if we can find out
how the GH receptor works, this information would help in designing drugs to treat
many immune and inflammatory disorders. With current NHMRC support we have
developed a model which describes how GH activates the receptor at a molecular
level. The model involves two pre-associated receptors at the cell surface binding to
the hormone, with the result that the receptors are rotated relative to each other, and
this brings the two JAK2 signalling units attached tothe receptor inside the cell into
alignment, so they can activate each other. We can activate the receptor without
hormone by artificially rotating it. This model is a prediction based on several
techniques, but lacks proof of rotation. There are also a number of issues relating to
the need for rigidity in the receptors, so the torque can be transmitted into the cell,
since many believe there is no rigidity just above the membrane. We predict there is ,
but need to prove this. This information is vital for designing small orally active
mimics of growth hormone, and for developing GH antagonists, likely to be useful
for breast and colon cancer. Finally, we have evidence that the specificity of receptor
signalling can be changed by mutating the outer part of the receptor (novel). We
believe this can be used to change the activity spectrum of GH, hence decrease side
effects, by developing analogs which activate one pathway or the other.
Research achievements (from final report):
We have developed a new model for GH receptor activation based on the concept of
activation by relative rotation of transmembrane domains (TMD) within a constitutive
receptor dimer. This was published in Nature Structural & Molecular Biology
including the crystal structure of the unbound receptor extracellular domain. We
validated the constitutive dimer model with molecular dynamics calculations,
cysteine crosslinking and ToxR assays. These revealed the interacting face of the
constitutive transmembrane dimer. We then showed that the receptor uses 2 tyrosine
kinases (JAK2 and a Src kinase), and that choice of signalling pathway was
determined by the conformation of a beta loop in the extracellular domain of the
receptor, published in Nature Cell Biology.
Expected future outcomes:
NHMRC Research Achievements - SUMMARY
Since cancer incidence relates to GH status, development of effective GH antagonists
would provide potential cancer therapies. Elucidating the nature of the receptor
activation mechanism will assist this process.
Name of contact:
Prof Mike Waters
Email of contact: m.waters@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 569742
Start Year: 2009
CIA Name: Prof George Muscat
End Year: 2012
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding:
$454,923.00
Admin Inst: University of Queensland
Grant Type: NHMRC Project
Grants
Title of research award:
Understanding the physiological role of COUP-TF orphan nuclear receptors in
skeletal muscle.
Lay Description (from application):
COUP-TF is a protein expressed in skeletal muscle, a tissue that accounts for ~40% of
the body mass and energy expenditure, and is a major site of nutrient metabolism.
COUP-TF is a member of the nuclear hormone receptor (NR) superfamily. These
proteins respond to physiological signals, and are targets of pharmaceuticals for the
treatment of inflammation, metabolic and endorcrine disorders. Our project is directed
toward understanding the role of COUP-TF in the context of metabolism and obesity.
Research achievements (from final report):
This project was focused on COUP-TFII, a gene/protein belonging to the Nuclear
Hormone Receptor superfamily. This family of proteins are targeted by the top 20%
of currently utilized pharmaceuticals. We demonstrated, utilizing in skeletal muscle
cell culture models that COUP_TFII regulates several critical gene inskeletal muscle
metabolism, including the direct regulation of the gene, Glut4, the major regulator of
skeletal muscle glucose uptake.
Secondly, we demonstrated that PRMT4, a protein that chemically modifies DNA and
controls heritable changes in gene function that occur without a change in DNA
sequence regulates the expression of genes involved in skeletal muscle glycogen
metabolism. Moreover, the PRMT4 target genes and have been implicated in several
glycogen storage diseases in humans
Expected future outcomes:
: We are continuing the PRMT4, and are endeavouring to use mouse models
Name of contact: Bronwyn Adams
Email of contact: Bronwyn Adams <b.adams@imb.uq.edu.au>
NHMRC Research Achievements - SUMMARY
Grant ID: 401626
Start Year: 2006
CIA Name: Dr Brett Collins
End Year: 2010
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding:
$462,290.00
Admin Inst: University of Queensland
Grant Type: Career
Development Fellowships
Title of research award:
Structural biology of endosomal membrane trafficking
Lay Description (from application):
Not Available
Research achievements (from final report):
My lab is interested in the spatiotemporal regulation of intracellular trafficking, with a
focus on understanding how discrete molecular interactions between proteins and
lipids control this process at the endosomal organelle. Trafficking at the endosome is
fundamental for normal cellular function and is involved in many different diseases,
notably Alzheimer's disease, pathogen invasion and inflammation. We aim to gain
insights into these processes by dissecting the basis for the receptor-mediated
transport processes central to endosome biology. We have determined molecular
structures of several protein complexes that are central regulators of endosome
trafficking. These have provided insights into how receptors undergo transport and
processing during organism development, cell homeostasis and neurodegenerative
disease.
Expected future outcomes:
We are now beginning to understand the molecular basis for endosomal transport and
processing of molecules critical in normal cell function and diseases including
infection and neuronal degeneration. Our work will continue to dissect these
processes and aims to develop approaches to modulate them for both scientific and
therapeutic outcomes.
Name of contact: Brett Collins
Email of contact: b.collins@imb.uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 401668
CIA Name: Prof Michael WATERS
Main RFCD: Endocrinology
Admin Inst: University of Queensland
Start Year: 2006
End Year: 2008
Total funding: $505,523.00
Grant Type: NHMRC Project
Grants
Title of research award:
STAT5 as an anti-obesity agent
Lay Description (from application):
An obesity epidemic is evident in first world countries including Australia. Twenty
seven percent of men aged 55-64 in this country are obese. Obesity results in
increased mortality and morbidity from type 2 diabetes, cardiovascular disease, renal
disease and endometrial cancer, among others. Given our flaccid lifestyles, it is
imperative that the metabolic processes underlying obesity be fully understood, to
allow development of suitable treatment modalities. This proposal seeks to establish
an important new element in our understanding of the development of obesity, the
transcription factor STAT5. With previous NHMRC support, we developed
sophisticated genetically modified mice which lack defined signalling processes
initiated by growth hormone, an anti-obesity agent. These studies showed a strong
correlation between ability to activate STAT5 and resistance to obesity. There is
fragmentary literature evidence to support our hypothesis, which could also explain
some of leptins anti-obesity actions. Using mice which lack STAT5, we shall
establish a role for STAT5 as an antiobesity agent. The actions of STAT5 are
normally blocked by feedback inhibitors referred to as SOCS, discovered by
Australians. We shall define which SOCS is the feedback regulator for obesity
control, allowing us to develop specific anti-SOCS agents which will act as novel
anti-obesity agents.
Research achievements (from final report):
Obesity is a major and increasing public health concern which impacts on mortality
from cardiovascular diseases, type 2 diabetes, renal diseases and cancer. Based on a
panel of targeted growth hormone receptor knockin mice we have created with
previous NHMRC support, we have evidence that an important transcription factor
used by GH and leptin, STAT5a/b, plays an important role in restricting development
of adult obesity. We have identified the metabolic genes regulated by STAT5a/b and
confirmed their actions using in vitro models. We have also shown that STAT5a/b is
required for insulin secretion and for the induction of insulin resistance by growth
hormone. Finally, using NMR-metabonomic analyses across the different mice
mutants, we have shown that taurine is insufficient in these obese mice, and this
would directly contribute to obesity.
Expected future outcomes:
Support for use of growth hormone or its secretagogues in treatment of obesity and
insulin insufficiency. Potential for use of dietary taurine supplementation in treatment
of obesity.
Name of contact: Prof Mike Waters
NHMRC Research Achievements - SUMMARY
Email of contact: m.waters@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 143007
CIA Name: Prof Jennifer Stow
Main RFCD: Protein Targeting and Signal Transduction
Admin Inst: University of Queensland
Start Year: 2001
End Year: 2005
Total funding: $666,117.00
Grant Type: NHMRC Project
Grants
Title of research award:
Regulators of G protein signalling on the Golgi complex
Lay Description (from application):
The secretion of proteins from cells involves a host of regulatory and signalling
proteins. G proteins, signal transducers, located on the Golgi membranes, participate
in the budding of transport vesicles in the secretory pathway. A newly-discovered
family of Regulators of G Protein Signalling (RGS) proteins perform the critical
function of turning off signals generated by G proteins. RGS proteins are powerful,
but as yet, ill-defined regulatory molecules. In this study we will identify and
characterize RGS proteins in macrophages that are located on Golgi membranes and
help to regulate cytokine secretion and other immune functions. More detailed studies
on selected RGS proteins will include mutational analysis of functional domains
within the proteins and identification of other proteins that interact with RGS proteins.
Overall these studies will lead us to understand how specific RGS proteins interact
with G proteins and other molecules to regulate signalling in the secretory pathway.
Anomalies in cell signalling have severe consequences in a variety of diseases and
can cause cancer. Similarly, abnormal secretion in cells contributes to inflammation,
diabetes and other disease processes. Information forthcoming from our studies on
RGS proteins will have wide-reaching implications and the potential to reveal new
targets for therapeutics in these diseases.
Research achievements (from final report):
This project focussed on the role of RGS proteins as regulators of G proteins; a new
role for an RGS protein as a regulator of G protein-mediated vesicle trafficking on the
Golgi was identified as part of this work. This finding then led to the examination of
related vesicle-trafficking regulators, molecules involved in the process of vesicle
budding off the Golgi complex. Several studies done as successful collaborations
with other Australian groups led to discoveries of new roles for actin-binding
tropomyosins, ubiquination enzymes and golgins in the process of vesicle budding off
the Golgi complex. These molecules all form part of a large regulatory structure
along with RGS proteins and G proteins. Components of this complex are mutated or
afffected in disease and also could form novel drug targets for control of protein
trafficking or signalling in cancer and other conditions.
Expected future outcomes:
N/A
Name of contact: Jennifer Stow
Email of contact: j.stow@imb.uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 455864
CIA Name: Prof Michael WATERS
Main RFCD: Endocrinology
Admin Inst: University of Queensland
Start Year: 2007
End Year: 2009
Total funding: $531,697.00
Grant Type: NHMRC Project
Grants
Title of research award:
The nuclear growth hormone receptor- its actions and mechanism of nuclear
translocation
Lay Description (from application):
We and others have found that cell surface receptors for growth factors such as EGF,
FGF and growth hormone can be found in the nucleus of proliferating cells. We have
shown that many cancers have elevated nuclear GH receptor including leukemia,
breast and colon cancer. If we artificially target the GH receptor to the nucleus, the
resulting cells are tumorigenic when injected into immunocompromised mice, rapidly
form ing metastasising tumours. To create more effective inhibitors of this
tumourogenesis, and to define the physiological roles of nuclear GH receptor, we will
define the transport process which carries the receptor to the nucleus and block it. We
will also seek to define how the receptor in the nucleus interacts directly with DNA
to inhibit programmed cell death. To carry out these projects we will use
sophisticated proteomics /mass spectrometry to identify the proteins interacting with
the receptor in the transport and gene activation processes. The role of candidates
will be tested by preventing their expression or by direct inhibition of their action
using drugs or dominant negative versions. These approaches will provide leads to
new anti-cancer therapeutics, and therapies for blocking diabetic blindness and kidney
failure.
Research achievements (from final report):
Growth hormone (GH) receptor defective individuals do not die from cancer and do
not have diabetes. We have identified and characterized GH receptor in the cell
nucleus of proliferating cells. We have shown that nuclear localized GH receptor
induces increased cell proliferation and transformation in vitro, and ectopic tumor
formation in vivo. We have identified a powerful nuclear transcriptional coactivator
which is associated with cancer which binds to the receptor in response to GH
addition, and is able to increase (double) the proliferative response to GH in vitro. We
have identified key oncogenic genes as upregulated by nuclear localized GH receptor,
and have shown that the GH receptor binds to a 60bp DNA sequence upsteream of
survivin, a key gene in oncogenesis. We have also shown that DNA-dependent
protein kinase binds to the receptor, and this is needed for DNA double strand break
repair.
Expected future outcomes:
Given the key role of the GH receptor in cancer incidence, creation of blockers of its
action would be a useful cancer therapy. Our efforts here are ongoing.
Name of contact: Prof Mike Waters
Email of contact: m.waters@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 401734
CIA Name: Prof George Muscat
Main RFCD: Endocrinology
Admin Inst: University of Queensland
Start Year: 2007
End Year: 2008
Total funding: $357,936.00
Grant Type: NHMRC Project
Grants
Title of research award:
ERRgamma and skeletal muscle: insights into lipid utilization and catabolism
Lay Description (from application):
The significance of Nuclear hormone receptors (NRs) in disease is underscored by
the range of pharmacopoeia for the treatment of NR-associated disorders (e.g 16% of
the top 100 drugs target NRs). ERRgamma receptors are abundantly expressed in
skeletal muscle, a major mass periperal tissue that acconts for ~40% of total body
weight, and energy expenditure. Muscle is the major site of glucose metabolism and,
fatty acid oxidation. Consequently, it has a significant role in insulin sensitivity, the
blood lipid profile, lipid metabolism and obesity. Understanding the functional role
of the orphan ERR receptors in skeletal muscle in the context of inflammation, lipid
and energy homeostasis is of paramount importance in further understanding the
mechanistic basis of dyslipidemia, chronic inflammation, insulin sensitivity, diabetes
and obesity. Identification of novel ERRgamma targets that regulate metabolism in a
major mass peripheral tissue, and positively influence the risk factors for
cardiovascular disease, provides platforms for potential therapeutic intervention.
Cardiovascular disease is the foremost cause of global mortality, and was responsible
for >15 million deaths in 2003.
Research achievements (from final report):
We demonstrated that a specific class of hormone regulated DNA binding proteins,
denoted as the Estrogen related receptors (ERRs) regulates glucocorticoid (and
glucocorticoid receptor) dependent gene expression in sketal muscle. In particular, we
f
genes in skeletal muscle cells, that are (also) activated during the adverse (myopathic)
effects on muscle by (the anti-inflammatory) glucocorticoids . This study highlights
the regulatory crosstalk between ERRgamma and GR signaling in skeletal muscle
cells, and suggests the ERRgamma agonist modulates the expression of critical genes
that control GR signaling and glucocorticoid sensitive gene expression. In addition,
this investigation indicates, future therapeutic exploitation or targeting of the Estrogen
related receptors, should consider potential activation of other signaling pathways
Expected future outcomes:
Elucidation of the signalling pathways and target genes controlled by the estrogen
related receptor subgroup of nuclear hormone receptors
Name of contact: George Muscat
Email of contact: g.muscat@imb.uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 290519
CIA Name: A/Pr Elizabeth Eakin
Main RFCD: Preventive Medicine
Admin Inst: University of Queensland
Start Year: 2004
End Year: 2007
Total funding: $765,984.00
Grant Type: NHMRC Project
Grants
Title of research award:
Addressing Multiple Risk Factors in Primary Health and Community Care settings: A
Cluster-Randomised Trial
Lay Description (from application):
The proposed study will evaluate an intervention designed to assist patients with
chronic medical conditions to make lifestyle changes that will benefit their health and
reduce the complications associated with their conditions. The study targets patients
in a disadvantaged Southeast Qld community and is led by researchers from QUT's
Centre for Public Health Research in collaboration with local-, state-, and nationallevel health service organizations. The health behaviour intervention model
emphasises the following: a) a partnership between general practice and community
care resources, b) a more coherent (ie, less fragmented) and sustained inter-sectoral
effort, c) an approach that is responsive to the needs of individual consumers, their
families and the community.
Research achievements (from final report):
The Logan Healthy Living Program was one of the first large-scale Australian studies
to evaluate a telephone counselling intervention for physical activity (PA) and diet. It
targeted patients with type 2 diabetes and hypertension from a disadvantaged
community. Ten primary care practices and 434 patients took part in the study.
Comparing those who received telephone counselling to those who did not,
improvements were seen in many aspects of diet, including fat intake, vegetable and
fruit serves and fibre, as well as physical activity. These are all outcomes that are
important for improving the health of people living with chronic conditions. The
program was also cost-effecive to deliver. Results suggest that telephone counselling
is a promising approach to physical activity and dietary change, with the potential for
wider spread application. As evidence of its impact, the program has been taken up
and is being delivered by the Division of General Practice in the community in which
the study was conducted.
Expected future outcomes:
Results from this study will help to inform the delivery of telephone-counselling
interventions, both in future trials and in the context of State Health and NonGovernmental Telephone Information services.
Name of contact: A/Prof Elizabeth Eakin
Email of contact: e.eakin@sph.uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 142935
CIA Name: A/Pr Joanne Shaw
Main RFCD: Endocrinology
Admin Inst: University of Queensland
Start Year: 2001
End Year: 2003
Total funding: $438,055.00
Grant Type: NHMRC Project
Grants
Title of research award:
The Identification of a Novel NIDDM Susceptibility Gene Localised to Human
Chromosome 12q
Lay Description (from application):
Non-insulin dependent diabetes mellitus (adult-onset diabetes) is very common in
Australia and is a major public health problem. It is a leading cause of kidney failure,
blindness, heart attacks, strokes and amputations. Over 3% of the Australian
population have adult-onset diabetes, and very few Australians have not been touched
in some way by the shadow of diabetes. The precise cause of diabetes is unknown,
however we do know that it tends to run in families, indicating that an inherited
tendency is important. By finding genes which cause diabetes we have the
opportunity to unravel much of the mystery of this condition. This research program
will find genes which cause diabetes by searching for them in large pedigrees in
which many family members are affected by diabetes. Finding the genes which cause
diabetes will have a significant impact in at least three major ways. Firstly, it will
increase our understanding of the disease process. Secondly, it will be possible to
develop tests to identify people at risk of diabetes at a very early stage so that therapy
can be introduced and complications averted. Thirdly, it will be possible to develop
new and more effective approaches for the prevention and treatment of diabetes.
Research achievements (from final report):
Our research program identified a region on chromosome 12q linked to the
development of diabetes in a large family. To date, we have managed to screen 12q
candidate genes within this region and are currently analysing this data to search for
the gene responsible for type 2 diabetes. A number of gene mutations have already
been identified in our study population and we are currently screening a wider
population in order to test the prevalence in the wider community. We have also
conducted a genome-wide scan and identified a candidate region on chromosome
3q13 and further fine mapping and candidate gene sequencing is underway.
Finding the genes which cause diabetes will have significant impact in at least three
major ways. Firstly, it will increase our understanding of the disease process.
Secondly, it will be possible to develop tests to identify people at risk of diabetes at a
very early stage so that therapy can be introduced and complications averted. Thirdly,
it will be possible to develop new and more effective approaches for the prevention
and treatment of type 2 diabetes.
Expected future outcomes:
We believe that this research will lead to the identification of a gene responsible for
type 2 diabetes. This will lead to an improved understanding of the disease and lead
to improved therapies. The identification of a gene for diabetes will also allow us to
screen individuals at risk.
NHMRC Research Achievements - SUMMARY
Name of contact: A/Prof. Shaw
Email of contact: jteshaw@hotmail.com
NHMRC Research Achievements - SUMMARY
Grant ID: 401643
Start Year: 2007
CIA Name: Prof Jennifer Martin
End Year: 2008
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding:
$515,565.00
Admin Inst: University of Queensland
Grant Type: NHMRC Project
Grants
Title of research award:
Deciphering the molecular basis of SM regulation of exocytosis
Lay Description (from application):
Diabetes, obesity, heart disease and physical inactivity are major and escalating health
problems within western societies. These problems are all linked to, or aggravate, the
condition known as insulin resistance. Insulin resistance occurs when normal levels of
insulin are insufficient to remove glucose from the blood. In the normal situation,
insulin regulates glucose uptake into muscle and fat cells by stimulating the
movement of a glucose transport protein from inside the cell to the cell surface. The
trafficking of this protein is somehow disrupted in insulin resistance. The purpose of
this research is to follow up our exciting preliminary results on this system to shed
light on the molecular processes that regulate the trafficking of the glucose
transporter. Information resulting from our studies will lead to a better understanding
of insulin-stimulated glucose transport and may also unravel the details of a related
cellular secretion system that regulates neurotransmission. Our hope is that by
understanding at the molecular level how cells regulate secretion, we can in the future
develop therapeutics to counteract many of today s major health problems.
Research achievements (from final report):
Vesicle trafficking is fundamental to life. We have investigated the interaction of two
proteins - Munc18c and Syntaxin4 - that regulate vesicle trafficking in muscle and fat
cells and which are key to the blood glucose-regulating actions of insulin. Similar
proteins - Munc18a and Syntaxin1 - regulate the release of neurotransmitters in
neurons. Previously, the literature had shown that the Munc18 protein prevented
Syntaxin involvement in vesicle trafficking, by holding it in an inactive conformation.
On the contrary, our work showed that Munc18 proteins stimulate the ability of
Syntaxin proteins to participate in vesicle trafficking. This conclusion was supported
by our biochemical, cell biology and structural biology evidence, and we showed that
the N-terminal 10 residues of Syntaxin proteins are critical for function. Because our
work was so unexpected and because it overturned the prevailing paradigm for these
fundamentally important proteins, our papers in Traffic and Cell have been very
highly cited and our work has led to numerous invitations to speak at international
conferences.
Expected future outcomes:
We are following up on this work through the currently funded Program grant and
through PhD student studies and expect to publish a number of high impact papers
over the next 12 months.
Name of contact: Jennifer Martin
Email of contact: j.martin@imb.uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 401573
CIA Name: Prof George Muscat
Main RFCD: Endocrinology
Admin Inst: University of Queensland
Start Year: 2007
End Year: 2008
Total funding: $582,547.00
Grant Type: NHMRC Project
Grants
Title of research award:
NR1 nuclear hormone receptors, and skeletal muscle metabolism: insights into
dyslipidemia and metabolic disease.
Lay Description (from application):
The significance of Nuclear hormone receptors (NRs) in disease is underscored by
the range of pharmacopoeia for the treatment of NR-associated disorders (e.g 16% of
the top 100 drugs target NRs). Orphan NR1 receptors are abundantly expressed in
skeletal muscle, a major mass peripheral tissue that accounts for ~40% of total body
weight, and energy expenditure. Muscle is the major site of glucose metabolism and,
fatty acid oxidation. Furthermore, it is an important regulator of cholesterol
homeostasis and HDL levels. Consequently, it has a significant role in insulin
sensitivity, the blood lipid profile, lipid metabolism and obesity. Understanding the
functional role of the orphan NR1 receptors in skeletal muscle in the context of
inflammation, lipid and energy homeostasis is of paramount importance in further
understanding the mechanistic basis of dyslipidemia, chronic inflammation, insulin
sensitivity, diabetes and obesity. Identification of novel NR1 targets that regulate
metabolism in a major mass peripheral tissue, and positively influence the risk factors
for cardiovascular disease, provides platforms for potential therapeutic intervention.
Cardiovascular disease is the foremost cause of global mortality, and was responsible
for >15 million deaths in 2003.
Research achievements (from final report):
We demonstrated that the orphan nuclear hormone receptor, RORγ, has a function
in regulating the expression of genes that control lipid homeostasis , muscle and fat
mass. Surprisingly, the investigation revealed a function for RORγ in the regulation of
reactive oxygen species production.
In addition, we demonstrated that the orphan nuclear hormone receptor, RORalpha
controls lipid metabolism in hepatic, adipose and muscle tissue in vivo. Mouse
models displaying decreased and dysfunctional Retinoic acid receptor-related orphan
receptor a (RORα) expression were characterised by reduced adiposity (associated
with decreased fat pad mass , adipocyte size and concordant suppression of the
lipogenic genetic program), and resistance to diet induced obesity. These studies
suggest these nuclear hormone receptors may be therapeutically exploited to treat
dyslipidemia and obesity.
Finally, we demonstrated that two orphan nuclear recepotrs, RORalpha and Reverbalpha directly regulated the expression of SREBP-1c, the major regulator of the
genetic program that controls fat biosynthesis.
Expected future outcomes:
NHMRC Research Achievements - SUMMARY
Elucidation of the signalling pathways and target genes controlling lipid homeostasis
controlled by the ROR subgroup of nuclear hormone receptors
Name of contact: George Muscat
Email of contact: g.muscat@imb.uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 401677
CIA Name: A/Pr Jonathan Whitehead
Main RFCD: Endocrinology
Admin Inst: University of Queensland
Start Year: 2007
End Year: 2008
Total funding: $478,845.00
Grant Type: NHMRC Project
Grants
Title of research award:
IMPDH and lipid accumulation
Lay Description (from application):
Inosine-5' Monophosphate Dehydrogenase (IMPDH) is an enzyme responsible for
providing a form of energy to cells, so that they may undertake their correct functions.
Recently, we have demonstrated that IMPDH also has a role in the formation of fat
droplets within cells, when they are exposed to excessive nutrients. In mammals,
excess consumed energy is stored as fat droplets within all cells. In fat cells, the
energy is stored in very large droplets, and we see this as extra body fat. This is
sometimes associated with an alteration in the hormone production of the cells,
leading to problems such as diabetes. In other cells, the excess energy is stored as tiny
fat droplets (lipid bodies) that can adversely affect the function of the cell. We have
shown that blocking the action of IMPDH can interfere with the accumulation of fat
in both fat cells and other types of cell. This suggests that IMPDH has an important
role in the development of obesity and associated problems such as diabetes. In this
study we aim to investigate in detail the role of IMPDH in the accumulation of fat
droplets in cells. We will do this by looking at the effects of different forms of
IMPDH in different cell types, including human fat cells. We will also study cells and
animals with increased or decreased amounts of IMPDH, and investigate the effects
of this on the development of increased fat stores and insulin resistance. These
studies will increase our understanding of the role of IMPDH in the development of
obesity, and may lead to identification of new avenues of treatment for obesity and
type 2 diabetes.
Research achievements (from final report):
More than 60% of adult Australians are overweight or obese and this is associated
with adverse health outcomes including diabetes and heart disease. Obesity is
underpinned by an increase in fat mass hence strategies to reduce fat mass, through
lifestyle intervention and/or pharmacolgical agents, decrease the likelihood of obesity
related complications. The overall aim of this grant was to determine whether
pharmacological inhibition of a specific enzyme, called IMPDH, would reduce fat
mass, and thereby improve metabolic parameters. Using model cell systems, we
demonstrated that inhibition of IMPDH reduced the ability of immature fat cells to
multiply and mature into fat cells. We extended these studies to mouse models of diet
induced obesity and showed that treatment with the inhibitor was able to reduce fat
mass, with a concomittant reduction in the size and number of mature fat cells, and
this correlated with improvements in metabolic parameters including circulating
hormones and lipids. Importantly, these changes occurred without any change in food
intake. Together, these studies suggest that targeting IMPDH may represent a
potential strategy to reduce obesity and associated complications.
Expected future outcomes:
NHMRC Research Achievements - SUMMARY
Future studies are required to determine the molecular mechanisms that underpin the
observations outlined above. We are particularly interested in determining the
metabolic profile of mice treated with the inhibitor, to establish whether metabolic
rate and inflammatory processes are altered by the treatment.
Name of contact: Jon Whitehead
Email of contact: j.whitehead1@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 455865
CIA Name: Prof Robert Parton
Main RFCD: Protein Targeting and Signal Transduction
Admin Inst: University of Queensland
Start Year: 2007
End Year: 2009
Total funding: $496,447.00
Grant Type: NHMRC Project
Grants
Title of research award:
Molecular Characterisation of Lipid Droplet Function
Lay Description (from application):
Fat is stored inside cells in spherical structures called lipid droplets. The accumulation
of fat within lipid droplets underlies obesity. This project aims to understand how fat
is stored within lipid droplets and how it is released when energy is required. In
particular, we will look at two types of protein which move to lipid droplets under
certain energy conditions and attempt to unravel how these proteins control fat storage
and release. The first protein we will study, caveolin, normally associates with regions
of the cell surface but moves to lipid droplets when cells are fed lipids. Mice which
lack this protein eat more food but remain leaner than normal mice. Understanding
how caveolin moves to lipid droplets and how it controls fat accumulation will
therefore provide new insights into obesity and conditions associated with obesity,
such as diabetes. The second protein to be studied, Rab18, is a member of a protein
family which controls membrane movement within cells. Rab18 moves to lipid
droplets when lipid release is stimulated. Therefore studies of Rab18 can provide new
insights into the way lipids are released from fat tissue under conditions of starvation.
The project will provide fundamental new insights into the basic mechanisms by
which we store energy and the energy imbalances which cause obesity and related
diseases.
Research achievements (from final report):
The storage of fats, and their mobilization in response to starvation, is a crucial
adaptation of mammals to cope with changes in the availability of foods. Storage of
fat in adipose tissue is abnormal in human disease conditions termed lipodystrophies.
One of the causes of lipodystrophy in human patients is the loss of a protein called
caveolin-1, which has also been linked to diabetes. To gain insights into mechanisms
of lipid storage in health and disease we have studied the major fat storage organelles,
lipid droplets and we have developed screens to identify regulators of lipid storage.
We have studied cells from animals lacking caveolin-1 to understand the role of
caveolin-1 in normal fat tissue and the effect of lack of caveolin-1. Lack of caveolin-1
makes the animals lean, even when fed a high fat diet. We could also show that fat
tissue from mice lacking caveolin-1 cannot respond to signals that would normally
cause lipids to be released from the adipose tissue. The tissue shows signs of
inflammation, a condition normally associated with obese animals. Our results
suggest that the adipose tissue of animals lacking caveolin-1 is more sensitive to
damage, leading to loss of fat and thus lipodystrophy.
Expected future outcomes:
This work lays the foundation for understanding the role of caveolin-1 in adipose
tissue under physiological conditions, and the effect of loss of caveolin-1 in patients
with lipodystrophy. The development of screens during the funded period has
NHMRC Research Achievements - SUMMARY
provided the opportunity to identify key regulators and inhibitors of lipid droplet
accumulation.
Name of contact: Prof. Robert G. Parton
Email of contact: r.parton@imb.uq.edu.au
r.parton@imb.uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 401612
CIA Name: A/Pr Jonathan Whitehead
Main RFCD: Endocrinology
Admin Inst: University of Queensland
Start Year: 2007
End Year: 2008
Total funding: $478,845.00
Grant Type: NHMRC Project
Grants
Title of research award:
Adiponectin - Multimerization, Secretion and Action
Lay Description (from application):
Adiponectin is a hormone produced by fat tissue. It functions to control blood glucose
levels and acts to prevent damage to blood vessels associated with heart disease and
stroke. Adiponectin levels in the blood are low in subjects with obesity, diabetes and
heart disease, and in animals with these conditions, additional adiponectin is of
benefit. It has recently been recognised that adiponectin is produced in different
forms - a low weight form made up of a small number of adiponectin molecules and a
higher weight form (HMW adiponectin) made up of large numbers of adiponectin
molecules complexed together. We and others have shown that the HMW adiponectin
is particularly beneficial. This projects aims to understand the processes regulating
the production of differing types of adiponectin by fat cells. It will also examine how
the different types of adiponectin have their effects in different tissues such as liver
and muscle. The information gained will increase our understanding of how illnesses
such as diabetes are associated with obesity. It may also lead to the development of
treatments aimed at increasing adiponectin levels - particulalry HMW adiponectin which may be of benefit in patients with diabetes and cardiovascular disease.
Research achievements (from final report):
More than 60% of adult Australians are overweight or obese. This is associated with
adverse health outcomes including diabetes and heart disease. The reasons for these
associations remain to be identified. One possibility is that changes in the hormone
adiponectin may underpin such associations. Fat secretes a number of hormones. Of
these, adiponectin is unique as it increases insulin sensitivity but, paradoxically,
circulating adiponectin levels are reduced in the overweight or obese. Our previous
work demonstrated that this reduction reflected a decrease in a specific form of
adiponectin, termed high molecular weight adiponectin. We have identified
mechanisms that contribute to the efficient formation of high molecular weight
adiponectin and have also shown that supplementation with a vitamin can increase its
production, establishing this as a potential therapuetic strategy to increase circulating
levels of high molecular weight adiponectin. We identified a novel mechanism that
leads to rapid clearance of adiponectin from the circulation. We identified a new
protein implicated in mediating adiponectin's effects in a variety of cell types and
have generated a number of tools to define the role of this protein in adiponectin
action.
Expected future outcomes:
Ongoing and future studies will define the mechanisms governing adiponectin
clearance and determine whether these mechanisms contribute to the reduction in
circulating adiponectin levels in states such as obesity.
NHMRC Research Achievements - SUMMARY
We are soon to begin a pilot study to examine the effects of vitamin supplementation
on adiponectin and glucose in obese subjects.
Name of contact: Jon Whitehead
Email of contact: j.whitehead1@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 264418
CIA Name: Prof John Prins
Main RFCD: Endocrinology
Admin Inst: University of Queensland
Start Year: 2004
End Year: 2008
Total funding: $750,000.00
Grant Type: NHMRC
Partnerships
Title of research award:
A collaborative research-based program of education, intervention and scientific
discovery in Type 2 Diabetes
Lay Description (from application):
Not Available
Research achievements (from final report):
This research investigated early markers of cardiovascular disease in obese
individuals who do not yet have diabetes but are at risk for developing diabetes. We
identified that in our patient population about 1 in 5 otherwise healthy obese men and
women will already have changes in the way the heart muscle works and in the
stiffness of the heart muscle, even before the onset of diabetes. We hypothesised that
these changes would be reversible and that they might be due to "insulin resistance"
which often precedes diabetes. We treated half the participants with a drug that
improved insulin action, metformin, and treated all participants with an aggressive
lifestyle intervention which aimed to get participants to lose about 7% body weight by
diet and exercise. We found that the lifestyle intervention was successful in reducing
body weight and improving fitness and that this was also a powerful way to improve
insulin resistance. Further, lifestyle intervention also had beneficial effects on heart
muscle function and stiffness - so these early markers of cardiovascular disease were
potentially reversible in this patient population. This research means that if we can
identify people with these early cardiovascular changes we can intervene to prevent
future irreversible heart disease - a significant burden to the individual and to society.
Expected future outcomes:
We anticipate that the techniques that we used to assess heart function and structure
will become more widely used in the clinical setting in the future. This research
confirms that cardiovascular disease can be present in obese individuals even before
more traditional risk factors, like diabetes, have become manifest. We showed that
early signs of heart disease are reversible .
Name of contact: Prof Johannes Prins
Email of contact: j.prins@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 401522
CIA Name: Prof Elizabeth Powell
Main RFCD: Hepatology
Admin Inst: University of Queensland
Start Year: 2006
End Year: 2010
Total funding: $296,892.00
Grant Type: Established
Career Fellowships
Title of research award:
Practitioner Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
To date, this Liver Research Program has helped to shape two new paradigms; the
importance of metabolic risk factors in the progression of chronic liver diseases, and
more recently proposing altered hepatic regeneration and the ductular reaction as a
potential driver of hepatic fibrosis. The current and future direction of the research
program involves the integration of scientific and clinical research projects. The
scientific projects are studying the mechanisms by which obesity-related factors
increase the extent of liver injury, accelerate disease progression and impair response
to therapy in patients with chronic liver diseases. The clinical research activities are
investigating the role of noninvasive techniques to diagnose liver injury and evaluate
specific therapeutic interventions to determine whether they favourably modify the
natural history of the liver disease and are cost-effective. The Practitioner Fellowship
has provided protected time to facilitate translation of the outcomes of this program
into clinical practice to benefit the health outcomes of the community affected by
liver disease. The translational nature of the Research Program is clearly evident, as
these studies address issues that are currently relevant to the health of the Australian
population such as increased awareness of the risk of obesity and type 2 diabetes and
the holistic management of patients with a chronic disease.
Expected future outcomes:
Delineation of mechanisms involved in liver injury will allow the development of
specific protective strategies.
Name of contact: Elizabeth Powell
Email of contact: e.powell@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 569665
CIA Name: Prof David Pow
Main RFCD: Opthalmology and Vision Science
Admin Inst: University of Queensland
Start Year: 2009
End Year: 2011
Total funding: $536,795.00
Grant Type: NHMRC Project
Grants
Title of research award:
Characterizing novel therapeutic interventions in a new model of focal retinopathy
Lay Description (from application):
Focal retinopathies such as age-related macular degeneration pose an immense burden
on our society, both socially and economically. We have recently developed an
animal model that allows us to investigate for the first time, drugs and therapies that
might be used to treat AMD both after its onset, and more significantly, in at-risk
populations before onset of the disease.
Research achievements (from final report):
This project has examined a novel rodent model that exhibits spontaneous small
bleeeds in their eyes . We have now shown that these animals develop lesions in their
eyes that are like human macular degeneration lesions. We developed methods of
sequential ERG (measuring the electrical activity of the eye) and ophthalmoscopic
observations over time to show that where bleeds occur, macrophage invasion
occursnd that retinal degeneration occurs months later. A key novel finding is that
we can immunocytochemically differentiate the macrophages from the resident
microglia; the marker IBA1 which should label macrophages, fails to label the
haemosiderin-containing macrophages; conversely our data indicates that there is a
zone around the lesion which is depleted of IBA1-positive microglia, suggesting that
the macrophages may not derive from a blood borne population but may instead
derive from the resident microglia. This study will be completed and written up in
2012.
One of the key questions in our study was the integrity of the blood retina barrier as
glutamate might leak in from the blood (from the choroid plexus) and can then cause
slow death of neurons due to chronic over-activation. To understand this we
examined the homologous choriocapillaris of the brain to detemine by PCR the
proteins such as glutamate transporters that were present there, and then examined
them in the eye. Brain aspects of this have been published and retinal studies are
being written
Expected future outcomes:
The application was originally for 5 years, so many of the ageing/ drug treatment
aspects of the study could not be brought to fruition in the shorter 3 year time line that
was funded. Other findings such as the complement proteins at sites of lesions have
been presented at abstract level but not finalised. All will be pursued as and when
funding is available
Name of contact: David Pow
Email of contact: david.pow@rmit.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 401738
CIA Name: A/Pr Gary Leong
Main RFCD: Endocrinology
Admin Inst: University of Queensland
Start Year: 2006
End Year: 2011
Total funding: $234,424.00
Grant Type: Career
Development Fellowships
Title of research award:
Molecular mechanisms of Glucocorticoid control of baby growth and development
Lay Description (from application):
Not Available
Research achievements (from final report):
In this project the focus of study was to understand the role of different hormones and
growth factors and their interaction with environment (e.g.) nutrition and exercise in
both human childhood and animal models of abnormal growth and development i.e.
osteoporosis and obesity. These included studies in children with i) excessive
glucorticoid secretion (Cushing syndrome) and ii) child obesity examining the effects
on growth and body composition development and iii) studies in transgenic mouse
models of anti-obesity examining the role of the Ski gene on skeletal muscle and
adipose tissue development. As a consequence of these studies there was improved
recognition of the long-term risk of osteoporosis and obesity as a consequence of
Cushing syndrome and socio-environmentally-related obesity in children. These
studies reinforced the importance of ongoing surveillance for signs of chronic disease
(osteoporopsis, diabetes and cardiovascualr disease risk factors) in these children into
adulthood. As a result of our studies conducted in the Ski transgenic mouse models,
we showed that the Ski gene regulates multipe other gene pathways to influence both
skeletal muscle and fat development. These included effects on expression of nuclear
hormone receptors, adipogenesis, myogenesis and energy expenditure genes. These
findings suggest that Ski may play a role in body composition development that may
influence risk for obesity and diabetes. Thus both genetic and environmental factors
interplay to modulate risk for osteoporosis and obesity and hence chronic disease.
Expected future outcomes:
1) Delination of preventive facors (e.g. nutrition and exercise) that may improve peak
bone mass and adipose mass in young adults with Cushing syndrome and childhood
obesity and 2) a better understanding of the skeletal muscle versus adipose (white and
brown)-specific gene reualtory networks that involves the Ski gene.
Name of contact: Gary M. Leong
Email of contact: g.leong@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 210194
CIA Name: A/Pr Peter Kaye
Main RFCD: Reproduction
Admin Inst: University of Queensland
Start Year: 2002
End Year: 2004
Total funding: $281,650.00
Grant Type: NHMRC Project
Grants
Title of research award:
Glucose, glucose transporters and blastocyst formation in the mouse
Lay Description (from application):
Embryo-based biotechnologies have the potential to improve human reproductive
health, notably in treating infertility by In vitro fertilisation (IVF). They are also
central to the future use of embryonic stem cells for human tissue replacement. This
project investigates the molecular mechanisms controlling one of the earliest
differentiations in the growth of the embryo. Using the mouse as an experimental
model it will investigate the importance of several factors in the changes which set up
the placenta and fetus as seperate tissues in the very early embryo. A key focus is the
supply of glucose to the newly fertilised embryo and how important this glucose
supply is for the survival of the embryo. Moreover there is great interest in the
possibility that metabolic events in utero can contribute to the development of
diseases in later life, notably, coronary heart diease, stroke, high blood pressure and
non-insulin dependent diabetes. The results from these studies will contribute to our
understanding of why some couples are infertile, lead to improved management of
infertility by diet and invitro fertilisation procedures. It will also be of benefit in
dietary advice to women with diabetes mellitus, seeking to have children. The
adenoviral strategy for gene delivery into early mouse embryos may in the long term
also find wide clinical application in the treatment of genetic defects at the very
earliest stages in development and as such is of enormous potential benefit in the
management of both animal and human reproduction.
Research achievements (from final report):
Optimal maternal nutrition during the first few days of embryonic development
following conception can have a significant impact on embryonic growth, affecting
the likelihood of cardiovascular and other diseases in adult life. The mechanism used
by the embryo to sense the nutrient status of the mother is not understood. This
project investigated how the embryo detected one important embryonic nutrient,
glucose during early pregnancy. Our studies show that the availability of glucose to
the embryo over these few days affects the growth of the embryo. In trying to
understand how this can happen, two mechanisms were identified. One seems to be
similar to the way cells become resistant to insulin in diabetes and the other resembled
the way cells respond to many hormones.
Although performed in mice, our studies suggest that a mother's nutritional status
immediately after conception may affect her fertility and perhaps the health of the
child as an adult. This is an important issue for modern society which is confronted
with falling fertility rates and an increasing incidence of diseases such as diabetes
mellitus which alters the normal supply of glucose. Public health programs therefore
targeted at women wanting to conceive, may be of benefit to our community in
dealing with reduced fertility and perhaps more importantly in limiting the number of
NHMRC Research Achievements - SUMMARY
people afflicted with cardiovascular and metabolic diseases in adult life. Animal
production industries are also potential beneficiaries from this knowledge since it may
lead to higher efficiency animal production via modified reproductive technologies.
Expected future outcomes:
The major outcome and benefit of this work to the community is a better
understanding of the importance of maternal nutrition on fertility and the ability to
maintain a healthy pregnancy. Ultimately this is more likely to lead to a healthy adult.
Name of contact: Peter Kaye
Email of contact: p.kaye@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 455839
CIA Name: Prof George Muscat
Main RFCD: Endocrinology
Admin Inst: University of Queensland
Start Year: 2007
End Year: 2009
Total funding: $323,750.00
Grant Type: NHMRC Project
Grants
Title of research award:
NR4A orphan nuclear receptor signalling in skeletal muscle: evidence for crosstalk
with the beta-adrenergic pathway.
Lay Description (from application):
The NR4A subgroup of are 'orphan' members of the nuclear hormone receptor (NR)
superfamily (that are all implicated in human disease). NRs are hormone-dependent
DNA binding proteins that translate nutritional and pathophysiological signals into
gene regulation. The importance of this 'drugable' gene family in the context of
promoting and maintaining human health is underscored by the diversity of
medicinals associated with dysfunctional hormone signalling, in the context of
inflammation, diabetes, dyslipidemia, and endocrine disorders (e.g ~15% of the top
selling therapeutic compounds target NRs). The NR4A subgroup are stress response
genes which are induced by a wide range of physiological stimuli and have been
implicated in the response to energy excess (over-eating) and diet induced obesity.
The NR4A subgroup are expressed in skeletal muscle, a major mass peripheral tissue
that accounts for ~40% of the body mass and energy expenditure. This lean tissue is a
major site of fat oxidation, insulin-stimulated glucose utilization and cholesterol
metabolism. Therefore this tissue plays a notable role in insulin sensitivity, the blood
lipid profile, and energy balance. Accordingly, muscle has a significant role in the
progression of dyslipidemia, diabetes and obesity. Surprisingly, the function of the
NR4A subgroup in skeletal muscle metabolism has not been examined. Nevertheless,
given the data on NR4A mediated gene regulation, and the potential therapeutic utility
for the treatment of metabolic disease, the contribution of skeletal muscle to NR4A
action must be defined. Correspondingly, the objective of this proposal is to examine
the role of the NR4A subgroup and is relevant to understanding the basis of
dyslipidemia and obesity.
Research achievements (from final report):
Global knockout of the beta1-3-adrenergic receptors (b-ARs) in vivo leads to
pronounced diet induced obesity. Epinephrine (adrenaline) and norepinephrine
released from sympathetic nerves activate the β-adrenergic receptor/cAMP-dependent
protein kinase pathways in skeletal muscle during the 'fight or flight ' response.
We identified novel links between the Nuclear Hormone Receptor NR4A subgroup,
skeletal muscle energy homeostasis and b- adrenergic signalling. We demonstrated
(in vitro and in vivo) β2-adrenergic receptor activation selectively and strikingly
activates the expression of the mRNAs encoding the three members of the NR4A
subgroup in skeletal muscle. This provided evidence of crosstalk between badrenergic signalling (that regulates metabolism) and NR4A signalling mediated by
CREB phosphorylation. We demonstrated that attenuation of NR4A nuclear receptors
in muscle cells, resulted in (i) decreased fat metabolism (coupled to increased
anaerobic metabolism) respectively; (ii) attenuated expression of genes that regulate
fat and sugar metabolism. Concordantly, we observed that in vivo b2-AR activation
NHMRC Research Achievements - SUMMARY
induced the expression of genes that activate lipid oxidation and modulate glucose
utilization.In a collaboration with Dr Aaron Smith and Assoc. Professor Rick Sturm
we have demonstrated crosstalk between Melanocortin and NR4A signalling in
melanoma cells. In adition we observed melanocytes from red haired individuals
(associated with increased risk of developing melanoma) exhibited an impaired
induction of NR4A genes in response to melanocyte stimulating hormone. Finally,
we showed attenuation of NR4A expression in melanocytes appears to impair DNA
repair in response to UV exposure.
Expected future outcomes:
IN collaboration with an Australia Fellow, we are endeavouring to identify novel
agonist for these receptors, that can potentially be used for thereapeutic purposes.
Name of contact: Bronwyn Adams
Email of contact: b.adams@imb.uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 569855
CIA Name: Prof Istvan Toth
Main RFCD: Pharmaceutical Sciences and Pharmacy
Admin Inst: University of Queensland
Start Year: 2009
End Year: 2010
Total funding: $209,471.00
Grant Type: NHMRC
Development Grants
Title of research award:
Neuropathic pain drugs based on the endogenous opioid peptide Endomorphin 1.
Lay Description (from application):
We have developed a new pain drug based on the natural pain killing opioid peptide,
Endomorhin 1. The new drug exhibits activity similar to morphine and gabapentin
against neuropathic pain in animals but seems to act through a different mechanism.
We will complete our preclinical investigation of this compound by assessing its side
effect profile and tolerance inducing properties in animals. We will also continue our
development of an orally active analogue of this important peptide
Research achievements (from final report):
Neuropathic pain is a condition associated with nerve damage and is a common
complication of diabetes, musculoskeletal injury, and cancer. The treatment of
neuropathic pain is a major unmet medical need. Currently, opioid drugs are used to
treat neuropathic pain, but result in a range of side effects, particularly tolerance,
respiratory depression, and constipation. Endomorphin-1, an endogenous opioid
peptide, has the potential to treat neuropathic pain but is unsuitable for clinical
application due to poor metabolic stability and poor oral absorption in its native form.
We created a range of derivatives aimed at improving the drug-like properties of
Endomorphin-1. These derivatives were screened in vitro to determine the μ-opioid
receptor binding and agonist activity. Promising candidates progressed to in vivo
screening in a rat chronic constriction injury model of neuropathic pain. The results of
in vivo testing identified Endomorphin-1 derivatives with dose-dependent activity
when delivered intravenously. Oral analgesic potential was also evaluated and was
comparable to that of morphine. Less tolerance developed to the analgesic effect of
the lead Endomorphin-1 derivative than morphine at equipotent doses. The
Endomorphin-1 derivative produced less side effects (respiratory depression,
constipation, tolerance) than morphine at antinoiciceptive doses.
Our findings suggest that Endomorphin-1 derivatives have the potential to be
developed as novel opioid analgesic agenst to treat neuropathic pain with a wider
therapeutic window in respect to constipation and respiratory depression. Further
development of the lead Endomorhpin-1 derivative may result in the production of a
clinical therapeutic for neuropathic pain.
Expected future outcomes:
After completion of further preclinical examinations we will pursue business partners
to progress to clinical trials.
Name of contact: Prof Istvan Toth
Email of contact: i.toth@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 401528
CIA Name: Dr Louise Hutley
Main RFCD: Endocrinology
Admin Inst: University of Queensland
Start Year: 2007
End Year: 2008
Total funding: $438,077.00
Grant Type: NHMRC Project
Grants
Title of research award:
FGF-1 in human adipogenesis
Lay Description (from application):
Obesity is becoming more common in Australian adults and children, and is a major
contributor to a number of diseases including type 2 diabetes, cardiovascular disease
and some cancers. Current weight loss strategies using either lifestyle modification
(diet & exercise) or drugs are relatively ineffective in the majority of obese
individuals. This is partly due to the fact that we have an incomplete knowledge of
the factors that regulate weight in humans. In laboratory studies we have shown that
human fat cell development can be dramatically accelerated by fibroblast growth
factor-1 (FGF-1). This growth factor is produced by human endothelial cells, which
are cells that line the blood vessels in fat tissue. When human fat cell precursors
(preadipocytes) are cultured in the presence of FGF-1 the preadipocytes divide much
more rapidly than normal and, additionally, then develop into mature fat cells much
more rapidly than normal. These processes involved in development of new fat cells
form the basis of fat tissue expansion in the body. The effect of FGF-1 on human fat
cell development is far greater in magnitude than that of other known factors that
promote fat cell growth. The aim of this project is to determine the actual
biochemical pathways that mediate the effect of FGF-1 in promoting fat cell growth
and development. Results obtained will provide insight into the cellular and
molecular mechanisms regulating expansion of fat tissue mass in humans. Research
aimed at identifying these underlying mechanisms, or at potentially contributing or
exacerbating factors, is critically important in development of novel and more
effective approaches to prevention and treatment of obesity.
Research achievements (from final report):
We previously identified a growth factor (FGF-1) with profound stimulatory effects
on conversion of precursor cells (preadipocytes) into mature fat cells. This process,
known as adipogenesis, underpins development of obesity. The current project has
firmly established this FGF-treated preadipocyte model as a powerful platform for
examination of the very complex process of human adipogenesis. Results gained
have greatly increased our understanding of regulatory mechanisms governing
acquistion of new fat cells in humans. Further, we have identified several signalling
molecules important for the adipogenic effects of FGF-1, including the previously
unknown role of FGF receptor 1 (FGFR1) in regulating all aspects of new fat cell
acquisition. We also demonstrated that targeted inhibition of components of this
pathway, including FGFR1, results in markedly decreased fat cell development in
vitro. The findings from this project have led directly to pre-clinical in vivo studies
providing proof-of-concept that targeting FGF/FGFR signalling reduces weight gain
and has beneficial effects on whole body metabolism in a mouse model of dietinduced obesity. The significance of these findings lies in the potential for
development of novel anti-obesity strategies directly targeting a reduction in
NHMRC Research Achievements - SUMMARY
excessive fat tissue by limiting the number of fat cells contained within the tissue.
Obesity is a major cause of premature death and disability due to cardiovascular
disease, stroke, type 2 diabetes and cancer throughout the world and current treatment
options are not proving effective. Therefore the findings from the current project are
highly significant and may form the basis for development of novel and more
efficacious anti-obesity therapies.
Expected future outcomes:
Current anti-obesity options are associated with low efficacy and several adverse
effects. Our current work is aimed at identification of components of adipogenic
FGF/FGFR signalling which are specifically expressed in preadipocytes. This
approach will allow development of future therapies which directly target adipose
tissue itself, thus decreasing the likelihood of associated adverse effects.
Name of contact: Louise Hutley
Email of contact: l.hutley@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 351669
CIA Name: Dr Ingrid Hickman
Main RFCD: Endocrinology
Admin Inst: University of Queensland
Start Year: 2005
End Year: 2009
Total funding: $272,813.00
Grant Type: Early Career
Fellowships (Australia)
Title of research award:
Type 2 diabetes and chronic liver disease: An emerging relationship between comorbid diseases of obesity.
Lay Description (from application):
Not Available
Research achievements (from final report):
This fellowship has provided invaluable training and career development. I have
extended my experience in managaing large clinical trials and have also up skilled
significantly in my knowledge of the mechanisms associated with disease
development through my association with the basic scientists in the research team at
the Diamantina Institute. This has strengthened my ability to design studies with
appropriate and robust outcome measures and gives strength to the clinical data
collected. Since 2005 I have published 16 peer reviewed articles including 3 invited
editorials and 1 invited review article. I have presented 33 abstract presentations and
given >20 invited speaker engagements. I co-authored the Australian Guide to
Healthy Eating for Hepatitis C in 2004 which is still the only nutrition resource in use
in clinical centres across the country today. During this fellowship I was successful in
obtaining independent project grant funding to continue my research ($517,000 over 3
years) and I have obtained independent funding for my salary to continue for the next
3 years through the Lions Medical Research Fellowship Program ($100,000 per year
for 3 years). During the course of my fellowship I have been successful in attracting
$95,000 in research funds from various sources. The fellowship has allowed me to
develop research capacity in others as I have supervised 2 Master's students to
completion and have 3 PhD students continuing their studies and have played a
mentoring role for many other researchers within the institute. The research conducted
during the fellowship has been translated into practice through the dissemination of
results which recommend dietetic intervention in people with diabetes and fatty liver
disease. This impacts patients directly by improved evidenced based practice within
the centre.
Expected future outcomes:
I expect another 3 manuscripts to be written based on the research completed during
this fellowship. I have also develoepd international collaborations during my
fellowship which will continue due to our colaborative efforts within the NHMRC
funded project grant.
Name of contact: Ingrid Hickman
Email of contact: i.hickman@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 219285
CIA Name: Prof Thomas Marwick
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Admin Inst: University of Queensland
Start Year: 2003
End Year: 2007
Total funding: $2,000,000.00
Grant Type: Centre of Clinical
Excellence
Title of research award:
Centre of Clinical Research Excellence in Cardiovascular Disease and Metabolic
Disorders
Lay Description (from application):
Cardiovascular complications are the main cause of morbidity in a number of
metabolic diseases, including diabetes and renal failure. The Centre's objective is to
bring together six successful clinical research groups in cardiovascular and metabolic
disorders in collaboration with specialists in telemedicine, to address the interface
between these diseases and to train a group of clinical researchers skilled in multidisciplinary research. The planned research includes mechanistic studies as well as
interventional studies that will be translated to clinical practice.
Research achievements (from final report):
1) Support of clinical research on cardiovascular disease in type 2 diabetes (T2DM),
obesity, chronic renal disease and hypertension that have the potential to lead to
improved health outcomes for the community (see translation);
- Cross-sectional studies showing the presence of subclinical heart muscle disease in
subjects with T2DM, obesity and primary aldosteronism
- Studies of screening strategies for coronary artery disease in renal disease and
T2DM
- Randomized trial showing response of this heart muscle disease to a lifestyle
intervention program (exercise and dietary modification) in the subgroup which
undertook the greatest activity (but not in unselected patients)
- Randomized trial showing a high prevalence of insulin resistance/impaired glucose
tolerance in patients with renal transplants, but no favorable effects of a disease
management program on cardiac function
- Randomized trials showing no improvements in vascular structure with a lifestyle
intervention program, implying the need for more intense pharmacologic intervention.
2) Fostered the training of clinical researchers who have developed the capacity for
independent research;
- Seven research higher degree completions (6 PhD, one MPH), six of whom were
medically-qualified
- Two postdocs moved on to independent funding and future leadership roles and one
PhD student to a practitioner fellowship
3) Effected translation of research outcomes into clinical practice;
- Influenced practice through leadership of the American Heart Association exercise
guidelines in T2DM and publication of coronary disease screening strategies in
T2DM and renal disease
- Published approximately 40 papers and 150 conference abstracts
- Recognized in research awards from American heart Association, American Society
of Nephrology, Sports Medicine Australia and the High BP Research Council of
Australia
NHMRC Research Achievements - SUMMARY
- Successful Australian/international patent application.
Expected future outcomes:
The information gathered in the 1st series of stiudies will support a targetted lifestyle
and anti-fibrotic drug intervention in metabolic heart disease, including studies of
diabetic cardiac autonomic neuropathy
Name of contact: Prof Tom Marwick
Email of contact: t.marwick@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 320860
CIA Name: Prof Kerin O'Dea
Main RFCD: Indigenous Health
Admin Inst: University of South Australia
Start Year: 2005
End Year: 2009
Total funding: $7,486,989.00
Grant Type: Programs
Title of research award:
Health Outcomes Monitoring and Evaluation: Learning about Activity, Nutrition, Diet
and Social Factors
Lay Description (from application):
Diabetes, Heart and Kidney disease occur in epidemic proportions among Indigenous
Australians. Of particular concerns is the early age of onset of conditions that are to
disease of older adulthood in the broader Australian community. While these chronic
diseases are known to cause premature death and suffering in Aboriginal and Torres
Strait Islander communities, there are gaps in our knowledge. For example, we know
very little about how these conditionsdevelop over time in different populations.
Probably the greatest knowledge gap is the area of effective intervention - both to
prevent to prevent diabetes, kidney and heart disease in young people, and to treat
existing cases effectivly. The main goal of this program is to bring together a multi
skilled team of researchers to better understand the development of these chronic
disease across the lifespan ( including differences between different populations), and
to guuide the development of diet, lifestyle, and clinical interventions. Such
interventions need to be simple, effective, acceptable to Indigenous people and able to
be sustained over the long term. All interventions will be rigorously evaluated. The
results will inform policies in ares such as quality and affordability of the food supply
in remote communnities; infrastructure to promote physical activity; and provision of
high quality primary health care focussing on early intervention and care of people at
risk of chronic disease.
Research achievements (from final report):
1. Completion of the longest and most comprehensive longitudinal study (10-14
years) of health and chronic disease profiles in a remote indigenous community ever
conducted. This allows us to track the onset on new disease and the course of existing
disease over time, to evaluate risk factors for these outcomes and, through prediction
of treatment and health services needs, to inform needs-based health service policy.
2. Initiation of a clinical trial of medicine to reduce the onset of disease in previously
unaffected people over time.
3. Better understanding of nature of heightened susceptibility to kidney disease and
hypertension through a multinational study, including indigenous Australians, of
kidneys in undiseased people at autopsy, and through a study of diseased kidney
biopsies in indigenous people nationwide in Australia.
4. Demonstration of 40% lower mortality in a Homelands community in Central
Australia relative to the NT Indigenous population. Contributing factors were an
excellent primary health care service, healthier diet and lifestyle living on country,
and strong sense of self determination (Rowley et al, MJA in early 2008).
5. Identification of low income of most Indigenous people in remote communities
being the driver of poor quality diets. Poor quality foods rich in sugar, fat and salt are
much lower cost (calories per $) than healthy foods such as fresh fruit and vegetables,
NHMRC Research Achievements - SUMMARY
lean meat and fish. This was published in the MJA in May 2009 (Brimblecombe and
O'Dea).
Expected future outcomes:
Interventions across the life course (community, clinical care and health systems) to
improve health outcomes in relation to chronic diseases for Indigenous people. This
will include a significant focus on food security in remote Indigenous communities, as
a healthy diet is a key building block underpinning good health - in partnership with
Indigenous communities and organisations.
Name of contact: Kerin O'Dea
Email of contact: kerin.o'dea@unisa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 512484
CIA Name: Prof Jurgen Gotz
Main RFCD: Central Nervous System
Admin Inst: University of Sydney
Start Year: 2008
End Year: 2010
Total funding: $468,119.00
Grant Type: NHMRC Project
Grants
Title of research award:
Comparative analysis of novel transgenic mouse models for brain and islet
amyloidoses
Lay Description (from application):
We aim to understand what two highly prevalent diseases, the brain disorder
Alzheimer's disease (AD) and the metabolic disorder Type 2 Diabetes mellitus (DM),
have in common. Through understanding pathogenesis and the development of novel
transgenic models our long-term research goal is to identify new drug targets, to
develop screening assays and to patent new findings. Collectively, this hopefully
leads to AD and DM drugs and reduces the socio-economic burden of both
debilitating diseases.
Research achievements (from final report):
Not Available
Expected future outcomes:
N/A
Name of contact: Jürgen Götz
Email of contact: juergen.goetz@sydney.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 153906
CIA Name: Prof Nicholas Talley
Main RFCD: Epidemiology
Admin Inst: University of Sydney
Start Year: 2001
End Year: 2003
Total funding: $271,528.00
Grant Type: NHMRC Project
Grants
Title of research award:
Chronic gastrointestinal symptoms and diabetes mellitus: risk factors and mechanisms
Lay Description (from application):
Why many people with diabetes mellitus are afflicted by gastrointestinal (GI)
symptoms remains uncertain. Irreversible damage to the nerves controlling the gut
(autonomic neuropathy) is often considered to be important. An alternative cause of
increased GI symptomatology in diabetics is poor glucose control. Some studies have
shown that acute shifts in glucose levels induce changes in the gut relevant to the
onset of GI symptoms. For example, high glucose levels acutely cause slower
stomach emptying times, leading to feelings of fullness. Though the effects of
chronic glucose levels are yet to be properly explored, population data show that poor
control in the long-term is related to an increase in symptoms. The aim of this
prospective study is to determine the roles played by both autonomic neuropathy and
glucose control in the development of GI symptoms among diabetics. All past
research has been cross-sectional, and so cannot tell us if one or both of these factors
cause GI problems in diabetes. For example, it is possible that autonomic neuropathy
causes an increase in GI symptoms such as nausea and fullness, which in turn induces
poor glucose control though lack of appetite or inadequate stomach emptying. Upon
study inclusion, all study participants will undergo a series of autonomic tests. At 3
month intervals for a period of 30 months, they will be asked to complete a 2-week
diary card detailing their GI symptoms and glucose readings, and also supply blood
and urine samples for analysis twice each year. Two years from the study outset,
participants will again complete the autonomic test series. Psychiatric co-morbidity
will be investigated using the Composite Diagnostic Interview (CIDI-Auto) at the
autonomic testing time points. The study will be undertaken at the Gastroenterology
Research Unit at Nepean Hospital, in collaboration with the Royal Adelaide Hospital,
centres with proven track records in diabetes investigation.
Research achievements (from final report):
N/A
Expected future outcomes:
If poor glycaemic control is the main determinant of increased GI symptomatology, a
randomised trial to document the benefits of tight blood glucose control in relieving
symptoms and preventing GI complications is likely to be worthwhile. We believe
this will result in the provision of more specific and clinically relevant guidance for
doctors looking after diabetic patients with GI complications.
Name of contact: Professor Nicholas Talley
Email of contact: Talley.Nicholas@mayo.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 349348
CIA Name: A/Pr Pu Xia
Main RFCD: Endocrinology
Admin Inst: University of Sydney
Start Year: 2005
End Year: 2007
Total funding: $375,750.00
Grant Type: NHMRC Project
Grants
Title of research award:
Investigation of pancreatic insulin-secreting cell function and survival
Lay Description (from application):
Diabetes remains a major health problem in Australia. Both type 1 and type 2 diabetes
is eventually due to pancreatic insulin-producing beta-cell destruction, which is
caused mainly by the cell death, so called 'apoptosis' or programmed suicide of the
cells. Thus, attempting to protect beta-cells against death and rescue their insulin
secretory function is emerging as a strategy for the treatment of diabetes. However,
how the beta-cells undergo death and how to protect the cell death are still not
completely understood. We have recently discovered a new protein, named
sphingosine kinase, that is a strong protector against cell death. We also found that
this enzyme is involved in process of insulin secretion. Thus, this application seeks to
establish a dual role of this enzyme in protecting beta-cells from death and promoting
insulin secretion by the cells. This will ultimately allow us to create new therapeutic
strategy to target this protein for the management of diabetes.
Research achievements (from final report):
By conducting the current project, we have uncovered a new enzyme that protects
pancreatic insulin-secreting cells from death and maitains normal insulin production.
This finding could help to create a new strategy for prevention and treatment of
diabetes.
Expected future outcomes:
It will help to develop new therapeutics for treatment of diabetes.
Name of contact: Pu Xia
Email of contact: p.xia@centenary.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 512299
CIA Name: A/Pr Martin Ng
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Admin Inst: University of Sydney
Start Year: 2008
End Year: 2011
Total funding: $306,502.00
Grant Type: NHMRC Project
Grants
Title of research award:
The Role of the Thioredoxin System in Angiogenesis and Impaired
Neovascularisation in Diabetes Mellitus
Lay Description (from application):
For many sufferers of heart disease who suffer from blocked coronary arteries, current
treatments (e.g. bypass surgery or angioplasty) are unable to offer relief from the
debilitating effects of occluded arteries. This is particularly true of patients with
diabetes who have more aggressive blockages. We plan to study a newly identified
mechanism to facilitate growth of new blood vessels to sites affected by vascular
disease . Ultimately, this may result in new treatments for heart disease.
Research achievements (from final report):
A major part of the morbidity and mortality from diabetes arises from its vascular
complications. We have discovered a new mechanism by which high glucose levels in
diabetes may lead to vascular complications. Our findings have important
implications for development of new treatments for diabetes.
Expected future outcomes:
Development of new therapies for prevention and treatment of the vascular
complications of diabetes.
Name of contact: Associate Professor Martin Ng
Email of contact: mkcng@med.usyd.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 457373
CIA Name: A/Pr Stephen Twigg
Main RFCD: Endocrinology
Admin Inst: University of Sydney
Start Year: 2007
End Year: 2009
Total funding: $445,578.00
Grant Type: NHMRC Project
Grants
Title of research award:
Novel regulators of fat cell differentiation
Lay Description (from application):
Overweight and obesity are at epidemic proportions in Australia, reflecting the pattern
in the developed and developing world. The main cause appears to be an energy
mismatch, with excessive caloric consumption. One response of the body to excessive
nutrient supply is energy storage in fat tissue and to aid in this the body also generates
new fat tissue, termed adipogenesis (also known in cells as fat cell differentiation). In
many people who gain excess body weight, fat tissue is abnormal and does not
respond well to the chemical insulin, thus causing insulin resistance. This insulin
resistant fat tissue is especially present in a central body (visceral) site. Insulin
resistance related to this visceral fat predisposes to both diabetes and premature death
from cardiovascular disease. Understanding how fat tissue develops and how it might
cause insulin resistance is thus important in human health. One of the factors in fat
that prevents normal development of fat tissue and which induces insulin resistance is
transforming growth factor- (TGF- ). We have generated new data showing that two
proteins which are increased by TGF- , termed connective tissue growth factor
(CTGF) and insulin like growth factor binding protein-3, (IGFBP-3), prevent
adipogenesis. We have shown this in cultured cells, and have found that CTGF and
IGFBP-3 are increased in visceral fat in animal models of obesity and insulin
resistance. Our preliminary work has further indicated how CTGF and IGFBP-3
might each work in the fat cell to prevent adipogenesis. This proposal will determine
if TGF- works through CTGF and IGFBP-3 to block adipogenesis, and it will define
how CTGF and IGFBP-3 have their inhibitory effects on fat cell differentiation. Cells
in culture will be utilised and an animal model of dietary induced obesity and insulin
resistance will help to define whether CTGF and IGFBP-3 prevent adipogenesis in
vivo, furthering our understanding in how abnormal fat tissue may develop.
Research achievements (from final report):
Determined how the ability of fat cells to take up and lay down fat as they
differentiate, is controlled by 3 proteins termed CTGF, IGFBP-3 and TGFbeta. The
mechanisms of action of these 3 proteins in fat cells was defined. As a result, new
ways to potentially prevent obesity and also the condition of insulin resistance (which
can lead to type 2 diabetes and heart disease) was defined. We published three papers
and 4 presentations at national or international meetings on work in the Project Grant.
Expected future outcomes:
2 further publications are expected (one has been submitted and is under second round
review)
Name of contact: Professor Stephen Twigg
Email of contact: stephen.twigg@sydney.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 512282
CIA Name: A/Pr Mark Gorrell
Main RFCD: Hepatology
Admin Inst: University of Sydney
Start Year: 2008
End Year: 2010
Total funding: $478,068.00
Grant Type: NHMRC Project
Grants
Title of research award:
Therapeutic potential of the dipeptidyl peptidase IV gene family
Lay Description (from application):
We will further investigate the therapeutic potential of the Dipeptidyl Peptidase (DP)
IV gene family by studying genes identified as probable therapeutic targets for stem
cell transplant, anti-inflammatory and cancer therapies. DPIV is an identified target
for diabetes therapy. Our research group is internationally recognised as expert in
both liver disease pathogenesis and the DPIV gene family.
Research achievements (from final report):
DPP4 inhibitors are a new type 2 diabetes therapy, so understanding how DPP4
functions in the body will help us understand this therapy, what additional benefits
and uses it may have, and whether DPP4-related proteins are also useful targets for
therapy.
We showed that DPP4 targetting will probably also benefit liver health and that
targetting the DPP4-related protein called FAP will probably be useful for diabetes
and for liver diseases. In contrast, the DPP4-related protein called DPP9 may
downregulate cancer growth but targetting DPP9 might be useful to enhance tissue
regeneration such as wound healing and recovery from liver damage.
Expected future outcomes:
This work will lead to showing that DPP4 inhibitors, which are used for glucose
control in type 2 diabetes patients, have added benefits in liver health.
Name of contact: Mark Gorrell
Email of contact: m.gorrell@centenary.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 402847
CIA Name: Dr Anthony Ashton
Main RFCD: Clinical Sciences not elsewhere classified
Admin Inst: University of Sydney
Start Year: 2006
End Year: 2010
Total funding: $462,290.00
Grant Type: Career
Development Fellowships
Title of research award:
Regulation of angiogenesis by thromboxane receptor activation
Lay Description (from application):
Not Available
Research achievements (from final report):
Identification of sequences and interacting proteins involved in TPβ induced
suppression of basal angiogenesis
Identification of sequences and interacting proteins involved in TPβ induced
suppression of VEGF mediated angiogenesis
Identification of the molecular switch required for modulating the anti-angiogenic
activity of TPβ
Confirmation of the anti-angiogenic nature of TPβ, an its downstream interacting
proteins, in vivo in both pathological and physiological models of neovascularization
Identification of TPβ as a human-specific disease modifier and anti-angiogenic
protein capable of modulating new blood vessel formation during disease
Expected future outcomes:
Re-formulation of pro-angiogenic therapy to increase effectiveness in small clinical
trial and development of new drugs for treatment of heart disease and cancer.
Name of contact: Anthony Ashton
Email of contact: aashton@med.usyd.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 457561
CIA Name: Prof Carol Pollock
Main RFCD: Nephrology and Urology
Admin Inst: University of Sydney
Start Year: 2007
End Year: 2009
Total funding: $566,947.00
Grant Type: NHMRC Project
Grants
Title of research award:
The role of peroxisome proliferator activated receptor gamma in sodium transport in
human proximal tubule cells
Lay Description (from application):
Renal failure accounts for a considerable component of the excess morbidity and
mortality observed in patients with diabetes mellitus. In addition, the emotional, social
and cost to the community of dialysis is enormous. PPARgamma is activated by drugs
that have been recently introduced for the treatment of type 2 diabetes mellitus. The
propensity for these drugs to cause fluid retention has emerged recently as the most
common serious adverse drug reaction associated with these compounds. the
definitive cause of fluid retention with the use of PPAR gamma agonists is not
known. Studies reported in the last 12 - 18 months have suggested that a common
pathway may be involved in the development of the fluid retention, the high blood
pressure and the scarring that occurs in the kidney. This project will be the first to
provide a comprehensive examination of the effect of PPARgamma induction on
renal sodium absorption and fluid retention in the human proximal tubule cells and
the potential molecular mechanisms underlying them. This will provide insight as to
potential adjuvant treatments for patients with diabetes.
Research achievements (from final report):
Five publications have arisen as a result of the funding and in vivo projects are being
explored based on our findings. To date we have confirmed the molecular
mechanisms contributing to salt and water retention in the setting of clinical use of
PPARg agonists. In summary the activation of PPARg improves glycaemic control
but activates mechanisms to retain salt via activation of the EGFR receptor. Our
future projects aim to confirm proof of concept in animal models and as agents to
block both PPARg and the EGFR are available in the clinical domain we aim to
determine the clinical efficacy of PPARg agonists and EGFR antagonits on the
progression of diabetic nephropathy.
Expected future outcomes:
We expect that future therapies will be directed to retaining the beneficial effects of
PPARg and limiting the side effects. We have submitted a grant application to further
this work.
Name of contact: Carol Pollock
Email of contact: carol.pollock@sydney.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 402559
CIA Name: A/Pr Stephen Twigg
Main RFCD: Endocrinology
Admin Inst: University of Sydney
Start Year: 2006
End Year: 2008
Total funding: $382,821.00
Grant Type: NHMRC Project
Grants
Title of research award:
Role and mechanism of connective tissue growth factor in diabetic cardiomyopathy
Lay Description (from application):
Diabetic cardiomyopathy is a condition where the heart muscle is directly damaged by
diabetes. It is being recognised as a prominent cause of both acute and chronic heart
failure in diabetes. It is common and occurs in up to 60% of diabetic patients . At
present however, no treatments are available to directly treat the cardiomyopathy.
This condition can also occur in people with diabetes who have high blood pressure
and/or coronary artery disease and may combine with these problems to worsen
patient outcomes. We have generated data in experimental diabetes in rodents that
strongly implicates a heart growth factor in causing diabetic cardiomyopathy. This
protein, called connective tissue growth factor (CTGF), is increased in diabetic
cardiomyopathy, and is elevated by high glucose and other factors in diabetes. We
have published data showing that CTGF causes tissue scarring like that which occurs
in cardiomyopathy, by affecting signals in cells called fibroblasts. It increases the
laying down of extracellular matrix (ECM) and also inhibits the degradation of ECM
by the proteins that break down matrix, known as the MMPand PAI systems. Such
accumulation of ECM is thought to be a major factor leading to abnormal muscle
function in cardiomyopathy. We now plan to block CTGF in this diabetic heart
model to determine if we can prevent diabetic cardiomyopathy. We have generated
two methods to inhibit CTGF in the animal model. Echocardiography (a heart
ultrasound test), and molecular analysis of the heart tissue will determine if we can
prevent the otherwise adverse functional and structural changes of diabetes in the
heart. We will also study our baboon model of diabetes to determine if diabetic
cardiomyopathy with increased heart CTGF is present in the primates. Cell culture
studies from rat heart fibroblasts and myocytes will determine how CTGF has the
effect on cells to cause cardiomyopathy and how we might further prevent this
condition developing in diabetes.
Research achievements (from final report):
The condition of diabetic cardiomyopathy is common and it describes a direct heart
muscle damage due to diabetes and portends an increased risk of heart failure and
death in people with diabetes. The current work generated novel data showing how
the protein connective tissue growth factor (CTGF) contributes to injury to the
diabetic heart, caused by high glucose and elevated fatty acids, and through effects on
the heart cells of fibroblasts and also cardiac myocytes. Such information firmly
implicates CTGF as a causative factor in diabetic cardiomyopathy and the way in
which CTGF causes diabetic cardiomyopathy, and it also identifies CTGF as a
potential target to prevent and treat in diabetic cardiomyopathy.
Expected future outcomes:
Two further publications are expected from the grant
NHMRC Research Achievements - SUMMARY
Name of contact: Assoc. Prof. Stephen Twigg
Email of contact: stwigg@med.usyd.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 153899
CIA Name: A/Pr Graham Robertson
Main RFCD: Hepatology
Admin Inst: University of Sydney
Start Year: 2001
End Year: 2003
Total funding: $438,055.00
Grant Type: NHMRC Project
Grants
Title of research award:
Pathogenesis of liver injury and hepatic fibrosis in Non-Alcoholic SteatoHepatitis,
NASH
Lay Description (from application):
Nonalcoholic steatohepatitis (NASH) is the most common form of liver disease in
affluent countries. In Australia at least 3% of the population and 20% of those with
obesity have NASH. This poorly understood disease covers a spectrum of liver
disorders - from relatively benign presence of excess fat in the liver - to cirrhosis and
liver failure. This pattern of liver damage is virtually identical to alcoholic hepatitis,
however alcohol consumption is excluded in NASH. It is often associated with type
II diabetes , obesity and lipid disorders. Although fatty liver by itself is thought to be
innocuous and reversible, a small number of cases with this mild syndrome progress
to a more severe form of NASH. One aim of this project is to identify and
characterise the factors which trigger injury in a fatty liver and lead to the destruction
of liver cells. In response to the initial liver injury in NASH, cells in the liver and
from the immune system mount an inflammatory reaction. However this may make
the liver even more susceptible to further injury by amplifying the effect of the initial
insult. The inflammatory response is controlled by key signalling molecules produced
by specific liver and immune cells. The second aim of this project is to identify such
molecules and their cellular source and to determine whether they perpetuate the
disease processes of NASH. One outcome of liver injury and the consequent
inflammatory reaction is that the liver repairs the damage by forming fibres of scar
tissue in a process similar to wound healing. When unchecked this process of
fibrosis leads to cirrhosis and the development of severe liver complications. The
final aim is to gain new insights into the links between liver cell injury, the
inflammatory response and fibrosis which will eventually lead to treatments to
prevent the initial triggers of this disease and also to interrupt the progression of
NASH to more serious fibrotic stage.
Research achievements (from final report):
Non-alcoholic steatohepatitis (NASH) is an important couse of liver injury in man.
We have a mouse model of methionine and choline deficient (MCD) dietary
manipulation where mice develop a histologically similar injury to that of NASH in
man. We have shown that in this model oxidative stress preceeds activation of
profibrogenic genes and that stellate cells are the mail cellular source of matrix
consitutents in MCD-accociated fibrosis, while hepatocytes were the main source of
oxidative stress. We have found that oxidative stress is crucial to the initiation and
perpetuation of liver injury and fibrosis in NASH. We identified many of the genes in
the MCD model with altered expression, including genes involved in oxidative stress,
hepatocyte regeneration and the initiation of the inflammatory process and antiapoptotic pathways.
NHMRC Research Achievements - SUMMARY
Expected future outcomes:
Introduction of new treatments to improve outcomes in human NASH.
Name of contact: Geoff Farrell
Email of contact: geoff_farrell@wmi.usyd.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 244905
CIA Name: Prof Stephen Hunyor
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Admin Inst: University of Sydney
Start Year: 2003
End Year: 2005
Total funding: $335,000.00
Grant Type: NHMRC
Development Grants
Title of research award:
Development of a chronically implantable, miniaturised device for monitoring
ventricular function, to assist tracking an
Lay Description (from application):
Heart failure (HF) is increasing - with ~5million sufferers (1/3rd in New York Heart
Association Class III/IV i.e. severe cases) in the US alone, and ~12-15 million
worldwide. Its management consumes health resources and strains sufferers, families
and institutions. The proposed monitoring/management device, chronically implanted
by minimally invasive surgery, will track the heart’s pumping pattern. It will allow
informed decisions to optimise therapy, thereby improving Quality of Life (QOL),
decreasing hospitalisations and decreasing healthcare costs. We aim to develop a
small, chronically and easily implantable device to track changes in heart function in
HF patients.
Research achievements (from final report):
A miniaturised monitoring system that can be chronically implanted in humans to
accurately monitor the heart's mechanical function has been tested to "Proof of
Principle" stage. The size of the device resembles modern cardiac pacemakers roughly three 50cent pieces on top of each other. Currently, bulky systems are used in
physiological/laboratory research, but the new device has been automated, and has
shown superior accuracy compared tor the benchtop models available. The
miniaturised device also has wireless (Bluetooth) communication capability. A
Provisional Patent application has been made for the novel aspects of the work, which
involved a close collaboration between the Cardiac Technology Centre, Kolling
Institute, University of Sydney at Royal North Shore Hospital and the University of
Technology, Sydney's Department of Electrical Engineering.
Expected future outcomes:
Given commercial/industrial interest and appropriate funding, the device could
undergo a series of rigorous, well defined animal experimental studies as a prelude to
clnical testing. Initially the conceptual "miniaturisation" would need to be
implemented in a mature prototype device, requiring collaboration with a firm that is
active in the field of chronically implantable cardiac devices.
Name of contact: Stephen N Hunyor
Email of contact: stephenh@med.usyd.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 253837
CIA Name: Dr Wayne Hawthorne
Main RFCD: Surgery
Admin Inst: University of Sydney
Start Year: 2003
End Year: 2005
Total funding: $310,500.00
Grant Type: NHMRC Project
Grants
Title of research award:
NON IMMUNOLOGICAL BARRIERS TO SUCCESSFUL TREATMENT OF
DIABETES BY XENOTRANSPLANTATION
Lay Description (from application):
Tragically patients whom suffer from diabetes mellitus develop major secondary
complications such as renal failure, even with today's tight glucose control. Insulin
injections minimise diabetic complications but restricts lifestyle and an alternative,
pancreatic islet cell transplantation, is limited by donor shortage. With genetic
technology, pig donor tissue is a feasible donor source. This project will use an inbred
pig colony to assess long term pig fetal and neonatal islet cell function in
combination with a kidney graft in the absence of an immune response. Using this
specifically inbred pig colony we will carefully catalogue the type, number and
distribution of endogenous retroviruses within pig genes. Using new and novel
techniques we will develop a new strategy by which we can block and overcome this
major concern of xenotransplantation. Ultimately a unique Australian resource will be
developed which may provide unlimited islets for safe, large-scale transplantation of
diabetics before they develop debilitating secondary complications from their diabetes
and provide an alternative to the only current method of curing endstage renal failure
with a combined pancreas and kidney transplant.
Research achievements (from final report):
This project has used the specially inbred "WESTRAN" pig to assess long term
porcine (FPPF and NICC) islet cell function in combination with a kidney graft in the
absence of an immune response. Also using this specifically inbred pig colony we
have carefully catalogued the type, number and distribution of porcine endogenous
retroviruses within these pigs genes. Using new and novel techniques we have begun
to develop a new strategy by which we can block and overcome this major concern of
xenotransplantation. Ultimately a unique Australian resource was developed which
may provide unlimited islets for safe, large-scale transplantation for patients that
suffer from diabetes before they develop debilitating secondary complications from
their diabetes. This may provide an alternative to the only current method of curing
endstage kidney failure and diabetes with a combined pancreas and kidney transplant.
Expected future outcomes:
With further funding we will be able to enhance these functional models for direct
application to the clinical setting. These ongoing studies will provide long-term data
providing the basis for potential clinical trials to treat diabetes and kidney failure.
Name of contact: Dr Wayne Hawthorne
Email of contact: N/A
NHMRC Research Achievements - SUMMARY
Grant ID: 512463
CIA Name: Prof Philip Clarke
Main RFCD: Health Economics
Admin Inst: University of Sydney
Start Year: 2008
End Year: 2010
Total funding: $400,397.00
Grant Type: NHMRC Project
Grants
Title of research award:
Development and validation of an Australian Diabetes Health Policy Simulation
Model
Lay Description (from application):
Diabetes imposes a heavy personal, societal and financial burden on Australia and this
is predicted to increase over time. The aim of this project is to develop a computer
simulation model that can be used to inform clinicians and policy makers in efficient
allocation of resources to improve the quality of diabetes care.
Research achievements (from final report):
We developed a new health economic diabetes computer simulation model that can
be used to inform clinicians and policy makers about potential outcomes of treatments
in order to improve the allocation of resources devoted to treatment and management
of this diease.
To date the project has generated seven peer-review medical publications focusing on:
oThe quality of life associated with major complications of diabetes and potential
downstream impacts on risk of death and major diabetes related events (e.g. heart
attacks);
oThe hospital resource use in terms of length of stay and costs for major
complications in various parts of the world including Australia;
oNew models for predicting life expectancy following major complications of
diabetes based on administrative data from Western Australia;
oTables for predicting life expectancy stratified by common risk factors including
blood pressure, lipid levels and smoking status;
Expected future outcomes:
Additional publications reporting models to predict risk of major complications based
on patient level data from the United Kingdom Prospective Diabetes Study are being
presented at the European Association for the Study of Diabetes conference (Portugal
2011). A fully integrated diabetes simulation model will be published in the near
future.
Name of contact: Prof Philip Clarke
Email of contact: philipc@med.usyd.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 358303
CIA Name: Prof Barbara Fazekas de St. Groth
Main RFCD: Immunology not elsewhere classified
Admin Inst: University of Sydney
Start Year: 2005
End Year: 2009
Total funding: $651,750.00
Grant Type: Established
Career Fellowships
Title of research award:
Uncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
1) I developed a new technique for identifying human regulatory T cells (Tregs), a
relatively rare white cell population that is crucial in preventing autoimmune disease
and allergy. Using this technique, we measured Tregs within human blood at different
ages, identified a novel subset of Treg cells in young adults and showed that Treg
cells increase in normal pregnancy but not in pre-eclampsia. We also identified Tregs
in patients with HIV. Our identification technique is now accepted world-wide as the
gold-standard technique for identifying live Treg cells. Its use will allow Treg therapy
to be tested in clinical trials in transplantation and autoimmune disease.
2) We developed new techniques to study the function of dendritic cells, which are a
crucial immune cell type required to stimulate T lymphocytes. We showed that
dendritic cells in different layers of the skin can have opposite functions. The most
superficial dendritic cells are responsible for the ability of our immune system to
tolerate the commensal bacteria that are a normal part of our skin.
3) We collaborated in the analysis of T lymphocyte responses to BCG and TB.
4) We collaborated in the analysis of T lymphocyte activation molecules.
Expected future outcomes:
Our new technique for identifying regulatory T cells, a relatively rare white cell
population that is crucial in preventing autoimmune disease and allergy, will
significantly accelerate the pace of research into human autoimmune and allergic
disease.
Name of contact: Prof B. Fazekas de St Groth
Email of contact: b.fazekas@centenary.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 153781
CIA Name: Prof Brian Morris
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Admin Inst: University of Sydney
Start Year: 2001
End Year: 2003
Total funding: $242,546.00
Grant Type: NHMRC Project
Grants
Title of research award:
TNF receptor 2 and iNOS genes in basis of cardiovascular disease
Lay Description (from application):
Cardiovascular diseases account for almost half of total deaths in Australia and other
industrialized countries. Hypertesnion, coronary artery disease and diabetes are major
contributing factors to mortality and morbidity. It is well known that each of these
have a genetic basis, as well as having environmental influences. A key focus of
reseach internationally is discovery of the molecular mechanisms involved. Our
recent findings point to a role for the inducible nitric oxide synthase gene (which
generates nitric oxide, a potent blood vessel dilator) and tumor necrosis factor
receptor 2 gene (whose product sends signals to the former gene) in heart, kidney and
blood vessel diseases. We now propose to find the actual gene changes responsible
and the molecules and mechanisms involved. By elucidating roles in cardiovascular
physiology and pathology the importance of these for cardiovascular function will be
ascertained, and may open up new avenues for treatment.
Research achievements (from final report):
The discovery of a functional genetic variant of the iNOS gene that predisposes to
complications of type 2 diabetes calls for patient screening. Those with the variant
will now be recognized as being at higher risk and be more intensively monitored, as
well as being targeted for early interventions that might prevent or reduce the their
progression to complications. We predict that his will save the health system
enormous amounts of money in costs of treatment, disability and support. We believe
that the research should be taken forward by clinicians working in conjunction with a
hospital-based genetic testing facility to help achieve these objectives.
Similarly, the association with overweight of an amino acid variant in the
glucocorticoid receptor should be followed up clinically to see if strategies that reduce
cortisol’s metabolic effects differ between individuals with each contrasting allele of
the genetic variant. This may contribute to obesity management and prevention, as
well as prevention of myocardial infarction.
Our findings of involvement in essential hypertension of a genetic variant in the
aldosterone biosynthesis pathway adds to evidence by others, so pointing to this as a
target for therapeutics and screening.
Expected future outcomes:
N/A
Name of contact: N/A
Email of contact: N/A
NHMRC Research Achievements - SUMMARY
Grant ID: 253838
CIA Name: Prof Phillip O'Connell
Main RFCD: Transplantation Immunology
Admin Inst: University of Sydney
Start Year: 2003
End Year: 2005
Total funding: $323,250.00
Grant Type: NHMRC Project
Grants
Title of research award:
The role and function of macrophages in cellular xenograft rejection
Lay Description (from application):
The long term objective of this project is to develop pig insulin secreting tissue as a
treatment for type 1 diabetes. At present the main barrier to this is rejection. In
paricular a type of white blood cell called macophages has an important role in
causing the rejection seen in xenotransplantation (the transplantation of pig tissue into
humans). Our reseach group has made novel observations which show that the way
macrophages respond to a xenotransplant is different to the way it behaves to the
transplant of an organ from the same species. In the rejection of pig insulin secreting
tissue, macrophages are able to respond in the absence of ongoing signals from T
cells. This project aims to identify the receptors on macrophages that are responsible
for this response. In particular those receptors that are important for facilitating the
migration of macrophages to the transplant site and the receptors that allow
macrophages to distinguish self from non-self will be analysed. Hopefully these
receptors will be used as targets for new therapeutic agents that could be used to
prevent the strong rejection response that occurs when pig insulin secreting tissue is
transplanted into humans.
Research achievements (from final report):
1. We have shown that once adtivated by CD4 T cells, macrophages have the ability
to migrate from the peripheral circulation and specifically destroy pig islet xenografts
in the absence of other effectors. This suggests that macrophages are able to migrate
to and recognise foreign material such as an organ from a different species.
2. This macrophage response described was surprisingly specific and was not seen
from macrophages activated by allografts. This suggests macrophages contain
receptors that allow them to differentiate between self and non-self.
3. The next section of the proposal dealt with trying to identify the types of receptors
on macrophages that allowed them to identify tissue from different species. TLR are
potential candidates in pig tissue recognition by macrophages. There was increased
TLR gene expression in macrophages. Our hypothesis is that the phylogenic disparity
and antigenic differences between donor and recipient promote innate immune
activation of macrophages [Manuscript submitted].
4. Studies using blocking antibodies to chemokines and chemokine receptor knock out
mice we showed that CCR5 is important for macrophage recruitment to islet
xenografts. (Publication).
5. Lack of CD40 had no effect on rejection or macrophage activation. Hence CD40
signaling was not essential for xeno rejection.
Expected future outcomes:
1. Better understanding of pancreatic islet xenograft rejection.
2. Development of better immunosuppressive protocols for xenotransplantation.
NHMRC Research Achievements - SUMMARY
3. Better understanding of macrophage biology.
Name of contact: Philip O'connell
Email of contact: philip_oconnell@wsahs.nsw.gov.au
NHMRC Research Achievements - SUMMARY
Grant ID: 457117
CIA Name: A/Pr Stephen Jan
Main RFCD: Health Economics
Admin Inst: University of Sydney
Start Year: 2007
End Year: 2011
Total funding: $471,059.00
Grant Type: Career
Development Fellowships
Title of research award:
Economics of chronic illness in socio-economically disadvantaged populations.
Lay Description (from application):
Not Available
Research achievements (from final report):
I held the NHMRC Career Development Award from 2007 to 2011. During this
period I have:
o
published 32 peer review journal articles (9 times in A* and 5 times in A
ranked journals), and 3 book chapters including invited chapters in the Oxford
Textbooks of Health Economics and the Oxford Textbook of Public Health. The
journals include the Lancet, BMJ, Social Science and Medicine and Stroke.
o
been an invited speaker to 9 national and international meetings including two
workshops run by the US Institute of Medicine on cardiovascular diseases in
developing countries.
o
been successful as CI in over $16 million worth of peer review grant funding
through the NHMRC or ARC; with $2.5 million as CIA.
o
been successful as CI-A on an NHMRC funded Capacity Building Grant
(2009-2013) that supports 9 early career health economists
o
been a successful applicant for an NHMRC Senior Research Fellowship,
Level A (2012-2016)
o
supported policy translation through my role as a committee member on the
economics subcommittee of the Pharmaceutical Benefits Advisory Committee, the
NSW Health Aboriginal and Population Health Priority Taskforce and the National
Prescribing Service Diagnostic Evaluation Advisory Panel.
I believe that during the period in which I was supported by the CDA, I have emerged
as a national leader in health economics research. Furthermore, through my role in
supervision and capacity building, I am also helping to address major skills shortages
in a field of research acknowledged as a national priority area.
Expected future outcomes:
I expect to consolidate my role as a leader in health economics research in Australia,
develop into an international leader in this field and to oversee the training and
development of a generation of early career researchers.
Name of contact: Stephen Jan
Email of contact: sjan@george.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 457332
Start Year: 2007
CIA Name: Prof Merlin Crossley
End Year: 2009
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding:
$549,447.00
Admin Inst: University of Sydney
Grant Type: NHMRC Project
Grants
Title of research award:
The regulation of gene expression during adipogenesis
Lay Description (from application):
The body stores energy acquired from ingested food as fat droplets within storage
cells termed adipocytes. The amount of fat varies between individuals and may also
vary during an individual's life. The variations reflect differences in physiology, diet,
and behaviour and have been the focus of intense study. Excessive accumulation of
fat is a serious health problem as it is associated with conditions such as heart disease
and diabetes. This grant application primarily concerns using a new line of genetically
modified mice that have reduced fat. These mice lack a key gene regulatory protein
that is implicated in fat accummulation and adipocyte formation. It is expected that a
knowledge of the genes regulating the formation and function of fat storage cells will
contribute to new strategies for controlling fat formation and will help in the
prevention of diseases such as diabetes and heart disease.
Research achievements (from final report):
In this project we have studied the roles of a number of DNA binding proteins in fat
cell formation (adipogenesis). These proteins are members of two important families
of gene regulatory molecules that have many different functions in mammalian
development- the Klf family and the Gata family. We have discovered that the gene
regulatory protein Klf3 can control adipogenesis. We have found that mice deficient
in Klf3 are lean. Our work in cell lines has shown that modulating the expression
levels of Klf3 can also affect fat cell formation.
We have made progress in understanding the molecular mechanisms that allow Klf3
to regulate adipogenesis. We have identified a number of target genes regulated by
Klf3, including the related family member Klf8. We have established that Klfs can
function in regulatory networks to achieve a balance of gene activator and repressor
molecules that in turn influences cellular development.
We have also investigated the roles of Gata2 and Gata3 proteins in adipogenesis. We
have established that the correct interaction of these regulatory molecules with their
partner proteins is essential for normal growth and differentiation of fat cells. We
have also found that overexpression of these proteins can block adipogenesis.
These results have furthered our understanding of the molecular mechanisms that
regulate adipogenesis. This knowledge will be of benefit in considering therapeutic
approaches to the management of diseases associated with obesity, including diabetes
and cardiovascular disease.
Expected future outcomes:
The gene regulatory proteins identified in this research, their partner proteins and
upstream regulators are all potential targets for the design of drugs to treat and prevent
obesity related disease.
NHMRC Research Achievements - SUMMARY
Name of contact: Professor Merlin Crossley
Email of contact: merlin.crossley@sydney.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 219171
CIA Name: Prof Phillip O'Connell
Main RFCD: Endocrinology
Admin Inst: University of Sydney
Start Year: 2001
End Year: 2006
Total funding: $4,380,000.00
Grant Type: International
Collaborations
Title of research award:
A preclinical model of pig islet xenotransplantation as treatment for type 1 diabetes
Lay Description (from application):
The object of this multi-disciplinary program grant is to develop a source of pig
insulin secreting tissue that will be used to treat type 1 diabetic patients. At present
the number of diabetic patients that would benefit from islet transplantation far
outnumber any human source of this tissue. Pigs that have been genetically altered to
avoid rejection and enhance survival could overcome this donor shortage problem.. It
is our belief that with the appropriate genetic modification pig insulin-secreting tissue
can avoid the aggressive rejection response that occurs with xenographs and provide
normal blood glucose control without insulin. This project concentrates on the five
main issues that need to be overcome before pig insulin-secreting tissue can be used
in diabetics. These are: identifying the best source of insulin secreting tissue to use;
adult islets, newborn or foetal islet cell clusters; overcoming the strong rejection
response to pig tissue; identifying a safe and effective immunosuppressive regime;
producing a new types of genetically modified pigs that will provide islets tissue that
will work in humans; and demonstrating that pig islet transplantation will not pose
undue infective risks for the patient or community. This truly collaborative program
grant has brought together a large group of investigators with strong research records
in diabetes, islet transplantation, xenotransplantation, pig transgenesis and pig
genetics and includes scientists and clinicians who look after diabetic patients.
Unique pig resources will be used including genetically manipulated pigs that have
been shown to avoid some of the rejection mechanisms associated with transplanting
pig tissue. There is a captive-bred baboon colony that provided a unique model of
diabetes. A world class pig transgenesis facility has been enlisted to generate new
lines of genetically altered pigs as new data is produced within the group. Finally
because of the involvement of the National Pancreas Transplant Unit any proven
therapeutic strategy can be brought quickly to clinical trials.
Research achievements (from final report):
The aim of this program was to develop a line of pigs that would be suitable for islet
transplantation. The main hypothesis was that pig insulin producing cells (ie islets)
have the potential to provide long-term pancreatic islet function in unstable diabetic
patients and overcome the problem of donor tissue supply that currently limits clinical
islet transplantation. During the tenure of this program we showed that newborn or
fetal pig islet tissue was a suitable donor source for correcting and controlling
diabetes in humans. We identified innate immune responses such as coagulation and
inflammation as a serious cause of immediate islet graft destruction. The hyperacute
innate response was confirmed in vivo where an immediate coagulative and
inflammatory response was seen within hours of transplantation. To overcome this
early innate response genetically modified pigs that lack the galactose alpha-1, 3
galactose epitope and pigs that express the ATPDase, CD39, have been deveoped.
NHMRC Research Achievements - SUMMARY
Early in vitro experiments have shown that removal of the alpha Gal epitope in
combination with expression of CD39 leads to less coagulation in vitro and studies
will soon be undertaken to ascertain its effect in vivo. Proof of principle that locally
secreted immunosuppression works and allows a reduction in systemic
immunosuppression has been demonstrated. This program has seen major advances in
the technologies necessary for the genetic manipulation of pigs. This will allow futher
refinement in the development of pigs for islet transplantation.
Expected future outcomes:
It is proposed to futher develop and refine the production of genetically altered pigs
suitable for use as islet donors. The use of locally secreted immunosupression will be
further developed. The ability of islet xenografts to control diabetes in an appropriate
animal model will be tested.
Name of contact: Philip O'connell
Email of contact: philip_oconnell@wsahs.nsw.gov.au
NHMRC Research Achievements - SUMMARY
Grant ID: 300565
CIA Name: A/Pr Philip Clarke
Main RFCD: Health Economics
Admin Inst: University of Sydney
Start Year: 2004
End Year: 2007
Total funding: $334,506.00
Grant Type: NHMRC Project
Grants
Title of research award:
A computer simulation model for the evaluation of interventions for the management
of type 2 diabetes in Austral
Lay Description (from application):
Diabetes imposes a heavy personal, societal and financial burden in Australia and this
is predicted to increase over time. It has been estimated that one million people in
Australia have diabetes and the annual cost of diabetes care is in the order of 3 billion
dollars. Many studies show that the current quality of diabetes care in Australia is
sub-optimal and therefore decisions must be made about prioritizing the allocation of
limited resources to correct these deficiencies. This project involves building a
computer simulation model to inform clinicians and assist policy makers in the
efficient allocation of resources to improve the quality of diabetes care in Australia.
Research achievements (from final report):
Diabetes is a major and growing health problem in Australia. It is associated with
reduced life expectancy and a range of serious illnesses including heart attacks and
strokes which are regarded as complications of diabetes. It imposes a considerable
financial burden on Australia as the management of diabetes requires regular contact
with health care professionals and people with diabetes have a higher chance of
hospitalisation.
The aim of this project was to develop a computer simulation model that can be used
to inform clinicians and policy makers about potential outcomes of treatments in order
to improve the allocation of resources devoted to diabetes care. Simulation modelling
is required, as it is necessary to predict future benefits and costs.
The project generated six peer-review medical publications in international journals
focusing on different elements of diabetes simulation modelling. These included:
o
Estimates of the annual Australian specific health care costs associated with
major complications based on large data sets from Western Australian and
Queensland;
o
Understanding the impact diabetes and associated risk factors such as being
overweight or obese has on quality of life.
o
The role that subjective rating of quality of life has on risk of subsequent
events;
o
Using a version of the diabetes simulation model to evaluate a range of
management strategies for diabetes.
The experience gained in developing this simulation model will be applied to the
development of future diabetes models and potentially for other chronic diseases.
Expected future outcomes:
Further development of the UKPDS Ouctomes model is being undertaken using
additional data collected from large scale studies in Australia and overseas. This
NHMRC Research Achievements - SUMMARY
model will help inform clinical and health policy decision relating to allocation of
resources for the treatment of type 2 diabetes.
Name of contact: A/ Prof Philip Clarke
Email of contact: philipc@health.usyd.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 457105
Start Year: 2007
CIA Name: Prof John Simes
End Year: 2011
Main RFCD: Medical and Health Sciences not elsewhere classified
Total funding:
$765,883.00
Admin Inst: University of Sydney
Grant Type: Established
Career Fellowships
Title of research award:
Uncoupled Research Fellowship
Lay Description (from application):
I am a clinical epidemiologist with a breadth of training and experience in medical
oncology, general medicine, biostatistics and clinical trials. My research
encompasses providing leadership in the design and conduct of clinical trials aimed at
improvin
Research achievements (from final report):
Professor John Simes is Senior Principal Research Fellow and founding director of
the NHMRC Clinical Trials Centre (CTC). He co-leads a team collaborating with
clinical investigators and other researchers nationally and internationally in a research
program aimed at improving clnical practice and health outcomes through the better
use of clinical trials research.
He has developed an international research track record in a broad range of areas in
clinical trial research with a significant impact on scientific knowledge, clinical
practice and health policy. Over the course of his career he has been successful in
obtaining over $150m in grant applications ($38m since 2007) and contributed to over
280 peer-reviewed articles (68 since 2007).
Professor Simes has taken leading roles in the establishment and growth of several
collaborative trials groups, and has helped develop the clinical trials expertise of
future leaders in the field through mentoring and teaching.
Examples of his research achievements with collaborating investigators include
improvements in survival and quality of life with new treatments in breast cancer,
better outcomes in colon cancer with molecular targeted therapies, more effective
lipid treatment for patients with cardiovascular disease and diabetes and new
evidence in determining optimal treatment strategies for the at risk newborn.
,
He has received the Harvard Alum Award (Biostatistics), Harvard University (2009)
in recognition of his work in research and the Medical Oncology Group of Australia's
Cancer Achievement award in 2010 for lifetime achievement in oncology.
Expected future outcomes:
Professor Simes will continue to co-lead a research program of clinical trials research
likely to influence future practice and policy in collaboration with major cooperative
groups. Research themes include the integration of basic molecular science into trial
design and the greater appropriate use of evidence-based medicine in practice.
Name of contact: Prof. R. John Simes
Email of contact: john@ctc.usyd.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 253853
CIA Name: A/Pr Stephen Twigg
Main RFCD: Cell Metabolism
Admin Inst: University of Sydney
Start Year: 2003
End Year: 2005
Total funding: $235,500.00
Grant Type: NHMRC Project
Grants
Title of research award:
NOVEL REGULATORS OF CONNECTIVE TISSUE GROWTH FACTOR
EXPRESSION AND BIOACTIVITY IN DIABETIC COMPLICATIONS
Lay Description (from application):
Diabetes mellitus is common in our community. It causes much premature death and
loss of quality of life. Recent data from Australian studies show that ~7% of adults
over 25 years, and ~20% of people aged over 65 have diabetes, and diabetes in both
children and adults is increasing in Australia. A critical problem caused by diabetes,
irrespective of its cause, is that blood glucose levels are higher than normal. High
blood glucose contributes to much of the damage to body tissues and to the early
death that can occur in diabetes. Unfortunately, given our current treatment methods,
in only a small number of patients can glucose levels in the body be consistently
controlled into the normal range. How does high blood glucose cause damage to the
body and its different tissues? This is a complex process. One way that damage occurs
is through an increase in some of the growth factors in the body. In diabetes, high
blood glucose can increase the production of some growth factors in an uncontrolled
way. In turn, these growth factors then cause tissue damage. One of the growth
factors that can be increased by the high glucose in diabetes is called connective tissue
growth factor, or CTGF. CTGF can cause scars to form in tissues, and it is increased
in diabetes in humans. Through NHMRC sponsored post-doctoral research over the
past four years, Dr Twigg has published findings showing pathways by which
diabetes causes increases in CTGF, and ways in which CTGF then causes tissue
scarring. The current grant proposal presents new data showing further novel
pathways by which CTGF is activated by diabetes and ways in which CTGF causes
scarring. The pathways involved will be studied in detail in the project. In addition,
methods to block CTGF and its harmful effects in diabetes will be developed in this
work. By controlling CTGF, it is envisaged that damage to tissues will be reduced,
leading to improved quality and quantity of life for people who have diabetes.
Research achievements (from final report):
Diabetes mellitus is common in our community. It causes much premature death and
loss of quality of life. Our sedentary and fast food lifestyle and an ageing population
are likely contributors to the increase in diabetes. A critical problem in diabetes,
irrespective of its cause, is that blood glucose levels are higher than normal. High
blood glucose contributes to much of the complications and damage to tissues in the
body that can occur in diabetes.
How does high blood glucose cause damage to the body and its different tissues?
This is a complex process. One way that these diabetes complications occur is
through elevated blood glucose causing an increase in the production of some growth
factors that are present in the body, in an abnormal and uncontrolled manner. In turn,
these growth factors then cause tissue damage, including scarring or fibrosis.
NHMRC Research Achievements - SUMMARY
This Project Grant studied ways in which growth factors cause tissue damage and
complications in diabetes. One of the growth factors that can be increased by high
glucose is called connective tissue growth factor (CTGF). CTGF can cause scars to
form in tissues, and it is increased in tissues in diabetes in humans. We studied
human cells called fibroblasts and kidney (mesangial) cells, which make fibrous
tissue. During this Grant wediscovered and published new ways in which high
glucose increases CTGF and new ways in which CTGF causes scarring to form in
diabetes. By better understanding these mechanisms, it is envisaged that therapies to
prevent and possibly reverse diabetic tissue damage will be achieved by controlling
key growth factors such as CTGF in human diabetes.
Expected future outcomes:
This work may well contribute towards understanding ways in which growth factors
can be controlled to prevent and also potentially reverse diabetes complications
Name of contact: A/Prof. Stephen Twigg
Email of contact: stwigg@med.usyd.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 457103
Start Year: 2007
CIA Name: Prof Anthony Keech
End Year: 2011
Main RFCD: Public Health and Health Services not elsewhere classified
Total funding:
$677,383.00
Admin Inst: University of Sydney
Grant Type: Established
Career Fellowships
Title of research award:
Uncoupled Research Fellowship
Lay Description (from application):
I am a cardiologist and epidemiologist whose research focus is on large-scale clinical
trials and epidemiological research into the prevention of cardiovascular disease,
particularly in relation to treatment strategies for acute coronary syndromes, dyslip
Research achievements (from final report):
Professor Keech continues major research to reduce vascular disease, and has
published 27 peer-reviewed original research articles during the grant period, many in
the highest impact medical journals available. The research team led by Prof Keech
has identified, through a large-scale clinical trial, a novel treatment that dramatically
reduces the eye, kidney and amputation complications of type 2 diabetes, using just a
single oral medication daily, with global implications for treatment policies and
patient quality of life. These findings have already resulted in new guidelines
internationally, and invitations to Professor Keech to testify at hearings at the FDA in
the USA and European Regulators about his research findings. His collaborations
during the grant have also reliably shown from randomised evidence that statin
treatment to lower cholesterol levels can reduce cardiovascular events in people with
diabetes at least as much as in other individuals, and more recently that high dose
statin treatment safely lowers cardiovascular risk more than regular statin dosing. This
has major implications for guidelines world-wide - aggressive treatment to lower
cholesterol levels as much as possible to maximally reduce cardiovascular risk in
people with existing disease or deemed at high risk is now a priority, resulting in
much scientific and media interest. Professor Keech has published a series of papers
in the Medical Journal of Australia on many aspects of clinical trials research, and
subsequently also a book to assist others in better understanding how to participate
effectively in clinical research to improve health outcomes of Australians.
Expected future outcomes:
Further important new trials will be undertaken, together with novel research into how
treatments lowering cardiovascular risk and also microvascular complications of
diabetes work, including biomarker, DNA and epigenetic research, and molecular
pathway research in basic science experiments.
Name of contact: Ms Katie Doyle
Email of contact: katie.doyle@ctc.usyd.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 402443
CIA Name: Prof Carol Pollock
Main RFCD: Nephrology and Urology
Admin Inst: University of Sydney
Start Year: 2006
End Year: 2008
Total funding: $557,523.00
Grant Type: NHMRC Project
Grants
Title of research award:
Epithelial-mesenchymal transformation in diabetic nephropathy: Roles of oxidative
stress and KLF transcription factors
Lay Description (from application):
Diabetes mellitus is responsible for the majority of kidney disease in the Western
world . Diabetic nephropathy now accounts for the single largest cost to the health
system in the USA. In Australia diabetic nephropathy, together with
glomerulonephritis accounts for over 50% of the cases of dialysis-requiring renal
failure. As the incidence of diabetes is increasing, current projections indicate an
expotential rise in patient population with kidney disease. As the presence of kidney
dysfunction is possibly the greatest predictor of subsequent cardiovascular events
(including heart attack, heart failure and stroke) a thorough understanding of the
mechanism of progressive kidney failure in patients with diabetes is required so that
effective therapeutic strategies may be developed. Preliminary data leading to the
development of this proposal, has shown that normal kidney tubule cells 'transform'
into fibroblastic-like cells, in a process known as epithelial-mesenchymal
transformation (EMT), under the metabolic disturbances inherent in diabetes mellitus.
These fibroblast-like cells are likely to be responsible for the progressive scarring in
the kidney that is characteristic of irreversible renal failure. We have documented that
a specific factor, transforming growth factor beta (TGFB1) is increased in kidney
cells in the presence of diabetes mellitus, and our preliminary data suggests the action
of TGB1 is regulated by the KLF-family of transcription factors. This project aims to
determine whether metabolic conditions such as exposure to high glucose and
oxidative stress induced by diabetes mellitus modifies the KLF factors within cells
that then alter susceptibility to TGFB1 induced EMT. The specific pathways
involved in EMT will be dissected using both cell culture models and animal models
of diabetes mellitus. These pathways will be selectively interrupted to assess
reversibility of the EMT process.
Research achievements (from final report):
The studies demonstrated the key roles of KLF transcription factors in mediating
kidney scarring and facilitation of the action of other cytokines involved in
progressive kidney disease, particularly diabetic nephropathy. The transcriptional
profiles of human proximal tubule cells exposed to high glucose using cDNA
microarray analysis were studied. Consistent with our hypothesis regarding the
relevance of oxidative stress to kidney fibrosis, thioredoxin interacting protein
(Txnip) was the gene most significantly increased. Increased expression of Txnip and
of nitrotyrosine, were confirmed in in vivo studies. Subsequent studies focused on the
dependence of Txnip expression on up-regulation of TGF-β1 under high glucose
conditions. Overexpression of Txnip and up-regulation of Txnip promoter activity
were observed in cells in which the TGF-β1 gene was silenced in proximal tubular
cells. High glucose increased both Txnip expression and its promoter activity in TGF-
NHMRC Research Achievements - SUMMARY
β1 silenced cells exposed to high glucose. Further studies suggested that high glucose
induced Txnip through a pathway mediated by KLF6/KLF4. Thiazolodinediones
attenuate Txnip expression by targeting KLF4 and -6 expression.
Results were presented at the Australian and New Zealand and American Society of
Nephrology in 2006 and in 2007. A PhD student involved in these studies was
awarded the Young Investigator of the Irish Nephrology Society in 2007. His PhD
was awarded by the University of Sydney in 2009. 4 publications and 1 book chapter
have arisen to date as a consequence of this research. 3 further grants have been
submitted and 2 additional PhD student projects are extending this work.
Expected future outcomes:
On additional grant has commenced and 2 further grants have been applied for to
continue this work. 2 further papers are in preparation and 2 PhD students have
commenced work on projects generated by this grant.
Name of contact: Professor Carol Pollock
Email of contact: carpol@med.usyd.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 512170
CIA Name: Prof Carol Pollock
Main RFCD: Nephrology and Urology
Admin Inst: University of Sydney
Start Year: 2008
End Year: 2010
Total funding: $540,639.00
Grant Type: NHMRC Project
Grants
Title of research award:
TGFbeta isoforms differentially regulate fibrosis and inflammation in diabetic
nephropathy via KLF transcription factors
Lay Description (from application):
Progressive scarring and inflammation in the kidney represent the final common
injury pathway for diseases that lead to kidney failure, including diabetic
nephropathy. This project explores the interplay between the molecular processes that
are triggered by high glucose levels in patients with diabetic nephropathy, some of
which are deleterious and some potentially 'protective'. By understanding these
mechanisms we will be able to prevent and more effectively treat kidney disease in
diabetes.
Research achievements (from final report):
To date we have demonstrated that all TGFβ isoforms are expressed in tubular cell
lines and in vivo models of diabetic nephropathy. All isoforms are increased in culture
after exposure to high glucose. Experiments have focused on the effects of
overexpressing or silencing TGFβ specific isoforms and assessing the effect on other
suggested Sphingosine kinase-1 (SK-1) as a potential mediator of renal fibrosis. We
have shown that a pharmaceutical inhibitor of SK-1, SK1-II, significantly suppressed
TGF1, -2 or -3 induced MCP-1 in kidney tubular cells. The role of SK-1 on all TGFβ
isoforms induced fibrotic responses in kidney cells is currently under investigation. In
addition, we have demonsted that TGFβ isoforms differentially induced expression of
KCa3.1, PAI-1, collagen IV, fibronectin and FSP-1 in renal cortical fibroblast cells
but their effects on MCP-1 similar. Current experiments are confirming the effects of
silencing each of the other isoforms on each other's expression, as well as downstream
effects on inflammation (MCP-1) and fibrosis (fibronectin). The effect of all isoforms
on NFkB phosphorylation and/or DNA binding ability (EMSA) in cells exposed to
high glucose and in cells in which the TGFβ isoform is silenced are unde
investigations. The outcome of this sudy has indicated targeting TGFβ isoform 3 will
be a potential therapeutical strategy for the treatment of renal fibrosis. Publication has
been somewhat hampered by a PhD student suspending her candidature due to illness
during the project.
Expected future outcomes:
The project is innovative in drawing together common mechanisms to bridge
inflammation and fibrosis in diabetic kidney. These studies will therefore collectively
define the biological process underpinning the biological basis of disease, which is
necessary to direct future therapeutic targets to prevent diabetic nephropathy.
Name of contact: Prof Carol Pollock
NHMRC Research Achievements - SUMMARY
Email of contact: carol.pollock@sydney.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 301936
CIA Name: Prof Ronald Grunstein
Main RFCD: Respiratory Diseases
Admin Inst: University of Sydney
Start Year: 2004
End Year: 2006
Total funding: $423,650.00
Grant Type: NHMRC Project
Grants
Title of research award:
Interaction Between Sleep Apnea and Metabolic Syndrome
Lay Description (from application):
In this proposal, we will study possible ways in which sleep disordered breathing
("snoring sickness" or sleep apnea) may cause or worsen metabolic syndrome. Sleep
apnea is a common disorder frequently linked to metabolic syndrome. Metabolic
syndrome is a cluster of health risk factors including increased risk of diabetes, high
cholesterol, high blood pressure and excess fat around the abdomen. Metabolic
syndrome is an important cause of increased death from cardiovascular disease and
affects about 3 million Australians. Our theory is that lack of oxygen during sleep
and disruption of normal sleep patterns leads to increased activity of the body stress
handling systems and damage to the lining of the body's blood vessels. In turn, this
may promote high blood fat levels and cause excess fat deposits in muscle and liver.
We will measure blood, muscle and liver fat changes with treatment of sleep apnea.
We believe that by damaging the lining of blood vessels, sleep apnea will also cause
an inability of the body's arteries to relax properly. We will measure sleep apnea and
the ability of the body's arteries to expand using novel techniques before and after
treatment of sleep apnea. We will also take people off treatment to see if these
changes get worse. Part of the proposal includes investigating whether snoring and
lack of oxygen during sleep leads to increased blood fat levels. Finally, in another
study, we will measure the change in metabolic syndrome related disorders in people
with sleep apnea losing weight.
Research achievements (from final report):
Our research has shown how Obstructive Sleep Apnea (OSA) may promote
cardiovascular and metabolic disease through its links with central obesity and the
Metabolic Syndrome (MSynd). We showed that in obese OSA patients, weight loss of
10% with a drug Sibutramine reduces the severity of OSA by one third.
Improvements in weight and OSA severity were accompanied by improvements in
MSynd components including reductions in abdominal (visceral) and liver fat and
improvements in insulin resistance and HDL cholesterol. Hence drug-assisted weight
loss in OSA patients could be used to improve OSA whilst also improving
components that contribute to MSynd and increased cardiovascular risk. In another
series of studies, we showed that OSA patients have increased arterial stiffness that is
partly dependent on the severity of OSA. Although treatment of OSA did not lower
peripheral blood pressure, it did reduce arterial stiffness and the blood pressure load
on the heart. These changes imply that OSA treatment is likely to significantly reduce
cardiovascular risk through improvements in large artery function. In contrast, we
showed that 1-week of withdrawal from OSA treatment does not alter arterial
stiffness, blood pressure or inflammatory markers in the blood but it does increase
sympathetic activity. We also discovered that large arteries relax when healthy
subjects are exposed to low levels of oxygen (hypoxia). In future studies we plan to
NHMRC Research Achievements - SUMMARY
determine whether the ability of large arteries to relax during hypoxia is inhibited in
OSA patients. Hypoxia is common during sleep in OSA patients and these studies will
improve our understanding of how hypoxia affects vascular function.
Expected future outcomes:
Our final study will assess the impact of OSA treatment on post-meal levels of blood
fat (triglyceride) or post prandial lipidemia (PPL) using a randomised controlled
design. We hope to show that PPL and therefore cardiovascular risk, improves with
OSA treatment. We have also collected blood samples from our CPAP withdrawal
study and our PPL study for future assessment of genetic polymorphisms.
Name of contact: Ms Lucy Williams
Email of contact: lawilliam@bigpond.com
NHMRC Research Achievements - SUMMARY
Grant ID: 632507
CIA Name: Prof Vlado Perkovic
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Admin Inst: University of Sydney
Start Year: 2010
End Year: 2012
Total funding: $510,640.00
Grant Type: NHMRC Project
Grants
Title of research award:
UTILITY OF NOVEL BIOMARKERS IN THE PREDICTION OF MAJOR
COMPLICATIONS OF TYPE II DIABETES MELLITUS
Lay Description (from application):
Diabetes is increasingly common. It can cause a variety of complications, the most
serious being heart and kidney disease. The reasons why some patients develop such
complications are not fully understood so it is difficult to predict who will be affected.
The current project will use samples from a large international study of patients with
diabetes to assess whether levels of specific markers in the blood help to predict major
complications and clarify why they occur.
Research achievements (from final report):
This grant has been completed on time and on budget. The first publication reporting
the results of this work is currently under review by a leading journal. This study
addressed the relationship between levels of the inflammatory markers C-reactive
protein (CRP), fibrinogen, and interleukin-6 and major cardiovascular events,
microvascular complications (eye and kidney disease) and death. Further work, partly
funded by this grant and partly by Diabetes Australia, assessing the ability of CRP,
high-sensitivity cardiac troponin T and N-terminal B-type natriuretic peptide to
predict cardiovascular events and death is also under review. Further analyses are also
underway, assessing the ability of these markers to predict microvascular
complications. We are currently analysing the data on the advanced glycation endproducts and their soluble receptor. A further research project that leveraged off this
award (and would not have been possible without this grant) has demonstrated that 2
novel biomarkers, circulating transforming growth factor-β1 and bone morphogenetic
protein-7 levels, are more accurate predictors of a decline in renal function in patients
with type 2 diabetes than conventional markers (glomerular filtration rate and
albuminuria).
We anticipate that the data from this work will have considerable impact. They will
improve our understanding of the pathogenesis of diabetic complications and our
initial analyses suggest that some of the markers tested are of sufficient predictive
value that they may be adopted clinically in this role. In addition, this grant has
enabled other research projects that have already identified important and exciting
novel biomarkers.
Expected future outcomes:
The data we have already analysed has important implications for the
pathophysiology of diabetic complications, identifies novel biomarkers of risk and
suggests that some of the markers tested may have a clinical role. We anticipate that
the data we are currently analysing will be of similar impact.
Name of contact: A/Professor Graham Hillis
NHMRC Research Achievements - SUMMARY
Email of contact: ghillis@georgeinstitute.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 352312
CIA Name: Dr Ronald Gillies
Main RFCD: Ophthalmology and Vision Science
Admin Inst: University of Sydney
Start Year: 2005
End Year: 2008
Total funding: $529,500.00
Grant Type: NHMRC Project
Grants
Title of research award:
A multicentre randomised clinical trial of laser treatment plus intravitreal traimcilone
for diabetic macular oedema
Lay Description (from application):
A diagnosis of diabetes immediately confers a 25 fold increase in a person's risk of
blindness. The macula is the vision centre of the retina, which is like the film in a
camera. In people with diabetes, swelling of the macula (macular oedema) due to
leakage of retinal blood vessels is the commonest cause of loss of vision. Laser
treatment is proven to be helpful in reducing the risk of vision loss in eyes with
diabetic macular oedema (DMO), but it does not work in 40% of cases. Injection of
slow release steroids is an emerging revolutionary treatment for DMO. We are the
first in the world to perform a randomised clinical trial of triamcinolone injection into
the eye with DMO that has failed laser treatment. A randomised clinical trial is when
an equal number of eyes are randomly allocated to the treatment and placebo (no
treatment) groups, so that none of the patients or the doctors knows whether each
particular eye is receiving treatment or placebo. The preliminary results of our study
in progress have proved that, at least in the short term, intravitreal triamcinolone
(IVTA) leads to reduction of macular oedema and improved vision. We now propose
a two year randomised clinical trial to test whether the combination of IVTA with
laser treatment will result in a further improvement in vision in eyes with DMO. We
are in a unique position to conduct such a study, having recently concluded the
world's first randomised clinical trial of IVTA for "wet" age-related macular
degeneration in 151 eyes. We have extensive experience of IVTA's significant but
manageable adverse event profile. The Australian Retinal Collaboration is a group of
academic retinal specialists who are committed to attaining the highest possible
standards in clinical research in Australia for common blinding conditions of the
retina. The results of the proposed study are likely to lead directly to a reduction of
the risk of vision impairment and blindness in people with diabetes.
Research achievements (from final report):
Recent clinical research has shown that diabetic macular oedema (DMO) is
responsive to intravitreal treatment with both steroids and anti-vascular endothelial
growth factor agents, with favourable results reported at least in the short term.
Although laser photocoagulation remains the "gold standard" treatment for DMO,
intravitreal steroids may be considered for recalcitrant DME in which laser treatment
is no longer feasible and multiple applications of both intravitreal steroid and laser are
often required in clinical practice. We conducted a two-year multi-centre,
randomized, double masked, placebo-controlled clinical trial to test the hypothesis
that intravitreal triamcinolone (IVTA) applied prior to laser treatment of eyes with
DMO results in better clinical outcomes. Eighty-four eyes of 54 participants were
entered into the study, with 42 eyes initially receiving IVTA and 42 placebo, 6 weeks
prior to standard laser treatment. Further laser was applied according to prospectively
NHMRC Research Achievements - SUMMARY
defined criteria. Two year patient follow up was completed in May 2009 and the 24
month data analysis is ongoing. The 6 month results demonstrated that, despite a
better anatomical outcome reflected by reduction in mean central macular thickness,
visual results and need for further laser treatment at 6 months were no better in the
IVTA-treated group. Therefore we found no evidence of a short-term synergistic
effect between IVTA and laser photocoagulation for DMO. The information obtained
from this study provides guidelines for retinal clinicians for the combination treatment
of IVTA with laser on eyes with DMO and may also benefit others in the future by
providing a better understanding of the disease.
Expected future outcomes:
Despite a reduction in central macular thickness, we found that pre-treatment with
IVTA did not improve outcomes of laser after 6 months. Two year outcomes will be
reported later this year. These data will have a direct effect on modifying treatment
patters to deliver the best and safest outcomes for eyes with diabetic retinopathy.
Name of contact: Prof Mark Gillies
Email of contact: mark@eye.usyd.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 302068
CIA Name: Prof Paul Mitchell
Main RFCD: Ophthalmology and Vision Science
Admin Inst: University of Sydney
Start Year: 2004
End Year: 2006
Total funding: $389,575.00
Grant Type: NHMRC Project
Grants
Title of research award:
Retinal vascular signs as predictors of systemic disease outcomes: 10-year evolution
in a population-based cohort
Lay Description (from application):
Recent U.S. data from two population-based studies have highlighted retinal
microvascular signs as being predictive of systemic vascular and other important
health outcomes in middle-aged or older individuals, particularly stroke and heart
attack and mortality, independent of traditional vascular risk factors. The present
application proposes to evaluate the 10-year development and progression of retinal
microvascular signs and their relations to the development of stroke and other
important systemic health outcomes in the population-based cohort of residents
attending the Blue Mountains Eye Study (BMES. Two types of retinal signs will be
evaluated: firstly, the presence of specific clinical signs, such as focal narrowing of
small retinal vessels (arterioles), nicking of retinal veins as arterioles cross them or
presence of retinopathy (haemorrhages and other signs) secondly, measures of
generalized retinal vessel calibre (narrowing) using a computer-assisted method
developed for the U.S. studies. We will also develop new grading methods for two
other signs. Late and will compare computer-assisted grading from 35mm slides to
automated grading of vessels using a scanning device (being developed) to screen the
eyes of older persons. This project builds upon our current 3-year NHMRC grant
(ID153948; 2001-2003) "Retinal vascular signs as risk markers for incident stroke or
cerebrovascular death: A population-based assessment" . In the last 2 years, this has
explored different aspects of measurement and grading of these signs, has
documented their relation to blood pressure and has begun to assess whether these
features predict vascular events and other systemic outcomes in older Australians. The
new project will assess the evolution of retinal microvascular signs over a 10-year
period, using data and retinal photographs from the 10-year examinations of the
BMES cohort, currently being collected, in a further current NHMRC grant
(ID211069; 2002-2004).
Research achievements (from final report):
We aimed in this study to evaluate the incidence and progression of retinal
microvascular signs and their relation to incident cerebrovascular disease (CVD) and
other systemic health outcomes in the Blue Mountains eye Study (BMES) cohort.
Two types of retinal signs were evaluated: 1) qualitative presence of specific focal
signs (focal retinal arteriolar narrowing, arteriovenous nicking, arteriolar wall opacity
(enhanced retinal arteriolar light reflex) and the presence of (non-diabetic) retinopathy
lesions), and 2) quantitative measures of generalised retinal vessel caliber (narrowing)
using computer-assisted methods. The BMES has retinal images available from more
than 95% of study participants at baseline and at 5 and 10-year follow-up visits.
Relationships between the incidence of these signs and cerebrovascular,
cardiovascular disease and other outcomes were assessed, together with findings from
NHMRC Research Achievements - SUMMARY
pooled analyses with data from the Beaver Dam Eye Study, Wisconsin. The findings
overall suggest that retinal microvascular signs represent a novel biomarker for the
long-term risk of cardio-vascular and cerebro-vascular disease, and as well, represent
a marker for risk of certain eye diseases (e.g. glaucoma, macular degeneration) amd
other conditions (e.g. hearing loss, cognitive impairment). Our data also support the
potential value of retinal photography for cerebrovascular and cardiovascular disease
risk prediction and stratification. The project commenced in 2004 and a number of
new graders were trained, both in Sydney and from other Centres (e.g. Melbourne,
Singapore). Data linkage to the National Death Index with detailed mortality data
indicated a significant predictive role for these signs on cardiovascular outcomes.
Expected future outcomes:
Detailed incidence data over 10 to 15 years will be developed, particularly for the
objective signs, and some novel measures of microvascular optimality (e.g. fractal
dimension), will be assessed. These may lead to the development of a simple,
automated photographic screening evaluation applicable to images available from
non-mydriatic cameras (i.e. without the need for pupil dilation).
Name of contact: Paul Mitchell
Email of contact: paul_mitchell@wmi.usyd.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 402573
CIA Name: Dr Ronald Gillies
Main RFCD: Ophthalmology and Vision Science
Admin Inst: University of Sydney
Start Year: 2006
End Year: 2008
Total funding: $167,734.00
Grant Type: NHMRC Project
Grants
Title of research award:
An open-label extension of a randomised clinical trail of intravitreal triamcinolone for
diabetic macular oedema
Lay Description (from application):
A 25 fold increase in the risk of going blind on diagnosis of diabetes is one of the
most daunting threats that patients face. Most cases of vision impairment in diabetes
are due to macular oedema that persists or recurs after laser treatment. There are now
a number of uncontrolled, anecdotal reports that intravitreal triamcinolone (IVTA) is
highly effective for the treatment of diabetic macular edema which is refractory to
conventional laser treatment. We commenced the first placebo-controlled, double
masked clinical trial of intravitreal triamcinolone for refractory macular oedema in
2002. The 3 month results from this study provide the first scientific proof of
principle that intravitreal triamcinolone reduces macular thickness and improves
vision. The two year results will be available in March 2005, but confidential interim
analysis of efficacy data in September 2004 suggested that the beneficial effect of
triamcinolone treatment persisted. Thus it appears that treatment with intravitreal
triamcinolone may be the most significant development for the prevention of
blindness in people with diabetes since the introduction of laser treatment. It would
also be a highly cost-effective intervention that could be administered by general
ophthalmologists. The treatment cannot be recommended for routine use, however,
until its long term efficacy and safety have been established. Since we already have a
well studied group of patients who have received treatment for 2 years, we are in a
unique position to extend the study in order to provide the long-term (5-year) safety
and efficacy data that does not appear to be forthcoming from any other source. The
results of this study will significantly improve knowledge of long-term outcomes of
local high dose steroids for diabetic macular oedema, allowing the treatment to be
used more rationally. Thus the study is very likely to directly reduce the risk of
blindness in people with diabetes.
Research achievements (from final report):
Diabetic macular oedema (DMO) due to leakage of retinal blood vessels is the
commonest cause of loss of vision in people with diabetes. Laser treatment is proven
to be helpful in reducing the risk of vision loss in eyes with DMO, but it does not
work in 40% of cases. Results from our first randomised clinical trial demonstrated
that treatment with intravitreal triamcinolone (IVTA) repeated as required, safely
improved vision and reduced swelling for up to 2 years in most eyes with diabetic
macular oedema which persisted or recurrred despite laser treatment. In the present
project, we conducted a three year open label extension of this study in which all the
eyes of study participants were treated with medication (intravitreal triamcinolone) as
required, as well as standard laser treatment where appropriate. We found
improvement in vision of (approximately one line on vision chart) over 5 years in
14/33 (42%) eyes initially treated with triamcinolone compared with 11/34 (32%)
NHMRC Research Achievements - SUMMARY
eyes initially treated with placebo.This study suggested that the beneficial effect of
intravitreal triamcinolone in eyes with DMO persists for up to 5 years in most eyes
without a large increase in treatment-related adverse events. A 2-year delay in
instituting treatment did not seem to adversely affect outcomes, although the
relatively small numbers remaining in the study may not have been sufficient to pick
up small but significant differences between the initial-triamcinolone and initialplacebo treated eyes. It would appear that the goal of treatment with triamcinolone is
to improve vision in the short term and prevent the development of irreversible
damage, however long-term resolution may depend on other factors, some
presumably genetic, other environmental, of which it is likely that attention to
systemic risk factors will continue to be crucial. .
Expected future outcomes:
We believe that treatment with eye injections of a steroid triamcinolone can be
considered in carefully selected cases of impaired vision from advanced diabetic
macula edema (swelling of the centre of the retina at the back of the eye) that are
losing vision because they are failing conventional treatment with laser.
Name of contact: Professor Mark Gillies
Email of contact: mark@eye.usyd.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 352600
CIA Name: Prof Michael Clark
Main RFCD: Endocrinology
Admin Inst: University of Tasmania
Start Year: 2005
End Year: 2007
Total funding: $304,375.00
Grant Type: NHMRC Project
Grants
Title of research award:
Nutrient and hormone delivery to muscle: interactions between insulin and exercise
Lay Description (from application):
Exercise is known to be beneficial in the treatment and prevention of Type 2 diabetes
and in particular muscle insulin resistance. Also, exercise and insulin share similar
acute actions on muscle. Firstly, muscle contraction has a well established action to
increase glucose uptake, and secondly, both muscle contraction and insulin act to
increase capillary recruitment. This latter phenomenon is thought to enhance nutrient
delivery and waste product removal. There is evidence that the increase in capillary
flow due to muscle contraction is accompanied by increases in total blood flow. For
insulin action we now have preliminary data to indicate that capillary recruitment
occurs within a 5-10 min application of a physiologic dose of insulin independent of a
change in total blood flow suggesting a redistribution of flow. Muscle contraction also
increases capillary recruitment and it raises the question of whether similar
mechanisms underlie insulin- and muscle contraction-induced capillary recruitment or
whether there are distinct and complementary pathways. In this project we plan to
define the mechanisms responsible for contraction- and insulin-induced capillary
recruitment in muscle. We hypothesize that similar mechanisms are operative, with
both insulin and muscle contractions acting via NO-dependent mechanisms. Because
of capillary reserve, and different initial steps of the signalling systems stimulated by
insulin and exercise, capillary recruitment by combined contraction and insulin
stimuli will be additive at both sub maximal and perhaps at maximal insulin pathway
stimulation. Signalling mechanisms will be compared and the role of non-nutritive
route as a flow reserve assessed.
Research achievements (from final report):
We have increased our understanding how insulin works to lower blood glucose
levels in muscle by increasing blood perfusion in a manner similar to, but different
from, exercise. we have also identified impaired blood perfusion of muscle as a
potentail cause of type 2 diabetes.
Expected future outcomes:
There is the possibility of novel therapeutic approaches for treating type 2 diabetes,
based on overcoming impaired blood perfusion of muscle.
Name of contact: Prof Michael Clark
Email of contact: Michael.Clark@utas.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 253900
CIA Name: Prof Michael Clark
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Admin Inst: University of Tasmania
Start Year: 2003
End Year: 2005
Total funding: $220,500.00
Grant Type: NHMRC Project
Grants
Title of research award:
Cyclic GMP phosphodiesterase inhibitors and facilitation of insulin-mediated
capillary recruitment in muscle
Lay Description (from application):
It would now seem clear that insulin has a major stimulatory effect on blood flow
within muscle to improve access for itself as well as nutrients such as glucose. When
this haemodynamic effect of insulin is impaired insulin resistance in terms of glucose
uptake by muscle results and there is the potential for type 2 diabetes to develop. Our
key contribution has been the development of new techniques to make this
observation possible and it would be fair to say that we are the world leaders in this
field because of these techniques. Using these methods we now wish to develop new
drugs for treating type 2 diabetes based on improving muscle capillary blood flow.
The approach we will use is similar to that used previously by others for the treatment
of erectile dysfunction with drugs targeted at a particular enzyme controlling the
metabolism of a substance (cyclic GMP) which in turn regulates blood flow to the
corpus cavernosum. In our case, the drugs will be targeted at another specific isoform
of the same enzyme, cyclic GMP phosphodiesterase, located at control points in the
skeletal muscle microvasculature. We expect to find that insulin-mediated capillary
recruitment in muscle will be enhanced by such drugs. As a consequence, insulin
resistance in muscle will be lessened.
Research achievements (from final report):
Several novel drugs targeted at an enzyme likely to control blood flow in muscle were
used in animal models to assess whether they enhanced insulin's action to alter muscle
blood flow and glucose uptake. Some were successful and some were not. Attempts
were then made to identify the various forms of the target enzyme in muscle and the
vascular elements of muscle. A number were found to be differentially expressed.
Expected future outcomes:
Novel drugs specifically targeted at the isoforms identified in the muscle vasculature
will be identified and developed as potential therapies.
Name of contact: Prof Michael Clark
Email of contact: Michael.Clark@utas.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 302200
CIA Name: A/Pr Stephen Rattigan
Main RFCD: Endocrinology
Admin Inst: University of Tasmania
Start Year: 2004
End Year: 2006
Total funding: $451,500.00
Grant Type: NHMRC Project
Grants
Title of research award:
The role of the endothelium in insulin's in vivo action upon skeletal muscle
metabolism.
Lay Description (from application):
A number of studies using novel techniques developed in association with our USA
collaborators, indicate that insulin has a major stimulatory effect on blood flow within
muscle in both animals and humans to improve access for itself as well as nutrients
such as glucose. As much as 50% of the glucose taken up by muscle in vivo during
continual exposure to insulin may be attributed to this effect. Moreover, this
haemodynamic effect of insulin in muscle is impaired in a number of animal models
and in obese humans when insulin mediated muscle glucose uptake is also impaired.
What is not known is how insulin mediates this haemodynamic effect of recruiting
capillary blood flow. Thus in the present study a number of aspects are to be explored,
with particular focus on the cells that line the blood vessels and constitute the
capillaries, the so called endothelium. First, we will explore the specific role of the
endothelium in insulin's action by using the novel approach of attaching insulin to a
large molecule that prevents it leaving the lumen of the blood vessel. This will mean
that insulin will be confined to interacting only with insulin receptors on the muscle
endothelium. Similarly, non activating anti insulin receptor antibody will be used in
the presence of insulin to selectively prevent activation of the endothelial insulin
receptors. In addition, we will investigate whether homocysteine, an amino acid found
to impair endothelial dependent vasodilatation, impairs the haemodynamic effects of
insulin. The impact that normal insulin release after a meal has upon the
haemodynamic actions in muscle and the role this has in muscle glucose uptake will
also be investigated by using the techniques developed in the first part of the project.
Our over riding hypothesis is that the endothelium plays a key role in controlling
insulin and possibly glucose access to muscle cells and thus a significant proportion
of insulin mediated metabolic events in muscle.
Research achievements (from final report):
Skeletal muscle glucose uptake is dependent upon the action of insulin on the vascular
system to increase microvascular blood flow to enhance delivery of insulin and
glucose to the muscle cells. Insulin has two actions on the vasculature to release the
signaling agents endothelin-1 and nitric oxide. An imbalance in these where there is
an excess of endothelin-1 can lead to the loss of the insulin-mediated increase in
microvascular blood flow and decreased insulin-mediated muscle glucose uptake.
Expected future outcomes:
Agents targetted to enhance insulin's vascular actions to recruit microvascular blood
flow may be beneficial in treating insulin resistance and preventing the development
of type 2 diabetes.
NHMRC Research Achievements - SUMMARY
Name of contact: Assoc Prof Stephen Rattigan
Email of contact: S.Rattigan@utas.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 211302
CIA Name: Prof Michael Clark
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Admin Inst: University of Tasmania
Start Year: 2002
End Year: 2004
Total funding: $315,990.00
Grant Type: NHMRC Project
Grants
Title of research award:
Mechanisms linking insulin-mediated muscle capillary recruitment and glucose
uptake
Lay Description (from application):
A number of studies over recent years including our own have suggested that insulin
acts in normal humans and animals to improve blood supply to muscle and that a
contributing factor to Type 2 diabetes is an impaired ability of insulin to achieve this
effect. Our key contribution to this field is the finding that insulin acts to alter blood
flow in muscle to improve access for itself and nutrients such as glucose. This
discovery of blood flow redistribution in muscle was made possible by newly
developed in-house methods. Using these methods we now wish to explore (a) the
mechanism by which insulin mediates this effect and (b) when this effect of insulin to
improve muscle blood flow is impaired in diabetes, how it might be recovered. We
expect to find that insulin-mediated capillary recruitment in muscle results from a
signal substance released from muscle that permeates nearby tissue reacting with the
blood vessels to improve blood flow. It is also exp