NHMRC Research Achievements - SUMMARY
END OF GRANT REPORTS
OUTCOMES OF NHMRC FUNDED RESEARCH INTO
ARTHRITIS, OSTEOPOROSIS AND OTHER MUSCULOSKELETAL DISORDERS
ENDING 2000 TO 2013
CONTENTS
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Austin Research Institute
Australian National University
Baker IDI Heart and Diabetes Institute
Children's Medical Research Institute
Curtin University of Technology
Deakin University
Edith Cowan University
Flinders University
Garvan Institute of Medical Research
Griffith University
Howard Florey Institute
La Trobe University
Ludwig Institute for Cancer Research
Macfarlane Burnet Institute for Medical Research and Public Health
Mater Medical Research Institute, Brisbane
Menzies Research Institute
Monash University
Murdoch Childrens Research Institute
Prince Henry's Institute of Medical Research
Queensland Institute of Medical Research
Queensland University of Technology
Royal Melbourne Institute of Technology
Sir Charles Gairdner Hospital
St Vincent's Institute of Medical Research
The Children's Hospital at Westmead
University of Adelaide
University of Canberra
University of Melbourne
University of New South Wales
University of Newcastle
University of Queensland
University of South Australia
University of Sydney
University of Tasmania
University of Western Australia
University of Western Sydney
NHMRC Research Achievements - SUMMARY
University of Wollongong
Victoria University
Walter and Eliza Hall Institute
Women's and Children's Hospital, Adelaide
NHMRC Research Achievements - SUMMARY
Grant ID: 250399
Start Year: 2003
CIA Name: A/Pr Denise Jackson
End Year: 2005
Admin Inst: Austin Research Institute
Grant Type: NHMRC Project Grants
Main RFCD: Immunology not elsewhere classified
Total funding: $265,500
Title of research award:
Regulating tolerogenic signals by inhibitory co-receptorsRegulating tolerogenic signals by inhibitory coreceptors
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
collagen-induced 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)., 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
NHMRC Research Achievements - SUMMARY
Email/Phone no. of contact:
d.jackson@burnet.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 153835
CIA Name: Dr Geeta Chaudhri
Admin Inst: Australian National University
Main RFCD: Cellular Immunology
Total funding: $453,055
Start Year: 2001
End Year: 2003
Grant Type: NHMRC Project Grants
Title of research award:
Pathophysiological significance of reverse signaling through membrane TNFPathophysiological significance of
reverse signaling through membrane TNF
Lay Description (from application):
Cytokines are molecules produced by cells that take part in immune and inflammatory responses. They
coordinate the activities of leukocytes and therefore are important in the host response against infections.
However, overproduction of some cytokines, particularly tumour necrosis factor, seems to cause the deleterious
consequences. Tumour necrosis factor is made by cells, particularly macrophages, T lymphocytes and natural
killer cells, in two stages: first, the cytokine is exposed on the surface of the cell and then it is 'clipped off' and
released as a smaller, soluble form. In either form it can interact with specific receptors on other cells and, in
this way, change the cells' activities. We believe that binding of tumour necrosis factor receptors to the
cytokine while it is in its membrane form can also send a message "backwards", into the cell bearing the
tumour necrosis factor. This process, known as "reverse signalling", then changes the activity of this cell. In
this project we will investigate this phenomenon in detail. The results will be extremely relevant to new
methods of treatment of diseases, that rely either on 'masking' tumour necrosis factor by administering soluble
forms of its receptor or on blocking the release of the soluble form of the molecule from the surface of the cell.
Our work will enable us to understand the consequences of these approaches more fully. We will also be
looking at the role of the membrane form of tumour necrosis factor in a model of infectious disease. Influenza
virus is responsible for a great deal of morbidity and mortality around the world. We, and others, have shown,
in a mouse model, that some cells in the lungs make tumour necrosis factor during the course of viral
pneumonia. Here we will determine whether the membrane form of this cytokine plays a role in clearing virus
or causing some of the complications of this disease. This also may have relevance to other inflammatory and
infectious disease.
Research achievements (from final report):
Cytokines are molecules produced by cells that take part in immune and inflammatory responses. They
coordinate the activities of leukocytes and therefore are important in the host response against infections.
However, overproduction of some cytokines, particularly tumour necrosis factor, seems to cause the deleterious
consequences, such as arthritis. Tumour necrosis factor is made by cells in two stages: first, the cytokine is
exposed on the surface of the cell and then it is 'clipped off' and released as a smaller, soluble form. In either
form it can interact with specific receptors on other cells and, in this way, change the cells' activities., , We
have shown that binding of tumour necrosis factor receptors to the cytokine while it is in its membrane form
can also send a message "backwards", into the cell bearing the tumour necrosis factor, changing the activity of
this cell. This is a previously undescribed way in which tumour necrosis factor can act. Our results are
extremely relevant to new methods of treatment of diseases currently in use, that rely either on 'masking'
tumour necrosis factor by administering soluble forms of its receptor or on blocking the release of the soluble
form of the molecule from the surface of the cell. , , We also looked at the role of the membrane form of
tumour necrosis factor in a model of infectious disease. Influenza virus is responsible for a great deal of
morbidity and mortality around the world. We have shown, in a mouse model, that some cells in the lungs
make tumour necrosis factor during the course of viral pneumonia and that tumour necrosis factor plays a vital
role in recovery from infection. This also may have relevance to other inflammatory and infectious disease, ,
Expected future outcomes:
A better understanding of the actions of a key player, tumour necrosis factor, in infection and inflammation
will lead to more targeted new therapies for infectious disease such as influenza and inflammatory disease such
as arthritis.
NHMRC Research Achievements - SUMMARY
Name of contact:
Geeta Chaudhri
Email/Phone no. of contact:
Geeta.Chaudhri@anu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 179811
Start Year: 2002
CIA Name: Prof Frances Shannon
End Year: 2004
Admin Inst: Australian National University
Grant Type: NHMRC Project Grants
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $452,310
Title of research award:
A functional proteomics approach to the study of inducible gene transcription in a chromatin context.A
functional proteomics approach to the study of inducible gene transcription in a chromatin context.
Lay Description (from application):
Cells of the immune system detect assaults on the body such as infection, inflammatory or allergy-causing
agents. Using a complex set of signaling pathways, the cells translate this information into a change in the
pattern of expressed genes in those cells. These changes in gene expression occur rapidly and are generally
transient. The changes that occur in gene expression pattern leads to functional changes in the cell that in turn
are critical for the downstream events of the immune response. One set of genes that is rapidly and transiently
switched on in response to immune stimuli in T cells (one important immune cell type) are those that encode
proteins known as cytokines. These cytokines function to send messages between cells thus activating
downstream events of the immune response. Thus understanding the mechanism of how these genes are
switched on and off is critical in understanding an immune response and in developing potential novel
therapeutics based on gene transcription. Genes exist in the nucleus of the cell in the context of a complex
structure known as chromatin. The process of RNA transcription from these genes, therefore, takes place in the
context of this complex structure. While there have been many studies defining the molecular mechanisms that
control the expression of cytokine genes, little attention has been paid to the role of chromatin in the inducible
and transient nature of this gene transcription. This proposal addresses the molecular mechanisms by which
inducible cytokine gene transcription occurs in a chromatin context. We will use both in vitro and in vivo
approaches to probe the structure of chromatin that overlies these genes and the mechanism by which this
structure is altered to allow the genes to be expressed.
Research achievements (from final report):
Activation of T cells by foreign antigens is one of the key events in an immune response. When T cells are
activated they produce a variety of cytokines that communicate with other cell types in the immune syatem or
act in an autocrine fashion to drive proliferation and differentiation of the T cells. Upon initial activation,
cytokines such as GM-CSF (a myeloid growth factor) and IL-2 (a T cell growth factor) are made in large
quantities. The mechanisms by which these genes are activated to express mRNA and hence protein is of great
interest in understanding how the immune syatem responds to foreigh or self antigens. , One important aspect
of gene activation is the changes that occur in the packaging of the DNA around the inducibal genes. In this
project we have shown that chromatin is remodelled across a very small promoter region, in the order of one
nucleosomes worth of DNA and that this remodelling involves the loss of histone proteins from this region. We
have charaterized the signaling needs for this histone loss and shown a specific need for the NF-kB but not the
NFAT familiy of transcription factors. In addition, we showed that the SWI/SNF chromatin remodelling
complexes may play an important role in the chromatin structure across these gene promoters. We have also
investigated the relationship between the SWI/SNF complexes and the NF-kB family of transcription factors.
Expected future outcomes:
Work from this project has underpinned further recent work on models of chromatin remodelling in T cells
which match models being proposed from yeast systems. Thus this work will lead to a better understanding of
gene transcription in eukaryotes in general.
Name of contact:
Prof Frances Shannon
Email/Phone no. of contact:
frances.shannon@anu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 316937
CIA Name: Prof Angela Dulhunty
Admin Inst: Australian National University
Main RFCD: Cell Physiology
Total funding: $258,000
Start Year: 2005
End Year: 2007
Grant Type: NHMRC Project Grants
Title of research award:
Characteristics of splice variants of the skeletal muscle ryanodine receptor: implications for myotonic
dystrophyCharacteristics of splice variants of the skeletal muscle ryanodine receptor: implications for
myotonic dystrophy
Lay Description (from application):
The project is to address some of the basic molecular changes that occur in skeletal muscle during development
and in myotonic dystrophy. Myotonic dystrophy is a significant health issue since it is the most common adult
muscular dystrophy, with an occurrence of ~1 in 7000. The results will provide much needed information
about the membrane-associated molecular mechanisms that regulate muscle contraction and may provide a
basis for drug design and treatment of myotonic dystrophy. Respiration and locomotion depend on the release
of calcium ions from stores inside muscle cells. Ryanodine receptor calcium channels regulate calcium release
from the stores. The essential nature of ryanodine receptors is underlined by death at or before birth when
ryanodine receptor expression is defective. In addition genetic defects in the ryanodine receptor cause cardiac
arrhythmias, malignant hyperthermia and central core disease. Ryanodine receptor function is compromised in
heart failure and fatigue. The essential role of ryanodine receptors makes them a potential therapeutic target,
but they are not used in this way because of our limited knowledge of the protein. Myotonic dystrophy is an
autosomal dominant multi-system disorder, in which an expansion of non-coding DNA leads to changes in
expression of several different proteins. Although the genetic basis of myotonic dystrophy is now reasonably
well understood, the contribution of molecular changes in the affected proteins to the myopathy has not been
investigated. Our group has recently discovered that the juvenile form of the ryanodine receptor protein is
highly expressed in adults suffering from myotonic dystrophy. By discovering more about the properties of the
juvenile isoform, we will understand more about the basic mechanisms of ryanodine receptor function in
developing muscle and in myotonic dystrophy and be able to design drugs to specifically modify ryanodine
receptor activity.
Research achievements (from final report):
There has been a substantial output from this project with 4 publications in the top internationally peer
reviewed journals in the field and one further manuscript to be submitted. The work revealed for the first time
that the myopathy in myotonic dystrophy is associated with expression innapropriate splaice variants of the
skeletal muscle ryanodine receptor (RyR1) and the SERCA calcium pump. The work continued to define the
significant role of the variably spice region of RyR1, the AS1 region, in the normal gating of the isolated
ryanodine receptor ion channel and in excitation-contraction coupling. The results led to the conclusion that the
ASI is an important regulatory domain of RyR1 and takes part in an interdomain interaction that dictates the
gating behaviour of the ion channel and the response of the ion channel to surface membrane depolarisation.
The research has identified a region of the skeletal RyR channel that might be targetted by drugs designed to
modify muscle contraction, such as muscle relaxants.
Expected future outcomes:
The expected furture outcomes are the possible developemnt of muscle relaxants based on our understanding of
this region and further basic research into the binding partners within the RyR1 complex for the ASI residues.
Name of contact:
Angela Dulhunty
Email/Phone no. of contact:
angela.dulhunty@anu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 316951
CIA Name: Prof James Butler
Admin Inst: Australian National University
Main RFCD: Health Economics
Total funding: $4,500,000
Start Year: 2005
End Year: 2012
Grant Type: NHMRC Strategic Awards
Title of research award:
ACERH- Inovative analyses of health insurance, ageing and the economic burden of illness and injuryACERHInovative analyses of health insurance, ageing and the economic burden of illness and injury
Lay Description (from application):
An inter-university collaborative research centre – the Australian Centre for Economic Research on Health
(ACERH) – will be established, undertaking applied health economics research within three research programs:
health insurance; ageing; and the economic analysis of illness and injury. ACERH will develop a unique, unit
record, linked data set, including data from private health insurance partners, providing longitudinal data on
health service utilisation in both public and private sectors.
Research achievements (from final report):
This grant was used to establish a new inter-university centre - the Australian Centre for Economic Research
on Health (ACERH). Over the life of the Centre, research was undertaken on a range of topics primarily in
health insurance and health care financing, the economic burden of illness and the cost-effectiveness of
interventions to reduce that burden, and the economics of ageing and aged care. Selected research highlights
included work on the economic aspects of health insurance arrangements in Australia and proposals for reform,
including an "opt-out" option for Medicare, analysis of the risk equalisation scheme for private health insurers,
and a proposal for a Medicare Hospital Benefits scheme (some aspects of which are manifest in the new public
hospital payment scheme currently being implemented by the Australian and State Governments). Other
significant research in the area of child health in Australia found that, although an increasing income gradient
by child age exists when the same covariates used in other international studies are included, the gradient
disappears when a richer set of control variables including parental health is included. Other significant and
policy-relevant research included an economic evaluation of alternative HPV vaccination strategies in
Australia, and a critical appraisal of government policy on GP Super Clinics. Extensive research has also been
undertaken on economic aspects of breastfeeding, resulting in an ACERH research fellow receiving several
invitations to provide advice internationally on public policy in this area.
Expected future outcomes:
Through its research outputs, and contribution to capacity building through the development of a cadre of PhD
students and early career researchers, ACERH's legacy will be its contributions to health policy debates and its
strengthening of the health economics workforce. This legacy will be evident for some time in the future.
Name of contact:
Jim Butler
Email/Phone no. of contact:
jim.butler@anu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 366771
Start Year: 2006
CIA Name: Prof Christopher Goodnow
End Year: 2008
Admin Inst: Australian National University
Grant Type: NHMRC Project Grants
Main RFCD: Humoral Immunology and Immunochemistry
Total funding: $536,628
Title of research award:
Mechanisms controlling antibody production by modulating B cell antigen receptor signallingMechanisms
controlling antibody production by modulating B cell antigen receptor signalling
Lay Description (from application):
This project will analyse mechanisms that regulate antibody production in health and disease. In health,
antibodies are normally made exclusively against infectious agents, providing long-lasting immunity.
Unknown errors in the control of antibody production result in autoimmune diseases such as systemic lupus or
rheumatoid arthritis, where antibodies are made against parts of our own bodies, or result in allergies where
antibodies are made against innocuous elements of our environment, or result in uncontrolled B cell
accumulation in lymphoma, leukemia and myeloma. In order to develop rational, specific methods for treating
these diseases, it is necessary to identify and understand the biochemical mechanisms that normally control
antibody formation against infectious agents, self components, and innocuous environmental agents. The
project focuses on defining the biochemical mechanisms by which the antibody-forming cells, B lymphocytes,
sense infectious, innocuous, or self components. These cells carry specific receptors that bind these
components and transmit signals into the B lymphocyte. The research will determine how different types of
signal are transmitted by the receptor so that, normally, large amounts of antibody are made against infectious
agents but very little antibody is made against self components, and that B cell accumulation is tightly limited.
By identifying how the types of signals are changed, the results of this project will reveal control mechanisms
that may be altered in autoimmunity, allergy, immune deficiency, or lymphoma, and that may be able to be
used as drug targets to cure these diseases.
Research achievements (from final report):
The study identified how the immune system's antibody-forming cells, B lymphocytes, diminish their capacity
to multiply and make antibody if this antibody reacts with parts of our own body, or enhance their capacity to
multiply and make antibody if this antibody has previously been proven to react with a foreign microbe. The
study provides fundamental insights into two central questions in all of immunology: how forbidden clones of
self-reactive cells are silenced, and how desired clones of microbe-fighting cells are able to make a greater and
more rapid response upon a second exposure to the same microbe. The results thus provide a mechanistic
understanding for future research to prevent and treat autoimmune diseases and to enhance the effectiveness
and longevity of immunization against infection.
Expected future outcomes:
We are continuing to define the components of the gene program that inactivates forbidden clones of B cells,
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/Phone no. of contact:
Chris.Goodnow@anu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 402750
Start Year: 2007
CIA Name: Prof Timothy Hirst
End Year: 2008
Admin Inst: Australian National University
Grant Type: NHMRC Project Grants
Main RFCD: Medical Microbiology not elsewhere classified
Total funding: $359,578
Title of research award:
Cholera toxin co-receptor interaction in the prevention of inflammatory autoimmune disordersCholera toxin
co-receptor interaction in the prevention of inflammatory autoimmune disorders
Lay Description (from application):
Vaccination is undoubtedly one of mankind's greatest achievements. While infections continue to be the major
cause of morbidity and mortality in the developing world, heart disease, cancer, chronic allergies and
autoimmune disorders are taking their toll in advanced societies. Our expanding knowledge of these 'modern
diseases' shows that the immune system plays a central role and hence it is important to learn if new
immunologically-based therapies can be developed for such chronic human disorders. This project takes
advantage of our recent discoveries on the immunological properties of a hitherto feared molecule - cholera
toxin. We have shown that one portion of the toxin, the B-subunit, responsible for binding to cell membranes,
possesses remarkable immunomodulatory properties that prevent the development of inflammatory
autoimmune disorders such as rheumatoid arthritis in animal models. The B-subunit, in contrast to the whole
cholera toxin, is non-toxic and has no adverse effects in humans. This has sparked considerable interest in the
development of such molecules as novel anti-inflammatory agents and highlighted the necessity to better
understand the B-subunit's mode of action. Current theory specifies that the B-subunit mediates its
immunomodulatory effects by binding and cross-linking a ubiquitous plasma membrane glycosphingolipid,
GM1 ganglioside. The essential role of GM1-interaction was recently challenged by our discovery that a
mutant B-subunit (H57A) was unable to modulate the immune system even though it still bound to GM1;
suggesting that the B-subunits interact with another receptor (or co-receptor), and that it is this second
interaction that directs the immune system to prevent development of autoimmune disease. The primary aims
are to characterize the nature of B-subunit interaction with the cell membrane and to identify the co-receptor.
This work has the potential to provide a new target for drug discovery and development of
immunotherapeutics.
Research achievements (from final report):
Our discovery that the non-toxic B-subunits of cholera toxin (CtxB) and Escherichia coli enterotoxin (EtxB)
are powerful modulators of the immune system has led to a keen interest in their development as novel
immunomodulatory therapeutics. CtxB and EtxB inhibit the development of a range of inflammatory
autoimmune disorders in animal models such as rheumatoid arthritis, type I diabetes and inflammatory bowel
disease. Recent findings, funded by this project, have revealed the B-subunits that are almost indestructible and
resistant to intestinal proteases such as trypsin, are broken down by an endosomal protease found the
intracellular compartments of cells. The endosomal protease releases just one specific peptide containing a
docking motif that should interact with, so-called, Mitogen Activated Protein Kinases (MAP kinases) and cause
disruption of signalling pathways that play a vital role in directing pro-inflammatory immune responses. These
key finding could explain the profound immunmodulatory property of these bio-active proteins. In long run, it
is conceivable the peptide released by this protease could be turned into a drug, or mimetic of it turned into a
drug, for treatment of debilitating autoimmune disorders.
Expected future outcomes:
Confirmation that the news hypothesis explaining the immunmodulatory effect of CtxB is correct. Potential to
development the endosomal released peptide (or mimetic therof) as a new therapeutic for debilitating
autoimmune disorders.
Name of contact:
Professor Tim Hirst
NHMRC Research Achievements - SUMMARY
Email/Phone no. of contact:
tim@hirstshabianhirst.com
NHMRC Research Achievements - SUMMARY
Grant ID: 471418
CIA Name: Prof Angela Dulhunty
Admin Inst: Australian National University
Main RFCD: Peripheral Nervous System
Total funding: $603,100
Start Year: 2008
End Year: 2011
Grant Type: NHMRC Project Grants
Title of research award:
Communication between calcium ion channels in skeletal muscle excitation-contraction
couplingCommunication between calcium ion channels in skeletal muscle excitation-contraction coupling
Lay Description (from application):
Ageing, injury, drugs or genetic defects cause muscle weakness, prevent exercise, compromise life style and
contribute to poor health and osteoporosis. In order to move signals travel from our brain to muscles, where
one calcium ion channel detects the signal and tells a second calcium channel to open and release calcium ions
to initiate contraction. The project will pave the way for developing drugs to help with muscle disorders by
trageting the site of interaction between the channels.
Research achievements (from final report):
Work supported by this grant enabled us to perform the first study of the second of three SPRY domains in the
skeletal muscle ryanodine receptor (RyR1). In this comprehensive work we used NMR, CD to examine the
structure the recombinant DHPR II-III loop bound to the SPRY2 domain of RyR1 and cryoelectron microscopy
to locate the domain in the RyR protein (Cui et al., 2009; Tae et al., 2009; Tae et al., 2011; Perálvarez-Marín et
al., 2011). We quantified DHPR alpha1s II-III loop, and the variably spliced AS1 region of RyR1, binding to
SPRY2. Mutation of specific acidic residues in SPRY2 or basic residues in the II-III loop or in the ASI region,
prevent the ASI/SPRY2 binding (Tae et al., 2009). A cyclised II-III loop was expressed using novel intein
technology and is a stronger activator of RyR1 that the linear version of the loop (Tae et al. 2011b). In an elite
international collaboration we show that mutation of the critical regions in the SPRY2 domain do not influence
EC coupling (Tae et al., 2011a), indicating unexpectedly, that there is a specific influence of the DHPR
complex on interactions of the SPRY2 domain, possibly involving the intracellular β1a subunit of the DHPR.
The grant further supported preliminary paradigm shifting work with the DHPR β1a subunit, and a peptide
corresponding to its C-tail, both of which bind to and activate RyR1 with pM affinity, supporting a role for β1a
in excitation-contraction coupling (Karunasekera et al., 2009; Rebbeck et al., 2011).
Expected future outcomes:
We have identified the SPRY2 domain as a potential therapeutic target for modulating calcium release through
RyR1, and thus skeletal muscle contraction. The β1a work provided background for current studies of β1a
interactions with RyR1 and the alpha1S II-III loop and mechanisms that allow β1a to contribute to EC coupling
Name of contact:
Angela Dulhunty
Email/Phone no. of contact:
angela.dulhunty@anu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 317840
Start Year: 2005
CIA Name: Dr Anita Wluka
End Year: 2008
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: Early Career Fellowships
(Australia)
Main RFCD: Epidemiology
Total funding: $331,500
Title of research award:
Identification of lifestyle factors which act as determinants of articular knee cartilage cost of knee cartilege loss
AuIdentification of lifestyle factors which act as determinants of articular knee cartilage cost of knee cartilege
loss Au
Lay Description (from application):
Not Available
Research achievements (from final report):
This award has enhanced our understanding of structures within the knee, and how they differ in those with and
without knee osteoarthritis. It has added to our understanding of how lifestyle and biomechanical factors affect
the knee in healthy people, which may provide insight into the mechanism of risk factors for knee
osteoarthritis. For example, body fat mass was shown to be detrimental to the amount of knee cartilage present.
It may be that for effective prevention of knee OA, weight reduction strategies should include muscle
maintenance: simple weight loss alone may be insufficient. Thus, these may facilitate more effective strategies
to prevent knee osteoarthritis in the future.
Expected future outcomes:
Extension of this work may provide a stronger basis to enable intervention studies to be performed to reduce
the risk of knee osteoarthritis.
Name of contact:
Anita Wluka
Email/Phone no. of contact:
anita.wluka@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 418961
Start Year: 2007
CIA Name: Dr Fahad Hanna
End Year: 2011
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: Early Career Fellowships
(Australia)
Main RFCD: Rheumatology and Arthritis
Total funding: $321,571
Title of research award:
Lifestyle factors and hip cartilage volume.Lifestyle factors and hip cartilage volume.
Lay Description (from application):
Not Available
Research achievements (from final report):
The research work undertaken in the last 4 years has yielded some important results that were published in high
impact international journals. I have shown that regular physical activity is protective of cartilage loss in the
knee joint and may delay the development of osteoarthritis is older people. I have also shown that obesity is a
risk factor for osteoarthritis as it is associated with cartilage loss in the knee joint. We also found, in a substudy that high level of testosterone in men is protective of cartilage loss in the knee joint. In a second substudy we found that occupation that requires frequent bending is associated with patella cartilage damage in
women. Other findings in other sub-studies were that high cholesterol and triglyceride levels were associated
with the incidence of bone marrow lesions in the knee joint over 2 years. This fellowship also resulted into a
number of systematic reviews published in international journals.
Expected future outcomes:
There are few papers that are work in progress with the focus shifted to burden of musculoskeletal conditions
in an attempt to broaden the area of research and potentially submit a grant/senior fellowship application in this
area of research.
Name of contact:
Fahad Hanna
Email/Phone no. of contact:
fahad.hanna@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 321701
Start Year: 2005
CIA Name: Prof Edna Hardeman
End Year: 2007
Admin Inst: Children's Medical Research Institute Grant Type: NHMRC Project Grants
Main RFCD: Neurosciences not elsewhere classified
Total funding: $464,500
Title of research award:
Novel features and mechanisms of congenital myopathiesNovel features and mechanisms of congenital
myopathies
Lay Description (from application):
Congenital myopathies are inherited diseases of skeletal muscle that typically present at birth or in early
childhood and are characterised by poor muscle tone and muscle weakness. This group of disorders includes
nemaline myopathy, central core disease, congenital fiber type disproportion, and myotubular myopathy. All of
these disorders are characterised by disorganisation of the sarcomere, the major structure within skeletal
muscle cells that is involved in contraction. In addition, the congenital myopathies have features in common
with virtually all muscle diseases such as slow fibre predominance and alterations in contractile force. We are
using nemaline myopathy as a representative congenital myopathy to examine features in common amongst the
myopathies, characteristic of the congenital myopathies and specific to nemaline myopathy. In nemaline
myopathy patients, mutations have been found in five genes that encode proteins of the filamentous systems of
the sarcomere. A feature specific to nemaline myopathy is the presence of abnormal structures of the sarcomere
called nemaline rods. We have analysed a large number of nemaline myopathy patients that have mutations in
the genes that encode the filament proteins alpha-skeletal actin and tropomyosin. In addition, we have
generated mouse models for nemaline myopathy and propose to generate an additional one with novel features.
Our mouse model has revealed that a feature previously thought exclusive to dystrophies, is also present in
nemaline myopathy. The combined analysis of well-characterised patient samples and mouse models will allow
us to address longstanding questions about this particular congenital myopathy and myopathies in general. We
will determine how rods form and their protein composition. Our mouse models in particular will allow us to
address the molecular mechanisms that underpin the increase in slow twitch fibres and the effects that a
particular mutation has on muscle function.
Research achievements (from final report):
Congenital myopathies are inherited diseases of skeletal muscle that typically present at birth or in early
childhool and are characterised by muscle weakness. A key feature of these disorders is disorganisation of the
sarcomere, the major structure in muscle cells involved in muscle contraction. We used nemaline myopathy
(NM), which has a diagnostic rod-like structure that disrupts sarcomeres, as a representative congenital
myopathy to examine features common amongst myopathies, characteristic of congenital myopathies and
specific to NM. During the course of this grant we found that NM has features of other muscle diseases which
has implications for disease diagnosis, identification of underlying gene mutations and mechanisms of disease
pathologies and weakness. Our finding that NM has features in common with dystrophies, the major category
of muscle diseases, raises the prominence of this disease. We successfully generated a mouse model for a
severe form of the disease which allowed us to follow the progression of the disease and correlate disease
features with disease severity. Most importantly, we trialled therapies on these mice and found that an amino
acid supplement, L-tyrosine, ameliorates reduced movement and that the protein insulin-like growth factor 1
improves muscle strength.
Expected future outcomes:
We predict that our findings will further break down the divisions between the categories of muscle diseases so
that common features will be more readily recognised. This is have impact on the design of therapies. We are
providing the mouse model that we have made for the severe form of the disease to 6 laboratories to test
therapies.
Name of contact:
Professor Edna Hardeman
NHMRC Research Achievements - SUMMARY
Email/Phone no. of contact:
e.hardeman@unsw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 111110
CIA Name: A/Pr Deborah Kerr
Admin Inst: Curtin University of Technology
Main RFCD: Clinical Chemistry
Total funding: $43,574
Start Year: 2000
End Year: 2000
Grant Type: NHMRC Project Grants
Title of research award:
The effects of a two year randomised exercise intervention on markers of bone turnover in postmenopausal
womenThe effects of a two year randomised exercise intervention on markers of bone turnover in
postmenopausal women
Lay Description (from application):
Osteoporosis is a condition where the bones become more fragile and can break more easily. In Australia
after age 60, three out of every five women and three out of every ten men will fracture a bone. When people
fracture a hip they lose their independence and become much less mobile. Exercise is one lifestyle approach
which may help in preventing osteoporosis by slowing bone loss and keeping the muscles strong. Previous
research has not been able to clearly demonstrate the usefulness of exercise due partly to the difficulty in
getting people to exercise for a least one year, which is how long bone studies must be carried out for. We have
conducted two large research studies in women past the menopause where they have done weight training
exercises. In the previous study we showed the greatest increase in bone mass occurred in those women lifting
the heaviest weights. In a recently completed two year study in 126 woman, which forms the basis of this
proposal, we found a weight training program was effective at increasing the bone mass at the hip, a common
fracture site. The fitness group did not show any increase. So although we have been able to show this type of
exercise helps increase bone mass we don't know how the bone is able to respond to this. The question we
wish to address with this proposal is does exercise slow the breakdown of bone or does it help form new bone?
The best way to be able to answer this question is by measuring certain products in blood, known as bone
markers. Bone is continually turning overthese markers are released from bone into the blood. By studying
these bone markers in blood samples taken from the subjects over two years it will helps us determine how
exercise is affecting bone. From our previous studies we know that weight training can help slow bone loss.
By measuring the bone markers we will then be able to make recommendations to people on how exercise will
help prevent bone loss.
Research achievements (from final report):
The evidence for the biochemical response to exercise comes from cross-sectional data and a limited number of
longitudinal studies. There have been a small number of studies examining the effect of exercise on bone
turnover. No study to date has examined the biochemical response to exercise over a two yaer strength training
regime. The aim of this study was to investigate the effects of a two year randomised exercise intervention on
the biochemical markers of bone turnover in postmenopausal women. The subjects consisted of 126 women
who were more than four years past the menopause and physically capable of exercising. Assignment was by
block randomisation to one of three groups: a strength, circuit or non-exercise control. All subjects were given
600 mg of elemental calcium daily. The strength group protocol emphasized skeletal loading wheras the circuit
group emphasized aerobic fitness and both exercise groups attended three supervised exercise sessions per
week. There was a significant difference between the groups for changes in total hip BMD (Kerr et al. JBMR
2001) but there was no significant difference between the groups for changes in serum and urine markers
measured. Vitamin D showed alternating changes which may be due to seasonal effects. The lack of effect
observed with the bone markers may reflect the timing of the sampling. As blood sampling occurred at six
monthly intervals, earlier sampling (at monthly intervals in the first six months) may have been able to detect
changes in the bone turnover markers. Alternatively the measurement error in the bone markers may have been
too large to detect changes. The CV error was 6% for bone-specific alkaline phosphatase and 7% for urine total
deoxypridinoline. The lack of effect observed suggests that exercise interventions need to measure bone
markers in the early stages of the exercise intervention. This may be important in understanding the mechanism
by which exercise may act on bone remodeling.
Expected future outcomes:
NHMRC Research Achievements - SUMMARY
The outcome of this study indicates the need for further research to examine the exercise effects on
biochemical markers of bone turnover. We still have little understanding of the mechanism by which exercise
acts on bone. This is important so that more concrete public health recommendations can be made on the
potential benefits of exercise in preventing osteoporosis.
Name of contact:
Dr Deborah Kerr
Email/Phone no. of contact:
d.kerr@curtin.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 323200
Start Year: 2005
CIA Name: Prof Leon Straker
End Year: 2008
Admin Inst: Curtin University of Technology
Grant Type: NHMRC Project Grants
Main RFCD: Clinical Sciences not elsewhere classified
Total funding: $682,800
Title of research award:
Physical, lifestyle and psychosocial determinants of spinal pain development in adolescentsPhysical, lifestyle
and psychosocial determinants of spinal pain development in adolescents
Lay Description (from application):
This project aims to understand the development of back and neck pain in adolescence. By the age of 16
around half of all adolescents have suffered back pain and one third have suffered neck pain. For many
adolescents this pain is disabling and over a third of sufferers miss school, miss recreation and seek medical
help. The current understanding of back and neck pain in adolescence is quite limited - restricting the
effectiveness of initiatives to prevent adolescents having to suffer spinal pain and of treatment of those
adolescents unlucky enough to have an episode. Better understanding and interventions for adolescent spinal
pain will also have longer term implications by reducing adult spinal pain. Four out of 5 adults will experience
spinal pain. In the USA treating adult back pain is the 4th largest health care cost. Many adults with chronic
back pain had their first episode during adolescence. A better understanding of spinal pain in adolescence may
help prevent it developing into a lifelong disability. We will collect information from 2,000 adolescents on
their experience of back and neck pain and on potential physical, lifestyle and psychosocial risk factors. We
believe factors such as their posture, muscle capacity, TV and computer use, mental health and social situation
all combine to influence whether a person develops back or neck pain. The project is unique as it will not only
collect a broad range of information during adolescence, but will also make use of a large database of health,
developmental and psychosocial information already collected from these children since birth.With a better
understanding of the development of spinal pain we will be able to develop guidelines to help prevent these
problems. We will also be able to develop better treatment plans for sub-groups of adolescents with a particular
combination of risk factors. Together these initiatives will assist in understanding and breaking the pathway to
chronic spinal pain.
Research achievements (from final report):
This project funded the collection and partial analysis of information about back and neck pain in adolescents
at 14 and 17 years in the Raine pregnancy cohort study. Spinal pain was found to be already common at 14
years of age and to already be associated with disability at 17 years of age. Information on a wide range of
physical, lifestyle and psychosocial risk factors was also collected. Posture, fitness, obesity, motor competence,
physical activity, computer use, school bag carriage, diet, smoking and alcohol use, depression, externalising
behaviours, self worth, parental pain experience, socioeconomic status, family functioning and life stress
events were all related to spinal pain. Subgroups of individuals with spinal pain were also identified suggesting
interventions could be targetted. The findings refuted a common misperception that adolescent spinal pain is
trivial. They also suggested windows for interventions to reduce spinal pain risk (early life and adolescence)
and arrest a trajectory to chronic, disabling adult spinal pain. Grant applications have been submitted to follow
this cohort into early adulthood.
Expected future outcomes:
The publiction of the results of this project will correct a misperception about the importance of adolescent
spinal pain. We have identified several opportunities to reduce risks and will apply for funding to assess the
efficacy of targetting specific interventions.
Name of contact:
Professor Leon Straker
Email/Phone no. of contact:
L.Straker@curtin.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 136928
Start Year: 2001
CIA Name: A/Pr Robin Daly
End Year: 2004
Admin Inst: Deakin University
Grant Type: Early Career Fellowships (Australia)
Main RFCD: Medical and Health Sciences not elsewhere classified
Total funding: $241,511
Title of research award:
Does increased calcium-vitamin D intake and exercise increase bone density in older men?Does increased
calcium-vitamin D intake and exercise increase bone density in older men?
Lay Description (from application):
Not Available
Research achievements (from final report):
Osteoporosis is recognised as an increasing public health problem in men. This highlights the importance of
identifying lifestyle interventions that are effective at maintaining bone strength in men. In a 2 year randomised
study involving 167 men aged over 50, we found that supplementing the diet with reduced fat calcium-vitamin
D3 enriched milk was effective for stopping or slowing the rate of bone loss at several clinically important
skeletal sites. Since milk is one of the most natural, convenient and readily absorbed sources of calcium,
fortifying milk with calcium and vitamin D may represent a simple, nutritionally sound and cost effective
approach to reduce the health and economic burden of osteoporosis in men. The second objective of this
program of research was to examine whether calcium-vitamin D3 fortified milk enhances the effects of
exercise on bone strength in older men. This study is currently in progress; 182 men have been randomly
allocated to one of four groups: 1) exercise+calcium-vitamin D3; 2) exercise alone; 3) calcium-vitamin D3
alone, or 4) a control group. As part of this trial, we developed an exercise algorithm to aid decision making for
exercise prescription for health care professional in the prevention and management of osteoporosis. This
algorithm is unique because it takes into account an individuals level of fracture risk based on their bone
density and functional/clinical risk status. Together, the findings from this work will provide the evidential
basis for health care professionals to make sound decisions with regard to exercise and diet for the prevention
and management of osteoporosis in older adults, particularly men.,
Expected future outcomes:
The findings from this program of research will provide the evidence base on which to develop physical
activity and nutrition guidelines and public health policy to promote improve musculoskeletal health in older
adults, particularly men., , , ,
Name of contact:
Dr Robin Daly
Email/Phone no. of contact:
robin.daly@deakin.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 229312
CIA Name: Prof Shona Bass
Admin Inst: Deakin University
Main RFCD: Endocrinology
Total funding: $180,000
Start Year: 2003
End Year: 2005
Grant Type: NHMRC Project Grants
Title of research award:
The effect of loading on the size, shape and strength of cortical bone during different stages of maturationThe
effect of loading on the size, shape and strength of cortical bone during different stages of maturation
Lay Description (from application):
Osteoporosis is a condition in which the skeleton becomes fragile and susceptible to fractures. It is a public
health problem that affects both men and women over the age of sixty. Although osteoporosis affects the
elderly, the most opportune time to prevent osteoporosis may be during childhood. Physical activity is a
lifestyle factor known to affect the strength of the skeleton. Bone density is commonly used as a measure of
bone strength because it is easily measured and is related to the breaking strength of bones. However changes
in the shape of bones can also affect bone strength with or without an increase in bone density. Changes in
bone shape in response to exercise in children or adults have rarely been investigated, and little is known about
the effects of exercise on bone shape during different stages of growth. This study is the first to investigate
how exercise during childhood may affect bone strength by changing bone shape. 45 elite female tennis
players aged between 6 to 18 years have completed two years of this study. 90 novice and competitive male
tennis players aged between 6 to 20 years and 60 healthy age matched controls will be asked to participate in
this study. Measurements will be made annually for three years. The bone shape and density of the dominant
and non-dominant arms of the players will be compared with the children who don't play tennis - comparisons
will also be made between i) different stages of puberty and ii) girls and boys. The findings of this study are
important because the lifestyle of children today may predispose them to a greater risk of osteoporosis late in
life. Physical activity may be the most important modifiable protective factor against fragile bones in old age.
The findings of this study will be the first to provide insight into whether there is a unique time during growth
when exercise will result in the greatest increase in bone strength by changing bone shape.
Research achievements (from final report):
The objective of this project was to investigate the effects of tennis playing (as a model of repetitive loading)
on bone strength in boys and girls during different stages of growth. The unique feature of the study was to use
magnetic resonance imaging to obtain cross sections of the bone in order to describe how the growing bones
respond to repetitive mechanical stimuli. Measuring the effects of exercise was obtained by comparing the
dominant and nondominant arms of young tennis players. The preliminary results show that loading the
skeleton before puberty leads to a significant improvement in bone strength in boys and girls. The prepubertal
skeleton has the capacity to respond to loading by adding more mineral on the external surface of the bone,
leading to a marked increase in bone size and bone strength. Interestingly, boys seem to have a larger window
of opportunity than girls to optimize their bone strength through exercise: the benefits obtained before puberty
in boys was further enhanced in peri-puberty if training was maintained whereas it was not the case in girls. If
confirmed by the analysis of the longitudinal data, these results would have important implications for exercise
recommendations to improve bone strength during growth. Children, and particularly girls, should be
encouraged to participate in impact-loading exercise from prepuberty, in order to maximize their peak bone
mass in early adulthood and decrease their fracture risk throughout life.,
Expected future outcomes:
The three-year data will provide valuable information on how much bone strength increases during growth,
what benefits can be obtained by participating in high-impact exercise and to what extent these benefits may
differ between boys and girls in terms of magnitude and timing. Exercise prescription for bone health could
then be re-designed according to maturity status and gender.
Name of contact:
Shona Bass
NHMRC Research Achievements - SUMMARY
Email/Phone no. of contact:
shona.bass@deakin.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 229320
CIA Name: Prof Shona Bass
Admin Inst: Deakin University
Main RFCD: Preventive Medicine
Total funding: $435,500
Start Year: 2003
End Year: 2007
Grant Type: Career Development Fellowships
Title of research award:
Promoting Physical Activity and Nutrition to Prevent Osteoperosis - A Lifespan ApproachPromoting Physical
Activity and Nutrition to Prevent Osteoperosis - A Lifespan Approach
Lay Description (from application):
Not Available
Research achievements (from final report):
The development of a healthy skeleton during the growing years has implications for adult skeletal health. This
research has used cutting edge technology (pQCT and MRI) to gain a greater insight into how the growing
skeleton responds to exercise and nutrition during different stages of maturation and in both genders. The
results show that even small amounts of regular exercise (20 minutes, 2 to 3 times per week) that involves
'impact' (hopping, skipping and jumping) can lead to clinically important improvements in bone strength. In
children who have less than the recommended dietary intake of calcium the inclusion of calcium rich foods
(dairy foods and foods fortified with calcium) in their daily diet can also add to the benefit of exercise. The
timing of when children exercise to gain the optimal skeletal benefit appears in the few years before and early
in adolescence. Preliminary findings suggest that the window of opportunity to make the most of exercise to
build a stronger skeleton most efficiently may be shorter in girls than boys. These findings highlight the
importance of children being involved in osteogenic (bone building) exercise before and early in adolescence.
Appropriate nutrition that provides enough energy and protein for all body functions, exercise, as well as
growth processes has been shown to be very important for optimal bone health. This research has shown that
poor bone health can result from inadequate nutrition due to delayed maturation, menstrual dysfunction (in
girls) and reduced growth in height.
Expected future outcomes:
Future outcomes from this work will include: defining the prescription of exercise that provides the optimal
stimulus for building stronger bones in children that will lead to long term adult bone health and a better
understanding of the effects of inadequate energy intakes on bone health and growth.
Name of contact:
Dr Gaele Ducher
Email/Phone no. of contact:
gaele.ducher@deakin.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 400391
CIA Name: Prof Richard Osborne
Admin Inst: Deakin University
Main RFCD: Health and Community Services
Total funding: $491,018
Start Year: 2006
End Year: 2010
Grant Type: Career Development Fellowships
Title of research award:
Advancing arthritis public health research and evidence-informed policy in Australia.Advancing arthritis public
health research and evidence-informed policy in Australia.
Lay Description (from application):
Not Available
Research achievements (from final report):
In this NHMRC Career Development Award in Population Health, I sought to gain the necessary skills and
experience to make substantial impacts in musculoskeletal health in Australia. The stated aims of the
Fellowship were achieved. During the Fellowship, I won funding to build and lead several teams of public
health researchers to undertake high-quality public health research. The teams ranged from 5 to 15 staff from a
base of 1 or 2. We published 10+ peer reviewed papers per year (including BMJ, NEMJ) and won funding of
between $0.3M and $1M per year. , The main achievements were the development and implementation of a
new model of care for prioritisation and management of people with hip and knee osteoarthritis in public
hospitals. The model was implemented into all Victorian public hospitals and improves equity, timeliness and
patient satisfaction. Care is now optimised and the model is being applied in most other states. , In the area of
patient education and chronic disease, I developed and validated new tools for quality and monitoring and these
are now available in 20 languages and used in numerous countries. The tools improve the quality of selfmanagement support provided to patients. The best example of its use is as a national quality tool in England. ,
I was invited to sit on
Commonwealth and State Advisory Groups and committees , Appointed to Associate Editor of the
international journal Arthritis Care and Research, Appointed to lead the Osteoarthritis
component of the WHO Global Burden of Disease update , - Convened two large international conferences , In
2011, my contribution to public health and musculoskeletal research was recognised by being awarded the
Lorin Prentice Memorial Award by the Arthritis Foundation of Victoria. Finally, my career development was
recognised by the academic system. I entered the Fellowship program as a Senior Lecturer and was promoted
to Professor in the fourth year of the program.
Expected future outcomes:
The process by which the questionnaires were developed, advanced in the field. The Orthopaedic Waiting List
reform will be implemented to more than 80% of public patients in this setting to improve equity and
outcomes.
Name of contact:
Richard Osborne
Email/Phone no. of contact:
Richard.Osborne@Deakin.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 425849
CIA Name: Prof Robin Daly
Admin Inst: Deakin University
Main RFCD: Preventive Medicine
Total funding: $471,059
Start Year: 2007
End Year: 2011
Grant Type: Career Development Fellowships
Title of research award:
Lifestyle Prescipition for Improving Musculoskeletal Health and function throughout the lifespanLifestyle
Prescipition for Improving Musculoskeletal Health and function throughout the lifespan
Lay Description (from application):
Not Available
Research achievements (from final report):
A summary of the key achievements from my CDA are highlight below: , 1.
In primary
school children we found that a specialist-taught general physical education program conducted twice weekly
over 4-years was not effective for improving bone strength, indicating that children need targeted bone loading
activities to optimize bone health during growth., 2.
In older men we found that a
community-based multi-model exercise program involving strength training with weight-bearing exercise was
safe and effective for improving bone and muscle mass, size and strength and functional performance. These
findings formed the basis for a 'research-to-practice' trial, termed 'Osteo-cise: Strong Bones for Life', which
was successfully implemented within the community for older adults. , 3. In elderly women we found that
combining strength training with increased dietary protein through the daily consumption of lean red meat led
to greater gains in muscle mass and muscle strength compared strength training alone. This suggests that the
elderly require a higher protein intake to maximise the anabolic response to strength training., 4. In the first
national, population-based study to have evaluated the vitamin D status of Australian adults, we found that
nearly one-third of all adults were vitamin D deficient. Low vitamin D levels were also found to be associated
with an increased risk of developing type 2 diabetes and the metabolic syndrome. These findings highlight that
vitamin D deficiency is major problem in our country and there is an urgent need to identify safe and effective
population-based strategies to combat this major public health problem.
Expected future outcomes:
The findings from my research will contribute to the development of targeted exercise and nutrition guidelines
for preventing and managing a range of chronic diseases together with the implementation of evidence-based
community programs.
Name of contact:
Professor Robin Daly
Email/Phone no. of contact:
rmdaly@deakin.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 534409
CIA Name: Prof Robert Newton
Admin Inst: Edith Cowan University
Main RFCD: Oncology and Carcinogenesis
Total funding: $519,331
Start Year: 2009
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
A Phase III clinical trial of exercise modalities on treatment side-effects in men receiving therapy for prostate
cancerA Phase III clinical trial of exercise modalities on treatment side-effects in men receiving therapy for
prostate cancer
Lay Description (from application):
Hormone therapy is very effective for treating prostate cancer however it produces a number of side effects
including muscle and bone loss, fat gain, and increased risk of death from heart disease and diabetes. In other
populations physical exercise has proven particulary effective for preventing such problems however no long
term studies with prostate cancer patients have ever confirmed this. Knowledge gained from this study has
potential to markedly reduce suffering and increase survival.
Research achievements (from final report):
This randomised controlled trial of different exercise modes is the longest and largest ever completed in men
with prostate cancer to our knowledge. With the primary outcome being bone mineral density it is also one of
the first to address bone loss as a devastating toxicity of androgen deprivation therapy. A particularly unique
feature of this project was the application of "impact" exercise as highly tailored and specific prescription to
slow or possibly prevent bone loss resulting from testosterone suppression. We observed for the first time that
exercise could totally prevent bone loss in men receiving androgen deprivation therapy while men receiving
usual care continued to exhibit declines in bone mineral density. Importantly in terms of current national and
international exercise recommendations a more standard exercise program consisting of aerobic and resistance
training did not appreciably slow bone loss in these patients. This was surprising given previous research
findings in men and women not receiving testosterone suppression received considerable benefit in terms of
bone health from such a standard program. In terms of muscle mass the combination of impact and resistance
training produced significantly greater gains in terms of muscle hypertrophy than the standard program and
usual care resulted in continuing muscle atrophy. This is also a novel finding as it appears that men with
prostate cancer undergoing testosterone deprivation appear much more susceptible to the interference effects of
aerobic exercise undertaken simultaneously with resistance exercise.
Expected future outcomes:
Exercise prescription for cancer patients appears to require much more specific attention to exercise mode and
dosage, in particular if treatment side-effects are to be prioritised for management. The principal future
outcome of this research should be the change to clinical practice with tailored exercise programs rather than
provision of current generic guidelines.
Name of contact:
Professor Rob Newton
Email/Phone no. of contact:
r.newton@ecu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 160062
CIA Name: Prof Jegan Krishnan
Admin Inst: Flinders University
Main RFCD: Orthopaedics
Total funding: $188,450
Start Year: 2001
End Year: 2003
Grant Type: NHMRC Project Grants
Title of research award:
The design, development and clinical assessment of a new metacarpophalangeal joint prosthesisThe design,
development and clinical assessment of a new metacarpophalangeal joint prosthesis
Lay Description (from application):
Rheumatoid arthritis is a crippling form of arthritis that affects many people in the community. It commonly
involves the finger joints in the hands resulting in deformity, pain and subsequent loss of function. There have
been implants designed for finger joint replacement, but unfortunately these implants have had only moderate
benefits and can break and lead to further joint destruction resulting in the worsening of deformity and pain. A
new implant for finger joint replacement has been developed. This implant has several potential advantages.
Firstly the unique design acts to prevent recurring deformity in the fingers with rheumatoid disease while
allowing functional motion. Secondly, it is thought that patients will return to function earlier and avoid the
need for further finger surgery as this implant design relies less on the tissues around it for stability. The
purpose of this study is to investigate the biomechanical and clinical benefits of this new implant for finger
joint replacement. The new design will undergo specific laboratory tests and be used in a clinical trial to
quantify the therapeutic benefits it provides to patients with rheumatoid arthritis.
Research achievements (from final report):
The reseach in the project assessed a newly developed implant for knuckle joint replacement. This joint was
tested biomechanically and manufacturing processes and the materials used to make the implant were refined
accordingly. Subsequent implant of this new joint into a person with rheumatoid arthritis showed that the joint
was effective in restoring function to the hand. One very important observation from this research was that the
tools available to assess hand function were limited, particularly for people with rheumatoid arthritis before and
after joint-replacement surgery. Therefore, considerable effort was made to improve and standardise the
available tools and to develop new and more appropriate tools and measurement devices.
Expected future outcomes:
Commercial development of the newly developed prosthesis is continuing with an Orthopaedic prosthesis
manufacturer., The development and assessment of hand-function testing tools and devices is also expected to
lead to new instruments more appropriate to the rheumatoid hand.
Name of contact:
Professor Jegan Krishnan
Email/Phone no. of contact:
jegan.krishnan@flinders.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 229980
CIA Name: Prof Trevor Hearn
Admin Inst: Flinders University
Main RFCD: Not Allocated
Total funding: $470,000
Start Year: 2003
End Year: 2006
Grant Type: NHMRC Development Grants
Title of research award:
Effects of pin biomechanics, coating material and surface roughness on the pin-bone interface in external
repairEffects of pin biomechanics, coating material and surface roughness on the pin-bone interface in external
repair
Lay Description (from application):
Some fractures require external fixation, anchored with metal pins in the bone fragments. The reatment is
generally successful, although the pin tracts often loosen and become infected. This complication may
jeopardise fracture healing and must be treated. The purpose of this project is to determine what aspects of pin
design predispose to these problems at the pin-bone interface. Is it the way the pins are initially inserted,
perhaps not tightly enough so that the pin is unstable, or perhaps too tight, causing microcracks in the bone? Is
it the material of the pin, which might be improved with a bioactive coating? Is it the surface roughness which
causes different responses of bone cells? Would it help to have an antibiotic pin? This proposal is designed to
answer these questions. The biomechanics of the pin will first be studied with computer models and then tested
in the laboratory. The loosening and infection associated with different types of pin will then be studied
biologically. The results of the study will clarify the roles of pin biomechanics, coating and surface roughness,
leading to improvements in design and better outcomes in fracture patients.
Research achievements (from final report):
This project has established the foundations for a new device for the fixation of common fractures of the wrist.
Curently used fixation pins have had a high rate of infection and loosening, with instability of the pin-bone
interface as the primary precursor. The new design will optimize the stability of this interface over the time
course of fracture repair.
Expected future outcomes:
Increasing the stability of this interface will reduce infection rates and decrease need for further medical care.
Name of contact:
Prof Trevor C Hearn
Email/Phone no. of contact:
tnahearn@ozemail.com.au
NHMRC Research Achievements - SUMMARY
Grant ID: 275547
CIA Name: Prof Malcolm Smith
Admin Inst: Flinders University
Main RFCD: Rheumatology and Arthritis
Total funding: $255,750
Start Year: 2004
End Year: 2006
Grant Type: NHMRC Project Grants
Title of research award:
Predictors of the outcomes for joint inflammation and damage in recent onset rheumatoid arthritis
patientsPredictors of the outcomes for joint inflammation and damage in recent onset rheumatoid arthritis
patients
Lay Description (from application):
Currently, it is difficult to predict what will happen to an individual patient who presents with newly diagnosed
rheumatoid arthritis, either as a result of the natural history of the disease or as a result of drug treatment. It is
also difficult to decide which drug treatment to offer a patient and when to decide to change the treatment to
obtain a better clinical response. This study will investigate whether it is possible to predict the outcomes for a
particular patient with rheumatoid arthritis for joint inflammation and joint destruction, based on the findings
in the joint lining tissue. This study will also investigate whether it is possible to make decisions on the likely
success of drug treatment given to a patient with rheumatoid arthritis based on the initial or subsequent joint
lining tissue biopsies. If successful, this study will lead to a greater ability to advise patients about likely
outcomes from their condition, either with or without treatment and also to predict whether a treatment is likely
to work at an early stage. In addition, this study may identify future potential treatments for rheumatoid
arthritis.
Research achievements (from final report):
We have identified a number of potential synovial tissue biomarkers for the clinical response to drug treatment
in rheumatoid arthritis in collaboration with several international research groups, which have been presented
at international meetings and resulted in 9 publications.
Expected future outcomes:
We have now developed further research projects to explore further these biomarkers and develop them for
clinical applications
Name of contact:
Professor Malcolm D Smith
Email/Phone no. of contact:
malcolm.smith@health.sa.gov.au
NHMRC Research Achievements - SUMMARY
Grant ID: 275576
CIA Name: Dr Fiona Goldblatt
Admin Inst: Flinders University
Main RFCD: Autoimmunity
Total funding: $450,336
Start Year: 2004
End Year: 2010
Grant Type: Early Career Fellowships (Overseas)
Title of research award:
The analysis of autoantibodies and development of therapeutic strategies for autoimmune rheumatic
diseasesThe analysis of autoantibodies and development of therapeutic strategies for autoimmune rheumatic
diseases
Lay Description (from application):
Not Available
Research achievements (from final report):
Systemic lupus erythematosus (SLE) is a prototypical autoimmune, multisystem disorder presenting mainly in
women aged between 30-50years.Whilst in the past 40 years mortality rates for patients with SLE have
declined, in part due to improvements in the management of the inflammatory manifestations,patients continue
to suffer significant morbidity and alternative causes of death have become more predominant. My study of
serious infections in British patients with SLE highlighted this, identifying infection accountable for 15% of
hospitalisations in the cohort and responsible for 25% of deaths. More specific studies of SLE patients
susceptibility to Streptococcus pneumoniae, demonstrated an impaired ability in a subset to optimally target
these bacteria, suggesting a possible way to identify those most at risk and consequently improve targeting of
preventative measures. , Extensive prevalence and disease defining studies specific for the Australian
population had not been previously performed. I have established a comprehensive computerised register to
store and assess the details of South Australian patients with SLE (initially those attending the Royal Adelaide
Hospital). To date, information from 50 patients has been collated, with detailed clinical information, including
disease manifestations, progress, disease related complications, treatment received and therapeutic
complications, in addition to serological information and stored serum and DNA samples. The database has
already proved a useful tool to optimise treatment regimens and address disease manifestations of South
Australian patients with SLE. In addition it will provide well characterised patient information for future
clinical and scientific research projects.
Expected future outcomes:
, It is expected the computerised South Australian SLE database will facilitate future development of screening
programs for complications of SLE disease and treatment and also screening for associated conditions, for
example cardiovascular disease (as women aged 30-44 with SLE have a 50x increased relative risk of heart
attack and stroke compared to age and sex matched controls).
Name of contact:
Dr Fiona Goldblatt
Email/Phone no. of contact:
fgoldblatt@internode.on.net
NHMRC Research Achievements - SUMMARY
Grant ID: 324777
CIA Name: Dr Elisabeth Isenring
Admin Inst: Flinders University
Main RFCD: Nutrition and Dietetics
Total funding: $305,250
Start Year: 2005
End Year: 2010
Grant Type: Early Career Fellowships (Australia)
Title of research award:
Nutrition intervention and clinical, functional, quality of life and service utilisation outcomes in older
adultsNutrition intervention and clinical, functional, quality of life and service utilisation outcomes in older
adults
Lay Description (from application):
Not Available
Research achievements (from final report):
This Australian Clinical Training Fellowship has had a significant impact on advancing knowledge in nutrition
assessment and interventions to improve nutritional status and independence outcomes in older adults. Dr
Isenring led research investigating the nutritional issues and resource needs of oncology patients receiving
cancer services at an Australian public hospital. This has resulted in improved resources and procedures for
addressing nutritional concerns. Dr Isenring led a research team validating and comparing nutrition screening
tools in residential aged care facilities which has the potential to improve practice and lead to earlier
appropriate nutrition intervention. With Deanne Gaskill and others, Dr Isenring published several papers on the
malnutrition prevalence of older adults in residential aged care facilities and demonstrated that a train-thetrainer nutrition intervention can lead to beneficial nutritional outomes compared to usual care. Collaborating
with A/Prof Leigh Ward, Dr Isenring has developed new resistivity data which will improve the accuracy of
body composition assessment by bioelectrical impedance spectroscopy. This has led to further work on
validating and comparing different methods of body composition which can be used to quickly and accurately
measure fat and lean tissue during prevalence and intervention studies. Determining malnutrition prevalence
and nutritional issues were investigated via collaborations at the Royal Brisbane and Womens hospital lead by
Dr Merrilyn Banks. Dr Isenring is translating this evidence into practice by being primary author on evidencebased nutritional guidelines for patients receiving radiation therapy and contributing to other sets of nutritional
guidelines on cancer cachexia and malnutrition across the continuum of care.
Expected future outcomes:
Two studies commenced during the training fellowship which are still continuing include assessing nutritional
issues in dyads of older adults with early onset dementia and investigating nutritional issues in older adults at
high risk of falls.
Name of contact:
Dr Elisabeth Isenring
Email/Phone no. of contact:
e.isenring@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 595931
Start Year: 2010
CIA Name: A/Pr Michelle Miller
End Year: 2013
Admin Inst: Flinders University
Grant Type: NHMRC Project Grants
Main RFCD: Nutrition and Dietetics not elsewhere classified
Total funding: $480,246
Title of research award:
A TriaL Assessing N-3 as Treatment for Injury-induced Cachexia (ATLANTIC trial)A TriaL Assessing N-3
as Treatment for Injury-induced Cachexia (ATLANTIC trial)
Lay Description (from application):
The anti-inflammatory properties of fish oil are well documented. Hip fracture is common and patients suffer
significant inflammation, unintentional weight and muscle loss leading to poor outcomes. This study aims to
reduce the weight loss suffered by hip fracture patients by prescribing an intervention of individualised
nutrition support and high dose fish oil.
Research achievements (from final report):
This trial has completed enrolment of 150 older adults following hip fracture and administered a 12 week
intervention where participants have received 20ml of a moderate dose of omega 3 fatty acids or 20 ml of a
very low dose of omega 3 fatty acids. The trial has provided these 150 participants with 12 weeks of intensive
monitoring by an Accredited Practising Dietitian and an additional 9 months of follow-up, a service which is
completely absent from current services. We hope to be able to demonstrate that the moderate dose omega 3
intervention has reduced the inflammatory burden post-surgery sufficient to allow for an acceptable response to
nutrition support, that is, prevention of further weight loss, in particular muscle mass. The data are currently
being analysed and the findings should be available soon. The trial has also allowed for training of future
researchers with two PhD students contributing to the trial and many student Dietitians having the opportunity
to observe.
Expected future outcomes:
We expect to publish at least 4 additional manuscripts using data from this trial and to present the key findings
at local, national and international conferences.
Name of contact:
A/Professor Michelle Miller
Email/Phone no. of contact:
michelle.miller@flinders.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 276411
Start Year: 2004
CIA Name: Prof Charles Mackay
End Year: 2006
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Project Grants
Main RFCD: Immunology not elsewhere classified
Total funding: $465,750
Title of research award:
The role of PAC-1 in leukocyte activation and inflammatory responsesThe 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/Phone no. of contact:
c.mackay@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 325601
Start Year: 2005
CIA Name: Prof Tuan Nguyen
End Year: 2007
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Project Grants
Main RFCD: Endocrinology
Total funding: $363,000
Title of research award:
GENETIC PREDICTION OF FRACTURE IN A RISK-STRATIFIED POPULATIONGENETIC
PREDICTION OF FRACTURE IN A RISK-STRATIFIED POPULATION
Lay Description (from application):
Osteoporosis is a condition characterised by excessive bone loss and impaired bone quality, which ultimately
results in fracture with minimal trauma. Osteoporosis affects 27% of women and 11% of men aged 60 years or
above in the community, and costs Australia around $7 billion each year. Individuals with low bone mineral
density (BMD) have a significantly higher risk of fracture than those with normal BMD. In the long-term (14year) Dubbo Osteoporosis Epidemiology Study, more than half of individuals with osteoporosis (e.g., low
BMD) did not sustain a fracture, while approximately 60% of fracture cases had BMD above the high risk
levels. Thus, BMD alone is not a good discriminant of fracture versus non-fracture cases. It is widely known
that the liability to fracture is determined in part by genes. Previous studies, including from our group, have
suggested a number of candidate genes that are associated with fracture risk. The fundamental issue that this
study is concerned is that how and whether genetic markers could be used to facilitate case finding. It is
proposed that common variations of certain genes are associated with fracture risk independent of BMD. That
is, they can identify individuals at relatively high and low fracture risk after stratification for BMD. Hence,
some markers may identify those individuals likely (and unlikely) to fracture even with low (osteoporotic)
BMD. Similarly, some, possibly the same, markers may identify individuals at high risk of fracture despite
relatively "good" (ie non-osteoporotic) BMD. It is further proposed that no single gene will achieve this
outcome, but rather a small set of such gene polymorphisms will provide clinically useful risk information.
This effect is entirely analogous to the use of clinical risk indicators (eg, age, weight, sex, family history, etc)
to assess the risk of future fracture.
Research achievements (from final report):
1. We have genotyped 85 SNP, including the vitamin D receptor (VDR), collagen I alpha-1 (COLIA1),
estrogen receptor, beta-3 adrenergic receptor, and LRP-5 genes, for 2178 men and women in the Dubbo
Osteoporosis Epidemiology Study., 2. We have completed a genome-wide association study as part of a multicentre collaborative study designed to search for osteoporosis genes. From this study, we have identified a
number of loci that were associated with fracture risk of bone mineral density. , 3. We have published 8 papers,
including 4 original contributions, in international peer-reviewed journals such as New England Journal of
Medicine, Nature Genetics, Journal of Clinical Endocrinology and Metabolism. We have published an
important finding on the association between polymorphisms of the VDR and COLIA1 genes and hip fracture,
in which carriers of the VDR CC genotype (16% prevalence) and COLIA1 TT genotype (5% prevalence) had
an increased risk of hip fracture. Approximately 20% and 12% of the liability to hip fracture was attributable to
the presence of the CC genotype and TT genotype, respectively., 4. We have developed a prognostic model
that incorporates genotypes for predicting fracture risk in an individual. This prognostic model represents the
first attempt in the world to translate genetic information into practical clinical use. We are planning to make
this model available worldwide through the internat implementation of the model.
Expected future outcomes:
Development of prognostic model incorporating genetic data for predicting fracture risk
Name of contact:
Tuan V. Nguyen
Email/Phone no. of contact:
t.nguyen@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 376001
Start Year: 2006
CIA Name: Prof Charles Mackay
End Year: 2006
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Development Grants
Main RFCD: Immunology not elsewhere classified
Total funding: $124,875
Title of research award:
Preclinical development of a humanised antibody to C5aR.Preclinical development of a humanised antibody to
C5aR.
Lay Description (from application):
Complement factor C5a is one of the most potent inflammatory mediators in the body. We have developed a
monoclonal antibody that blocks the C5a receptor in vitro, and completely shuts down disease in a mouse
model of rheumatoid arthritis. We plan to develop this promising new antibody into a potent therapy to treat a
range of chronic and acute inflammatory diseases. The antibody has been humanised and this will be tested in
three models of inflammation (rheumatoid arthritis, sepsis and colitis) to determine the efficacy of the
antibody, safety, the most effective dose, timing and route of administration. These studies are a necessary
prelude to human clinical trials, which we hope to perform in approximately 24 months.
Research achievements (from final report):
We are developing a novel antibody-based drug for treatment of chronic and acute inflammatory diseases such
as rheumatoid arthritis, sepsis and ischaemia-reperfusion injury. The antibody targets the receptor C5aR, and
blocks binding and signalling by the potent pro-inflammatory molecule C5a. A humanised form of the antibody
suitable for human therapy has been produced and tested for effectiveness in an animal model of inflammatory
arthritis. We were able to completely block new inflammation and reverse established inflammation using the
anti-C5aR antibody. We showed that the antibody blocked influx of leukocytes (neutrophils, monocytes) into
the joints of the mice, and that it did this by blocking migration of the cells from the blood into the tissue. The
antibody did not kill the leukocytes. These studies provided important information for designing clinical trials.
The antibody appears safe and effective in animals, and if the same is shown in humans, the drug should
provide a new option for treating patients with chronic inflammatory disease, potentially alleviating the pain,
suffering and reduced functioning associated with such diseases.
Expected future outcomes:
The anti-C5aR antibody has been licensed by Novo Nordisk A/S, and is currently in preclinical development.
Clinical trials in chronic inflammatory diseases are planned over the next few years. If the treatement proves
safe and effective, a new anti-inflammatory therapy will become available.
Name of contact:
Prof Charles Mackay
Email/Phone no. of contact:
c.mackay@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 376028
Start Year: 2006
CIA Name: Dr Paul Baldock
End Year: 2008
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Project Grants
Main RFCD: Endocrinology
Total funding: $472,771
Title of research award:
Hypothalamic signalling in cortical and trabecular bone anabolic activityHypothalamic signalling in cortical
and trabecular bone anabolic activity
Lay Description (from application):
Osteoporosis is a disease associated with an exponential rise in the number of fractures in the elderly. These
fractures are so common that around 1 in 3 women and 1in four men will be affected. They cause pain,
disability that can be permanent disability and are associated with premature death. Current treatments are able
to effectively increase bone strength in osteoporotic patients but can not return bone strength to normal. Some
new treatments can restore bone strength to some extent but these are limited by expense and safety concerns.
We have discovered a pathway in the brain that reduces bone formation and by blocking this pathway we can
achieve doubling of the amount of bone in key bone sites. This occurs due to a marked increase in the amount
of new bone formed. In fact, genetic manipulation of this pathway was able to double the speed at which bone
is made by the skeleton. Excitingly, these increases in bone were possible in adult mice, suggesting such
changes could be potential therapy for human patients. However, in order to be able to harness this pathway we
must understand what molecules within the brain are responsible for the signals that reach the bone. Our
proposal aims to identify the nerve signalling molecule(s) and the receptor for these signals within the brain
that initiates the increase in bone formation. This project ultimately aims to identify a target for new therapies
that could cause this beneficial effect by administration of a simple treatment, preferably by mouth in adult
humans.
Research achievements (from final report):
N/A
Expected future outcomes:
N/A
Name of contact:
Dr Paul Baldock
Email/Phone no. of contact:
p.baldock@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 427632
Start Year: 2007
CIA Name: Dr Paul Baldock
End Year: 2009
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Project Grants
Main RFCD: Endocrinology
Total funding: $662,065
Title of research award:
Neuropeptide control of bone cell functionNeuropeptide control of bone cell function
Lay Description (from application):
Osteoporosis is a disease associated with a progressive rise in the number of fractures in the elderly. These
fractures are so common that around 1 in 3 women and 1in 4 men will be affected. They cause pain, disability
that can be permanent and are associated with loss of independence even premature death. Current treatments
are able to partially restore bone strength in osteoporotic patients but can not return bone strength to normal.
Some new treatments can restore bone strength to some extent but these are limited by expense and safety
concerns. We have discovered a pathway in the brain that when blocked, results in a doubling of the amount of
bone in key bone sites and dramatic increases in bone strength. This occurs due to a marked increase in the
amount of new bone formed. In fact, genetic manipulation of this pathway was able to double the speed at
which bone is made by the skeleton. Excitingly, these increases in bone were possible in adult mice,
suggesting such changes could be potential therapy for human patients. We went on to test the effectiveness of
this pathway in animal models of human skeletal weakness and have shown that it is capable of remarkable
benefits. However, in order to be able to harness this pathway we must understand what molecules within the
bone that are responding to the signals from the brain. Our proposal aims to identify the nerve signalling
molecule(s) and pathways for these signals within the bone that initiate the increase in bone formation. This
project ultimately aims to identify a target for new therapies that could achieve this beneficial effect by
administration in osteoporotic women and men
Research achievements (from final report):
This project was the first to link a centrally mediated pathway to bone. We had previously identified
hypothalamic actions of the neuropeptide pathway involving Neuropeptide Y (NPY) and its powerful control
of bone metabolism. The peripheral mechanism was unknown. This project defined the action at the osteoblast
and further reported it to be a peripheral action of NPY, which was notable for it was mainly considered a brain
active molecule. , Moreover, this work lays open the possibility of direct modulation of osteoblast activity by
modulation of the local NPY Y1 receptor. This is currently the focus of a NHMRC project grant [ID_535932].
Models developed in the grant have enabled detailed expression profiling of Y1 action in osteoblasts and the
potential for cross regulation bet ween bone and fat cells., This project also enabled assessment of the time
course off NPY action during osteoblast differentiation. It highlighted a far more complex and involved
interaction between neural signalling and the cells of bone than previously thought. , This information will be
critical in considering NPY as a potential treatment for altered bone mass.
Expected future outcomes:
Curentl work is fi=ocussed upon preclinical models to assess the potential for Y1 receptor modualtion for
control of beon metabolism
Name of contact:
Dr Paul Baldock
Email/Phone no. of contact:
p.baldock@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 481313
Start Year: 2008
CIA Name: Prof Tuan Nguyen
End Year: 2013
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Research Fellowships
Main RFCD: Epidemiology
Total funding: $738,163
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
My research activities can be broadly classified into three strands: epidemiology of fracture, genetics of
osteoporosis, and application of Bayesian approach in medical research. The major epidemiological work has
included the development of models for in
Research achievements (from final report):
My research seeks to discover risk factors and genes that are associated with fracture, and to translate these
findings into personalised assessment, diagnosis and treatment of osteoporosis. With the NHMRC Research
Fellowship support, I have been able to conduct important research projetcs within the Dubbo Osteoporosis
Epidemiology Study in which I am a Principal Investigator. My research group and I have developed and
implemented a fracture risk assessment model called "Garvan Fracture Risk Calculator", which has been used
by doctors and patients worldwide. We have further defined the seminal relationship between fracture and
mortality which has fundamentally changed the way doctors think about osteoporosis. We have continued
working on the genetics of osteoporosis, and by working with international colleagues, we have discovered
genes that are associated with fracture and bone mineral density.
Expected future outcomes:
The above work and discoveries lead us to develop a new model for individualised assessment of fracture risk.
This work will move us a step closer to the idea of personalised medicine.
Name of contact:
Tuan V. Nguyen
Email/Phone no. of contact:
t.nguyen@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 481389
Start Year: 2008
CIA Name: Prof Charles Mackay
End Year: 2009
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Development Grants
Main RFCD: Clinical Pharmacology and Therapeutics
Total funding: $174,867
Title of research award:
Development of anti-CXCR2 monoclonal antibodies for tumour therapyDevelopment of anti-CXCR2
monoclonal antibodies for tumour therapy
Lay Description (from application):
New therapies to treat cancers and inflammatory diseases are urgently required. Our aim is to develop a new
treatment for cancer and inflammation, by blocking the chemokine receptor CXCR2 which is central to
angiogenesis (blood vessel growth) and inflammation. We have produced a highly effective monoclonal
antibody (mAb) inhibitor of CXCR2, which is suitable for preclinical and clinical development. The project
aims to examine the efficacy of this mAb in mouse tumour models and inflammation.
Research achievements (from final report):
Unfortunately we were unable to show involvement of an important role for chemokine receptors in tumor
development. mAb based drugs against chemokine recptors have promise in inflammation, but their role in
cancer is yet to be fully validated.
Expected future outcomes:
Anti-chemokine receptor mAbs may have much more utility in other conditions such as fibrosis, and future
effort will be directed in this line of work.
Name of contact:
Charles Mackay
Email/Phone no. of contact:
c.mackay@me.com
NHMRC Research Achievements - SUMMARY
Grant ID: 511132
Start Year: 2008
CIA Name: Prof Matthew Brown
End Year: 2011
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Project Grants
Main RFCD: Quantitative Genetics
Total funding: $882,723
Title of research award:
Australian Genomewide Association Study in OsteoporosisAustralian Genomewide Association Study in
Osteoporosis
Lay Description (from application):
Osteoporosis is a common condition in which bone strength is reduced due to reduced amount and quality of
bone. Reduced bone strength means an increased risk of fracture. Osteoporotic fractures occur in 1 in 2 women
and 1 in 3 men in their lifetime, and the likelihood of suffering osteoporotic fracture increases with age. Most
of the risk of developing osteoporosis is genetic, but few of the genes involved have been identified. Our goal
is to identify those genes.
Research achievements (from final report):
This study identified seven novel genes as being involved in determining the risk of the common disease,
osteoporosis. Osteoporosis is a common condition in which bone weakness leads to increase fracture risk. Hip
fractures due to osteoporosis are a major problem in the elderly; identifying the genes involved helps us work
out what causes osteoporosis, and enables the development of genetic tests to help identify individuals at high
risk of the condition. When this study began, only one gene had been definitively shown to be involved in
osteoporosis in the general community. Our one study identified a further seven genes, and confirmed a further
21 genes which were identified by other studies running in parallel with our own. These findings have
highlighted new mechanisms by which osteoporosis arises, and thus contribute to the development of new
therapies for the condition.
Expected future outcomes:
We expect that our findings will be the subject of further research into osteoporosis pathogenesis, and the
development of genetic diagnostic tests.
Name of contact:
Matthew Brown
Email/Phone no. of contact:
matt.brown@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 535931
Start Year: 2009
CIA Name: A/Pr Daniel Christ
End Year: 2012
Admin Inst: Garvan Institute of Medical Research Grant Type: Career Development Fellowships
Main RFCD: Medical Bacteriology
Total funding: $387,490
Title of research award:
Afinity maturation and development of an anti-inflammatory monoclonal antibodyAfinity maturation and
development of an anti-inflammatory monoclonal antibody
Lay Description (from application):
Antibodies are a relatively new class of drugs that directly target molecular mechanisms of disease. Antibody
therapies, such as the breast cancer drug Herceptin, have significantly increased our arsenal of effective
therapeutics. In collaboration with G2 Therapies, we will use cutting-edge genetic engineering technology to
produce fully human antibodies for the treatment of inflammatory diseases, such as rheumatoid arthritis.
Research achievements (from final report):
Monoclonal antibodies are effector molecules of the immune system that attack bacteria and viruses. They laso
constitute over 50% of all new drugs entering clinical studies. Here we have investigated methods to increase
the efficacy of such therapeutics, by increasing binding strength (affinity).
Expected future outcomes:
Our results provide a blueprint for the development of powerful new drugs for cancer and inflammatory
conditions.
Name of contact:
Alison Heather
Email/Phone no. of contact:
Alison Heather <a.heather@garvan.org.au>
NHMRC Research Achievements - SUMMARY
Grant ID: 596840
Start Year: 2010
CIA Name: Dr Paul Baldock
End Year: 2012
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Project Grants
Main RFCD: Endocrinology
Total funding: $620,648
Title of research award:
Sex steroids modulate the neuronal control of bone formationSex steroids modulate the neuronal control of
bone formation
Lay Description (from application):
It is well recognised that changes in sex hormones are pivotal to the development of osteoporosis in both men
and women. Our group has been instrumental in identifying a novel and powerful system regualting bone mass
and strength by neural activity. Recent findings indicate critical interactions between these two pathways in the
control of bone formation. Greater understanding of these interactions could lead to therapies capable of
controlling this extremely common disease.
Research achievements (from final report):
At its broadest, this project identified a novel mechanism contributing to the metabolic and skeletal effects of
sex steroid deficiency in both females and males. We hypothesised a link between the endocrine and neural
systems during sex hormone deficiency, such as occurs at the menopause, and which is responsible for a period
of marked, irreversible bone loss and significant weight gain. We were able to demonstrate the action of the
neuropeptide Y (NPY) system to suppress bone formation and increase fat storage in the critical early stages
post-ovariectomy. The ablation of this NPY effect significantly delayed the loss of bone and gain of fat
following oestrogen deficiency. We were also able to isolate an androgen-dependent effect on the regulation of
bone mass by NPY to an interaction directly with the bone forming osteoblast. The potential benefit to come
from this work involves therapaeutic modualtion of the NPY system manopausal women, whcih may be able to
reatin boen and aid in weight control durring the critical peri/post menopausal period.
Expected future outcomes:
The project identifies a window of maximum benefit for such anti-NPY action in the posy menopausal period.
Orally administrable drugs are available and are being examined for co-incident weight reduction and bone
mass gain in preclinical animal models.
Name of contact:
Paul Baldock
Email/Phone no. of contact:
p.baldock@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 596868
Start Year: 2010
CIA Name: Ms Michelle Linterman
End Year: 2013
Admin Inst: Garvan Institute of Medical Research Grant Type: Early Career Fellowships (Overseas)
Main RFCD: Cellular Immunology
Total funding: $217,806
Title of research award:
The role of microRNAs in T follicular helper cell mediated humoral immunity and autoimmunity.The role of
microRNAs in T follicular helper cell mediated humoral immunity and autoimmunity.
Lay Description (from application):
Media Summary not available
Research achievements (from final report):
To neutralise threats from viruses and bacteria the immune system generates antibodies that interact with
pathogens and prevent them from establishing an infection. While this process is highly effective it is not
infallible. In some people the immune system can generate antibodies that bind components of the body it is
designed to protect, this can lead to autoimmunity. This research proposal aimed to understand how a particular
type of immune reaction, the germinal centre, is controlled to avoid production of auto-antibodies. This
research had two main focal points. 1) The role of the costimulatory molecule CD28 as targetting CD28 is used
to treat autoimmune and inflammatory disease. Here, we showed that CD28 is required to maintain the
germinal centre response and this may help to explain why blocking CD28 is an effective therapeutic in
autoimmune disease. 2) How the B cell depleting therapeutic rituximab affects the germinal centre response in
humans. We show that rituximab depletes the germinal centre B cells, but that germinal centre T cell remain,
this has implications for how rituximab is used to treat autoimmune disease. Together, this research programme
has advanced our understanding of the germinal centre, particularly with respect to therapeutic targets for
autoimmunity.
Expected future outcomes:
A better understanding of how T follicular helper cells are maintained. This may have implications for
targetting these cells theraputically in autoimmunity.
Name of contact:
Michelle Linterman
Email/Phone no. of contact:
michelle.linterman@babraham.ac.uk
NHMRC Research Achievements - SUMMARY
Grant ID: 231421
CIA Name: A/Pr Nigel Morrison
Admin Inst: Griffith University
Main RFCD: Rheumatology and Arthritis
Total funding: $330,375
Start Year: 2003
End Year: 2005
Grant Type: NHMRC Project Grants
Title of research award:
Gene variants related to bone density and fracture.Gene variants related to bone density and fracture.
Lay Description (from application):
Bone density and osteoporosis have a genetic component. Identifying genes that are involved in determining
bone density may permit advances in controlling osteoporosis. We have identified a variant that is related to
bone density high enough to protect individuals four fold against Colle's fracture, the common wrist fracture
seen in women. In addition, some people with bone fracture at the hip, or low bone density, have mutations in
this gene. The gene is a master regulator of the cells that make bone: this gives hope that it may be possible to
alter bone formation through this master regulator.
Research achievements (from final report):
The RUNX2 gene is expressed in both bone and cartilage and is therefore a candidate gene for both
osteoporosis (OP) and osteoarthritis (OA). Not only is RUNX2 important for OP and OA, this gene impacts on
periodontal disease, rheumatoid arthritis, osteomyelitis, loosening of prosthetic devices, and bone loss from
malignant cancer. At least 20% of the population will suffer from one of these conditions in a life time. Runx2
gene variants have considerable effect on fracture and bone density (BMD). In an average sized school (say
1000 children), 5 will be carriers of Q-mutants. In a community of 100,000 people, 377 will be carriers of the
RUNX2 Q deletions that confer -0.6SD lower BMD and 133 others will have the 30Q allele that confers -1.1
SD BMD. For every 1SD decline in BMD, fracture increases two fold. Based on Australia's population,
102,000 people are carriers of Q mutations and will start life with an increased fracture risk. OP and OA are
major causes of morbidity and reduced productivity due to the demographic trend of increased aged persons as
a proportion of the total population. Osteoporosis Australia estimates that the cost of OP-related fractures and
hospitalisation will be $1 billion by 2010. Access Economics claims that the cost of OA to Australia in 2004
was $19.4 billion dollars. This project has contributed to understanding the genetic influences of RUNX2 on
bone and future work will cover influences on OA.
Expected future outcomes:
Three journal publications are in the process of final editing for submission to top journals such as JBMR.
These papers cover the resubmitted paper on Q-repeat in RUNX2, the influence of 11-Ala polymorphims on
fracture risk and targets of RUNX2 in osteoblasts.
Name of contact:
Nigel Morrison
Email/Phone no. of contact:
N.Morrison@griffith.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 481946
CIA Name: A/Pr Nigel Morrison
Admin Inst: Griffith University
Main RFCD: Rheumatology and Arthritis
Total funding: $424,288
Start Year: 2008
End Year: 2010
Grant Type: NHMRC Project Grants
Title of research award:
Chemokines in osteoclast differentiationChemokines in osteoclast differentiation
Lay Description (from application):
Chemokines are small molecules that are released by a number of cell types, particularly monocytes, when
inflammation occurs. Chronic inflammatory disease is associated with severe bone erosion and loss of bone
quality. Surprisingly, chemokines control osteoclast development as well as macrophage activation; even if the
osteoclast has formed, blocking chemokine signalling prevents bone resorption. Chemokines are a new and
exciting target to control osteoclast formation.
Research achievements (from final report):
We validated that chemokines are needed for differentiation of human osteoclasts via use of dominant negative
proteins and chemical inhibitors. Additionally we showed that knockout mice for chemokines and receptors
have altered bone phenotypes.
Expected future outcomes:
This work lead to a new grant, where we have found that the bone producing effect of PTH hormone is
dependent on MCP1 chemokine signalling, opening up new avenues of cell-cell signalling in bone. The link
between inflammatory regulators and bone loss is now established - further work could lead to therapeutics.
Name of contact:
Nigel Morrison
Email/Phone no. of contact:
N.Morrison@griffith.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 508600
CIA Name: Prof Suresh Mahalingam
Admin Inst: Griffith University
Main RFCD: Medical Virology
Total funding: $626,460
Start Year: 2008
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
Novel insights into the mechanisms of how viruses cause arthritis-arthralgiaNovel insights into the mechanisms
of how viruses cause arthritis-arthralgia
Lay Description (from application):
Many viruses are known to cause arthritis (e.g. HIV, hepatitis viruses, mosquito borne viruses). Symptoms of
viral arthritis include joint pain, stiffness, and swelling. The mechanism of disease is poorly understood. We
have developed a novel animal model of disease by which to study arthritic disease caused by viral infections.
This model provides an excellent opportunity to explore the mechanisms of rheumatic disease in a complete
functioning animal and to explore new treatment regimes.
Research achievements (from final report):
Numerous viruses are able to cause arthritis following infection. We are studying Ross River virus (RRV), an
alphavirus that is endemic to Australia and some Pacific islands. It is transmitted by mosquitoes. In fact it is the
major cause of mosquito-borne disease in humans in Australia. RRV cause a chronic inflammatory disease that
lasts several months. One of the major consequences of infection with RRV is arthritis. Despite considerable
research, it is not known how viruses such as RRV can cause arthritis. In this project we aimed to identify
factors produced by the human immune system following infection that can lead to arthritis. We identified one
such factor: macrophage migration inhibition factor (MIF). We also identified that during RRV infection
macrophages, which are an important cell in the human immune response, contribute to the development of
arthritis. Indeed, treatment of mice with a drug that inhibited macrophage entry into the joint was able to
completely protect against the development of arthritis. This discovery is of major importance and we are now
taking this drug into clinical trials with patients with viral arthritis.
Expected future outcomes:
Our discoveries have led to major improvements in understanding how viruses can cause arthritis. THey have
also identified an exciting new anti-inflammatory drug for the treatment of arthritis that is now entering clinical
trials.
Name of contact:
Professor Suresh Mahalingam
Email/Phone no. of contact:
s.mahalingam@griffith.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 566305
CIA Name: Dr Yung-Chang Su
Admin Inst: Griffith University
Main RFCD: Rheumatology and Arthritis
Total funding: $402,767
Start Year: 2009
End Year: 2013
Grant Type: Early Career Fellowships (Australia)
Title of research award:
The role of specific innate and adaptive immune system components in regulating viral-induced arthritisarthralgiaThe role of specific innate and adaptive immune system components in regulating viral-induced
arthritis-arthralgia
Lay Description (from application):
Many viruses are known to cause arthritis (e.g. HIV, hepatitis viruses, mosquito borne viruses). Symptoms of
viral arthritis include joint pain, stiffness, and swelling. The mechanism of disease is poorly understood. We
have developed a novel animal model of disease by which to study arthritic disease caused by viral infections.
This model provides an excellent opportunity to explore the mechanisms of rheumatic disease in a complete
functioning animal and to explore new treatment regimes.
Research achievements (from final report):
This project has significantly increased our knowledcge and understanding of the pathogenesis in allergic
asthama and with the demonstration of inhibitory effects by new drug MCP-2 antagonist Bindarit, provided
applications for use in new treatment regimes.
Expected future outcomes:
N/A
Name of contact:
Steven Su
Email/Phone no. of contact:
suychang@gmail.com
NHMRC Research Achievements - SUMMARY
Grant ID: 597481
CIA Name: A/Pr Nigel Morrison
Admin Inst: Griffith University
Main RFCD: Rheumatology and Arthritis
Total funding: $690,436
Start Year: 2010
End Year: 2013
Grant Type: NHMRC Project Grants
Title of research award:
Monocyte chemotactic protein-1 (MCP1) and the PTH anabolic effect in bone.Monocyte chemotactic protein-1
(MCP1) and the PTH anabolic effect in bone.
Lay Description (from application):
Chemokines and their receptors are major regulators of cell-cell interactions in many tissues. This project
explores the strong increase of monocyte chemotactic protein-1 (MCP1 or CCL2) in bone, in a treatment where
parathyroid hormone (a controller of calcium homeostasis) is used to increase bone mass to prevent
osteoporosis. MCP1 was previously thought to be an inflammatory regulator, induced during infection and
important in autoimmune conditions, so its role in bone was highly unexpected.
Research achievements (from final report):
The project validated that the chemokin MCP1 is a component of the anabolic effect of PTH on bone. In this
effect PTH stimulates bone formation and is a treatment for osteoporosis. Data suggests that MCP1 is a cellcell signalling molecule in bone.
Expected future outcomes:
Further publications are being drafted, concerning he use of double knockouts and MCP1 and receptors, as well
as osteoblast knockout using CRE/LOX.
Name of contact:
Nigel Morrson
Email/Phone no. of contact:
N.Morrison@griffith.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 145703
CIA Name: Prof Patrick Sexton
Admin Inst: Howard Florey Institute
Main RFCD: Basic Pharmacology
Total funding: $227,037
Start Year: 2001
End Year: 2003
Grant Type: NHMRC Project Grants
Title of research award:
Analysis of calcitonin - receptor interactionsAnalysis 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/Phone no. of contact:
N/A
NHMRC Research Achievements - SUMMARY
Grant ID: 433027
CIA Name: A/Pr Hylton Menz
Admin Inst: La Trobe University
Main RFCD: Geriatrics and Gerontology
Total funding: $730,975
Start Year: 2008
End Year: 2009
Grant Type: NHMRC Project Grants
Title of research award:
Randomised controlled trial of a tailored podiatry intervention to enhance mobility and prevent falls in older
peopleRandomised controlled trial of a tailored podiatry intervention to enhance mobility and prevent falls in
older people
Lay Description (from application):
Foot problems affect 1 in 3 people over the age of 65 years and are associated with reduced walking speed,
difficulty performing activities of daily living, impaired balance and increased risk of falls. Although a range of
health professionals provide treatment for foot disorders, the most common chronic foot problems in older
people (such as corns and calluses, nail disorders and toe deformities) are frequently managed by podiatrists
using treatments such as scalpel debridement of lesions, foot orthoses, exercise prescription and footwear
modifications. The 1995 National Health Survey reported that persons aged 80 years or over were most likely
to have reported visiting a podiatrist in the previous two weeks, followed by those aged 65-79 years. Similarly,
the Australian Department of Veterans Affairs, which provides podiatry services to veterans and their
dependants, documented 606,706 episodes of podiatry care to 103,540 veterans in 1998-1999, at a cost of
$23M. Podiatry therefore plays a substantial role in the maintenance of foot health and mobility in older
Australians. Despite the detrimental effects of foot problems and the widespread utilisation of podiatry
services by older people, very few studies have been undertaken to ascertain the efficacy of podiatry
treatments. Therefore, the aim of this study is to evaluate the efficacy of an individualised podiatry intervention
designed to reduce pain, enhance functional mobility and prevent falls in older people. Given the high
prevalence of foot-related disability and falls in older people and their associated health care costs, the study
findings will be of considerable public health importance. If found to be clinically effective, the intervention
could be easily implemented into a range of healthcare settings and adopted in both state and federal falls
prevention policies.
Research achievements (from final report):
The project investigated the effectiveness of a multifacated podiatry intervention to prevent falls in older
people. 305 people aged over 65 years with disabling foot pain and an increased risk of falling were allocated
to a usual care control group or an intervention group. The intervention group received foot orthoses, footwear
advice and footwear cost subsidy, and a home-based exercise program. All participants were then followed for
12 months to record the incidence of falls. At the end of the study, there were 36% fewer falls in the
intervention group, indicating that the multifacated podiatry intervention was effective in preventing falls in
older people.
Expected future outcomes:
We plan to roll out the intervention to practicing podiatrists in both public and private sector settings and in
multidisciplinary falls prevention clinics and evaluate its effectiveness under 'real world' conditions.
Name of contact:
Prof Hylton Menz
Email/Phone no. of contact:
h.menz@latrobe.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 433049
CIA Name: Prof Hylton Menz
Admin Inst: La Trobe University
Main RFCD: Podiatry
Total funding: $471,059
Start Year: 2007
End Year: 2011
Grant Type: Career Development Fellowships
Title of research award:
Epidemiology and managemnet of foot disorders in community-dwelling older AustraliansEpidemiology and
managemnet of foot disorders in community-dwelling older Australians
Lay Description (from application):
Not Available
Research achievements (from final report):
Research conducted as part of this award has resulted in: (i) the development of valid and reliable tools for the
assessment of foot disorders in older people; (ii) the ascertainment of the prevalence and risk factors for
common foot disorders in community-dwelling older people; (iii) a greater understanding of the impact of foot
disorders on health-related quality of life, and (iv) the conduct of three clinical trials to assess the effectiveness
of interventions for the treatment of common foot disorders in older people.
Expected future outcomes:
This work provides the basis for the further development and evaluation of interventions for foot disorders in
older people, thereby improving mobility and quality of life in older Australians.
Name of contact:
Prof Hylton B Menz
Email/Phone no. of contact:
h.menz@latrobe.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 471424
Start Year: 2008
CIA Name: Dr Mark Hulett
End Year: 2011
Admin Inst: La Trobe University
Grant Type: NHMRC Project Grants
Main RFCD: Cellular Interactions (incl. Adhesion, Matrix, Cell Wall)
Total funding: $580,849
Title of research award:
Dissecting the function of heparanase in inflammatory disease using genetic tissue-specific ablationDissecting
the function of heparanase in inflammatory disease using genetic tissue-specific ablation
Lay Description (from application):
This project aims to define the role of the enzyme heparanase in a number of important diseases, namely
Inflammatory/autoimmune diseases such as multiple scelorosis and rheumatiod arthritis, and the growth and
spread of cancer. Heparanase has been implicated for many years in promoting these diseases however its
precise contribution has not beed defined. These studies will provide definitive information whether
heparanase is a valid therapuetic target in these important disease settings.
Research achievements (from final report):
The aims this project were to define the role of the heparan sulphate degrading enzyme heparanase in
inflammatory disease using constitutive gene knockout mice. Heparanase KO mice were generated and
characterised in the context of: (i) the vascular compartment, (ii) the role of heparanase in leukocyte migration
using inflammatory models, and (iii) establishing the Rip1-tag2 tumour progression model in the heparanse KO
mice. Characterisation of the blood vascular of the heparanase knockout mice indicated that the mice showed
no significant differences to wild-type mice. Detailed analysis of the role of heparanase in leukocyte migration
was investigated using 3 models (i) DC migration using an antigen-skin paint model, (ii) a DC-dependent
mouse dust mite airways hypersensitivity model, and (iii) actively induced EAE model. In each of the 3 models
there was evidence of reduced leukocyte migration with (i) significantly lower numbers of dermal DC and
Langerhan's cell migration from the skin to the local lymph node, (ii) reduced infiltration of airways with
migrating DC and other leukocytes e.g. eosinophils resulting a significant reduction in the Th2-mediated
inflammatory response, and (iii) reduced T cell infiltrate in the CNS of mice with EAE, respectively. These
data provide direct evidence that heparanase plays an important role in promoting leukocyte migration during
inflammation and thus identifies the enzyme as a potential target for the treatment of inflammatory disease.
Expected future outcomes:
This research lays the platform for ongoing detailed studies into the role of heparanase as a key contributor to
inflammation and investigation of the potential of the enzyme as a drug target for the treatment of
inflammatory disease.
Name of contact:
Dr Mark D Hulett
Email/Phone no. of contact:
m.hulett@latrobe.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 381407
Start Year: 2006
CIA Name: Prof Andrew Scott
End Year: 2007
Admin Inst: Ludwig Institute for Cancer Research Grant Type: NHMRC Development Grants
Main RFCD: Rheumatology and Arthritis
Total funding: $283,000
Title of research award:
Development of an Anti-GM-CSF Antibody for Treatment of Rheumatoid ArthritisDevelopment of an AntiGM-CSF Antibody for Treatment of Rheumatoid Arthritis
Lay Description (from application):
The aim of this project is to develop assays for the evaluation of the efficacy and safety of an anti-GMCSF
neutralizing antibody in a Australian first-in-man clinical trial in patients with severe rheumatoid arthritis (RA).
This chimeric antibody has been developed by the Ludwig Institute for Cancer Research, Melbourne Branch, in
conjunction with KaloBios Pharmaceuticals, Inc., USA. It is intended to use the assays developed in this
project to facilitate commercial development of this antibody, and result in the development of an improved
treatment for this devastating disease.
Research achievements (from final report):
Rheumatoid arthritis is a debilitating disease affecting 1-2% of the adult population and remains an unmet
medical need because despite some therapeutic options there is a significant number of patients (50-60%) that
do not respond or become resistant to treatment. There is a significant amount of experimental data that
supports the concept that the cytokine/growth factor GM-CSF is involved in the pathological processes of
Rheumatoid arthritis. We were the first to test the effect of neutralising the activity of GM-CSF in Rheumatoid
arthritis patients with active disease, however, it is essential to establish and validate the clinical assays which
will allow us to determine the most effective protocol for achieving a safe anti-arthritic effect. The aim of this
project was to develop and validate assays for the evaluation of the efficacy and safety of a novel therapy, an
anti-GM-CSF neutralizing antibody, in an Australian first-in-man clinical trial in patients with severe
rheumatoid arthritis. This chimeric antibody has been developed by the Ludwig Institute for Cancer Research,
Melbourne, in conjunction with KaloBios Pharmaceuticals, Inc., USA. The assays were successfully developed
and implemented during this project and will facilitate commercial development of this antibody, and result in
the development of an improved treatment for this devastating disease.
Expected future outcomes:
The work funded under this project resulted in the development of laboratory assays critical to the clinical
assessment of the pharmacokinetics and pharmacodynamics of the chimeric anti-GM-CSF antibody. These
assays will facilitate commercial development of this antibody, and result in the development of an improved
treatment for inflammatory disease conditions.
Name of contact:
Andrew Scott
Email/Phone no. of contact:
andrew.scott@ludwig.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 266800
Start Year: 2004
CIA Name: A/Pr Denise Jackson
End Year: 2008
Admin Inst: Macfarlane Burnet Institute for Medical Research and Public Health
Established Career Fellowships
Main RFCD: Pathology
Total funding: $549,750
Grant Type:
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
Research Achievements include: Immunoreceptors 1). Identified that PECAM-1-regulated signalling
thresholds control peripheral tolerance in B-cells; 2). Defined that a deficiency of PECAM-1 is sufficient to
alter in vitro and in vivo T cell function including negative selection of double positive thymocytes; 3).
Identified that CEACAM1 serves as a negative regulator of platelet-collagen interactions and thrombus growth
in vitro and in vivo; 4). Identified that PECAM-1 regulates Salmonella typhimurium infection in vivo; 5).
Defined that PECAM-1 regulates the 'outside-in' signalling properties of integrin alphaIIbbeta3 in murine
platelets; 6). Defined that palmitoylation of PECAM-1 at Cys595 is essential for PECAM-1 localisation into
membrane microdomains and for efficient PECAM-1-mediated cytoprotection; and 7). Defined that
CEACAM1 regulates the 'outside-in' signalling properties of integrin alphaIIbbeta3 in murine platelets., Other
research achievements include: Tetraspanins: 1). Defining that the haematopoietic specific tetraspanin, TSSC6
regulate the 'outside-in' signalling properties of integrin alphaIIbbeta3 in murine platelets and thrombus
stabilisation in vivo; 2). Defined that CD151 plays an essential role in platelet thrombus stabilisation and
embolisation in vivo; and 3). Identified a relationship between CD151 and P2Y12 signalling pathway that
involves Erk-1/2 and released ADP/thromboxane generation.
Expected future outcomes:
This research defines the importance of contact-dependent regulation of thrombogenesis mediated by
immunoreceptors including PECAM-1 and CEACAM1., This research defines the importance of plateletplatelet interactions mediated by tetraspanins, CD151 and TSSC6 in regulating platelet thrombus formation and
stability., It highlights the importance of immunoreceptors in infection and immunity.
Name of contact:
A/Prof. Denise Jackson
Email/Phone no. of contact:
djackson@burnet.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 315425
Start Year: 2005
CIA Name: Prof Phillip Hogarth
End Year: 2007
Admin Inst: Macfarlane Burnet Institute for Medical Research and Public Health
NHMRC Project Grants
Main RFCD: Cellular Immunology
Total funding: $468,750
Grant Type:
Title of research award:
The role of Fc Receptors in inflammatory diseaseThe role of Fc Receptors in inflammatory disease
Lay Description (from application):
Role of antibodies and their receptors in chronic inflammation: The activation of inflammatory white blood
cells is a major mechanism of tissue destruction in certain autoimmune diseases such as systemic lupus
erythematosus and rheumatoid arthritis. It is well known that destructive chemicals, enzymes and hormones
are released by these cells into affected tissues, for example joints and kidneys. What is lacking is knowledge
of the earliest steps in the immune system that activate the inflammatory white blood cells and drive this
inflammation cascade to the point where chemicals are released and tissued destroyed. This project
investigates the role of one of the major receptor families involved in the activation of inflammation. These are
receptors for antibodies called FcR. The binding to these receptors of unusual antibodies produced in
autoimmune disease initiate events that stimulate white blood cells leading to their activation and the secretion
of inflammatory substances. Our work leading up to this project has been very exciting and has shown that one
receptor in particular, FcgammaRIIa is unique to humans, is the most widespread FcR in the body and is the
most potent activator of inflammatory substance release. We will be studying animal models to precisely
define how this human receptor works. Mice have been generated which contain this uniquely human receptor
and these mice develop many features of human autoimmune disease such as the joint destruction, kidney
destruction and lung destruction seen in both rheumatoid arthritis and lupus. The principal aim of our study is
to define the role of this human receptor in the development of inflammatory conditions with the ultimate goal
of using this information to generate new treatments for these diseases.
Research achievements (from final report):
The aim of this project was to define the role of the uniquely human FcgammaRIIa in the develolpment of
antibody dependent tissue destruction with a view to developing new treatments for rheumatoid arthritis and
lupus. We have shown that Fcgamma Receptors play a major role in the development of autoimmune disease
by the characterisation of a unique transgenic mouse showing that FcgammaRIIa is a major activator of
antibody-initiated tissue destruction. The human FcgammaRIIa mice provide a unique, slow onset model for
the analysis of the role of this key receptor in antibody-mediated tissue destruction.
Expected future outcomes:
New targets for therapy and an understanding of the processes that lead to the disruption of regulation of
normal immunity resulting in autoimmune disease. New intellectual property in the form of drug or biological
based therapies protected by patents.
Name of contact:
P. Mark Hogarth
Email/Phone no. of contact:
pmhogarth@burnet.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 315625
Start Year: 2005
CIA Name: Prof Phillip Hogarth
End Year: 2007
Admin Inst: Macfarlane Burnet Institute for Medical Research and Public Health
NHMRC Project Grants
Main RFCD: Humoral Immunology and Immunochemistry
Total funding: $748,500
Grant Type:
Title of research award:
Structure and Function of Receptors for IgG (FcgammaR)Structure and Function of Receptors for IgG
(FcgammaR)
Lay Description (from application):
How FcR function in normal and destructive immunity: This research project is studying one of the most
important receptor families of inflammatory white blood cells known in immunology. These receptors called
Fc Receptors (FcR) bind complexes of specialised proteins called antibodies with foreign antigens, i.e. bacteria,
viruses, called immune complexes. As a direct consequence of this binding, a chain of events in inflammatory
white blood cells is set in motion, leading to the destruction of foreign pathogens, however in autoimmune
diseases this same processes leads to the severe inflammation causing destruction of joints in rheumatoid
arthritis and kidneys in glomerulonephritis or allergies, bleeding disorders. Our studies are aimed at
understanding the very first events that initiate this inflammatory cascade, i.e. how immune complexes bind to
FcR and having bound these, how these receptors are organised to initiate the inflammatory cascade. Our
studies will use new techniques such as X-ray crystallography to take 3D photographs of FcR interacting with
immune complexes and genetic engineering studies to validate our 3D photographs. If we understand how
immune complexes bind to FcR and how the receptors are organised on the cell membrane, we will be able to
apply this information to the development of new treatments that either interfere with immune complex binding
or receptor organisation. Although these concepts are well established in other fields e.g. growth hormone
receptors, very little is known about the organisation of receptors involved directly in immunity. These novel
studies will provide us with powerfully useful insights into the first steps in antibody driven tissue destruction.
Research achievements (from final report):
The principal aim of this work was to understand how IgG interact with Fc receptors and the biological
consequences of this interaction (eg. activating and/or regulatory responses and relevance to pathology). It was
a multidisciplinary project using Xray crystallography, protein reconstitution studies, mutagenesis and cellbased functional assays to analyse IgG and FcR family member interactions. The work we accomplished
includes: 1) the first crystal structure of a human IgG in complex with the activating receptor FcgammaRIIa; 2)
extended our analysis to other related FcgammaR's; 3) been able to show that anti-FcgammaRIIa antibodies
may be effective therapeutics in arthritis.
Expected future outcomes:
This work will lead to the design of new anti-inflammatory protein and drugs that antagonise Fc receptor
function. Also to understandingt the mechanisms by which antibodies and Fc receptors activate/inhibit
leukocytes in normal and autoimmunity. In addition, understanding of Ig FcR interaction will lead to improved
therapeutic antibodies for the treatment of diseases such as cancer.
Name of contact:
Professor Mark Hogarth
Email/Phone no. of contact:
pmhogarth@burnet.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 434105
Start Year: 2007
CIA Name: Prof Mark Hogarth
End Year: 2012
Admin Inst: Macfarlane Burnet Institute for Medical Research and Public Health
NHMRC Research Fellowships
Main RFCD: Humoral Immunology and Immunochemistry
Total funding: $927,557
Grant Type:
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
Immunologist researching mechanism of antibody effector function in resistance to infection and in
pathological immunity e.g. rheumatoid arthritis.
Research achievements (from final report):
Fc Receptors are one of the most important families of recpetors of the immune sysyem . Normally they help
regulate immune resonses but and they can be used by biological druds called monoclonal antibodies to
activate inflammatory cells to treat cancer. My grpoup has alos discovered that the FcReceptors are major
factors in the destruction caused by abberent autoantibodies in disesases like rheumatoid arthritis.
Expected future outcomes:
New engineere antibodies for treatmetn of cancer and infectin and new drugsto treat inflammationi
Name of contact:
Prof Mark Hogarth
Email/Phone no. of contact:
pmhogarth@burnet.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 488403
Start Year: 2008
CIA Name: Prof Mark Hogarth
End Year: 2010
Admin Inst: Macfarlane Burnet Institute for Medical Research and Public Health
NHMRC Project Grants
Main RFCD: Cellular Immunology
Total funding: $538,206
Grant Type:
Title of research award:
The role of Fc RIIa in antibody dependent tissue destruction in autoimmunityThe role of Fc RIIa in antibody
dependent tissue destruction in autoimmunity
Lay Description (from application):
These studies will attempt to identify the cause autoimmune diseases such as rheumatoid arthritis and systemic
lupus erythematosus we are using a unique strain of mice carrying a unique human protein called Fc receptor
that triggers inflammatory cells. We will identify the processes that start inflammation, and those that continue
throughout chronic autoimmune disease. These studies will be applied to the development of new treatments
for autoimmune disease.
Research achievements (from final report):
Significance: We have identified a major cause of autoimmune inflammation and can prevent this in
"humanised" animal models which will pave the way for the development of new diagnostics and therapeutics
in a number of major diseases., We have discovered how a molecule called Fc receptor acts as a "lock" on
inflammatory white blood cells. In disease like rheumatoid arthritis or lupus or bleeding disorders such as
antiphospholipid syndrome, aberrant blood proteins, called immune-complexes, open this Fc receptor "lock"
allowing the inflammatory cells to cause tissue destruction. Our discovery was made using "humanised" mouse
that has been engineered to express the human Fc receptor "lock". These mice develop inflammation and
destruction of joints similar to rheumatoid arthritis patients and develop kidney inflammation as found in lupus
patients. Importantly we are able to completely inhibit disease by blocking the human Fc receptor i.e.
effectively by "plugging" the lock. We aim to identify the initial trigger disease in the humanised mouse and
have examined the expression of 32,000 gene products in the in the immune system before, during and after
tissue destruction has commenced. We have discovered a number of major changes well before any evidence
of inflammation.
Expected future outcomes:
This work will lead to programs to develop novel treatments for arthritis and similar inflammation. i.e. new
monoclonal antibodies or drugs that target Fc receptors. The analysis also suggests that it is possible to
discover the trigger of autoimmune diseases which may lead to early diagnosis and possibly prevention.
Name of contact:
Mark Hogarth
Email/Phone no. of contact:
pmhogarth@burnet.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 488405
Start Year: 2008
CIA Name: Prof Mark Hogarth
End Year: 2010
Admin Inst: Macfarlane Burnet Institute for Medical Research and Public Health
NHMRC Project Grants
Main RFCD: Humoral Immunology and Immunochemistry
Total funding: $772,315
Grant Type:
Title of research award:
Structure and Function of Receptors for IgG (FcgammaR)Structure and Function of Receptors for IgG
(FcgammaR)
Lay Description (from application):
We are investigating one of the most important receptor families of inflammatory white blood cells - so called
Fc receptors. These are critically important in resistance to infection. Unfortunately they are also crucial in
tissue destruction in autoimmune diseases such as rheumatoid arthritis. We will determine how these receptors
trigger inflammation and use this information for the development of new drugs to treat rheumatoid arthritis
and lupus.
Research achievements (from final report):
We have discovered how antibodies bind and activate inflammatory white blood cells to cause inflammation.
Normally a controlled inflammatory response by antibodies protects against infection and is the basis of all
successful vaccines. Furthermore many modern cancer therapies using genetically engineered monoclonal
antibodies depend on this inflammation to eliminate cancers. By contrast in autoimmune diseases such as
rheumatoid arthritis and lupus the inflammation or antiphospholipd syndrome is uncontrolled and leads to
severe tissue destruction and severe life threatening illness. Our discoveries show how antibodies bind to cellsurface receptors called Fc receptors and switch on inflammatory cells. As a result we can develop strategies to
prevent antibody interaction with receptor and thereby prevent inflammation. Indeed we have successfully
tested a range of potential new compounds that it prevent inflammation in animal models. Furthermore we
have also found genetic differences in the Fc receptors lead to different levels of inflammatory cell activation
and are associated with a number of life-threatening complications of diseases such as lupus. A further
application of our discovery is its use in the development and improvement of new selective antibody-based
treatments for cancer. New so-called biological therapies used genetically engineered monoclonal antibodies
which target cancer cells and eliminate these by activating inflammatory cells through their Fc receptors.
Manipulating the activation of the Fc receptors will lead to improved monoclonal antibody therapeutics. This
pioneering work may lead to the development of new treatments for several intractable human diseases.
Expected future outcomes:
Broader understanding of how Fc receptors activate inflammatory leucocytes in inflammatory disease and in
normal immune responses.New anti-inflammatory therapeutics that prevent immune complex activation of
with Fc receptors; therapeutics include small chemical entities and biological "blockers".Improved cancer
antibody therapeutics.Further development of Australian intellectual property.
Name of contact:
P.Mark Hogarth
Email/Phone no. of contact:
pmhogarth@burnet.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 434515
Start Year: 2007
CIA Name: A/Pr Jean-Pierre Levesque
End Year: 2009
Admin Inst: Mater Medical Research Institute, Brisbane
Grant Type: NHMRC Project Grants
Main RFCD: Cellular Interactions (incl. Adhesion, Matrix, Cell Wall)
Total funding: $461,197
Title of research award:
Mechanisms of haemopoietic stem cell mobilisation: Role of the cross-talk between bone marrow and
bone.Mechanisms of haemopoietic stem cell mobilisation: Role of the cross-talk between bone marrow and
bone.
Lay Description (from application):
Blood or Haematopoietic stem cells (HSCs) are found in the bone marrow and make all the blood cells we
require life-long. This process must be carefully regulated. The production of too many blood cells leads to
leukaemia while too little means anaemia. However we still have much to learn on how this regulation occurs.
Scientists have recently found that osteoblasts (the cells that normally form bone) are responsible for some of
this regulation. In fact osteoblasts create a type of 'home' for HSCs. Our laboratory has recently found that this
relationship also works the other way around. That is bone marrow cells themselves regulate osteoblast
numbers and thus bone formation. To show this, we used a therapy that forces haematopoietic stem cells to
leave the bone marrow and migrate into the blood (a process called mobilisation). Mobilisation is used
clinically to harvest large numbers of HSCs for transplantation into cancer patients to prevent bone marrow
failure following chemotherapy. To our surprise, we found that when we mobilise HSCs, the rate of bone
formation dropped. As osteoblasts (the bone forming cells) are also involved in creating the HSC 'home', we
aim to test whether treatments which increase bone formation boost the number of HSCs that are available to
be mobilised and collected for transplantation. Thus, by manipulating bone formation we may ultimately be
able to improve the long-term survival rates of cancer patients that require high dose chemotherapy and
subsequent transplantation. This proposal also aims to better understand (i) how blood-forming cells control
bone formation, and reciprocally (ii) how bone-forming cells regulate haematopoietic stem cells in the bone
marrow.
Research achievements (from final report):
During this project, we have discovered that a special type of cells called macrophages, which normally
eliminate germs and damaged tissues, regulate both the cells that form the solid bones and the stem cells that
replace all our blood and immune cells. These rare specialised macrophages cover the interface between bone
and bone marrow where bone forming cells and blood stem cells reside. We have discovered that when
treatments to force blood stem cells out of the bone marrow into the blood are given (this process called "stem
cell mobilisation" is done in order to harvest large number of stem cells to transplant into cancer patients
treated with chemotherapies that also kill healthy blood stem cells), these specialised bone marrow
macrophages disappear, stopping bone formation and forcing blood stem cells out of the marrow into the
blood. Similarly, drugs that target these macrophages stop bone formation and mobilise stem cells into the
blood. This discovery will enable the development of new drugs to target these macrophages in order to
increase the efficacy of blood stem cell mobilisation. These will accelerate and improve cancer patients'
recovery from blood stem cell transplantations. Finally, we have also discovered that treatments which prevent
bone degradation (used for osteoporotic patients) do not stop blood stem cell mobilisation as initially thought,
but improve it. Therefore, the use of anti-osteoporotic treatments in patients with increased bone destruction is
not incompatible with blood stem cell mobilisation and the two types of treatments can be combined if
necessary.
Expected future outcomes:
Bone biology, haematology/immunology have so far been two separate fields of biology and medicine. Our
results clearly show that bone formation, blood cell replacement and immunity are intertwined and functionally
linked. Additional studies on the interplay beetween bone formation, blood cell formation and immunity are
warranted as treatments that affect one are likely to affect the other two.
NHMRC Research Achievements - SUMMARY
Name of contact:
Jean-Pierre Levesque
Email/Phone no. of contact:
jplevesque@mmri.mater.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 488817
Start Year: 2008
CIA Name: Dr Ingrid Winkler
End Year: 2011
Admin Inst: Mater Medical Research Institute, Brisbane
Grant Type: Career Development
Fellowships
Main RFCD: Haematology
Total funding: $380,559
Title of research award:
Interactions between haematopoietic, bone, vascular and endocrine systems control stem cell fate and
mobilizationInteractions between haematopoietic, bone, vascular and endocrine systems control stem cell fate
and mobilization
Lay Description (from application):
Haemopoietic stem cells (HSC) normally reside in the bone marrow (BM) where they make blood and immune
cells. We can force HSC to move from the BM into the blood, a process called mobilisation, used to collect
large numbers of HSC for transplantation into cancer patients. My research involves identifying factors that
control HSC fate within the BM (that is survival, growth, differentiation) and what happens during
mobilisation to force them to leave with the aim of improving transplant success.
Research achievements (from final report):
About 1/3 of cancer patients will suffer from an infection during or soon after their chemotherapy. This
happens because chemotherapy is made to kill rapidly growing cells, like cancer cells (which are the target) but
chemotherapy also kills the normal cells in the bone marrow whose job it is to replenish your blood and
immune system. The damage to these normal cells leaves a patient very vulnerable to infection. , In Australia
alone, over 5000 cancer patients will be hospitalised each year solely due to the side effects of their
chemotherapy treatment, not their underlying disease. , To help these patients, my research has focused on
ways to protect the healthy cells in the BM from the chemotherapy drugs. In this project I discovered the
molecular switch the body uses to make these bone marrow cells either go to sleep (which means they are
resistant to chemotherapy), or wake up and regenerate the blood and immune system now. Even better I can
now achieve this with a small antagonist. When I give this antagonist, normal BM cells go to sleep and are
protected from chemotherapy, when I remove the antagonist they wake up., Thanks to my NHMRC funding,
under which I made these (now patented) discoveries, I am now in a position to attract commercial funding
from overseas to continue this work in Australia. For patients these discoveries may make the chemotherapytreatment itself far less dangerous, enabling more rapid return to work and family, while at the same time
decreasing overall healthcare costs.
Expected future outcomes:
My research has discovered a way to limit some of the severe side-effects of chemotherapy. For patients this
research may make their chemotherapy-treatment far less dangerous, so they can more rapidly return to work,
re-engage with their community, with overall lower hositalisaton and healtcare costs.
Name of contact:
Ingrid Winkler
Email/Phone no. of contact:
iwinkler@mmri.mater.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 488821
Start Year: 2008
CIA Name: Dr Falak Helwani
End Year: 2011
Admin Inst: Mater Medical Research Institute, Brisbane
Grant Type: Early Career Fellowships
(Australia)
Main RFCD: Haematology
Total funding: $178,524
Title of research award:
Cellular and molecular determinants that regulate osteoblasts at the endosteal niche during HSC
mobilisationCellular and molecular determinants that regulate osteoblasts at the endosteal niche during HSC
mobilisation
Lay Description (from application):
Treatments for leukaemia (e.g. chemotherapy) severely deplete immune and blood cells from patients.
Transplantation of new blood forming cells (blood stem cells) into these patients is essential, but challenges are
faced with isolating sufficient numbers in ways that preserve their ability to reconstitute the blood post
transplant. My research aims to advance understanding of current methods used to isolate these cells and
ultimately to improve the success of blood stem cell transplantation.
Research achievements (from final report):
Background and rationale: Hematopoetic stem cells (HSC) are essential to the daily replenishment of all cells
in the blood and immune system. The purpose of my research was to improve our understanding of the
interactions between HSC and the cells within the bone marrow (BM) niche where these cells reside.
Mobilisation of HSC from BM to blood is common practice in the clinic for the easy collection of HSC, as
aposed to direct collection of BM from donors. Osteoblasts OB (bone forming cells) are one of the main
components of the HSC endosteal niche in BM. During mobilisation of HSC to OB are completely ablated
from the endosteal niche. Therefore we sought to further define the mechanisms governing this event to better
understand the processes of HSC mobilisation. , Achievements and outcomes:, * Proved that OB are depleted
from the endosteal niche during HSC mobilisation and that this is not mediated by osteoclasts (bone absorbing
cells)., * Identified that stimulating bone formation and inhibiting bone absorbtion can improve mobilisation of
multilineage repopulating or potent HSC. This is a potential method that could be used in conjunction with
mobilisation in the clinic to harvest better quality HSC for transplant., * Generated a molecular signature of the
factors that surround and maintain HSC at the endosteal niche. This identified a myriad of novel targets with
potential involvement in the maintainence of HSC quiesence and self renewal.
Expected future outcomes:
With these studies we have identified a number of novel genes to the field of HSC biology. These genes could
hold the secrets to HSC biology and ultimately provide new drug targets for improved mobilisation of HSC, or
better yet, allow us to identify the factors necessary to farm the most effective repopulating HSC in vitro for the
treatment of malignant hematopoietic diseases.
Name of contact:
Falak Helwani
Email/Phone no. of contact:
falak.helwani@gmail.com
NHMRC Research Achievements - SUMMARY
Grant ID: 403035
CIA Name: Dr Tania Winzenberg
Admin Inst: Menzies Research Institute
Main RFCD: Preventive Medicine
Total funding: $305,500
Start Year: 2006
End Year: 2009
Grant Type: Early Career Fellowships (Australia)
Title of research award:
Chronic disease prevention: investigating how to improve bone mass, fracture risk and obesity at different lifestages.Chronic disease prevention: investigating how to improve bone mass, fracture risk and obesity at
different life-stages.
Lay Description (from application):
Not Available
Research achievements (from final report):
With the award of this GP Training Fellowship, Dr Winzenberg has undertaken a range of projects
investigating chronic disease prevention in both adults and children, focussing work initially on prevention of
osteoporosis and other musculoskeletal conditions. With the recognition of the range of issues shared across
prevention other chronic diseases, this work expanded to also consider prevention of cardiovascular diseases.
Key outcomes of her work include: , *demonstrating that informing women of their fracture risk could lead to
them making lifestyle changes to improve not only their own bone health, but potentially that of their children
as well; , *providing definitive evidence that calcium supplements in healthy children have only minor effects
on bone mineral density and do not affect body weight, thus clarifying that calcium supplements have only a
limited place as a public health intervention;, *developing an easy-to-take dosage regimen to treat vitamin D
deficiency in adolescents; , *identifying the previously unrecognised issue of poor accessibility of the bone
mineral testing (an important test for osteoporosis diagnosis and management) in rural areas;, *defining general
practitioners' views of their role in assessing their patients' physical activity levels and determining how well
the methods GPs have to do this perform in practice. This showed that GPs perform targeted assessments of
their at-risk patents but that a commonly short questionnaire to assess physical activity performs less well than
GPs' usual assessment processes. The need for further research in how to best help GP's assess their patients'
physical activity was highlighted in these studies.
Expected future outcomes:
Dr Winzenberg is investigating further ways to improve children's bone health including determining if vitamin
D supplementation is effective in either healthy children or children who have sustained a broken bone. She is
also studying whether informing people of their risk of cardiovascular disease might cause them to improve
their lifestyle, as seen with fracture risk feedback.
Name of contact:
Tania Winzenberg
Email/Phone no. of contact:
tania.winzenberg@utas.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 490006
CIA Name: Dr Changhai Ding
Admin Inst: Menzies Research Institute
Main RFCD: Rheumatology and Arthritis
Total funding: $301,977
Start Year: 2008
End Year: 2009
Grant Type: NHMRC Project Grants
Title of research award:
Does childhood physical activity, fitness and fatness impact on knee structural change 20 years later?Does
childhood physical activity, fitness and fatness impact on knee structural change 20 years later?
Lay Description (from application):
Interventions to increase participation of physical activity (PA) and to reduce obesity in childhood are
advocated to reduce the risks of cardiovascular and other diseases in adulthood, but the associations of
childhood PA and obesity with knee osteoarthritic changes in adulthood are unknown. This study, with followup of a large cohort of Australian children over 20 years, will be the first to determine these associations using
the powerful technique of magnetic resonance imaging.
Research achievements (from final report):
The aim of this study is to determine the associations between physical activity and fatness in childhood, and
knee cartilage defects, tibial bone area and cartilage volume in young adults 25 years later. In addition, the
associations between physical activity and fatness in childhood, and adult knee pain will be determined., We
have recruited 298 young subjects (aged 31-41 years, 48.7% female) from the Childhood Determinants of
Adult Health study. They underwent T1-weighted fat- supressed magnetic resonance imaging of their dominant
knee and knee structures including cartilage volume and tibial bone area were measured. , Currently we have
looked the associations between childhood physical measures (physical work capacity at 170 beats per minute
(PWC170), leg and hand muscle strength, sit-ups, long-run, and short-run) and knee structures in adulthood.,
We found that there were consistent and significant associations of all childhood measures with adult total
tibial (medial plus lateral) bone area in multivariable linear regression. Similarly, there was a significant
positive association between childhood PWC170 and adult medial tibial cartilage volume after adjustment for
covariates including adult PWC170. The magnitude of the association decreased by 33% but remained
significant (p=0.048) after further adjustment for tibial bone area. Other childhood measures were significantly
associated with medial tibial cartilage volume, but these became non-significant after further adjustment for
medial tibial bone area. The significant associations were independent of current physical fitness., This
suggests physical activity in childhood can independently influence adult knee joint health possibly though
adaptive mechanisms.
Expected future outcomes:
We will look at the associations betweenchildhood obesity measures (BMI, waist & hip girths, sum of
skinfolds) and knee structures in adulthood, and expect that childhood obesity measures are associated
positively with knee cartilage defects, tibial bone area, and negatively with cartilage volume. These will be
independent of current body composition. ,
Name of contact:
Changhai Ding
Email/Phone no. of contact:
chding@utas.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 490014
Start Year: 2008
CIA Name: Dr Adele Holloway
End Year: 2011
Admin Inst: Menzies Research Institute
Grant Type: NHMRC Project Grants
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $521,961
Title of research award:
How does basal chromatic structure predict cytokine gene responses?How does basal chromatic structure
predict cytokine gene responses?
Lay Description (from application):
To recognise foreign pathogens and eradicate them from the body, immune cells need to quickly switch on
genes encoding factors which communicate between cells and drive the immune response. Incorrect expression
of these genes contributes to immune diseases such as asthma, arthritis and leukaemia. The aim of this project
is to study how the DNA environment of immune genes controls their ability to be switched on and off, and
how altering this environment leads to incorrect gene expression.
Research achievements (from final report):
To recognise foreign pathogens and eradicate them from the body, immune cells need to quickly switch on
genes encoding factors which communicate between cells and drive the immune response. Incorrect expression
of these genes contributes to immune diseases such as asthma, arthritis and leukaemia. , This research
investigated the DNA environment of one of these immune genes (called GM-CSF) to determine how this
environment controls the ability of the gene to be switched on and off. The research identified DNA-associated
factors that control the ability of the gene to respond to immune signals. Further, the study found that there is a
set of immune genes that have similar DNA environments in immune cells to the GM-CSF gene and this
allows them to respond to immune signals in a similar way. These genes have a particular DNA environment
which maintains them in a tightly repressed state in the absence of an immune signal. Finally the study found
that changes to the DNA environment of the GM-CSF gene occur in leukaemic cells, and that this contributes
to the dysregulated activity of the gene in these cells. These findings are significant because unlike changes to
the DNA sequence, changes to the DNA environment are reversible with pharmacological agents, and therefore
suggests a potential avenue for therapeutic intervention in disease states in which these immune genes are
aberrantly expressed.
Expected future outcomes:
Expected future outcomes are a better understanding of how DNA environment controls the response of genes
to immune signals, and how changes to these environments contribute to immune diseases.
Name of contact:
Dr Adele Holloway
Email/Phone no. of contact:
a.f.holloway@utas.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 490049
CIA Name: A/Pr Changhai Ding
Admin Inst: Menzies Research Institute
Main RFCD: Rheumatology and Arthritis
Total funding: $420,872
Start Year: 2008
End Year: 2011
Grant Type: Career Development Fellowships
Title of research award:
Longitudinal studies of knee osteoathritic changes using magnetic resonance imaging (MRI)Longitudinal
studies of knee osteoathritic changes using magnetic resonance imaging (MRI)
Lay Description (from application):
The associations between MRI-assessed knee structural changes and radiographic changes over 5 years in
older people will be determined. The effects of physical activity in adults and childhood, and the roles of
inflammation will be described. The study represents a cost-effective comprehensive approach to osteoarthritis,
a major public health problem, and is a natural progression of previous work that supports the objectives of the
Bone and Joint Decade and addresses a national health priority.
Research achievements (from final report):
The aims of the NHMRC CDA grant are to enable myself to:, 1) Conduct research that is internationally
competitive;, 2) Develop a capacity for original independent research;, 3) Develop leadership skills in
research;, 4) Establish myself as independent, self-directed, health and medical researchers., The aims of the
study are to determine the risk factors (such as inflammatory cytokines) associated with knee structural
changes over 3-5 years, and to determine the associations between changes in knee structure assessed by MRI
and radiographic changes over 5 years in older people. , In these 4 years (2008-2011), I published 38
manuscripts and had 22 oral presentations. I obtained 3 NHMRC grants totalling $1.5 million and University of
Tasmania Rising Star grant ($75,000). I set up my own research team including 8 CIs, 1 AI, 5 research officers
(3 from Menzies: O'Loughlin E, Nguo and Barling J), 1 research assistant (Warren R ), and 2PhD students
(Stannus O and Antony B). I have been an Associate Editor for 2 International journals, and an Editorial Board
Member of 6 international journals. I have peer-reviewed papers for 30 journals including Lancet, BMJ and
Arthritis & Rheumatism. , In the end of the fellowship, I successfully obtained ARC Future Fellowship
($765,216).
Expected future outcomes:
I expect that I will publish 5-8 papers per year, most of them will be the senior atuthor. 2-3 grants will be
obtained in the next 4 years, and 1-2 PhD students each yer will be supervised. I will apply for NHMRC Senior
Research Fellowship in the end of ARC Future Fellowship.
Name of contact:
Changhai Ding
Email/Phone no. of contact:
chding@utas.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 143549
CIA Name: A/Pr Merrill Rowley
Admin Inst: Monash University
Main RFCD: Rheumatology and Arthritis
Total funding: $227,037
Start Year: 2001
End Year: 2003
Grant Type: NHMRC Project Grants
Title of research award:
Functional effects of antibodies to collagen on cartilage synthesis and degradationFunctional effects of
antibodies to collagen on cartilage synthesis and degradation
Lay Description (from application):
It has been shown that antibodies to collagen type II in cartilage occur in ~70% of patients with early
rheumatoid arthritis, suggesting that autoimmunity to cartilage collagen may play a part in the devleopment of
this destructive arthritis. An animal model widely used as a model of human RA is the disease collagen
induced arthritis (CIA). It is induced by immunisation of mice with collagen II; antibodies to collagen II are
critical for the development of CIA. However not all such antibodies are disease-associated. There may be
particular regions on the collagen molecule where antibody-binding causes damage. This project is based on
the hypothesis that antibodies to collagen type II, which transfer arthritis in mice, are those that react
specifically with regions of the collagen fibrils that are crucial for cartilage stability and function. We plan to
test this hypothesis in an in vitro system using cultured cartilage. We predict, based on our preliminary data,
that antibodies to collagen II from mice with CIA will interfere with the normal assembly and structure of
cartilage. We will test this by adding antibodies under precisely defined conditions to cultured cartilage, and
analysing the matrix that is synthesised. The study would then be extended to RA with a comparison of the
regions of collagen II that react with antibodies of mouse and human origin. Showing that antibodies to
collagen II are directly destructive, allowing for an understanding of their site and mode of action, would
greatly advance our understanding of the cause of RA and would lead to more effective forms of treatment.
Research achievements (from final report):
Antibodies to type collagen II (CII, cartilage collagen) occur in serum and synovial fluid from patients with
rheumatoid arthritis (RA), and can be detected in most patients early in the disease. The aim of this project was
to establish whether antibodies to CII that are present in the serum of patients with rheumatoid arthritis (RA)
could affect the development and stability of the collagen fibrils that are an essential component of normal
articular cartilage. , We used monoclonal antibodies to CII from mice with collagen-induced arthritis (CIA),
that results from immunization with collagen II; the mouse antibodies react with precisely the same regions of
the CII molecule as human antibodies in RA. Antibodies to CII are critical for the development of CIA, but not
all such antibodies are disease-associated and there may be particular regions on the collagen molecule where
antibody-binding would cause damage. The cartilage in the joint is a complex network of fibrils of collagen
that entraps highly charged proteoglycans. The interactions between these components gives cartilage its
structural stability, and particular antibodies to CII may interfere with such interactions. , We examined the
effects of antibodies to CII on the development of cartilage in cultures of chondrocytes, the cells that produce
cartilage, and also their effects on pre-formed cartilage, using cartilage explants. The study showed that mouse
antibodies to CII that could transfer arthritis in vivo interfered with the molecular interactions essential to
cartilage structure and integrity, causing changes in the structure of the collagen fibrils and adversely affecting
the chondrocytes themselves. The changes observed occurred both in newly formed cartilage, and also in preformed cartilage, and were associated with antibodies that could transfer arthritis in vivo, but not with nonarthritogenic antibodies. They represent an entirely new and unsuspected mechanism of joint damage in
arthritis.
Expected future outcomes:
The demonstration that autoantibodies to type II collagen can affect the structural stability of cartilage, and
hence could lead to further joint destruction, provides important new insights into mechanisms of damage in
rheumatoid arthritis, in which such antibodies are known to occur. The knowledge could be important for the
development of new forms of treatment of RA.
NHMRC Research Achievements - SUMMARY
Name of contact:
Merrill Rowley
Email/Phone no. of contact:
Merrill.Rowley@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 143707
CIA Name: A/Pr Michelle Leech
Admin Inst: Monash University
Main RFCD: Rheumatology and Arthritis
Total funding: $333,055
Start Year: 2001
End Year: 2003
Grant Type: NHMRC Project Grants
Title of research award:
Macrophage Migration Inhibitory Factor (MIF) and p53 in rheumatoid arthritis .Macrophage Migration
Inhibitory Factor (MIF) and p53 in rheumatoid arthritis .
Lay Description (from application):
Rheumatoid arthritis (RA) is an inflammatory disease affecting approximately 1% of the population. It is
characterised by severe inflammation and destruction of joints resulting in significant health problems. The
lining tissue of joints is known to be infiltrated by inflammatory cells. In addition to this infiltration of
inflammatory cells, there is overgrowth of the normal lining cells of joints. These overgrowing cells contribute
significantly to joint damage by invading cartilage and bone and allowing inflammatory cells to reach these
areas. The abnormal growth of these cells has been related to the malfunction of certain genes that usually
restrain abnormal growth. These genes called tumour suppressor genes are known to be damaged in joint lining
cells derived from RA. The best known of these abnormal tumour suppressor genes is called p 53. The product
of the p53 gene, the p 53 protein, is particularly important in slowing down the growth of cells. The applicant
has recently shown that an inflammatory product called MIF is released in large quantities by joint lining cells
in RA. Previous studies by the applicant have shown that blocking MIF using an antibody almost completely
prevents arthritis development in a rat model. These studies indicate that MIF is likely to be an important
contributor to disease in RA. Recent preliminary studies in the applicant s laboratory have shown that MIF can
decrease p53 levels in joint lining cells from RA patients and also that MIF can increase the growth rate of
these cells. These preliminary data indicate that MIF may contribute significantly to disease in RA by
overriding control of normal cell growth by p53. Confirmation and full exploration of the regulation of p53
expression and function by MIF may highlight a novel way to treat the excessive growth and invasion by joint
lining cells which characterises RA.
Research achievements (from final report):
The aim of this study was to examine the role of an inflammatory substance (cytokine ) in this case called
macrophage migration Inhibitory factor (MIF) to influence a protein involved in cell growth control called
protein 53 (p 53). The capacity of inflammatory substances produced in the arthritis process to influence cell
growth is particularly relevant in rheumatoid arthritis where the overgrowth of inflamed joint lining cells and
tissue is important in causing joint damage and deformity. In these studies it was shown that animals deficient
in this cytokine (MIF knock-out mice) have reduced severity of arthritis and this is associated with a protective
effect of increases in p53 which could function to slow down overgrowth of inflammatory tissue. It was also
shown that this cytokine could directly decrease levels of this growth protein p53 in cells derived from human
rheumatoid arthritis patients.
Expected future outcomes:
Therapeutic strategies which target MIF are currently in development and are intended for the treatment of
chronic inflammatory diseases, including RA. Understanding the role of this cytokine in the regulation of a key
cell cycle protein like p53 is an important prelude to the application of such therapies.
Name of contact:
Dr Michelle Leech
Email/Phone no. of contact:
michelle.leech@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 143789
Start Year: 2001
CIA Name: Prof Stephen Holdsworth
End Year: 2005
Admin Inst: Monash University
Grant Type: Programs
Main RFCD: Clinical Sciences not elsewhere classified
Total funding: $4,146,944
Title of research award:
The Regulation of Organ Specific Inflammatory DiseaseThe Regulation of Organ Specific Inflammatory
Disease
Lay Description (from application):
Not Available
Research achievements (from final report):
o
Demonstration of the relative
contributions of the coagulant and immune stimulating contributions of tissue factor to glomerular
inflammation, o
Confirmation that tissue factor on
immune cells signals immune activation, o
Definition of the involvement of
tissue factor (as well thrombin) via signally through PAR receptors induces arthritis in an antigen induced
model in mice, o
Demonstration of the important role
of tissue factor in endotoxaemia, , T-cells in Crescentic Glomerulonephritis, Definition of:, o The relative
contributions and mechanisms of action of CD80 and CD86 in experimental crescentic GN, o The multiple
independent roles of CD40 in the generation and mediation of nephritogenic immunity in crescentic GN,
including the role of CD40 on intrinsic glomerular cells, o
The role of cytokines determining
critical pathological outcomes in GN including IL-18, IL-13 and IL-12, , o
Developed a
new model of murine experimental anti-neutrophil antibody mediated crescentic GN that demonstrated a key
role for T-cell effectors, o
Firmly established the cytokine
network between immune cells and intrinsic cells inducing crescentic GN, o
Established a
system for defining migration of leukocytes into glomeruli. This system was establised using intra vital
microscopy, o
That ANCA can directly induce
neutrophil migration into glomeruli, o
Defined the protective roles of costimulatory molecule OX40 experimental anti-GBM GN and interferon gamma in autoimmune anti-GBM GN,
, Cytokine and Glucocorticoid Regulation of Inflammatory Arthritis, o Discovery and development of small
molecule antagonists of the cytokine MIF, which form a potential new class of therapy for immune and
inflammatory diseases, o
Definition of the role of Annexin-1 in
arthritis, o
Dissection of MIF induced cell
signalling in regulating inflammation, o
The expression and function of
glucocorticoed induced MAP kinases in inhibiting MKP-1 in human arthritis was demonstrated
Expected future outcomes:
These studies have defined critical molecular steps in the induction of injurious inflammation in the kidney and
joints. These advances will allow new therapeutic approaches to add to the treatment of arthritis and
glomerulonephritis. Growing biotech commercial partnerships are advancing new therapies based on this work.
Name of contact:
Professor Stephen Holdsworth
Email/Phone no. of contact:
Stephen.Holdsworth@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 166902
CIA Name: A/Pr Michael Hickey
Admin Inst: Monash University
Main RFCD: Rheumatology and Arthritis
Total funding: $377,037
Start Year: 2001
End Year: 2003
Grant Type: NHMRC Project Grants
Title of research award:
Role of Adhesion Molecules in Autoimmune VasculitisRole of Adhesion Molecules in Autoimmune Vasculitis
Lay Description (from application):
Lupus is a disease which causes inflammation and pain throughout the body. The inflammation is caused by
white blood cells attacking the lining of blood vessels in tissues. The aim of this project is to understand the
reasons why these white blood cells attack the blood vessel lining. This process is impossible to study in
humans. However, there is a strain of mouse which is affected by a disease which is very similar to human
lupus. This disease occurs spontaneously in these mice. Using a microscope, it is possible to study the tiny
blood vessels which are affected by this disease in these mice . Under the microscope, it is possible to see the
white blood cells as they undergo the process of attacking the blood vessel lining. Visualizing this attack then
allows us to study it and determine which molecules are important in causing this damaging inflammatory
response. Specifically I will examine diseased blood vessels in the skin and brain of these mice, two of the
tissues most dramatically affected by this disease. This information should help us gain an increased
understanding of lupus as it affects humans.
Research achievements (from final report):
The results of these studies indicate that white blood cells are attracted to the blood vessel lining of various
tissues in the human disease, systemic lupus erythematosus (SLE) where they can act to injure the blood vessel
and tissue. We were also able to work out which molecules on the blood vessel lining were responsible for this
attraction. This knowledge allows us in future experiments to test ways of stopping these molecules from
working or preventing from being made by the blood vessel lining. These types of interventions have the
potential to reduce the damaging inflammation which occurs in the tissues of SLE patients.
Expected future outcomes:
N/A
Name of contact:
N/A
Email/Phone no. of contact:
N/A
NHMRC Research Achievements - SUMMARY
Grant ID: 194318
CIA Name: A/Pr Peter Tipping
Admin Inst: Monash University
Main RFCD: Nephrology and Urology
Total funding: $610,500
Start Year: 2002
End Year: 2006
Grant Type: Established Career Fellowships
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
This project investigated mechanisms of inflammatory injury in nephritis, arthritis and sepsis. It explored the
interactions between coagulation molecules (and their receptors) and inflammatory pathways in murine models
of inflammation, and demonstrated that activation of these receptors agumented systemic , renal and joint
injury. Therapies targetted at these coagulation molecules and their receptors may prove beneficial in these
inflammatory diseases.
Expected future outcomes:
This project aims inprove knowledge of pathogenic mechanisms in inflammatory diseases affecting the kidney,
and joints and in systemic sepsis and define new targets for therapetic internention.
Name of contact:
A/Prof Peter Tipping
Email/Phone no. of contact:
peter.tipping@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 194439
CIA Name: Prof Flavia Cicuttini
Admin Inst: Monash University
Main RFCD: Epidemiology
Total funding: $76,380
Start Year: 2002
End Year: 2003
Grant Type: NHMRC Project Grants
Title of research award:
The predictors of knee cartilage loss: A 5 year natural history study based on an existing cohortThe predictors
of knee cartilage loss: A 5 year natural history study based on an existing cohort
Lay Description (from application):
Osteoarthritis (OA) is the single biggest cause of disability in Western society. Despite this, relatively little is
known about the factors that effect disease progression. This will be the first extended follow up study of
cartilage volume in people with early OA. This study will build on our existing work where we have developed
a cohort study of adults with early knee OA. These people were initially recruited in 1997/8. An extensive data
base of potential risk factors for OA has been collected and both X-rays of the knee and MRI have been
performed at baseline and 2 years. Extending the follow up from 2 to 5 years will allow not only more precise
estimation of rates of cartilage loss and assessment of risk factors, but also enable assessment of the assumption
of linearity of cartilage volume loss. It will also be possible to partition the observed variability in rates of loss
into true between-subject variability and within subject residual variability. This partitioning will provide
valuable information for the design of future studies in OA, similar to the establishment of statistical design
principles for patterns of loss in bone mineral density.
Research achievements (from final report):
We have been able to show that the rate of knee cartilage loss as measured by a novel MRI based method for
measuring knee cartilage, predicts who proceeds to a knee replacement among those with knee osteoarthritis
Expected future outcomes:
We are now exploring both lifestyle factors (such as diet and physical activity) to determine which factors will
prevent the loss of knee cartilage and thus joint replacement.
Name of contact:
Flavia Cicuttini
Email/Phone no. of contact:
flavia.cicuttini@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 237048
CIA Name: Prof Eric Morand
Admin Inst: Monash University
Main RFCD: Medical Biotechnology
Total funding: $85,000
Start Year: 2003
End Year: 2004
Grant Type: NHMRC Development Grants
Title of research award:
Development and Biological Evaluation of Cytokine Macrophage-migration Inhibitor (MIF) Non-Steroidal
antagonistsDevelopment and Biological Evaluation of Cytokine Macrophage-migration Inhibitor (MIF) NonSteroidal antagonists
Lay Description (from application):
The cytokine macrophage-migration inhibitory factor (MIF) has a broad range of pro-inflammatory effects in
the innate and adaptive immune system. CIA’s lab has demonstrated the potential importance of MIF in the
pathology of chronic inflammation via studies in models of rheumatoid arthritis (RA). Similarly to other
chronic inflammatory diseases, MIF is overexpressed in human RA, and induces activation of key pathological
processes in RA cells. Moreover, antagonism of MIF with mAb profoundly inhibits models of RA and other
inflammatory diseases, confirming MIF as a therapeutic target in human inflammatory disease. The X-ray
crystal structure of MIF has been published and the putative active site fully characterised. We have deduced
structural features of MIF that reveal aspects of the structural complementarity of host-guest affinity. This
information has been used in the synthesis of new compounds to antagonise MIF. We have designed,
synthesised and tested several classes of compounds, which have shown activity from milli to nano-molar
levels in novel in-house in vitro bioassays.
Research achievements (from final report):
Inflammation is the causative process of human diseases as diverse as rheumatoid arthritis and
atheroscloerosis. Current treatments for inflammatory diseases are limited by side ffects, ineffectiveness, cost,
or all of these. There is a need for better, more economical treatments to inflamamtory diseases. , Macropahge
migration inhibitory factor (MIF) is a protein critical to the development of inflammation. Blocking MIF has
been shwon to be helpful in models of inflammatory diseases, but no current drugs act by blocking MIF. The
research funded by this grant supported the development of antagonists or 'blockers' of MIF which have the
potential to be developed into new treatments which deal with the problems of current drugs. , The major
outcome of this work was the confirmation that MIF antagonist compounds can indeed be made and do indeed
have the expected effectiveness in models of inflammatory diseases such as arthritis. This has lead since to a
major commercial udnertaking via a 'startup' company, to develop MIF antagonists as human therapies.
Expected future outcomes:
Further development of the prototype 'lead' compounds under investigation could lead to the commencement of
clinical trials in the next 2 years.
Name of contact:
Eric Morand
Email/Phone no. of contact:
eric.morand@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 284231
Start Year: 2004
CIA Name: A/Pr Michelle Leech
End Year: 2006
Admin Inst: Monash University
Grant Type: NHMRC Project Grants
Main RFCD: Immunology not elsewhere classified
Total funding: $239,250
Title of research award:
Regulation of leukocyte trafficking by macrophage migration inhibitory factor (MIF).Regulation of leukocyte
trafficking by macrophage migration inhibitory factor (MIF).
Lay Description (from application):
The entry of white blood cells in to tissues is a primary event which drives tissue and organ damage in a
number of inflammatory and immune mediated conditions. Diseases as diverse as rheumatoid arthritis, lupus or
shock due to bacterial infection (septic shock) have many different triggers and manifestations. However
almost all autoimmune and inflammatory diseases have one common feature: white blood cells must leave the
blood and enter tissue in order to cause tissue inflammation and ultimately tissue damage and loss of function.
The mechanism whereby white blood cells leave the blood stream and cross blood vessel walls to get into
tissues is a multi-step process often referred to as white blood cell trafficking. Most of the current treatments
for immune and inflammatory conditions have the primary aim of keeping white blood cells out of tissue in
order to prevent damage. Some of these treatments, like steroids (cortisone), are very effective but cannot be
used for prolonged periods because of the risk of problems like bone thinning (osteoporosis), high blood
pressure or diabetes. Other treatments and immunosuppressive agents can also be effective but are themselves
associated with toxicity and risk of organ damage. Although substantial progress has been made in the
management of immune and inflammatory conditions in the last 50 years, the current treatment options are far
from ideal. Macrophage migration inhibitory factor (MIF) is an inflammatory substance released by cells
which comprise the blood vessel wall as well as by white blood cells themselves. It is known to contribute to
the build up of white blood cells in inflamed tissue. The effect of MIF on white blood cell trafficking has never
been examined. Understanding how MIF promotes white cell entry in to tissues could be crucial in our
understanding of this important process and blocking MIF may prove to be a useful and effective way to
prevent it.
Research achievements (from final report):
Macrophage migration inhibitory factor (MIF) is important in the development of inflammatory responses such
as arthritis and experimental models of multiple sclerosis. Although some mechanisms to explain this have
been determined, little is known about the ability of MIF to regulate one of the damaging components of
inflammation - white blood cell (leukocyte) recruitment. Therefore the aim of this project was to test the
hypothesis that MIF enhances inflammation via the promotion of leukocyte recruitment. To achieve this aim
we compared inflammatory responses in blood vessels of normal mice with those in mice genetically-deficient
in MIF (MIF-/- mice). In response to various inflammatory stimuli, we observed that in mice lacking MIF,
white blood cells stuck to blood vessel walls and entered inflamed tissues much less efficiently, indicating that
MIF promotes this process of leukocyte accumulation. Further analysis indicated that this effect was not due to
an interaction of MIF with the circulating anti-inflammatory hormones known as glucocorticoids (GC). These
were the first experiments to show that MIF affects this key element of the inflammatory response. We also
found that application of MIF directly to tissues caused leukocyte migration into that tissue. Importantly MIF
attracted one type of leukocyte predominantly - the macrophage. This type of white blood cell is an important
damaging cell in diseases such as atherosclerosis and arthritis. Our findings suggest that MIF may contribute to
these diseases by promoting accumulation of this damaging cell type in affected tissues, and that inhibiting
MIF may be protective in these diseases.
Expected future outcomes:
This project has identified a new function for the inflammatory protein MIF, in that it promotes the entry of
white blood cells into inflamed tissues. This work suggests that drugs designed to inhibit the function of MIF
may reduce inflammation in various diseases, in part by preventing white cell accumulation
NHMRC Research Achievements - SUMMARY
Name of contact:
Dr. Michael Hickey
Email/Phone no. of contact:
michael.hickey@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 284354
CIA Name: Prof Rachelle Buchbinder
Admin Inst: Monash University
Main RFCD: Endocrinology
Total funding: $586,250
Start Year: 2004
End Year: 2007
Grant Type: NHMRC Project Grants
Title of research award:
Efficacy and safety of vertebroplasty for treatment of painful osteoporotic spinal fractures: a randomised
trialEfficacy and safety of vertebroplasty for treatment of painful osteoporotic spinal fractures: a randomised
trial
Lay Description (from application):
Painful spinal or vertebral fractures are a substantial and growing public health problem and are a burden on
the health care system. In Australia, 20-25% of women and 15-20% of men over the age of 50 will develop one
or more fractures of their spine in their lifetime. Up to a half of these fractures will result in severe pain and
disability. While the fractures generally heal within weeks or a few months, some are so painful that they
require narcotic pain control, hospitalisation, and/or long-term nursing home care. Other problems include
chronic pain, spinal deformities, loss of height and mobility and restricted breathing. Vertebroplasty is a new
procedure consisting of injection of a type of 'bone cement' into the vertebrae to mend the break. It is an
exciting treatment because for some people, this results in an immediate and sustained improvement in pain.
Although rare, complications such as rib fracture, cement leakage and fractures in other vertebrae do occur.
One particular concern is that the mechanical changes to the spine caused by the bone cement may cause longterm complications such as an increased risk of future fractures of treated or adjacent vertebrae. So far, there is
very little evidence of the efficacy and safety of this new technology. Importantly, it has not been compared
with usual medical care for fractures. In medical research it can be difficult to properly evaluate an exciting and
'apparently' effective treatment that doctors and patients demand. The main aim of this project is to determine
whether vertebroplasty is an effective and safe treatment compared to usual medical care. We have a unique
opportunity to evaluate vertebroplasty through a strong collaborative effort between the 3 centres currently
offering this procedure in Melbourne. If vertebroplasty can be demonstrated to be an effective, safe and costeffective treatment for painful osteoporotic spinal fractures this will be a valuable addition to current treatment
options.
Research achievements (from final report):
Painful vertebral fractures complicating osteoporosis are a substantial and growing public health problem
leading to severe morbidity and an increased burden on the health care system. Vertebroplasty is becoming an
increasingly accepted treatment for vertebral fractures despite the lack of scientific evidence of its benefit. The
outcome of our proposed research will be to establish whether vertebroplasty is efficacious, safe, and costeffective compared to placebo for painful osteoporotic spinal fractures. If positive, we will have scientific
evidence to support the currently uncorroborated widespread endorsement of this intervention. If, on the other
hand, our results indicate that its efficacy is no greater than placebo (and it may do more harm), then the
resources spent on performing these procedures might be put to better use. We have published an editorial
outlining our concerns about use of vertebroplasty without high quality evidence of its benefit.
Expected future outcomes:
We will determine the short term efficacy and safety of vertebroplasty for alleviating pain and improving
function for acute painful osteoporotic vertebral fractures and examine if there is excess risk of further
vertebral fractures within two years.
Name of contact:
Professor Rachelle Buchbinder
Email/Phone no. of contact:
rachelle.buchbinder@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 334067
Start Year: 2005
CIA Name: Prof Stephen Holdsworth
End Year: 2009
Admin Inst: Monash University
Grant Type: Programs
Main RFCD: Immunology not elsewhere classified
Total funding: $5,527,670
Title of research award:
Pathogenic mechanisms of inflammatory diseasesPathogenic mechanisms of inflammatory diseases
Lay Description (from application):
This research is directed by a team of medical and basic scientists with expertise in mechanisms of
inflammation relevant to human disease. The program will investigate the molecular and cellular events that
are responsible for inflammation in the kidneys, joints and blood vessels which lead to diseases such as
glomerulonephritis, arthritis and atherosclerosis. The aim of the research is to find new therapeutic targets
which may be specific to certain organs or disease processes, in order to develop more effective and selective
treatments ofchronic inflammatory disease in humans.
Research achievements (from final report):
Theme 1: Mechanisms of nephritogenic immune responses and renal injury, Glomerulonephritis (GN) is a
major cause of renal failure. These studies have revealed many of the molecular events which determine the
generation of immune responses that target the kidney. Inhibition of many of the key molecules involved
prevented or attenuated injury in animal models of human disease. , Theme 2: Glucocorticoid induced
molecules in the control of inflammation and arthritis , Glucocorticoids are widely used in the treatment of
inflammatory diseases. They work through mechanisms which include increasing the production of a number
of proteins that regulate immune system. The function of some of these proteins, including MIF, MKP1,
Annexin 1, and the more recently described GILZ, has been investigated in rheumatoid arthritis and lupus. ,
Theme 3: Pro-inflammatory roles for coagulation proteins and their receptors, Coagulation and inflammation
are closely intertwined in common diseases that affect the kidney, liver and blood vessels. Cellular receptors
for coagulation factors (protease activated receptors (PAR's) and tissue factor) have the potential to modulate
tissue injury in these diseases and are potential therapeutic targets. These studies have demonstrated
coagulation receptors modulate inflammatory tissue injury in an organ and disease specific manner. , Theme 4:
Control of leukocyte recruitment and vascular permeability during inflammation, These studies improved our
understanding of the processes whereby damaging white blood cells infiltrate tissues affected by inflammatory
diseases. A greater understanding of this process may allow development of new approaches to limit the
contribution of white blood cells to inflammatory disease.
Expected future outcomes:
Tissues from diseased patients will be assessed to determine whether molecules found to be critical to the
development of inflammation in relevant animal models are prominent participants in human diseased tissues.
Strategies used to prevent disease in relevant animal models will be assessed for their applicability to human
disease.
Name of contact:
Professor Stephen Holdsworth
Email/Phone no. of contact:
stephen.holdsworth@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 334150
CIA Name: Prof Flavia Cicuttini
Admin Inst: Monash University
Main RFCD: Rheumatology and Arthritis
Total funding: $236,500
Start Year: 2005
End Year: 2007
Grant Type: NHMRC Project Grants
Title of research award:
Effect of lifestyle factors on knee cartilage volume and rate of cartilage loss in a normal populationEffect of
lifestyle factors on knee cartilage volume and rate of cartilage loss in a normal population
Lay Description (from application):
Osteoarthritis (OA) has been described by the WHO as a potential epidemic and a major health and care
services cost driver in an aging society. OA has the largest impact on burden of disease borne in later life. This
has been acknowledged by its listing as the 7th health priority in Australia. To date, most research has focused
on treating the resulting pain and disability. However, in order to reduce the burden of OA, identifying
modifiable risk factors in the normal population is important. This proposal aims to identify life-style factors,
such as diet, physical activity and obesity that effect knee cartilage health in healthy subjects, thereby
identifying potential targets for future prevention of OA. This will provide us with the opportunity to promote a
better quality of life as people age and reduce the economic burden on the community.
Research achievements (from final report):
In this cohort study, we examined the relationship between lifestyle factors including diet, obesity, and physical
activity and knee cartilage and bone health in healthy people without history of knee osteoarthritis or injury.
We have found that intake of vitamin C and fruit, muscle mass, and physical activity are beneficial to joint
health, and that intake of fatty acids and fat mass are detrimental to joint health. Osteoarthritis is a major cause
of pain and disability in elder population. It has been described by the WHO as a potential epidemic and major
health and care service cost driver in an aging society and listed as the 7th national health priority in Australia.
There is no cure for knee osteoarthritis and joint replacement is approached for the treatment of end-stage
symptomic osteoarthritis. Osteoarthritis has the largest impact on burden of disease borne in later life. To date,
most research has focused on patients with established osteoarthritis. Therefore, in order to reduce the burden
of osteoarthritis, it is more important to identify modifiable lifestyle factors which may contribute to the risk of
osteoarthritis in the normal population. This study has the potential to identify potential targets for future
prevention of knee osteoarthritis, and provide us with the opportunity to promote a better quality if life as
people age and reduce the economic burden on the community.
Expected future outcomes:
We will continue the research to examine the effect of bone marrow lesions in the development of knee
osteoarthritis. We will aslo examine the relationship between body composition and physical activity and the
change in knee structures.
Name of contact:
Flavia Cicuttini
Email/Phone no. of contact:
flavia.cicuttini@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 334151
CIA Name: Prof Flavia Cicuttini
Admin Inst: Monash University
Main RFCD: Orthopaedics
Total funding: $654,530
Start Year: 2005
End Year: 2008
Grant Type: NHMRC Project Grants
Title of research award:
Role of musculoskeletal biomechanical factors in cartilage loss in those who undergo partial medial
menisectomy.Role of musculoskeletal biomechanical factors in cartilage loss in those who undergo partial
medial menisectomy.
Lay Description (from application):
The novel outcomes from our project are that we will identify whether musculoskeletal-biomechanical factors
that can be modified are associated with adverse cartilage changes in a subgroup of individuals with an
increased risk of developing knee OA, those who have undergone an APM. The findings of this research are
timely and of major international significance as there is increasing attention being paid to preventing OA
rather than merely treating the signs and symptoms. Our state-of-the-art measure of cartilage changes will
allow us to detect those at risk much sooner than traditional measures using radiographs. The measures are also
leading edge internationally. We chose these specific factors to investigate as there is evidence that they can be
modified with appropriate interventions. For example, static joint alignment could be modified with foot
orthoses [Crenshaw, 2000 #1016], muscle weakness can be addressed with strength programs and mechanical
loading across the knee could be reduced via weight loss programs or techniques to alter gait patterns.
Currently, formal supervised post-operative rehabilitation is not routinely prescribed following APM because it
is considered a routine procedure. If our research identifies risk factors for increased cartilage loss then we will
be able to develop appropriate intervention strategies for individuals following an APM. These interventions
can then be formally tested as to their effectiveness in reducing adverse cartilage changes using randomised
controlled trials. In particular, this could lead to changes in current post-operative clinical practice for this
patient group. Ultimately, this could reduce the risk of OA in the future and the resultant personal and societal
costs of this condition.
Research achievements (from final report):
menisecomty is a common procedure and is assocaited with long terms damage to the knee joint. We identified
characteritics of patients particualry in realtion to muscle weakness that resulted in abnormal forces through the
knee joint, futher aggrevatign joint damage. In contrast , patients who were stronger and had greater range of
motion at the knee also had better knee outcomes at at one year. This highlights the importance of addressing
these issues in order to prevent the development of knee OA in this population.
Expected future outcomes:
Further clarification of the specific biomechanical abnormailites that may be contributing to progression of
knee damage after menisecomty.
Name of contact:
Flavia Cicuttini
Email/Phone no. of contact:
flavia.cicuttini@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 384233
CIA Name: Prof Flavia Cicuttini
Admin Inst: Monash University
Main RFCD: Orthopaedics
Total funding: $475,388
Start Year: 2006
End Year: 2008
Grant Type: NHMRC Project Grants
Title of research award:
The effect of weight loss on the risk of knee osteoarthritis and potential modification by biomechanical
factorsThe effect of weight loss on the risk of knee osteoarthritis and potential modification by biomechanical
factors
Lay Description (from application):
Osteoarthritis (OA) has the largest impact of any chronic disease on burden of disease borne in later life. This
has been acknowledged by its listing as the 7th health priority in Australia. Knee OA is the most common
reason for a joint replacement, thus imposing a huge financial burden to the community. Treatments which
slow/prevent OA progressioning are limited and so prevention must play a key role. Obesity is the most
significant, potentially modifiable risk factor for knee OA. The combination of the current epidemic of obesity
in Western countries and the aging of the population is likely to have a synergistic effect on the prevalence and
incidence of knee OA. Despite the consistent relationship between obesity and OA, little work has been done
on the relationship between obesity and biomechanical factors such as knee angle and muscle mass and how
these may interact with obesity and weight loss in modifying the risk of knee OA. It may be that weight loss
programs could be more effective at reducing the risk of OA if they are combined with programs aimed at
correcting muscle weakness and malalignment. This has the potential to promote a better quality of life as
people age and to reduce the economic burden of knee OA in the community.
Research achievements (from final report):
Obesity is associated with significant knee pain and structural joint damage. This is largely explained by
increasing fat mass. Our work has shown that the adverse effect of obesity is not simply due to loading on the
joint but due to a systemic effect related to the metabolic activity of fat. We also observed this at other joints
including the back and the foot. This supports the important of weight loss, focussing of reduction in fat mass
as imptorant in the prevention and management of musculoskeletal disease.
Expected future outcomes:
Prevention strategies aimed at reducing musculoskeletal disease by targetting fat mass. Further work
understandign the systemic effects of fat mass on pain and disability due to musculoskeletal disease.
Name of contact:
Flavia Cicuttini
Email/Phone no. of contact:
flavia.cicuttini@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 384330
CIA Name: Prof Rachelle Buchbinder
Admin Inst: Monash University
Main RFCD: Rheumatology and Arthritis
Total funding: $1,568,125
Start Year: 2006
End Year: 2012
Grant Type: NHMRC Enabling Grants
Title of research award:
Australian Rheumatology Association DatabaseAustralian Rheumatology Association Database
Lay Description (from application):
We plan to collect health information from Australian patients with arthritis to monitor the benefits and safety
of new treatments. All patients being treated with the new injectable biologic agents and other patients taking
conventional drugs will be invited to take part in the follow up program. We will measure the impact of
arthritis on quality of life and physical function and the long-term effects of all arthritis drugs. This will be of
immense value to the Australian community as this data are not routinely available from any other source. It
will help rheumatologists and patients make the best decisions regarding long-term arthritis treatments.
Research achievements (from final report):
We have successfully set up and maintained a national arthritis database that provides valid and reliable
longitudinal clinical data of arthritis sufferers in Australia. In particular we have established a valuable ongoing
resource for studying the long-term impact (both effectiveness and safety) of biologic therapy for inflammatory
arthritis in Australia and for facilitating the study of important clinical questions that may arise over time.
There are currently 4804 participants from all over Australia participating in the registry and approximately 25
new participants are recruited monthly. Participants have either rheumatoid arthritis (n=3352), psoriatic
arthritis (n=423), ankylosing spondylitis (n=605) or juvenile arthritis (n=149)(another 275 provide linked data
only and diagnosis is not known for these), and participant data is collected 6-monthly by web-based or mailed
surveys. Participant and rheumatogist surveys have reported a high level of satisfaction with the registry and
acknowledge the value of the data collection. Significant achievements to date include establishing that people
commencing on biological therapy in Australia have severe disease and substantial comorbidities including
prior malignancy and that there is a dramatic improvement in quality of life with commencement of biologic
therapy that is sustained for more than 5 years. We have also determined that there does not appear to be a
significant increased risk of malignancy with exposure to biologic therapy over 10 years of follow up. Data
from the registry was also invaluable in informing a 2009 PBAC cost-effectiveness review of biologic agents
currently listed on the Pharmaceutical Benefits Scheme (PBS) for RA.
Expected future outcomes:
Our registry is now of a size and scale for its true benefit to the community and to clinical practice to be
realized. If the registry can be maintained with financial support from other sources, it will continue to be able
to address numerous clinical and economic questions of interest.
Name of contact:
Rachelle Buchbinder
Email/Phone no. of contact:
rachelle.buchbinder@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 410505
Start Year: 2007
CIA Name: Dr Neal Williams
End Year: 2009
Admin Inst: Monash University
Grant Type: Early Career Fellowships (Australia)
Main RFCD: Biotechnology not elsewhere classified
Total funding: $373,250
Title of research award:
Structure determination of Fms and Kit kinases and their inhibtors for directed drug designStructure
determination of Fms and Kit kinases and their inhibtors for directed drug design
Lay Description (from application):
Tyrosine kinases are a large and important family of enzymes that play a fundamental role in the control and
communication between cells. When damaged or uncontrolled, these enzymes can contribute to the
development of diseases such as cancer and immune related disorders. This proposal aims to develop
therapeutics targeted at the tyrosine kinases using a combination of the Structure Biology expertise at Monash
University and the drug discovery platform technologies of Cytopia Pty Ltd. Promising drug candidates already
identified by Cytopia will be analysed at their site of action using X-ray crystallography. This information will
enable a rational process of modification and improvement of the candidate drugs. The development of a range
of therapeutics for Phase I clinical trials will be of enormous benefit to Australia’s medical industry and pubic
health.
Research achievements (from final report):
Protein Tyrosine Kinases are a large, pivotal family of signaling molecules that play prominent roles in human
diseases such as cancers, cardiovascular diseases and immune related disorders, offering a fertile ground for
drug discoveries. This research award entitled "Rational drug design using protein kinase structures" aimed to
develop potent kinase inhibitors of a number of PTKs in collaboration with a leading Melbourne-based
Biotechnology company, Cytopia. We have been focusing on the JAK kinases that play a prominent role in
cytokine signalling. While members of the JAK family each present themselves as excellent drug discovery
targets for diseases of the immune system, JAK2 is an important therapeutic target for a number of
haematological cancers and cardiovascular diseases. The JAK2 structure has been determined by us previously,
but the closely related JAK1 structure was unknown and desirable for designing drugs with sufficient
specificity. A major research achievement has been the determination of the crystal structure of JAK1 kinase in
complex with potent and specific JAK kinase inhibitors. This has enabled new insights into the way JAK2
inhibitors exert their mode of action. A number of JAK2 inhibitors arising from this research have already enter
formal drug development for the treatment of haematological cancers and cardiovascular diseases and will lead
to the creation of a portfolio of phase II therapeutics, which will be of substantial benefit in the medical health
area.
Expected future outcomes:
The generation of drugs against JAK2 kinase could have a multimillion dollar potential. The work generated
during this award may prove to be a significant contribution to the discovery of improved JAK2 inhibitors that
could potentially have a huge impact on the health of the Australian population.
Name of contact:
Prof. Jamie Rossjohn
Email/Phone no. of contact:
jamie.rossjohn@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 427620
CIA Name: Prof Charles Mackay
Admin Inst: Monash University
Main RFCD: Autoimmunity
Total funding: $16,509,154
Start Year: 2007
End Year: 2011
Grant Type: Programs
Title of research award:
Molecular and cellular studies of the adaptive immune response in health and diseaseMolecular 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/Phone no. of contact:
charles.mackay@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 436665
CIA Name: Dr Anita Wluka
Admin Inst: Monash University
Main RFCD: Rheumatology and Arthritis
Total funding: $199,176
Start Year: 2007
End Year: 2009
Grant Type: NHMRC Project Grants
Title of research award:
Factors that affect knee structure in healthy womenFactors that affect knee structure in healthy women
Lay Description (from application):
Osteoarthritis (OA) has the largest impact of any chronic disease on burden of disease borne in later life,
affecting women more often than men. The importance of OA has been acknowledged by its listing within
musculoskeletal disease, the 7th health priority in Australia. It is 4 times as common in women as in
men.Treatments which slow or prevent OA progressing are limited, so prevention must play a key role. With
increasing disease severity, joint cartilage is lost. We have recently developed a method to measure joint
cartilage from magnetic resonance imaging (MRI) scans which is able to assess the severity of structural
changes in the knee. Using this method will allow us to assess 2 issues: 1) Obesity is the only identified
modifiable risk factor for knee OA. However, the mechanism is poorly understood. Weight loss programs may
be more effective at reducing the risk of OA if they are combined with programs aimed at maintaining muscle
mass. 2) Bone is important in development of Knee OA, but its role is poorly understood. Understanding how
bone metabolism relates to risk of knee OA may allow us to prevent disease. Bone is more likely to respond to
pharmacological manipulation than cartilage. Thus it may prove a more effective target for intervention than
cartilage. The Geelong Osteoporosis Study was begun in 1994 to study bone health in Australian women
(urban and rural). Much information relevant to the risk of OA has been collected over the past decade. By
performing MRI of the knee now and in 2 years time, we will determine the effect of different measures of
obesity and bone metabolism on structural change at the knee which predisposes to OA. Since both of these
factors (obesity and bone metabolism) are potentially modifiable, this study may offer new avenues of
prevention and therapy in knee OA. This has the potential to promote a better quality of life as people age and
to reduce the economic burden of knee OA in the community.
Research achievements (from final report):
Musculoskeletal diseases include osteoarthritis, the most common form of arthritis and osteoporosis. These
conditions share risk factors related to a person's lifestyle. We have shown that socioeconomic status, is related
to risk factors for both of these diseases, with lower socioeconomic status being related to higher rates of
obesity, smoking and risk factors for osteoporosis. Thus the distribution of these factors in the population is
likely to impact on the risk of both of these conditions. Despite this, we have reviewed the literature relating
the relationship between lifestyle factors and risk of osteoporosis and found limited evidence to support this
finding. In a community based population, we have found that both low and high socioeconomic status is
related to low bone mineral density which is related to increased risk of fracture. However, for men, this
relationship differ. When we examined knee structure, we found that increased obesity and gain in weight over
10 years, even in an asymptomatic group of women, is related to the early changes of knee osteoarthritis.
Expected future outcomes:
This work is likely to inform risk factores for the early changes in knee structure over 2 years.
Name of contact:
Dr Anita Wluka
Email/Phone no. of contact:
anita.wluka@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 436692
CIA Name: Dr Yuan Yang
Admin Inst: Monash University
Main RFCD: Rheumatology and Arthritis
Total funding: $533,828
Start Year: 2007
End Year: 2009
Grant Type: NHMRC Project Grants
Title of research award:
REGULATION OF GLUCOCORTICOID SENSITIVITY BY ANNEXIN-1REGULATION OF
GLUCOCORTICOID SENSITIVITY BY ANNEXIN-1
Lay Description (from application):
Steroids like prednisolone or cortisone are very effective at reducing inflammation in diseases like rheumatoid
arthritis and are particularly known to decrease substances involved in inflammation. Almost 70% of patients
with rheumatoid arthritis are treated more or less continuously with steroids. Steroid resistance (need for higher
doses) or changes in steroid-sensitivity has been widely recognized in asthma, inflammatory bowel disease, and
rheumatoid arthritis. Many new drug therapies however have the aim of keeping cortisone use to a minimum
because of undesirable side effects like osteoporosis. Annexin-1 is an anti-inflammatory substance important
in arthritis development which is also known to mediate many of the actions of steroids. However, the possible
contribution of annexin-1 to mediate the effect of steroids in the regulation of these substances has not been
examined. Moreover, how annexin-1 turns genes on is not known. Our studies will therefore reveal whether the
absence of annexin-1 will increase inflammatory substances turn genes, and secondly, by determining the
possible substances regulated by annexin-1 if the treatment with steroids are less effective in the absence of
annexin-1. If annexin-1 is found either to increase anti-inflammatory substances or to mediate the effect of
therapeutic steroids, its capacity to be involved in the beneficial effect of steroids may have an important
impact in treatment of arthritis and other inflammatory diseases. If annexin-1 functionally acts as steroids, the
reduction or discontinuation of steroid use will be possible.
Research achievements (from final report):
Anxa1 is a steroid-induced anti-inflammatory protein, important in arthritis development. However, the
possible contribution of Anxa1 to mediate the effect of steroids in the regulation of these substances has not
been examined. , Our data reveal Anxa1 as a key inhibitor of inflammation and identify two other proteins
MKP-1 and GILZ as a previously unrecognised mechanism of the anti-inflammatory effects of Anxa1 in mice.
Two papers have been published in J Immunol (2006, 2009). Translation studies have been successfully
performed in human rheumatoid joint cells by silencing Anxa1 using small RNA interference. Current data
have demonstrated that deficiency of Anxa1 in rheumatoid arthritis cells reduced the inhibitory effect of
steroids on proinflammatory cytokine production. Anxa1 has been found to mediate the effect of therapeutic
steroids, so that its capacity to be involved in the beneficial effect of steroids will have an important impact in
treatment of arthritis and other inflammatory diseases. Thses findings have a significant impact on the potential
development of Anxa1 based therapies, in that agents binding to the receptor FPRL1 may not replicate the full
range of effects of intracellular Anxa1, especially in regards to the involvement of Anxa1 in the actions of
steroid. If Anxa1 functionally acts as steroids, the reduction or discontinuation of steroid use will be possible.
Expected future outcomes:
Modulation of MKP-1 and GILZ expression by manipulation of Anxa1 may afford a mechanism of inhibiting
inflammation without GC, which would be an attractive modality for treatment of acute and chronic
inflammatory diseases.
Name of contact:
Yuan Yang
Email/Phone no. of contact:
yuan.yang@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 436779
CIA Name: Prof Patrick Sexton
Admin Inst: Monash University
Main RFCD: Basic Pharmacology
Total funding: $362,207
Start Year: 2007
End Year: 2008
Grant Type: NHMRC Project Grants
Title of research award:
Understanding selective drug signaling at G protein-coupled receptorsUnderstanding selective drug signaling at
G protein-coupled receptors
Lay Description (from application):
The maintenance of optimum health and function living cells, and consequently that of the whole organism,
depends on how cells respond to a multitude of physical and chemical stimuli that continually bombard them.
The majority of the chemical stimuli such as hormones and neurotransmitters impart their actions not by
directly entering the cell, but instead, by binding to a specific reciever protein at the cell surface called
receptor. In one class of such receptors called G protein-coupled receptors, the transmission of the message to
the interior of the cell involves yet another protein called G protein. These receptors are the most abundant type
of cell surface receptors and form the targets for nearly 50% of currently used therapeutic drugs. It is, therefore,
extremely important to unravel how each of these components works, and in particular to know how they work
in living cells. This project utilizes state-of-the-art methodologies to examine interactions between receptors
and their cognate G proteins, in living cells and in real-time. The work will answer fundamental questions
about the nature of G protein-coupled receptor signaling, in particular whether new classes of drugs can be
identified that more selectively activate signaling pathways or factors that attenuate signaling. This work has
potential for future development of more effective therapeutic agents.
Research achievements (from final report):
G protein-coupled receptors (GPCRs) are the largest family of cell surface receptor proteins and consequently
are important targets for therapeutic intervention. Recently, new paradigms in GPCR function have been
unravelled and one of these is the capacity of individual ligands (both naturally occuring, and synthetic drugs)
to generate distinct profiles of response, even via the same receptor. This behaviour is termed ligand-directed
signalling. This type of behaviour may well provide a mechanistic basis for why very similar drugs can have
markedly different therapeutic outcomes. , We have established new assays for evaluating response profiles
from individual receptors following ligand treatment. One utilises yeast signaling systems and allows
examination of individual G protein responses. The second uses an assay of proximity, based on resonance
energy transfer, to identify receptor-G protein interactions. These systems have revealed unique liganddependent behaviours. In other work we have shown that a novel class of drug, termed allosteric modulators,
can change the signaling profile of endogenous neurotransmitters or hormones. This work has implications for
current and future drug development.
Expected future outcomes:
The new assays will be applied to elucidating the extent to which ligand-directed signaling occurs for both
physiological ligands and potential therapeutic compounds. This is particularly relevant to understanding
physiological systems with multiple ligands and to understanding the spectrum of activity for novel allosteric
drugs.
Name of contact:
Patrick Sexton
Email/Phone no. of contact:
patrick.sexton@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 436780
Start Year: 2007
CIA Name: Prof Patrick Sexton
End Year: 2008
Admin Inst: Monash University
Grant Type: NHMRC Project Grants
Main RFCD: Protein Targeting and Signal Transduction
Total funding: $382,821
Title of research award:
Analysis of calcitonin receptor binding and functionAnalysis 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 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/Phone no. of contact:
patrick.sexton@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 465142
CIA Name: Dr Yuanyuan Wang
Admin Inst: Monash University
Main RFCD: Rheumatology and Arthritis
Total funding: $282,008
Start Year: 2007
End Year: 2010
Grant Type: Early Career Fellowships (Australia)
Title of research award:
The effect of sociodemographic and lifestyle factors on the risk of primary and revision joint replacement.The
effect of sociodemographic and lifestyle factors on the risk of primary and revision joint replacement.
Lay Description (from application):
Not Available
Research achievements (from final report):
The project explored the ethnic disparity in total joint replacement utilization in Australia, and examined
associations between lifestyle factors including obesity, physical activity, and diet, and the risk of total joint
replacement for osteoarthritis. The research on the disparities of joint replacement utilization is crucial to
healthy policy in terms of the issue of equity: health service and resources should be fairly distributed on
clinical needs, but not by patient's cultural or socioeconomic background. The findings of the research identify
the potentially modifiable risk factors for osteoarthritis, contribute better understanding of the pathogenesis of
osteoarthritis, and inform novel preventive strategies for osteoarthritis. For example, muscle mass was shown
to be beneficial to knee cartilage, and fat mass to be detrimental to knee cartilage and associated with an
increased risk of total joint replacement. It may be that for effective prevention of osteoarthritis, weight loss
programs should focus on both fat mass reduction and muscle maintenence: simple weight loss alone may be
insufficient. Thus, these may facilitate more effective strategies to prevent osteoarthritis in the future.
Expected future outcomes:
Patient-related factors associated with the risk of revision joint replacement and the effect of adult weight gain
on the risk of total joint replacement will be further explored. Extension of this work may provide a stronger
basis to enable intervention studies to be conducted to reduce the risk of osteoarthritis.
Name of contact:
Yuanyuan Wang
Email/Phone no. of contact:
Yuanyuan.Wang@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 481309
Start Year: 2008
CIA Name: Prof Charles Mackay
End Year: 2009
Admin Inst: Monash University
Grant Type: Established Career Fellowships
Main RFCD: Immunology not elsewhere classified
Total funding: $342,540
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
I am an immunologist working on the molecular basis of immune
responses, particularly inflammatory responses. My research also
focuses on mechanisms of cell migration, and cytokines and
chemokines for immune responses. My research also has considerable
re
Research achievements (from final report):
The two main achievements were progression of a new drug to human clinical trials, and identification of a
receptor, GPR43, as a major regulator of inflammatory responses.
Expected future outcomes:
I will progress our C5aR drug through human clinical trials, and identify mechanisms that connect diet with gut
microbiota, and immune responses.
Name of contact:
Charles Mackay
Email/Phone no. of contact:
c.mackay@me.com
NHMRC Research Achievements - SUMMARY
Grant ID: 508926
Start Year: 2008
CIA Name: Prof Anthony Purcell
End Year: 2013
Admin Inst: Monash University
Grant Type: NHMRC Research Fellowships
Main RFCD: Immunology not elsewhere classified
Total funding: $665,541
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
I am interested in determining the molecular basis of immune recognition of foreign and self-antigens in the
context of viral, tumor and auto-immunity as well as transplantation. In addition to fundamental observations
this knowledge is also applied in va
Research achievements (from final report):
My fellowship has allowed me to build novel expertise in the rapid and accurate identification of targets of
immunity in allergy, infectious disease, autoimmunity and cancer. This work has had broad application to
several diseases. Notable achievements include defining new mechanism of drug allergies, identifying novel
bacterial vitamin metabolites as targets of gut associated T cells, analysis of peptides presented on the surface
of pancreatic beta cells during diabetes development, quantitation of MHC-peptide complexes on the surface of
antigen presenting cells, analysis of immune signalling and the definition and exploration of posttranslationally modified T cell epitopes in autoimmune disease and cancer. The identification of these immune
targets provides opportunities to intervene and enhance or ablate immune recognition in a very specific
manner. Such immunotherapies may facilitate new treatment modalities in a range of human diseases.
Expected future outcomes:
With the renewal of my fellowship in 2013 I will continue and expand on this work with a particular emphasis
on post-translationally modified antigens in cancer and autoimmunity, the detailed quantitative study of the
molecular machinations of viral infections and further studies of drug hypersensitivity.
Name of contact:
Anthony Purcell
Email/Phone no. of contact:
anthony.purcell@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 519512
CIA Name: Prof Eric Morand
Admin Inst: Monash University
Main RFCD: Rheumatology and Arthritis
Total funding: $398,157
Start Year: 2008
End Year: 2010
Grant Type: NHMRC Project Grants
Title of research award:
MIF regulation of MKP-1 and glucocorticoid responses in RAMIF regulation of MKP-1 and glucocorticoid
responses in RA
Lay Description (from application):
Rheumatoid arthritis (RA) is a common chronic inflammatory disease which affects 1% of Australians. Up to
70% of patients are treated with 'steroids', which are drugs with major side effects. Recent research has shown
that sensitivity to steroids is controlled by a number of natural proteins, and that balance between these proteins
controls the effectiveness of steroids. The proposed research will define the interactions between these proteins.
Research achievements (from final report):
The aim of this project was to determine the interation of two key molecules that are involved in the control of
inflammation. Inflamamtion is the process which underlies many common diseases, including rheumatoid
arthritis, a disease affecting 1% of Australians. This and other inflammatory diseases are often treated with
steroids, drugs which while effective are associated with severe side effects. Thus, to determine better ways to
treat inflammation, it is necessary to better understand how steroids work.In this project we investigated the
control of the anti-inflammatory (or beneficial) protein MKP1 by the pro-inflammatory (or harmful) protein,
MIF. We were able to demonstrate a novel means by which MKP1 is controlled by MIF, and this might
represent a future therapeutic target.
Expected future outcomes:
We hope that future therapies may take advantage of the knowledge we have gained in this work to devise
better ways to achieve the beneficial effects of steroids without their harmful effects.
Name of contact:
Eric Morand
Email/Phone no. of contact:
eric.morand@monash,edu
NHMRC Research Achievements - SUMMARY
Grant ID: 543141
CIA Name: Prof Steve Gerondakis
Admin Inst: Monash University
Main RFCD: Cellular Immunology
Total funding: $492,991
Start Year: 2009
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
The transcription factors c-Rel and RelA serve distinct roles in the devlopment and function of CD4 Regulatory
T cellsThe transcription factors c-Rel and RelA serve distinct roles in the devlopment and function of CD4
Regulatory T cells
Lay Description (from application):
An unfortunate consequence of immune function is that occasionally rogue immune cells are produced that
attack the host and lead to the development of so-called autoimmune diseases such as arthritis. Normally a
white blood cell called a regulatory T cell suppresses these self reactive immune cells. We have identified
factors that govern genetic programs in regulatory T cells. Understanding how these factors work should permit
the development of new strategies to combat autoimmune diseases.
Research achievements (from final report):
CD4 regulatory T cells that express Foxp3 (Tregs) play a critical role controlling normal immune responses as
well as preventing the development of autoimmune disease. Accordingly, understanding how the development
and function of this T cell lineage is regulated is an important goal of biomedical research. Research funded by
this grant established that the c-Rel transcription factor plays an essential role in promoting the development of
Tregs in the thymus, but it has a lesser role in the function of these cells once thymic development is complete.
The role of c-Rel in thymic Treg development was found to be one that involved the commitment of CD4 T
cells to the Treg lineage. This finding that c-Rel is a key regulator of Treg development could potentially offer
therapeutic avenues for manipulating Treg numbers in order to regulate the impact this lineage has in various
pathological conditions such as autoimmune disease and cancer.
Expected future outcomes:
This work has provided a foundation for determining how c-Rel controls the pattern of gene expression
responsible for Treg development and which specific c-Rel regulated genes contribute to the formation and
function of this T cell lineage.
Name of contact:
Steve Gerondakis
Email/Phone no. of contact:
steven.gerondakis@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 545876
CIA Name: A/Pr Anita Wluka
Admin Inst: Monash University
Main RFCD: Rheumatology and Arthritis
Total funding: $387,490
Start Year: 2009
End Year: 2012
Grant Type: Career Development Fellowships
Title of research award:
Using good measurement principles to examine musculoskeletal disease and improve the evaluation of new
diagnostic testsUsing good measurement principles to examine musculoskeletal disease and improve the
evaluation of new diagnostic tests
Lay Description (from application):
This proposal will apply good measurement principles to 2 important but under-resourced areas: 1) To examine
risk factors for musculoskeletal disease (particularly osteoarthritis or “wear and tear” arthritis) and to determine
how changes in these risk factors in our community will affect the burden of disease, thus identifying new
targets for disease prevention. 2) To improve our ability to evaluate how well new diagnostic tests function
when introduced into our healthcare system.
Research achievements (from final report):
This Career Development Award has allowed me to lead pioneering research into osteoarthritis and
musculoskeletal conditions, with two critical outcomes in sight. The first has been to identify how to delay the
onset of osteoarthritis. The second is to make the disease easier for patients to manage. Whilst current
treatment strategies for the disease rely almost solely on losing weight, I have been looking to find something
to limit the spread of the problem and slow down the pain and joint damage. My main achievements are to
have highlighted the role of systemic factors such as obesity, bone metabolism and vascular risk factors in the
development and experience of musculoskeletal conditions. For example, I have shown that it is not just how
heavy one is, but the amount of fat present that is important in foot and back pain, 2 very common conditions.
These observations suggest that reducing the amount of fat present may be a useful way of managing painful
conditions, supplementing usual management. I have also characterised the role in the development of painful
knee osteoarthritis that some specific changes seen on MRI scans before the onset of painful knee osteoarthritis
play. These may be used as targets to develop new ways to prevent knee osteoarthritis, a major cause of loss of
mobility in our increasingly obese and aged community.?????
Expected future outcomes:
Using these findings, future studies may be designed to delay the onset and progress of disease. Even a small
reduction in risk across the country would make a significant difference to the wellbeing of patients and to
public health costs in terms of joint replacements.
Name of contact:
Anita Wluka
Email/Phone no. of contact:
anita.wluka@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 545974
CIA Name: Prof Arthur Christopoulos
Admin Inst: Monash University
Main RFCD: Basic Pharmacology
Total funding: $744,943
Start Year: 2009
End Year: 2011
Grant Type: NHMRC Project Grants
Title of research award:
Understanding the pharmacoregulation of the extracellular calcium sensing receptor.Understanding the
pharmacoregulation of the extracellular calcium sensing receptor.
Lay Description (from application):
Calcium sensing receptors (CaSR) are important regulators of hormone release and modulators of kidney
transport, digestion/absorption/satiety and bone mass. In each case, CaSRs adopt a characteristically distinct
activating mechanism that we will unravel in detail sufficient for the development of novel chemotherapies
e.g., for osteoporosis and obesity. We also anticipate early application of CaSR-based therapies to clinically
significant genetic disorders e.g., neonatal hyperparathyroidism.
Research achievements (from final report):
This project has identified signalling bias at the human CaSR, which has important implications for treatment
of CaSR-associated diseases. We have identified signalling bias in the actions of both positive and negative
allosteric modulators and have discovered that naturally occurring mutations in the CaSR, which cause
dysregulation of calcium homeostasis, alter signalling bias. We have additionally gained insight into how
allosteric drugs bind to the receptor by quantifying the effects of both naturally occurring and engineered
mutations on drug-receptor interactions. This enables a better understanding of drug action at the CaSR, which
will lead to the development of superior therapeutic agents.
Expected future outcomes:
A key outcome will be the use of allosteric CaSR modulators to treat mutation-induced CaSR diseases and
targeting drugs more specifically towards disease relevant signalling pathways.
Name of contact:
Arthur Christopoulos
Email/Phone no. of contact:
arthur.christopoulos@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 546243
Start Year: 2009
CIA Name: Prof Henry Krum
End Year: 2009
Admin Inst: Monash University
Grant Type: NHMRC Development Grants
Main RFCD: Pharmaceutical Sciences and Pharmacy
Total funding: $200,600
Title of research award:
Development of Novel Anti-Inflammatory AgentsDevelopment of Novel Anti-Inflammatory Agents
Lay Description (from application):
There is an unmet need for safe and effective anti-inflammatory drugs. Because P38 MAPK intracellular
signalling modulates multiple pro-inflammatory cytokine actions, it appears to be an ideal candidate pathway.
P38 inhibitors have been limited by their toxicity within hepatocytes. The aim of this program therefore is to
develop agents with enhanced P38 MAPK inhibitory effects as well as reduced liver toxicity based on known
structure activity relationships.
Research achievements (from final report):
Not Available
Expected future outcomes:
N/A
Name of contact:
Henry Krum
Email/Phone no. of contact:
henry.krum@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 606952
CIA Name: Prof Charles Mackay
Admin Inst: Monash University
Main RFCD: Innate Immunity
Total funding: $549,093
Start Year: 2010
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
Regulation of immune and inflammatory responses by short chain fatty acids and GPR43Regulation of immune
and inflammatory responses by short chain fatty acids and GPR43
Lay Description (from application):
Innate immune mechanisms provide essential signals that determine the outcome of immune responses. The
identity of these innate mechanisms may provide opportunities for manipulating immune responses, or
controlling inflammatory responses. This proposal centers around a new and little-studied receptor, GPR43,
which binds products of bacterial metabolism. This molecular pathway may explain how diet affect immune
responses.
Research achievements (from final report):
GPR43 deficient mice showed increased inflammation in DSS-induced or TNBS-induced colitis models,
K/BxN serum-induced arthritis model and OVA-induced asthma model. We have dissected additional
mechanisms and, in addition to GPR43 mediated effects, we find a very potent effect of SCFAs operating
through another pathway for development of asthma. This involves promotion of Tregs.
Expected future outcomes:
This research has strengthened the case for the effects of diet on immune and inflammatory responses. we
expect to validate a diet hypothesis for the pathogenesis of numerous inflammatory diseases
Name of contact:
Charles Mackay
Email/Phone no. of contact:
charles.mackay@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 1007830
Start Year: 2011
CIA Name: Prof Phillip Bird
End Year: 2013
Admin Inst: Monash University
Grant Type: NHMRC Project Grants
Main RFCD: Cellular Interactions (incl. Adhesion, Matrix, Cell Wall)
Total funding: $605,963
Title of research award:
The impact of granzyme B on cytotoxic T cell migration through tissueThe impact of granzyme B on cytotoxic
T cell migration through tissue
Lay Description (from application):
Cytotoxic T cells (CTL) are white blood cells that move in an orchestrated way into body tissues to target, and
destroy, virus-infected or cancer cells. Destruction of these abnormal cells is achieved when they ingest
cytotoxic enzymes (proteases) released by CTL. We propose that one of these cytotoxins, granzyme B, has a
dual function, and that it is also involved in helping CTL to efficiently move towards the target cells by
clearing a path through the local tissue structure.
Research achievements (from final report):
Cytotoxic T cells (CTL) are white blood cells that move in an orchestrated way into body tissues to target, and
destroy, virus-infected or cancer cells. Destruction of these abnormal cells is achieved when they ingest
cytotoxic enzymes (proteases) released by CTL. In this project we demonstrated that one of these cytotoxins,
granzyme B, has a dual function, and that it is also involved in helping CTL to efficiently move towards the
target cells by clearing a path through the local tissue structure. Emerging evidence suggests that unfettered
granzyme B can exacerbate inflammatory disease and impair wound healing. Our work suggests the source of
this pathogenic granzyme B is CTL recruited to the inflamed site.
Expected future outcomes:
Our work suggests development and application of granzyme B inhibitors to ameliorate normal tissue damage
during inflammation, and potentiate wound healing.
Name of contact:
Prof Phillip Bird
Email/Phone no. of contact:
phil.bird@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 1008991
CIA Name: Dr Yuan Yang
Admin Inst: Monash University
Main RFCD: Rheumatology and Arthritis
Total funding: $612,886
Start Year: 2011
End Year: 2013
Grant Type: NHMRC Project Grants
Title of research award:
Regulation of arthritis and skin inflammation by annexin-1Regulation of arthritis and skin inflammation by
annexin-1
Lay Description (from application):
Annexin-1, an antiinflammatory substance, mediates many of the actions of steroids. Our studies will reveal
whether annexin-1 will reduce inflammatory and immune responses, and secondly, determine the substances
regulated by annexin-1 in immune responses. If annexin-1 is found to mediate the immune regulatory effect of
steroids, its capacity to be involved in the beneficial effect of steroids may have an important impact in
treatment of arthritis and other inflammatory diseases.
Research achievements (from final report):
Annexin A1 (AnxA1), an anti-inflammatory substance, mediates many of the actions of steroids. Our studies
reveal that AnxA1 reduces inflammatory and immune responses in experimental animal models which mimic
human inflammatory and immune mediated diseases, including rheumatoid arthritis, and secondly, identify the
substances regulated by AnxA1 in immune responses. The results of this research show that AnxA1 mediates
the immune regulatory effect of steroids, thus its capacity to be involved in the beneficial effect of steroids, but
not side effects, may have an important impact in treatment of arthritis and other inflammatory diseases.
Expected future outcomes:
Through this research, the researchers have made a significant contribution to knowledge of the role of annexin
A1, an anti-inflammatory substance, in inflammation, and potentially identify new therapeutic strategies for
human chronic inflammatory diseases, including rheumatoid arthritis.
Name of contact:
Eric Morand
Email/Phone no. of contact:
eric.morand@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 1011670
CIA Name: Prof Eric Morand
Admin Inst: Monash University
Main RFCD: Rheumatology and Arthritis
Total funding: $675,031
Start Year: 2011
End Year: 2013
Grant Type: NHMRC Project Grants
Title of research award:
Defining the role of GILZ in inflammatory arthritisDefining the role of GILZ in inflammatory arthritis
Lay Description (from application):
Corticosteroids are commonly used to treat inflammatory diseases such as arthritis. Their action is based on
effects on natural inflammation control pathways. One such pathway is that mediated by the protein known as
GILZ (glucocorticoid induced leucine zipper). The function of this protein in disease is not well understood,
and the research proposed here will increase understanding of its role. This knowledge could yield new
treatments for arthritis and other inflammatory diseases.
Research achievements (from final report):
In this project we sought to define the role of GILZ, a protein induced by steroids, in the control of
inflammation. Steroids are widely used as medicines for inflammatory diseases such as arthritis, but have many
side effects. We studied GILZ to determine if it might offer a pathway to develop safer alternatives to steroids.
The results indicate that GILZ is able to suppress inflammation in rheumatoid arthritis, and preliminary
indications suggest a lack of the side effecs of steroids. We were able to generate numerous key tools for future
research on this exciting pathway, which we believe has relelvance to a range of diseases.
Expected future outcomes:
With funding support we hope to pursue the development of a GILZ-based therapy in the future.
Name of contact:
Eric Morand
Email/Phone no. of contact:
eric.morand@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 284524
Start Year: 2004
CIA Name: Prof John Bateman
End Year: 2006
Admin Inst: Murdoch Childrens Research Institute Grant Type: NHMRC Project Grants
Main RFCD: Cellular Interactions (incl. Adhesion, Matrix, Cell Wall)
Total funding: $482,500
Title of research award:
The role of a novel extracellular matrix protein, WARP, in cartilage development, function and pathologyThe
role of a novel extracellular matrix protein, WARP, in cartilage development, function and pathology
Lay Description (from application):
The environment outside all cells is absolutely essential for normal growth and development. In order to
undertand many disease and developmental processes it is critical that we acquire a detailed understanding of
the various extracellular matrix components and how they interact to form a functional extracellular matrix.
We recently discovered a new extracellular matrix protein which we have named WARP for von Willebrand
factor A-domain-related protein. Our experiments demonstrate that WARP is an important constituent of the
three-dimensional structure of the extracellular matrix of the articular surface of cartilage. We can show that
WARP forms large-scale structures in tissue culture experiments and in extracts from mouse cartilage, and we
have some new data which suggests that WARP interacts specifically with collagen II, a large and
quantitatively major component of cartilage. We will explore the function of WARP in cartilage and include
in vitro experiments that will reveal information about its distribution, tissue forms, and interactions with other
extracellular matrix components (PART 1). To define the in vivo role of WARP we will generate a WARP
gene knockout mouse (PART 2). These experiments will provide valuable information about the structure of
the cartilage in the joint on the surface of bone and in particular the function of WARP in this structure. Since
WARP is at the articular cartilage surface we asked whether WARP is lost in cartilage degeneration. In
cartilage tissue grown in vitro under conditions that promote cartilage degradation, WARP is fragmented and
released from the cartilage surface. We will explore this further in in vitro and in vivo models of cartilage
breakdown (PART 3). Thus, in addition to promoting a new understanding of cartilage structure WARP has
the exciting potential to become a specific biomarker for arthritis a major joint degenerative disease with high
medical and financial cost to the community.
Research achievements (from final report):
We discovered and chararerised a new protein in cartilage, showing how it interacted with other proteins to
establish the intergrity of the cartilage tissue. We studied when and when this protein was prodcued during
development of the mouse skeleton. This new protein, called WARP, was found exclusively at the surface of
the articular cartilage, making it a good candidate for use as a clinical marker of cartilage destruction in
arthritis. Studies were initiated to determine its utility as a biomarker of arthritis.
Expected future outcomes:
A clinical testing procedure will be developed to evaluate its use as a biomarker of arthritis in patients with
arthritis.
Name of contact:
John Bateman
Email/Phone no. of contact:
john.bateman@mcri.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 350347
Start Year: 2005
CIA Name: Prof John Bateman
End Year: 2010
Admin Inst: Murdoch Childrens Research Institute Grant Type: Established Career Fellowships
Main RFCD: Cellular Interactions (incl. Adhesion, Matrix, Cell Wall)
Total funding: $952,661
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
I am a biochemist/molecular geneticist determining the molecular mechanisms that underlie skeletal
development and disease.
Research achievements (from final report):
INHERITED MUSCULOSKELETAL DISORDERS, Molecular genetics has defined collagen disease
mechanisms - Our studies on collagen disease have been at the forefront in defining new mutations and
mechanisms. New insight was gained from osteogenesis imperfecta transgenic mice. This ground-breaking
work was seminal in developing the "collagen disease paradigm" , ER-stress - We demonstrated for the first
time ER-chaperone involvement and ER-associated degradation of mutant collagens. This presaged our
findings that collagen misfolding causes ER-stress (unfolded protein response, UPR) and this is an important,
previously unrecognised, contributor to pathology. Our data provides an exciting new mechanistic
understanding of broad significance that may underpin new therapies., New mechanisms of mutant mRNA
surveillance (NMD) - We defined mutations causing NMD . Of great significance was our discovery of a new
molecular pathway of NMD that is providing new insights into mRNA surveillance in genetic disease,
OSTEOARTHRITIS - We developed novel methods for RNA expression profiling of mouse cartilage and
conducted the first comprehensive analysis of gene expression during OA initiation. These data, combined with
new proteomic studies have identified novel OA genes and pathways., DEVELOPMENT - We published the
first global gene expression analyses of cartilage development revealing new regulatory genes that are being
functionally assessed. In vitro and mouse knockout studies on a novel ECM gene demonstrated a critical role in
ECM organisation and in the pathogenesis of arthritis.
Expected future outcomes:
My studies on inherited musculoskeletal disease will continue and focus on how the unfolded protein response
contributes to the disease pathology and on how we can intervene in this process with new therapeutic agents.
The arthritis research has identified novel genes involved in the initation and progression of cartilage damage
and this work will lead to new therapeutic options and biomarkers
Name of contact:
Prof John Bateman
Email/Phone no. of contact:
john.bateman@mcri.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 384414
Start Year: 2006
CIA Name: Prof John Bateman
End Year: 2008
Admin Inst: Murdoch Childrens Research Institute Grant Type: NHMRC Project Grants
Main RFCD: Orthopaedics
Total funding: $457,518
Title of research award:
Molecular mechanisms of cartilage degeneration in osteoarthritisMolecular mechanisms of cartilage
degeneration in osteoarthritis
Lay Description (from application):
Arthritis affects 15% of the entire Australian population and 50% in people over 60. The most common form of
joint disease by far is osteoarthritis (OA). One of the central features of OA is the breakdown of the cartilage
that covers the ends of bones in joints, and this is a major determinant of the long term outcome and need for
joint replacement surgery. There are no current therapies that halt or reverse cartilage breakdown in OA. This
is largely due to our incomplete understanding of the molecular changes and pathways involved in both the
onset and progression of cartilage breakdown. Powerful new genomic approaches allow simultaneous
screening of changes in a broad profile of genes, particulalrly in humans and mice following complete
sequencing of their genomes. By applying this new technology in the earliest stages of cartilage degeneration
in OA, the role of novel genes and the pathways involved in the onset of this disease process can be discovered.
However, to investigate changes at the initiation of disease, tissue from animal rather than human joints must
be used due to the difficulty in obtaining pre-symptomatic human cartilage. In order to maximise the number of
genes screened, cartilage from a novel surgically induced model of OA in mice will be used in this study. We
have developed micro dissection and linear mRNA amplification methods to overcome inherent problems with
tissue availability from this small animal species. Successful completion of these studies will for the first time
allow identification of the complex changes that occur in early OA. An important and likely outcome of this
research will be identification of novel matrix proteins and regulatory molecules that will provide critical
information for the development of new diagnostic and therapeutic approaches to OA.
Research achievements (from final report):
This is the first study to comprehensively determine the gene expression patterns of cartilage during the
initiation and progression of osteoarthrtitis. It has identified new genes that may play a role in either the onset
or development of joint disease. Because these studies have identified possible new molecular pathways that
may be involved in OA, the information obtained in these studies has potential for the development of novel
biomarkers ans therapeutic approaches
Expected future outcomes:
The novel OA candidate genes identified in this study will be examined in detail ongoing studies. The outcome
of these studies is likely to be a more complete elucidation of OA disease mechanisms.
Name of contact:
John Bateman
Email/Phone no. of contact:
john.bateman@mcri.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 491203
Start Year: 2008
CIA Name: Dr Fraser Rogerson
End Year: 2009
Admin Inst: Murdoch Childrens Research Institute Grant Type: NHMRC Project Grants
Main RFCD: Rheumatology and Arthritis
Total funding: $299,228
Title of research award:
Identifying a novel aggrecanase in mouse cartilageIdentifying a novel aggrecanase in mouse cartilage
Lay Description (from application):
Destructive enzymes degrade cartilage in arthritis. Aggrecan is a major structural molecule that gives cartilage
its cushioning properties, and aggrecan is also destroyed by harmful enzymes in arthritis. We have discovered a
new enzyme that degrades aggrecan. This project aims to identify and study this new enzyme, and to determine
its role in aggrecan degradation.
Research achievements (from final report):
Skeletal growth is a very complex process involving the conversion of cartilage to bone. The proteins that
make up cartilage must be removed before bone can be formed, a process that is very poorly understood.
Cartilage also has a very important cushioning role at the ends of the bones in our joints. Our laboratory's
major interest is in the loss of cartilage that is a hallmark of arthritis. In the course of our studies we discovered
an enzyme that breaks down aggrecan, a major component of cartilage. We could find no evidence that this
enzyme is involved in aggrecan degradation in arthritis. However we did find evidence that it is important for
the removal of aggrecan where cartilage is converted to bone.
Expected future outcomes:
We expect to identify the novel enzyme responsible for cleaving aggrecan, and study its role in the conversion
of cartilage to bone.
Name of contact:
Dr Fraser Rogerson
Email/Phone no. of contact:
fraser.rogerson@mcri.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 491237
Start Year: 2008
CIA Name: Prof John Bateman
End Year: 2010
Admin Inst: Murdoch Childrens Research Institute Grant Type: NHMRC Project Grants
Main RFCD: Orthopaedics
Total funding: $592,034
Title of research award:
Proteomics of arthritis: Exploring mechanisms of cartilage degradation and biomarker identificationProteomics
of arthritis: Exploring mechanisms of cartilage degradation and biomarker identification
Lay Description (from application):
Arthritis is a major clinical and socio-economic problem. Arthritis involves the destruction of cartilage in
joints. However, the mechanisms of initiation and progression of cartilage destruction remain poorly
understood. Our studies will use new proteomic approaches to identify the changes in protein synthesis and
degradation in mouse models of arthritis. This will provide critical information on disease mechanisms and for
the development of diagnostic biomarkers and therapeutic approaches
Research achievements (from final report):
This grant was to develop new proteomic approaches for analysing cartilage and the application of these to
gaining a better understanding of cartilage degradation in osteoarthritis. The major achievements were to:,
Develop proteomic methodologies for mouse cartilage analysis, Using this approach to define novel proteins
and interactions during cartilage development, Characterisation of new proteins involved in the pathology of
cartilage degeneration, Identification of new proteins and protein degradation productions that may have utility
as disease biomarkers
Expected future outcomes:
Future work will explore the novel biomarkers as indications of diseqease initiation and progression, Candidate
proteins identified in this project will be explored further to determine their roles in the arthritis disease process
and whether they offer possibilities as therapeutic targets
Name of contact:
Prof John Bateman
Email/Phone no. of contact:
john.bateman@mcri.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 607343
Start Year: 2010
CIA Name: A/Pr Amanda Fosang
End Year: 2013
Admin Inst: Murdoch Childrens Research Institute Grant Type: NHMRC Project Grants
Main RFCD: Rheumatology and Arthritis
Total funding: $540,236
Title of research award:
ADAMTS-5 activity and the effect of a dominant-negative mutantADAMTS-5 activity and the effect of a
dominant-negative mutant
Lay Description (from application):
Cartilage loss is a feature of arthritis and is caused by enzymes. We discovered that loss of a critical cartilage
component is caused by the enzyme ADAMTS-5. We also discovered that a mutant form of ADAMTS-5
blocks the normal emzyme, possibly by a novel binding interaction. If we can understand how this interaction
works, we can exploit it for the design of new arthritis therapies. This project aims to identify the novel
interaction and improve out understanding of cartilage destruction.
Research achievements (from final report):
The proteoglycan aggrecan is vital to the weight-bearing function of cartilage. Loss of aggrecan is a key feature
of arthritis and is mediated by destructive ADAMTS enzymes. We and others have shown that the major
aggrecanase in mouse cartilage is ADAMTS-5, and pharmaceutical companies are now designing ADAMTS-5
active site inhibitors as arthritis therapies. Evidence suggests that the specificity of these inhibitors could be
improved if other regions of the enzyme are also targeted. We have discovered that interrupting the ancillary
domains of ADAMTS-5 inhibits its catalytic activity and that ADAMTS-5 must form dimers or multimers for
full catalytic activity. We hypothesise from this research that blocking formation of ADAMTS-5
dimers/multimers could be an alternative therapeutic approach to targeting the enzyme active site.
Expected future outcomes:
Information from this project will inform the design of ADAMTS-5 inhibitors by the pharmaceutical industry,
for use as arthritis therapies.
Name of contact:
Amanda Fosang
Email/Phone no. of contact:
amanda.fosang@mcri.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 607385
Start Year: 2010
CIA Name: A/Pr Amanda Fosang
End Year: 2012
Admin Inst: Murdoch Childrens Research Institute Grant Type: NHMRC Project Grants
Main RFCD: Rheumatology and Arthritis
Total funding: $360,019
Title of research award:
Chondrocyte hypertrophy in development and diseaseChondrocyte hypertrophy in development and disease
Lay Description (from application):
Whereas chondrocyte hypertrophy is a normal feature of skeletal growth, in adult chondrocytes it is associated
with osteoarthritis (OA). We propose that collagen II fragments provide signals for hypertrophy in cartilage.
The lack of collagen II fragments in our collagenase-resistant mouse provides a unique opportunity to address
the role of collagen II fragments in driving cellular hypertrophy. We will identify bioactive collagen II
fragments that represent novel targets for OA therapies
Research achievements (from final report):
We have produced a mutant mouse (Bailey) with cartilage collagen that is resistant to degradation by
collagenase enzymes. Bone growth in young Bailey mice is disrupted. The mice show a distinct skeletal
phenotype, caused by the failure of the cartilage cells (chondrocytes) to mature in a timely fashion prior to
bone formation. We hypothesised that collagen fragments generated by collagenase degradation (fragments
missing in Bailey) signal chondrocytes to mature (hypertrophy) during bone growth. We tested the hypothesis
in vitro by applying a crude source of collagen fragments to chondrocytes in culture. These collagen fragments
were able to 'rescue' the abberant gene expression patterns displayed by Bailey chondrocytes. Purified 30mer
and 45mer collagen fragments (not found in Bailey) failed to reproduce the rescue seen with crude collagen
fragments, indicating that we have to look further for the bioactive fragments. We have secured funding from
the Australian Research Council to test the bioactivity of smaller fragments of collagen that are generated
during further degradation of collagen. We will test the new hypothesis that these fragments regulate blood
vessel invasion during bone growth. The question of whether chondrocyte hypertrophy is a feature of
osteoarthritis (OA) is controversial. In the DMM mouse model of OA, we found that Bailey mice were
significantly protected against cartilage erosion. Importantly, we could detect no difference in markers of
cellular hypertrophy between wildtype and Bailey mice in DMM. Our in vivo data suggest that OA pathology
leading to cartilage erosion and joint dysfunction is independent of the cellular events leading to chondrocyte
hypertrophy in OA, at least in the DMM model. These results support arguments by some that although
chondrocyte hypertrophy is associated with OA pathology, it is not an initiating or driving event in mouse
models or human OA.
Expected future outcomes:
Our aim is to inform those seeking to design therapies to control chondrocyte hypertrophy and maturation.
Experiments relating to this project are ongoing and we expect that therapies targeting collagen fragments may
yet prove to be a way of manipulating bone growth.
Name of contact:
A/Prof Amanda Fosang
Email/Phone no. of contact:
amanda.fosang@mcri.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 607399
Start Year: 2010
CIA Name: Prof John Bateman
End Year: 2011
Admin Inst: Murdoch Childrens Research Institute Grant Type: NHMRC Project Grants
Main RFCD: Orthopaedics
Total funding: $441,058
Title of research award:
Bone-specific sclerostin and SIBLING proteins in osteoarthritis: novel contributions to cartilage and bone
pathologyBone-specific sclerostin and SIBLING proteins in osteoarthritis: novel contributions to cartilage and
bone pathology
Lay Description (from application):
Arthritis is a major clinical problem and involves the destruction of cartilage in joints. However, the
mechanisms of how this cartilage destruction is initiated and progresses remain poorly understood. We
recently discovered that that three proteins that play a role in bone are also produced in cartilage and are
increased in cartilage during osteoarthritis. We will determine the role of each of these in the disease
mechanism to provide new therapeutic and biomarker targets.
Research achievements (from final report):
Cartilage and bone changes in osteoarthritis (OA) have long been associated, but the mechanisms behind this
remain unclear. We hypothesized that expression of proteins previously reported to be "bone-specific" in
articular cartilage, and their regulation during post-traumatic OA, may link the bone pathology in arthritis. Our
studies found that three bone specific proteins, SOST (sclerostin), DMP1 and MEPE are expressed in cartilage
and that SOST was dysregulated in OA. Our studies showed that SOST expression was increased by
mechanical loading which is an imprortant contribution to the development of OA. We found ithat the
increased SOST decreased expression of MMP1, MMP13, ADAMTS4 and ADAMTS5, all key enzymes in
cartilage degradation. These results implicate SOST in regulating the OA disease processes, but suggest
opposing effects by promoting disease-associated subchondral bone sclerosis while inhibiting degradation of
cartilage. The paper describing these studies was cited as a "Research Highlight" in Nature Reviews
Rheumatology 2011:7:438, and cited in Faculty of 1000 (September 2011 "I'm pleased to inform you that one
of your articles, Increased chondrocyte sclerostin may protect against cartilage degradation in osteoarthritis.
(Osteoarthritis Cartilage 2011 Jul), has been selected and evaluated by Mark Johnson, a Member of the Faculty
of 1000 (F1000), which places your work in our library of the top 2% of published articles in biology and
medicine."
Expected future outcomes:
These studies have indentified sclerostin as a possible therapeutic agent to modify the course of osteoarthritis
since increased sclerostin inhibits the enzymes involved in cartilage degeneration. However sclerostin has
multiple effects and current studies are focussed on detailed analysis of the in vivo effects of sclerostin using
mouse models.
Name of contact:
John Bateman
Email/Phone no. of contact:
john.bateman@mcri.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 436603
Start Year: 2007
CIA Name: A/Pr Peter Tipping
End Year: 2012
Admin Inst: Prince Henry's Institute of Medical Research
Grant Type: NHMRC Research
Fellowships
Main RFCD: Immunology not elsewhere classified
Total funding: $820,332
Title of research award:
Gene Regulation, Cytokine regulationGene Regulation, Cytokine regulation
Lay Description (from application):
I am a physician-scientist investigating cellular mechanism of inflammatory injury in animal models of human
diseases.
Research achievements (from final report):
My work has improved understanding of the mechanisms of kidney filtration, inparticulatr the leakage of
albumin which is a risk for development of chronic kidney disease in humans. This knowledge will eventually
lead to better prevention an dtreatment of kidney failure. In addition, my work has improved understanding of
the role of the immune system in atherosclerosis which this the major cause of heart attacks and strokes. It has
demonstrated an important role for B lymphocytes in the development of disease which may allow the trialing
in human atherosclerosis of current therapies which block B cell function.
Expected future outcomes:
Improve understanding and treatment of inflammatory disease in humans including chronic kidney disease and
atherosclerosis.
Name of contact:
A/Prof Peter Tipping
Email/Phone no. of contact:
peter.tipping@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 611805
Start Year: 2010
CIA Name: Dr Julian Quinn
End Year: 2012
Admin Inst: Prince Henry's Institute of Medical Research
Grant Type: NHMRC Project Grants
Main RFCD: Orthopaedics
Total funding: $592,575
Title of research award:
Novel roles for IL-33 in the maintenance of bone mass and as a locally derived anabolic factor for boneNovel
roles for IL-33 in the maintenance of bone mass and as a locally derived anabolic factor for bone
Lay Description (from application):
Over 10% of the population have thin, brittle bones that fracture easily, and is often seen in elderly people.
When diagnosed, a fracture has usually already occurred and the bone is already thin. Drugs are available to
stop further bone weakening, but building new bone would be best. We have found a protein in bone that
reduces bone loss and stimulates bone formation processes. This project seeks to determine how this protein
works and how to exploit it to design new bone building therapies.
Research achievements (from final report):
We extended our previous findings that IL-33 is produced in bone and found that IL-33 is regulated by PTH
(bone anabolic factors), that it increased osteoblast (OB) activity. We have identified a number of mean by
which this may be occurring, and have also found that OSM a factor that IL-33 can induce, can drive the
formation of primitive osteoblasts. We have found that in mice that lack receptors for IL-33 ("ST2 knockout
mice") their bone density is fairly normal, disagreeing with others findings that bone density of such mice is
slightly higher than normal. Indeed, all of our evidence suggests that rather than normal bone physiology, IL33
is principally involved with bone damage, as fracture of bone drastically increases its levels of expression. IL33 also inhibited osteoclast formation through a number of mechanisms that we have identified - it may
however slightly stimulate formation of small numbers of osteoclasts specifically from human monocytes, an
unusual finding although the importance of this is currently unclear. These data point to a significant regulatory
role for IL-33 in bone biology, to its potentially displaying a net pro-anabolic activity on bone i.e., that enhance
bone mass. The indirect actions of locally produced IL-33 (e.g. via production of OSM) is probably the most
important thing that we have identified and which we are carrying forward with further work. We are also
working on notions that IL-33 participates in the healing that follows bone fracture.?????
Expected future outcomes:
We anticipate that IL-33 and factors that are induced by IL-33 will be of continued interest in bone biology,
and that the induction of IL-33 by drugs will need to be investigated for possible beneficial or negative effects
on bone cells, with corresponding implications for bone health in patients
Name of contact:
Matthew T. Gillespie
Email/Phone no. of contact:
matthew.gillespie@princehenrys.org
NHMRC Research Achievements - SUMMARY
Grant ID: 241901
Start Year: 2003
CIA Name: Prof Andreas Suhrbier
End Year: 2005
Admin Inst: Queensland Institute of Medical Research
Grant Type: NHMRC Project Grants
Main RFCD: Medical Virology
Total funding: $252,750
Title of research award:
The biology of Ross River virus and its cellular receptorThe biology of Ross River virus and its cellular
receptor
Lay Description (from application):
Ross River virus (RRV) causes a principally rheumatic disease in up to 8000 Australian annually. The disease
is severe at onset comparable to that suffered by patients with osteoarthritis awaiting hip replacement.
However, the disease usually resolves within 6 months. This grant intends to continue our studies on how and
why RRV causes disease and develop an understanding of why only 1 person in 20 infected with RRV actually
develops disease. We believe RRV arthritis is cause by RRV persisting in specific white blood cells residing
within joint tissues. The grant intends to exploit the recent observation that to infect cells RRV uses a receptor,
which human cells normally use to bind to collagen. Armed with this new information we intend to unravel
how RRV can persist despite the patient making good antibody responses against the virus, and determine
whether high levels of this receptor predispose to disease. The ultimate goal for these studies is the
identification of potential new treatments for this and perhaps other arthritic diseases caused by viruses. We
have also recently identified a new virus in seals that is related to RRV, but fortunately appears not to pose a
health threat to humans. However, we intend to test whether this new virus uses the same receptor as RRV and
begin to explore using computer technology some of mutations these viruses would need before they could
successfully infect humans.
Research achievements (from final report):
The grant identified a receptor for Ross River virus and further developed our understanding of arthritogenic
processes of the globally distributed alphaviruses. The technologies developed also found application in
understanding the mechanism of action of Cpn10 a potent new biological, which has had substantial success in
rheumtoid arthritis.Publications arising; AS85. Linn ML, Eble JA, Lübken C, Slade RW, Heino J, Davies J,
Suhrbier A. 2005. An arthritogenic alphavirus uses the a1b1 integrin collagen receptor. Virology 336:229239.AS84. Rulli NE, Suhrbier A, Hueston L, Heise MT, Tupanceska D, Zaid A, Wilmes A, Gilmore K,
Lidbury BA, Mahalingam S. 2005. Ross River virus: Molecular and cellular aspects of disease pathogenesis.
Pharmacol Ther. 107(3):329-42. AS81. Johnson BJ, Le TTT, Dobbin CA, Banovic T, Howard CB, Flores
FDML, Naylor DJ, Hill GR, Suhrbier A. 2005. Heat shock protein 10 inhibits lipopolysaccharide-induced
inflammatory mediator production. J Biol Chem. 280(6):4037-47. AS80. Mylonas AD, Harley D, Purdie DM,
Pandeya N, Vecchio PC, Farmer JF, Suhrbier A. 2004. Steroid therapy in an alphaviral arthritis. J Clin Rheum.
10(6):326-330.AS79. A. Suhrbier and M.L. Linn. 2004. Clinical and pathological aspects of arthritis due to
Ross River virus and other alphaviruses. Current Opinion in Rheumatology 16; 374-379.AS70. M.L. Linn and
A. Suhrbier. 2003. Suppression of anti-viral responses by antibody dependent enhancement of macrophage
infection. Trends in Immunology 24;165-168. ASP12. WO2005067959. 16/1/2004. Chaperonin 10 modulation
of Toll-like receptor-inducible cytokine and chemokine secretion. Inventors: B Johnson, A. Suhrbier, D.
Naylor, C Dobbin, C. Howard.
Expected future outcomes:
A greater understanding of the arthritogenic processes of Ross River virus is finding application in
understanding and finding treatments for related diseases, specifically chikungunya disease a virus that has
been imported by tourists into Australia and that has recently caused >250,00 cases and > 200 deaths in
Reunion Island.
Name of contact:
Andreas Suhrbier
NHMRC Research Achievements - SUMMARY
Email/Phone no. of contact:
andreasS@qimr.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 613622
Start Year: 2010
CIA Name: Prof Andreas Suhrbier
End Year: 2013
Admin Inst: Queensland Institute of Medical Research
Grant Type: NHMRC Project Grants
Main RFCD: Medical Virology
Total funding: $709,194
Title of research award:
Inhibition of interferon-alpah-beta by chikungunya virus and the induction of arthritisInhibition of interferonalpah-beta by chikungunya virus and the induction of arthritis
Lay Description (from application):
Chikungunya virus is a mosquito borne virus which has caused epidemics of arthritis around the world
(recently 260,000 people Reunion Island, France and 1.6 million people in India). The virus is ordinarily very
sensitive to the main mammalian anti-viral defence system (interferon alpha-beta). This grant seeks to
understand how, despite the activation of this system during infection, the virus manages to persist and cause 36 months of debilitating arthritis.
Research achievements (from final report):
We developed the first wild mouse model of CHIKV viremia and arthritic disease, a model that has been
widely adopted internationally both by academia and industry. Research highlights include, - illustrating that
virus persists in macrophages and thereby gives rise to chronic arthropathy , - showing that insufficient
interferon responses are sufficient for haemorrhagic shock , - showing that targeting macrophages for therapy
may be a problem as they protect against neutrophil mediated disease., - illustrating that rheumatoid arthritis
(RA) and CHIKV arthritis share many inflammatory pathways, suggesting drugs developed for RA may find
ultility for alphviral arthritides. , - showing for the frist time that CD4 T cells are important for driving
arthropathy, - illustrating that vaccines are relatively easy with antibodies sufficient to mediate protection
Expected future outcomes:
We hope to be able to use our insights into immunopathogenesis to be able to provide better treatment options.
Critical will be anti-inflammatory treatments that (i) do not compromise clearance of peristent arthritogenic
viral RNA and (ii) do not cause even worse immunopathology.
Name of contact:
Andreas Suhrbier
Email/Phone no. of contact:
Andreas.Suhrbier@qimrberghofer.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 138711
Start Year: 2001
CIA Name: Dr James Smeathers
End Year: 2003
Admin Inst: Queensland University of Technology Grant Type: NHMRC Project Grants
Main RFCD: Biomechanical Engineering
Total funding: $185,665
Title of research award:
QUANTITATIVE ASSESSMENT OF LOOSENING IN HIP ARTHROPLASTIES USING MECHANICAL
VIBRATION DIAGNOSTICSQUANTITATIVE ASSESSMENT OF LOOSENING IN HIP
ARTHROPLASTIES USING MECHANICAL VIBRATION DIAGNOSTICS
Lay Description (from application):
Recent advances and improvements made to the mechanical design of artificial joints have led to greater
strength, fatigue life and wear resistance. However, this extension to the working life of joint replacements has
led to patients becoming increasingly vulnerable to the problem of joint loosening. There are over 500 000 hip
joint replacements performed every year, on a worldwide basis. Of these 7 to 13% will require revision surgery
because of loosening at some stage of their working life. This is becoming a major concern to health services
around the world since revision surgery is associated with a higher risk to the patient and costs are far greater
than for the primary operation. Current diagnostic techniques using radiographic imaging are both invasive and
lack diagnostic accuracy. The ability to detect joint loosening and to discriminate between the various causes of
joint loosening following arthroplasty is of great importance to the success of subsequent care plans. This study
will be the first in the world to assess the validity of a new diagnostic test that uses low energy mechanical
vibration to quantify the degree of loosening in both components of the implanted hip joint. Once the technique
has been proven it could readily be extended to evaluate the degree of fixation of other implanted prostheses
used to replace the knee, ankle or joints of the upper limbs.
Research achievements (from final report):
This research program has significantly advanced the way that loosening of artificial hip joints is detected by
using low energy mechanical vibration to provide a safe additional means of evaluating the integrity of an
implant in the human body. The significance of this relates to the 500 000 hip joint replacements that are
performed worldwide annually. Unfortunately, up to 8% of these implants will suffer from aseptic loosening
which, is thought to be caused by tissue reaction to wear debris and resorption of the supporting bone. There is
growing concern over the increasing numbers of artificial joints that are failing by loosening due impart to the
large numbers in service and the trend to earlier implantation in younger more active patients. It is still difficult
to diagnose aseptic joint loosening with current clinical imaging techniques where loosening is confirmed by a
combination of invasive radiographic techniques, radio-opaque dyes injected into the joint space, pain
provocation tests and ultimately, physical assessment at the time of surgery. Hence this research evaluates a
complimentary diagnostic technique that is based on mechanical vibration to detect structural changes within
the human body. The principles of vibration based monitoring previously developed by engineering and
aerospace industries to detect failure in machinery is now being applied to the human body and the problem of
loosening in artificial joints. The potential of this novel application to the clinical problem of artificial joint
loosening has been examined by this research project under extensive laboratory tests and early clinical trials.
In principle, this additional diagnostic test will help improve the health of Australians through improved
accuracy of diagnosis and efficiency of surgical care by assisting the surgeon to make better informed decisions
on whether or not to reoperate on the joint and how to optimise the timing of revision procedures.
Expected future outcomes:
In the longer term knowledge gained from this research coupled with improvements in technology will enable a
clinical diagnostic device, for detecting loosening of artificial joints, to be manufactured in Australia and
marketed throughout the world. The diagnostic principles of this system will also have relevance to a wide
range of other structural problems and discipline areas.
Name of contact:
James Smeathers
NHMRC Research Achievements - SUMMARY
Email/Phone no. of contact:
j.smeathers@qut.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 497268
Start Year: 2008
CIA Name: Prof Adekunle Oloyede
End Year: 2011
Admin Inst: Queensland University of Technology Grant Type: NHMRC Development Grants
Main RFCD: Biomechanical Engineering
Total funding: $230,633
Title of research award:
Development of a smart arthroscopy system and prototype probe for joint tissuesDevelopment of a smart
arthroscopy system and prototype probe for joint tissues
Lay Description (from application):
This project relates to the ever growing use of arthroscopy in the management of joint defects. An innovative
probe that will combine all the molecular, microstructural and biomechanical characteristics of joint articular
cartilage and bone for the purposes of diagnosis, treatment, treatment-related decisions, comparison of the
effectiveness of treatment methods and post treatment evaluation will be developed. This system will produce
spin-offs for arthroscopy of other soft tissues and bodies.
Research achievements (from final report):
The aim of the research was to conduct further research into the assessment of cartilage viability. The expected
outcome was a prototype proof-of-concept (POC) probe that combines near infrared, ultrasound and
mechanical loading technologies into one easily applied probe. The potential benefit is an advancement in the
field of arthroscopy that removes subjectivity and hence unnecessary surgery for patients with related cost
reduction to the national health budget. The innovative POC probe has been developed with a new interface
that both controls data acquisition and all related analysis of raw data, outputting parameters that enable precise
surgical decisions. The POC probe was demonstrated on December 4th 2009., The new stand-alone graphical
user interface (GUI) application was built in the MATLAB environment. It implements multivariate statistical
protocols such as partial least squares regression (PLSR), principal component analysis (PCA) and principal
component regression (PCR) from the statistics toolbox. Accepting raw data in any of three different formats
(.csv, .xls, .txt), this application implements the necessary statistical protocol based on user preferences and
outputs the required parameter for assessment.
Expected future outcomes:
Further resolution of the ultrasound and NIR spectra information for precise mapping of layer-by-layer
property of a piece of cartilage. We are also going to incorporate the new IP system that has been developed
into an existing arthroscope so that we can carry out preliminary clinical tests. It has also been decided that the
IP would be better protected by secrecy with blackbox implementation.
Name of contact:
Prof. Adekunle Oloyede
Email/Phone no. of contact:
k.oloyede@qut.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 202011
Start Year: 2002
CIA Name: E/Pr Herbert Bolotin
End Year: 2004
Admin Inst: Royal Melbourne Institute of TechnologyGrant Type: NHMRC Project Grants
Main RFCD: Medical Physics
Total funding: $411,980
Title of research award:
The Effects Of Inherent Inaccuracies In DXA In Vivo BMD Measurements On Osteopenic/Osteoporotic
Diagnostics/PrognositicsThe Effects Of Inherent Inaccuracies In DXA In Vivo BMD Measurements On
Osteopenic/Osteoporotic Diagnostics/Prognositics
Lay Description (from application):
Osteoporosis (porous bone) and consequent associated bone fractures of mainly post-menopausal women and
the elderly of both genders constitutes a significant, widespread and rapidly growing public health problem. It
is already a major health-cost burden in Australia and worldwide and is set to increase dramatically over the
next few decades as the proportion of the population at or above the osteoporosis-prone age increases sharply.
Current diagnostic evaluations of osteoporosis, bone mineral status of the skeleton, mechanical integrity of
bone, and bone fracture risk are mainly based on X-ray absorption measurements of a given individual's bone
mineral density (BMD) using Dual-energy X-ray Absorptiometric (DXA) bone densitometer instrumentation.
New drugs to retard, ameliorate, or reverse the low bone mineral density condition of osteoporosis are now
becoming available, but cannot be prescribed unless sufficiently low BMD is demonstrated for a given patient.
The efficacy of these drugs is usually held to be greatest at the earliest stage of osteoporosis (osteopenia) and
their effectiveness evaluated on the basis of DXA-measured bone mineral density. The Chief Investigator of
this project has already shown by published quantitative analysis and simulation studies that such BMD
measurements are inherently inaccurate; that errors of 20% and greater can readily pertain, particularly for
those patients at the early stages of osteoporosis and those at or above the osteoporosis-prone age -- the very
individuals for whom bone mineral density values are often of paramount interest and concern. These
systematic DXA inaccuracies can be large enough to either mask the presence of osteoporosis or lead to false
diagnoses and patient monitoring results. The present project, for the first time anywhere, is desiged to
quantitatively establish the extent of these inaccuracies using actual DXA densitometers utilizing sophisitcated
and precise methods.
Research achievements (from final report):
The research carried out in this project has definitely established that in vivo bone densitometry carried with
dual-energy X-ray absoroptiometric (DXA) instrumentation is beset with inherent inaccuracies due to the
presence in all scan regions of interest of fat, muscle tissue, red marrow, and yellow marrow. The extent of
these inaccuarcies range up to 50% and make bone density measurements of dubious reliability. This intrinsic
shortcoming has been shown to make DXA an unreliable and misleading indicator of bone mineral status and
to make questionable the validity and usefulness of DXA-based diagnostic and prognostic interpretations..
Expected future outcomes:
The development of alternative means of bone mineral status evaluation that is reliable and dependable.
Name of contact:
Professor H. H. Bolotin
Email/Phone no. of contact:
herb.bolotin@rmit.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 294402
CIA Name: A/Pr Scott Wilson
Admin Inst: Sir Charles Gairdner Hospital
Main RFCD: Quantitative Genetics
Total funding: $330,500
Start Year: 2004
End Year: 2006
Grant Type: NHMRC Project Grants
Title of research award:
Linkage disequilibrium mapping and positional cloning for gene identification in osteoporotic familiesLinkage
disequilibrium mapping and positional cloning for gene identification in osteoporotic families
Lay Description (from application):
The increasing number of older women in Australia presents a significant challenge to our health system.
Preventative and health promotion strategies must be developed for this important group of Australian's if
chronic disease and disability are to be contained and the decline in functional capacity attenuated. One
potential intervention strategy is regular exercise. However, if exercise is to have multi-systems benefits, the
dose of the exercise must be known. We do not know the exercise prescription that will maximize those health
benefits required for this group of Australian's. We propose to resolve this situation via two related experiments
involving women aged 65-74 yr. Experiment 1 will select moderate-intensity treadmill walking for 30
min/session with the weekly exercise frequency varied from 1 to 5 session/wk for 64 sessions. Experiment 2
will also select moderate-intensity treadmill walking with the total exercise time per week (120 min/wk) and
the number of weeks of training (24 wk) fixed but varying the exercise duration per session (24 to 120
min/session) and the exercise frequency per week; 5 (x 24 min) to 1 (x 120 min) session/wk. Each subject will
undergo lung function tests, body fat test, fitness tests and blood tests at selected time intervals throughout each
experiment. A separate fitness test will be conducted on the subjects' leg muscle to help us understand what is
happening directly in the muscle. We will also conduct a tilt test to help us understand how regular exercise
might lessen the likelihood of 'falls' in older individuals. We expect to determine the optimum exercise
prescription to improve health and minimize injury and misadventure. It is essential that GP's who have the
main responsibility for prescribing exercise for their older patients, have access to knowledge on the optimum
exercise prescription to maximize the beneficial changes in health and functional capacity in females aged 6574 yr.
Research achievements (from final report):
The aim was to identify disease-associated genes from linkage data on bone mineral density (BMD). We
previously completed genome scans of twins and families with a history of osteoporosis and identified regions
for study. First, we refined the support intervals and selected 2 linkages for study (1p36, 3p21). We
characterised genes within the regions using a bioinformatics approach and generated detailed lists of the
candidate genes. We defined haplotype tag SNPs (HT-SNPs) in 94 candidate genes and across the interval at
3p21 and genotyped these creating a dense SNP map (~1,2 million genotypes). A significant association was
defined with a SNP in a gene in the 1p36 linkage region (BMD at the total hip (P = 0.023) and femoral neck (P
= 0.008). The average reduction in BMD was 3.4-4.1% for homozygous individuals. We replicated this finding
in an independent population-based cohort (Femoral neck BMD, P < 0.005; see Mullin, 2007)). In addition, we
showed that a coding SNP (rs17563) in the BMP4 gene, also under a linkage peak, is associated with total hip
and intertrochanter BMD. Homozygotes show a 3.1% difference in BMD at the hip site (Ramesh-Babu, 2004).
We then demonstrated associations with HT-SNP in three potentially interacting genes on 3p21, an acting
binding protein (Femoral Neck BMD, P = 0.0001), a small GTPase (Femoral Neck BMD, p= 0.0004) and a
nucleotide exchange factor (Femoral Neck BMD, P = 0.0004). Finally, we replicated these associations in
population-based cohorts, thus verifying the findings (P = 0.02, 0.04, 0.04 respectively).
Expected future outcomes:
The three novel genes we have identified as associated with BMD within the 3p21 genomic region require
further study to determine the functional basis of the observed effect. The data resulting from this project
provides new tragets for the potential development of diagnositc and therapeutics options relating to low BMD
and osteoporosis.
NHMRC Research Achievements - SUMMARY
Name of contact:
Lynell Belardo
Email/Phone no. of contact:
Lynell.Belardo@health.wa.gov.au
NHMRC Research Achievements - SUMMARY
Grant ID: 343603
CIA Name: A/Pr Scott Wilson
Admin Inst: Sir Charles Gairdner Hospital
Main RFCD: Quantitative Genetics
Total funding: $403,625
Start Year: 2005
End Year: 2007
Grant Type: NHMRC Project Grants
Title of research award:
Genetic regulation of hip geometry, structure and fractureGenetic regulation of hip geometry, structure and
fracture
Lay Description (from application):
Osteoporotic hip fracture is common in the elderly and a major cause of hospitalization. Hip fracture may lead
to surgery, chronic reduced mobility, loss of function, institutionalization or death. The term osteoporosis
covers a heterogeneous syndrome including juvenile, secondary (e.g. corticosteroid induced) and
postmenopausal osteoporosis. This later broad grouping shows evidence of a strong familial association.
Previous work has shown that a family history of fracture increases the risk of fracture by more than four fold.
Furthermore, studies in twins have persistently shown that phenotypes such as bone mineral density (BMD),
broadband ultrasound attenuation of bone and hip structural indices are strongly inherited. This confirms a
genetic basis for the disease in some individuals. Community health in general has improved substantially in
Australia in the past four decades and this has resulted in increased longevity. In contrast, the incidence of hip
fracture and the resulting drain on public health funding continues to increase rapidly. Presently the cost of
osteoporosis in Australia is $7.5 billion per annum. Hip fracture accounts for the majority of these costs.
Instituting effective prevention strategies is essential. This project aims to contribute to one of Australia's
National Research Pritoities by improving understanding about the way in which inherited aspects of hip
geometry and structure contribute to the hip fracture susceptibility. We have successfully completed genome
screen projects studying genetic linkage in the families to localize genes regulating BMD in the past.
However, BMD is only one of a number of relevant phenotypes. In relation to hip fracture, geometry and
structure are thought to be particularly important. In this project we will make use of existing resources to
advance studies of both genetic linkage and association to examine fundamental issues related to hip facture.
Research achievements (from final report):
Osteoporotic hip fracture is common in the elderly and is a major cause of morbidity and mortality, the goal of
this project was to find genes that control hip structure, particularly those which are relevant to hip fracture.
The study used existing radiographs and dual x-ray absorptiometry (DXA) scans on a large cohort of women
and derived important new phenotypes on hip structure and geometry from these resources. That phenotype
data was then used in analyses with existing genetic data for these study subjects to identifying genes with a
potential role in the regulation of hip geometry and structure. We identified 13 discrete genomic regions that
showed genetic linkage to hip structure and geometry phenotypes. Furthermore, we identified 23 individual
genes with replicated evidence of statistically significant association with hip structure traits. These results
assist in improving knowledge and understanding of the genetic control of hip structure. The long-term goal of
the research program is to develop intervention strategies to reduce hip fracture incidence.
Expected future outcomes:
This data will enable targeted validation studies of the mechanisms involved in the genetic regulation of hip
structure and geometry. Although further replication and molecular biology studies are necessary to fully
validate the findings, some of the genes identified may be useful in the development of diagnositic and
therapeutic approaches for osteoporosis and osteopeania.
Name of contact:
Lynell Belardo
Email/Phone no. of contact:
Lynell.Belardo@health.wa.gov.au
NHMRC Research Achievements - SUMMARY
Grant ID: 280924
Start Year: 2005
CIA Name: Dr Kim Branson
End Year: 2008
Admin Inst: St Vincent's Institute of Medical Research
Grant Type: Early Career Fellowships
(Australia)
Main RFCD: Protein Targeting and Signal Transduction
Total funding: $264,790
Title of research award:
Therapeutic regulation of Interleukin 6 receptor signallingTherapeutic regulation of Interleukin 6 receptor
signalling
Lay Description (from application):
Not Available
Research achievements (from final report):
none
Expected future outcomes:
N/A
Name of contact:
Dr Kim Branson
Email/Phone no. of contact:
kim@discoveryengine.com
NHMRC Research Achievements - SUMMARY
Grant ID: 345400
Start Year: 2005
CIA Name: Prof Matthew Gillespie
End Year: 2008
Admin Inst: St Vincent's Institute of Medical Research
Grant Type: Established Career
Fellowships
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $539,250
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
N/A
Expected future outcomes:
N/A
Name of contact:
Matthew Gillespie
Email/Phone no. of contact:
matthew.gillespie@princehenrys.org
NHMRC Research Achievements - SUMMARY
Grant ID: 395513
Start Year: 2006
CIA Name: A/Pr Natalie Sims
End Year: 2011
Admin Inst: St Vincent's Institute of Medical Research
Grant Type: Established Career
Fellowships
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $665,060
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
Work funded by this fellowship discovered multiple factors that influence the processes of bone formation and
bone destruction in the context of normal physiology, osteoporosis, rheumatoid arthritis, the spread of cancer to
bone, and bone damage that occurs as a result of anti-cancer therapies. , Multiple factors with key effects on
bone metabolism were identified. I list the seven most exciting here: (1) a factor called Cardiotrophin-1 (CT-1)
previously thought only to be involved in heart function was found to be produced by the cells that destroy
bone (osteoclasts), and to be a key factor that stimulates them, and stimulates bone formation. (2) Oncostatin M
(OSM) was found to be produced by osteoblasts, and was also found to stimulate bone formation, but
significantly, this factor was found to stimulate bone resorption and stimulate bone destruction through two
different mechanisms, thus revealing a potential therapeutic pathway for treatment of osteoporosis; work is
continuing to define the pathways through which this happens. (3) Ciliary Neurotrophic Facotr (CNTF), a third
related factor was found to inhibit bone formation and to have no influence on osteoclast formation. In
addition, my collaborative work identified roles for many other factors in skeletal disease (4) Calcitonin, a
hormone that has long been known to inhibit bone destroying cells was found to act also on cells deeply
embedded in the skeleton, called osteocytes; work is continuing on this factor, (5) Leukemia Inhibitory Factor
(LIF) was found to be required for normal develoment of the embryonic skeleton, and for bone growth during
childhood, (6) Interleukin-23 was found to regulate osteoclast formation during bone growth, and lastly (6)
EphrinB2 was found to be stimulated by parathyroid hormone, and to be required for normal activity of bone
forming cells in cell culture. Work on this factor is continuing and we are coming close to defining its roles in
bone formation and bone destruction.
Expected future outcomes:
Novel therapies could be developed from this work in the future. These therapies could benefit patients with
skeletal disorders including osteoporosis, childhood skeletal abnormalities, rheumatoid arthritis, osteoarthritis,
the spread of cancer to bone, and bone damage resulting from anti-cancer therapies.
Name of contact:
Natalie Sims
Email/Phone no. of contact:
nsims@svi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 502612
Start Year: 2008
CIA Name: A/Pr Louise Purton
End Year: 2010
Admin Inst: St Vincent's Institute of Medical Research
Grant Type: NHMRC Project Grants
Main RFCD: Haematology
Total funding: $589,425
Title of research award:
Mechanisms underlying the effects of TNFalpha in bone and haemopoiesisMechanisms underlying the effects
of TNFalpha in bone and haemopoiesis
Lay Description (from application):
Recent studies have identified that bone plays an important role in blood cell production. We have discovered
that elevated levels of TNF alpha (which increases with ageing and can negatively impact on health)
contributes to a blood cell disorder that can progress to leukaemia. There are also reduced numbers of blood
stem cells and bone in this mouse model. In these studies we will determine how TNFalpha contributes to
blood and bone defects, which may lead to better treatment of such diseases.
Research achievements (from final report):
We have a mouse model that develops a blood cell disease called a myeloproliferative syndrome (MPS). This
type of blood cell disease is very difficult to treat as we do not understand why it occurs. Our research has
demonstrated that non-blood cells within the bone cavity that help to regulate blood cells can cause the MPS.
One complication has been that this mouse model has high levels of a substance involved in inflammation that
may have contributed to the blood cell disease. We have therefore generated another mouse model in which
this inflammatory substance has been deleted, allowing us to determine whether the blood cell disease still
persists or not. We have determined that this blood cell disease does indeed still persist in the absence of the
inflammation-related substance. We are now determining how the MPS occurs in order to develop better
treatments for such blood cell diseases.
Expected future outcomes:
We anticipate that research following on from these studies will provide insight into how the bone marrow
microenvironment cells regulate blood cell production and in turn blood cell diseases.
Name of contact:
Dr Louise Purton
Email/Phone no. of contact:
lpurton@svi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 620200
Start Year: 2010
CIA Name: E/Pr Thomas Martin
End Year: 2012
Admin Inst: St Vincent's Institute of Medical Research
Grant Type: NHMRC Project Grants
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $538,460
Title of research award:
ROLE OF EPHRIN-EPH SIGNALLING IN THE FORMATION PHASE OF BONE REMODELLINGROLE
OF EPHRIN-EPH SIGNALLING IN THE FORMATION PHASE OF BONE REMODELLING
Lay Description (from application):
Bone is constantly being renewed through bone remodelling. An amount of bone is removed by osteoclasts,
and bone-forming osteoblasts make just enough to fill the space. We discovered that proteins known as ephrins
are produced by osteoblasts, and act on neighbouring osteoblasts to help them make new bone. We aim to
define how ephrins increase bone formation in remodelling, how that is controlled and how it might be used to
find ways to increase bone formation.
Research achievements (from final report):
In this project we established that the process of bone formation, which is carried out by cells called
osteoblasts, depends on signals initiated by a protein called ephrinB2 expressed by osteoblasts. When the
interaction of ephrinB2 with its receptor EphB4 is blocked with a pharmacological agent, this leads to impaired
bone formation, and enhanced bone destruction by osteoclasts. This has major implications for the use of
ephrinB2/EphB4 inhibitors in cancers that metastasize to bone. The work is continuing as we assess what
signals are produced by ephrinB2 in the osteoblast that control osteoblast activity, as this may have
implications for future therapy for osteoporosis. This work has been published in major academic journals and
presented at numerous international conferences.
Expected future outcomes:
Future work identifying how ephrinB2 regulates osteoblast function will provide novel targets for treatment of
bone diseases, including osteoporosis and arthritis.
Name of contact:
Natalie Sims
Email/Phone no. of contact:
nsims@svi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1002728
Start Year: 2011
CIA Name: A/Pr Natalie Sims
End Year: 2013
Admin Inst: St Vincent's Institute of Medical Research
Grant Type: NHMRC Project Grants
Main RFCD: Orthopaedics
Total funding: $652,745
Title of research award:
gp130 signalling in bone formation and resorptiongp130 signalling in bone formation and resorption
Lay Description (from application):
gp130 is a protein expressed in all cells in the body; this project will analyse the influence of gp130 within the
cells that form bone, the cells that destroy bone, and the cells that form a communication network within the
bone matrix. Understanding the way this protein works will help us to understand how current therapies for
osteoporosis work, and will help us to design new therapies.
Research achievements (from final report):
In this project, we demonstrated that the IL-6 family of cytokines, known to be involved in inflammatory
conditions also act in the body to stimulate the formation of bone that is strong and healthy. When we deleted
the receptor for this family of cytokines in cells that form bone (osteoblasts) or in osteocytes, cells embedded in
the bone matrix, we observed the same result - skeletons with low bone density that fractured more easily. This
means that inhibition of this family of cytokines, as is currently achieved with treatments for rheumatoid
arthritis and for juvenile idiopathic arthritis are likely to lead to increased fracture risk in patients. , Secondly,
we showed that mice that lack leukemia inhibitory factor (LIF) are a faithful model of Stuwe-Wiedemann
sydrome, a life-threatening congenital defect. This provides a model that can be used to develop therapies for
this condition.
Expected future outcomes:
A requirement to monitor bone density in patients currently being treated with IL-6 inhibitors for rheumatoid
arthritis, juvenile idiopathic arthritis and colitis; development of safer therapies for these conditions without
skeletal side-effects. A new model for testing therapies for Stuwe-Wiedemann Sydrome.
Name of contact:
Natalie Sims
Email/Phone no. of contact:
nsims@svi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1002730
Start Year: 2011
CIA Name: A/Pr Natalie Sims
End Year: 2013
Admin Inst: St Vincent's Institute of Medical Research
Grant Type: NHMRC Project Grants
Main RFCD: Orthopaedics
Total funding: $586,965
Title of research award:
Influence of osteocytes on anabolic bone therapiesInfluence of osteocytes on anabolic bone therapies
Lay Description (from application):
This project seeks to define the influence of changes in gene expression in cells called osteocytes, that exist
within the substance of bone. These cells form a communication network within the bones of the skeleton, and
appear to influence bone formation; changes in gene expression by these cells could influence the efficacy of
current and emerging osteoporosis therapies.
Research achievements (from final report):
In this project, we confirmed that osteocytes, cells deeply embedded within the bone matrix, express a receptor
for Calcitonin, a hormone produced by the thyroid gland, but that this is most highly expressed in osteocytes
from young mammals, suggesting that it may play a significant role in bone development. We also developed
new methods for purifying osteocytes, and discovered that some genes thought to be expressed by osteocytes,
are actually expressed by contaminating cells of the haemopoietic lineage (blood cells) contaminating earlier
cell preparations. We discovered that osteocytes purified in this way cannot be cultured in the laboratory, but
transform into a different cell type when cultured. Our new method for purifying osteocytes will allow more
accurate determination of the role these cells play in bone metabolism in health and disease.
Expected future outcomes:
More accurate understanding of how osteocytes control bone metabolism in health and disease.
Name of contact:
Natalie Sims
Email/Phone no. of contact:
nsims@svi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1010027
Start Year: 2011
CIA Name: Dr Nicole Walsh
End Year: 2013
Admin Inst: St Vincent's Institute of Medical Research
Grant Type: NHMRC Project Grants
Main RFCD: Rheumatology and Arthritis
Total funding: $561,535
Title of research award:
The therapeutic value of targeting Wnt signalling for the treatment of OsteoarthritisThe therapeutic value of
targeting Wnt signalling for the treatment of Osteoarthritis
Lay Description (from application):
Osteoarthritis (OA) affects 1.62 million Australians and imposes a significant burden on healthcare. It is
characterised by damage to joint cartilage, and increased bone formation with formation of bone spurs. Our
studies will determine the importance of the Wnt signalling pathway in mediating OA joint degeneration and
identify mechanisms that regulate the activation of this pathway in OA. This will inform the development of
novel therapeutic strategies which could halt joint damage in OA.
Research achievements (from final report):
Using a mouse model of post-traumatic osteoarthritis, we have characterised the changes that occur in bone
that underlies the articular cartilage (subchondral bone) following acute joint injury leading to osteoarthritis
onset and progression. We have demonstrated using novel microCT techniques developed during this project,
along side histologic methods that osteoblast-mediated bone formation is activated as early as 1 week post
injury within the subchondral bone resulting in increased bone volume. This increase in bone is associated with
the downregulation in expression of two known bone formation and Wnt signalling inhibitors sclerostin and
DKK-1. We have also identified that this newly formed subchondral bone area is not healthy: it resembles
osteonecrotic bone with the absence of viable osteocytes (cells normally found buried wtihin the bone matrix);
the extent of osteocyte cell death correlates with the extent of cartilage damage (specifically aggrecan loss) in
the overlying articular cartilage. This work represents the first time that osteocyte cell death within the
subchondral bone has been identified in an animal model of osteoarthritis and it is the first time that loss of
aggrecan has been associated with changes in bone health., In associated studies we have identified that mice
lacking expression of the cytokine recepotr oncostatin M (OSMR) are protected from cartilage damage
following acute joint injury; however instead of gaining subchondral bone, they lose bone at this site. This
identifies OSM signaling via OSMR as a mediator of cartilage damage following joint injury, and highlights a
novel role for this cytokine in limiting bone loss in the context of inflammation.
Expected future outcomes:
We are currently pursuing the potential for molecules released from damaged cartilage to affect the underlying
bone following joint injury. This may lead to the identification of novel ways in which the onset of
osteoarthritis may be prevented following acute joint injury.
Name of contact:
Nicole Walsh
Email/Phone no. of contact:
nwalsh@svi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 249400
Start Year: 2003
CIA Name: A/Pr David Little
End Year: 2005
Admin Inst: The Children's Hospital at Westmead Grant Type: NHMRC Project Grants
Main RFCD: Orthopaedics
Total funding: $199,750
Title of research award:
Effect zoledronic acid and risedronate on the preservation of the femoral head in a rat model of Perthes
diseaseEffect zoledronic acid and risedronate on the preservation of the femoral head in a rat model of Perthes
disease
Lay Description (from application):
Perthes Disease (Legg-Perthes Disease) is a common childhood disorder, which leads to collapse and
deformity of the growing hip joint. This can lead to arthritis in adult life, as well as a short leg on the affected
side. The cause is as yet unknown. A class of drugs called bisphosphonates has been shown to help children
with osteogenesis imperfecta (brittle bone disease). We believe, based on our extensive studies of the effect of
these drugs on bone healing, that they could also help children with Perthes disease. Although proving to be
safe and effective in children with osteogenesis imperfecta, before exposing children with Perthes disease to
the risk of any side effects, animal studies are needed. A certain type of rat called the spontaneously
hypertensive rat gets a condition almost exactly the same as Perthes disease. This study will treat a large
number of these rats and perform detailed study into whether it has a positive effect on preserving the shape of
the hip joint, as well as looking into how this actually occurs. A successful outcome would pave the way for
trials in children with Perthes disease, and could result in the avoidance of surgery and improved health
outcomes for the children.
Research achievements (from final report):
Perthes disease is a childhood disorder where the head of the femur loses its blood supply (osteonecrosis).
These series of experiments have shown for the first time that a class of commonly used drugs,
bisphosphonates, can change outcome in a model of spontaneous osteonecrosis. We used the bisphosphonate
zoledronic acid (ZA) in an animal model called the spontaneously hypertensive rat (SHR). 50% of male rats
sustain a Perthes-like onset of osteonecrosis during growth. , We had previously shown that ZA was effective
in improving outcome in a model where we induced osteonecrosis in the femoral head of Wistar rats. This is
useful information,direct applicability to Perthes disease could be questioned as the osteonecrosis was induced
and did not occur spontaneously., In the SHR model we have definitively shown:, 1. Early treatment with ZA is
effective in preserving the architecture of the femoral head
2. Ossification of the femoral head is advanced by ZA treatment
3. Late treatment is ineffective
4. Ossification of the femoral head can also be advanced in normal rats with ZA treatment, All of these
outcomes have important implications in the future treatment of children with Perthes disease or other
disorders involving osteonecrosis in the growing skeleton.
Expected future outcomes:
This study represents an important componant of an emerging body of work both from our lab and from
overseas. It documents that bisphosphoante drugs, by slowing resorption of necrotic bone, can improve the
structural retention of shape in a femoral head recovering from osteonecrosis. These concepts are now being
clinically translated, highlighting the extremely high impact of these studies.
Name of contact:
David Little
Email/Phone no. of contact:
davidl3@chw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 157970
CIA Name: Prof Leslie Cleland
Admin Inst: University of Adelaide
Main RFCD: Rheumatology and Arthritis
Total funding: $453,693
Start Year: 2001
End Year: 2005
Grant Type: NHMRC Project Grants
Title of research award:
Dietary n-3 fats and outcomes in early-onset rheumatoid arthritisDietary n-3 fats and outcomes in early-onset
rheumatoid arthritis
Lay Description (from application):
There is considerable evidence that positive health benefits flow from increasing the dietary intake of omega-3
polyunsaturated fats. Benefits are seen in rheumatoid arthritis, other inflammatory disorders and heart disease.
Previous studies of rheumatoid arthritis and dietary omega-3 fats had a common design which probably
reduced the magnitude of the beneficial dietary effects. Therefore, a 'second generation' study is needed which
addresses these common design issues in order to establish optimal conditions for the use of dietary omega-3
fats in therapy for rheumatoid arthritis. The current proposal will address the previous design shortcomings by
changing the background diet, measuring functional disability and joint damage as well as symptoms, starting
treatment in early disease before joint damage has occurred, and by regulating concurrent drug use. The study
will also evaluate a novel blood test that indicates the effect of advice to increase dietary omega-3 fats upon
omega-3 nutritional status. If this nutritional index correlates with more favourable outcomes, a base will have
been established for guiding treatment with omega-3 fats in routine clinical situations. This study is important
because dietary treatment in rheumatoid arthritis: (a) offers sufferers with rheumatoid arthritis a more active
role in the life long management
of their disease. (b) has no on-going cost to the government health budget,
and in fact, has the potential
to decrease treatment costs in rheumatoid arthritis considerably (c) has wider
applicability, e.g. for prevention and treatment of other inflammatory conditions
and heart disease (d) needs
to be tested with modern treatment protocols that involve multiple therapies started
early in the course of
rheumatoid arthritis, before irreversible impairment and disability has occurred (e) requires a nutritional
index to guide treatment (f) must be evidence based.
Research achievements (from final report):
The project shows a way in which rheumatoid arthritis can be treated more effectively. The approach is multifactorial and involves systems for , oearly referral of recent onset polyarthritis, o
triage based on
perusal of referrals (allows priority early assessment and early treatment of suitable cases), o use of
combinations of inexpensive treatments in combination (with avoidance of oral steroids), o drug choices,
adjustments in dose and substitutions according to predefined rules (allows orderly, reproducible application of
treatments), o
proforma assessment of joints and
blood tests (triggers dose adjustments when disease is active), o
documentation of unwanted effects
and reasons for treatment withdrawals (allows safety to be assessed)., Against this background, the value, as a
component of the program, of fish oil, in an anti-inflammatory dose, has been has been assessed. The overall
results show that treatment of patients with combination therapy according to the rules, achieves favourably
results safely (remission rate 50%, good responses in 85% at 12 months, sustained to at least 3 years, no serious
drug related unwanted events). In patients taking fish oil regularly results were especially favourable
(remission rates 70%). In these patients compared to those not taking fish oil, there was a significant reduction
in disability, composite scores of disease activity, tender joint counts, discretionary 'NSAID' use and multiple
indicators of risk for serious cardiovascular events. The project has allowed the Early Arthritis Clinic approach
and procedures to become part of routine practice and ongoing observations will allow longer term outcomes to
be monitored and refinements made.
Expected future outcomes:
The program sets a new standard for treatment of rheumatoid arthritis (RA). Future directions include the
development of a computer-aided clinical assessment and decision support tool which will guide practitioners
through procedures needed to assess disease activity, to monitor for unwanted drug effects and to prescribe
drugs safely according to protocol.
NHMRC Research Achievements - SUMMARY
Name of contact:
Professor Leslie Cleland
Email/Phone no. of contact:
lcleland@mail.rah.sa.gov.au
NHMRC Research Achievements - SUMMARY
Grant ID: 207701
CIA Name: Prof Nicola (Nick) Fazzalari
Admin Inst: University of Adelaide
Main RFCD: Orthopaedics
Total funding: $317,640
Start Year: 2002
End Year: 2004
Grant Type: NHMRC Project Grants
Title of research award:
Molecular determinants of bone remodelling in the bone microenvironmentMolecular determinants of bone
remodelling in the bone microenvironment
Lay Description (from application):
There is little information regarding the expression of specific molecules in human bone tissue or their role in
skeletal disease. The process of bone remodelling is fundamental for the maintenance of skeletal integrity. Our
understanding of the molecular signalling involved in activating bone remodelling is principally derived from
tissue culture and animal experiments. We will study human cancellous bone samples donated by patients
undergoing surgery, and with the consent of the next-of-kin, taken at autopsy. These molecular and
histomorphometric studies will determine whether the understanding derived from tissue culture and animal
experiments is consistent with associations demonstrable in the human cancellous bone microenvironment. The
elucidation of the molecular signalling in the human bone microenvironment is essential for the effective
diagnosis and treatment of bone disease. Recently reported studies have shown very persuasively that fatigue
microdamage accumulates in the skeleton and is targeted for repair by remodelling. Our preliminary data
shows that microcrack length is positively correlated with IL-11 mRNA gene expression. We will further
investigate mRNA gene expression of a number of cytokines involved in bone cell signalling and their
association with the level of microdamage in the bone. Using a animal model of controlled bone microdamage
induction we will seek to determine the bone remodelling causal relationship between microdamage and
cytokine signalling. Furthermore, the cellular and molecular mechanisms that lead to trabecular structures are
not well understood. These studies will provide new insight into the processes that determine trabecular
structures. This project will investigate these mechanisms and increase our understanding of bone cell function,
essential for diagnosis and design of rational treatment for bone diseases.
Research achievements (from final report):
In this project, we have investigated the expression of key regulatory molecules of bone renewal in the
microenvironment of trabecular bone samples from patients who have suffered osteoporotic fragility fractures
and osteoarthritis. We have combined investigation of gene expression in human bone with measurement of
tissue morphology (histomorphometry), to investigate links between molecules that participate in bone
renewal. Bone samples were taken from patients undergoing hip replacement for a fragility fracture of the
femur and total hip replacement for osteoarthritis. We have found that the expression of a number of key genes
that control bone renewal, RANK and IL-6 mRNA and RANKL/OPG mRNA ratio, was significantly elevated
in the osteoporotic fracture group compared to an age-matched control group. These data suggest a relative
increase in the expression of the molecular promoters of osteoclast formation (cells that remove bone) and
activity in osteoporotic fragility fracture bone, which may lead to the imbalance between bone formation and
removal associated with fragility fracture. When the same bone samples used for molecular analysis were
examined by histomorphometry, bone formation parameters were significantly reduced in the fracture patients
compared to controls. These data are important because they are among the first to draw attention to a
reduction in bone formation, rather than increased bone removal, in association with osteoporotic fragility
fractures. In additional work, we have performed microarray experiments, comparing gene expression in
osteoporosis and osteoarthritis bone samples. A number of different classes of genes have been identified as
being up-regulated in osteoporosis compared to osteoarthritis, which is consistent with the reduced bone mass
seen in osteoporosis compared to osteoarthritis. This project grant increased our understanding of the
mechanisms of bone renewal and potentially identified new tragets for novel drug development.
Expected future outcomes:
NHMRC Research Achievements - SUMMARY
Our studies have shown that the disregulation of bone cell signals and their relationship to bone tissue
properties is a potential determinant of fragility fracture risk. The elucidation of the mechanism of bone
renewal identifies potential new tragets for novel drug development.
Name of contact:
Nick Fazzalari
Email/Phone no. of contact:
nick.fazzalari@imvs.sa.gov.au
NHMRC Research Achievements - SUMMARY
Grant ID: 219305
CIA Name: Prof Nicola (Nick) Fazzalari
Admin Inst: University of Adelaide
Main RFCD: Orthopaedics
Total funding: $262,500
Start Year: 2003
End Year: 2006
Grant Type: SRDC - Research
Title of research award:
Osteoarthritis: a community health issue & a vision to identigy new diagnostic & treatment
strategiesOsteoarthritis: a community health issue & a vision to identigy new diagnostic & treatment strategies
Lay Description (from application):
Not Available
Research achievements (from final report):
Osteoarthritis is the most prevalent musculoskeletal disease. The most pressing healthcare need for the majority
of individuals with osteoarthritis is non-operative care, to help relieve symptoms, improve function, and slow
disease progression. Essential for effective non-operative care is the development of tools to enable the early
diagnosis, and monitoring of treatments, together with new insight into the molecular mechanisms that lead to
primary osteoarthritis, which can provide new opportunities for the development of effective drug therapies.
New patient management and treatment strategies will arise from a better understand of the pathogenesis of this
prevalent disease. Associate Professor Fazzalari's research team has used microarray based gene expression
profiling of bone from patients with hip osteoarthritis to show systemic changes to the skeleton that likely
predispose individuals to the disease. Though joint cartilage degeneration is a hallmark sign of osteoarthritis, in
the past 50 years cartilage researchers have made little progress to develop treatments for the many patients
with osteoarthritis. Novel Wnt and TGFβ signalling pathway components, among others, have been identified
that promise new insight into osteoarthritis disease mechanisms and potentially therapeutic intervention.
Researchers are currently exploring the role that these genes have in altered bone structure seen in osteoarthritis
and are also using the identified genes to develop a diagnostic screening test for osteoarthritis. This research
program will provide essential new understanding both for early diagnosis and monitoring the effect of
treatments or changes in patient lifestyle that may delay the progression to severe joint degeneration, or prevent
the disease.
Expected future outcomes:
We are working to develop a genetic screening test to identify individulas at risk of osteoarthritis. In addition,
seeking to understand the functional role of genes we have identified as being linked to the onset and
progression of osteoarthritis. This understanding will provide apportunities to develop new treatments to
prevent or slow the progression of osteoarthritis.
Name of contact:
Nick Fazzalari
Email/Phone no. of contact:
nick.fazzalari@imvs.sa.gov.au
NHMRC Research Achievements - SUMMARY
Grant ID: 250301
CIA Name: Prof Nicola (Nick) Fazzalari
Admin Inst: University of Adelaide
Main RFCD: Orthopaedics
Total funding: $423,625
Start Year: 2003
End Year: 2005
Grant Type: NHMRC Project Grants
Title of research award:
Interrelationships between the disc and bone of lumbar spinal segmentsInterrelationships between the disc and
bone of lumbar spinal segments
Lay Description (from application):
The cause of back pain due to osteoarthritis, osteoporotic vertebral crush fracture, and ageing is poorly
understood. Vertebral deformity, intervertebral disc disorganisation, and change to vertebral bone structure are
features associated with degeneration of the spine and with back pain. Degenerative disc disease is one of the
major causes of back symptoms and is believed to be associated with degeneration of the spine. Spinal
degeneration includes disc degeneration, facet joint osteoarthritis, compromised vertebral body bone quality,
muscle and ligament alterations. It is assumed that these changes result in increased or abnormal spine motion
and modified load distribution across the spinal joint. It has been found that with age, there is increased
disorganisation of the intervertebral disc and decreased quality of vertebral cancellous bone. However, bones
with the same density within the range of normal subjects, can show selective loss of bone structure and
reduced load-bearing capacities of these vertebrae. An important concept here is that even for a given bone
mass, fracture risk increases with age, supporting the view that there is a component of bone fragility that is
independent of mass. Increased bone fragility may be associated with compromised cancellous bone structure.
While the relationship between disc degeneration and changes in vertebral bone is commonly invoked, the
mechanisms of this relationship have largely been overlooked, with age changes given more attention.
However, it may be that intervertebral disc disorganisation modulates age-related bone changes within the
spine. Disc degeneration may influence trabecular bone responses before changes with age put the patient at
risk of vertebral crush fracture. We propose that the mature disc cannot effectively regenerate after damage,
and thus responses to disc damage will be more readily observed in vertebral bone architecture than in the disc.
Research achievements (from final report):
We have developed and implemented a novel MRI protocol to measure the water content of the intervertebral
discs in the human spine. This protocol is breaking new ground in that it provides a new clinical tool to
measure the water content of the intervertebral disc of patients with back pain. We have been able to show that
the MRI scans are reliable and reprobucible. Until the development of this technique, assessing the amount of
water in the intervertebral disc has been based on the subjective interpretation of an MRI image by a
radiologist. There are few studies of this nature that have been reported and a patent application is pending. , In
addition, this study has provided a novel perspective of the bone in the spine. The thickness of the bone wall
that surrounds the spongy bone structure in the vertebral body was thicker in the front of the vertebra than the
back of the vertebra, suggesting that the bone wall in the front of the vertebra has to support a greater load than
the back wall of the vertebra. Combined with the data we have on the deformation of the vertebral body bone
wall under load and how the load is transmitted through the spongy bone in the vertebral body we have a
unique insight into vertebral body mechanics. This places us at the forefront of understanding the mechanism
of vertebral body fracture where the patient has fragile bones. The study has enabled us to better understand the
relationship between the intervertebal disc and the vertebral body bone. These unique data from the human
spine have not been previously reported and hold significant potential to understand bone quality factors that
ultimately determine bone strength and what factors should be the target of treatment.
Expected future outcomes:
This was a pioneering study using a multidisciplinary approach and our unique experience to elucidate the
mechanisms of spinal degeneration. The MRI protocol to measure the water content of the disc will provide a
new clinical tool to identify the presence of disc degeneration, monitor progression of disc degeneration and
monitor the efficacy of treatment of disc degeneration in patients.
NHMRC Research Achievements - SUMMARY
Name of contact:
Nick Fazzalari
Email/Phone no. of contact:
nick.fazzalari@imvs.sa.gov.au
NHMRC Research Achievements - SUMMARY
Grant ID: 250411
CIA Name: Prof Leslie Cleland
Admin Inst: University of Adelaide
Main RFCD: Orthopaedics
Total funding: $380,250
Start Year: 2003
End Year: 2005
Grant Type: NHMRC Project Grants
Title of research award:
Effect of lipid mediators and dietary fats in bone remodellingEffect of lipid mediators and dietary fats in bone
remodelling
Lay Description (from application):
Osteoporosis in a major public health problem which directly affects about 10% of the population, which is
currently around 2 million Australians. With aging of the population, it is projected that this proportion will
increase to more than 13% over the next 20 years. When it is considered that the direct hospital and residential
care costs attributable to osteoporotic fractures currently approaches $2 billion per annum, low-cost
interventions for increasing bone strength which are easily applied to the elderly population have enormous
potential for health benefits in Australia. Thus study will examine the effects of dietary omega-3 fats, of the
kind found in fish and fish oil, on the biology of bone metabolism and on bone strength. The results will
provide information which may be used in developing simple drug or dietary strategies for large-scale use for
increasing bone mass and strength in the elderly population. A strength of the study arises from the
combination of research expertise in (a) dietary fats, and (b) molecular biology of bone cells, and (c) animal
models of bone metabolism which are amenable to dietary interventions. This combination is unique, but
builds on well established systems which hitherto have existed in separate research paradigms. The Chief
Investigator has considerable experience in development of diets enriched in omega-3 fats which are practical
and suitable for daily use on a long-term basis. This adds considerably to the potential significance of the
outcomes because, if favourable effects of omega-3 fats are observed and are characterised with regard to
mechanisms, the results can be rapidly translated into large-scale clinical use.
Research achievements (from final report):
This work follows a report that fish oil (mixed with evening primrose oil) could prevent bone loss in the
elderly. We examined this issue using dietary fish oil in a well characterised rat model of post-menopausal
bone loss. The results indicated that dietary fish oil had a modest positive effect on bone formation, but no
effect on bone loss in this experimental system.
Expected future outcomes:
Dietary fish oil has positive effects for heart disease and inflammatory conditions such as rheumatoid arthritis.
However, this study provided support for only a modest effect on bone formation in an animal model. If this
were to be pursued it would require a large clinical trial in the elderly.
Name of contact:
Professor Les Cleland
Email/Phone no. of contact:
leslie.cleland@health.sa.gov.au
NHMRC Research Achievements - SUMMARY
Grant ID: 250426
CIA Name: A/Pr Graham Mayrhofer
Admin Inst: University of Adelaide
Main RFCD: Autoimmunity
Total funding: $473,250
Start Year: 2003
End Year: 2005
Grant Type: NHMRC Project Grants
Title of research award:
The immunological microenvironment in the synovium during experimental polyarthritis in the ratThe
immunological microenvironment in the synovium during experimental polyarthritis in the rat
Lay Description (from application):
In this project, we aim to understand the process by which some forms of arthritis, as exemplified by
rheumatoid arthritis (RA), cause inflammation and destruction of multiple joints. Such forms of arthritis are
referred to collectively as "polyarthritis". There is a strong evidence that RA has an immunological basis and
that abnormal recognition of components of the joints by T lymphocytes orchestrates the inflammation that is
characteristic of the disease. We believe that dispersal of disease-causing activated T lymphocytes in the blood
accounts for the involvement of many joints. We have used a model of polyarthritis in rats to study the nature
of the activated T lymphocytes, where they come from, how they are delivered to the blood stream and how
they enter the joints. This project focuses on the crucial tissues that line the joints. We want to understand
how the disease-causing activated T cells cause inflammation and how the immune system reacts to restrain
them. We can undertake this work because we have developed three unique tools. Firstly, we can transfer
arthritis with activated T lymphocytes and, therefore, study their behavior in an otherwise normal body. In this
way, we can see how the body responds to the presence of disease causing cells. Secondly, we have introduced
a genetic "marker", which is essential if one wishes to distinguish the separate activities of the "donor' and
"host" cells. Thirdly, we can collect cells from the diseased paws, allowing us to examine their activities in
vitro as well as in vivo. This model offers the opportunity to study the activities of the disease-causing cells
and to identify points at which the disease cycle can be broken. It will allow us to design and/or test new
treatments aimed at these points.
Research achievements (from final report):
This project aimed to achieve a better understanding of the disease process that causes inflammation and joint
destruction in diseases such as rheumatoid arthritis. The work was undertaken in an animal model because this
allows syudy of the very early events and because it allows experimental interventions that are not possible in
humans. Rheumatoid arthritis is believed to result from an attck by the immune system on components of the
joint linings (synovium). In the model, we were able to study the part of the disease that is due to infiltration of
the synovium with T lymphocytes. We found that disease causing T cells localise selectively in synovium and
proliferate there. This was shown by transferring genetically marked cells from donors that have arthritis to
normal recipients and then examining both host- and donor-derived cells in the synovium. We found that the
period of proliferation was limited and that continuation of the disease was dependent on a continuous supply
of new T cells. This suggests that the rheumatoid process may not be confined to the joints and that the seat of
production of disease causing T cells may lie outside of the joints. We have also studied another key player in
the disease process. The dendritic cell is essential to activate T cells. We have characterised the dendritic cells
in normal and arthritic synovium. This work has applications for other forms of inflammatory diseases that
involve self-reactive T cells.
Expected future outcomes:
Understanding the dynamics of T cells and dendritic cells in synovium should lead to the identification of
points in the disease process that are tragets for new therapies.
Name of contact:
Graham Mayrhofer
Email/Phone no. of contact:
graham.mayrhofer@adelaide.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 278806
CIA Name: Dr Claudine Bonder
Admin Inst: University of Adelaide
Main RFCD: Autoimmunity
Total funding: $308,579
Start Year: 2005
End Year: 2008
Grant Type: Early Career Fellowships (Australia)
Title of research award:
The role of sphingosine kinase and endothelial cell activation in autoimmun diseasesThe 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 de-differentiating 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/Phone no. of contact:
claudine.bonder@health.sa.gov.au
NHMRC Research Achievements - SUMMARY
Grant ID: 298933
CIA Name: Prof Howard Morris
Admin Inst: University of Adelaide
Main RFCD: Orthopaedics
Total funding: $399,750
Start Year: 2004
End Year: 2006
Grant Type: NHMRC Project Grants
Title of research award:
Vitamin D Depletion and Femoral Bone LossVitamin D Depletion and Femoral Bone Loss
Lay Description (from application):
An understanding of the way cells control their complex internal circuitry is relevant to diseases like cancer
and leukemia. The main focus of this project is a cellular regulator we identified several years ago called
BORIS. Normally dormant in all cells outside the male reproductive organs, BORIS is reactivated in many
cancers. We will study the network of factors perturbed when BORIS becomes inappropriately active in cancer
cells. Ultimately this project may lead to new treatments for cancer.
Research achievements (from final report):
A robust rodent model of vitamin D depletion has been developed. These animals have vitamin D levels that
are considered low but are the maximum achieved by some 50% or more of the community. Our studies
demonstrated that these rodents developed osteoporosis at early adulthood, that is just one quarter through their
life span, which was surprising. It was proposed that osteoporosis would not develop until they were older.
Similar biochemical markers were measured in the rodent model as have been measured in humans who have
low vitamin D levels. A very similar relationship was found suggesting that the findings with this model are
likely to be useful for estimating human vitamin D requirements. A minimum level of vitamin D for optimal
bone striucture was identified. As well the study identified the optimal form of vitamin D for skeletal health.
The loss of bone that occurred with low vitamin D levels was due to high bone resorption due to high levels of
bone resorbing cells. Evidence for the molecular mechanism of the increased number of bone resorbing cells
was obtained. Evidence has been obtained that a lower level of vitamin D is required to maintain optimal
skeletal health as dietary calcium levels increase.
Expected future outcomes:
The effects of age and dietary calcium intake on the level of vitamin D required for optimal skeletal health and
bone strength will be elucidated. It is expected that as we age we require higher levels of vitamin D to maintain
our health. Currently there is no understanding of the basis for such increased requirement and these studies
will provide the first indications.
Name of contact:
Professor Howard Morris
Email/Phone no. of contact:
howard.morris@imvs.sa.gov.au
NHMRC Research Achievements - SUMMARY
Grant ID: 298993
CIA Name: Prof Antonio Ferrante
Admin Inst: University of Adelaide
Main RFCD: Medical Biochemistry: Lipids
Total funding: $481,500
Start Year: 2004
End Year: 2006
Grant Type: NHMRC Project Grants
Title of research award:
Polyunsaturated fatty acids mimetics with anti-inflammatory propertiesPolyunsaturated fatty acids mimetics
with anti-inflammatory properties
Lay Description (from application):
Autoimmune diseases are responsible for a high incidence of morbidity and mortality in our community.
Immunosuppressive drugs/anti-inflammatory agents have played important roles in treatment of these diseases
as well as in helping to prevent rejection of transplanted tissues/organs. There is an ongoing search by the
medical community for better immunosuppressive drugs and agents for use for these purposes. Based on
studies conducted in the last few years, we have partially identified structural elements on polyunsatrated fatty
acids (PUFA) which are responsible for specific biological functions. Using this information, we have
synthesized a large panel of previously unavailable PUFA which we can use to target T lymphocytes and drive
the biological activity of these compounds, preferentially towards immunosuppression. By conducting the
research outlined in this project, we are likely to either identify a lead immunosuppressive compound or
generate new information for further synthesis of PUFA-based compounds for further examination as potential
immunosuppressive agents.
Research achievements (from final report):
The studies have identified a unique property which can be bestowed on polyunsaturated fatty acids to make
them more potent and selective in suppressing uncontrolled pathways in inflammatory diseases which cause
substantial morbidity and mortality in our community. this includes arthritis, asthma, allergy etc. Our research
group has desgined new polyunsaturated fats which act on the immune system in the test tube and translated
these findings to experimental models of the human diseases. The fatty acids were able to block the
immunological pathways which endanger the body when these inflammatory reactions take place. This has not
been described previously. Our research has defined both the cells and the molecules which are targeted by the
novel fats. When the hormones of the immune system were investigated both at the protein and gene level, it
became evident that the type and levels expressed correlated with the protection against inflammation.
Expected future outcomes:
We have identified a fatty acid which has unique anti-inflammatory properties so that future work could use
this prototype to developing anti-inflammatory, anti-infective and anti-cancer agents. This technology has now
been partly commercialised and the group is cautiously optomistic that some of the fatty acids will become
useful therapeutic agents.
Name of contact:
Prof Antonio Ferrante
Email/Phone no. of contact:
antonio.ferrante@adelaide.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 299031
CIA Name: Dr Gerald Atkins
Admin Inst: University of Adelaide
Main RFCD: Orthopaedics
Total funding: $436,450
Start Year: 2004
End Year: 2006
Grant Type: NHMRC Project Grants
Title of research award:
Relationships Between Human Osteoblasts and Haemopoietic Cells in Bone RemodellingRelationships
Between Human Osteoblasts and Haemopoietic Cells in Bone Remodelling
Lay Description (from application):
Bone diseases, such as osteoporosis and osteoarthritis, currently afflict more than 4 million Australians. These
diseases are characterised by abnormal bone remodelling, which can result in a net loss of bone (for example,
in osteoporosis) or abnormal bone structure (for example, in osteoarthritis). We are seeking to better
understand the factors that regulate bone remodelling, and particularly the cells involved in this process.
Physiological bone remodelling results from the intimate collaboration between osteoblasts and osteoclasts.
Osteoblasts stimulate the formation of osteoclasts and also produce new bone at resporption sites. However,
the way that the same type of cell can perform both these tasks, is not clear. Our studies are designed to
increase our understanding of the development of human osteoblasts and of the factors that cause them to be
sequentially pro-osteoclastic and then pro-osteogenic. We believe that an important factor in this process is
vitamin D and we will test the hypothesis that this molecule is produced in bone and acts locally to regulate
bone turnover.
Research achievements (from final report):
The aims of this proposal were: 1.
To further define the link between the
osteoblast differentiation state and the formation of osteoclasts in response to various factors that act on the
skeleton;, 2.
To further characterise the signals
between, and the influences of, haemopoietic cells and osteoblasts during both osteoclastogenesis and
osteogenesis;, 3.
To define the role of
1,25(OH)2vitamin D3 metabolism in human bone cell biology., This has been a highly successful and
productive period of research, resulting to date in 11 publications including two book chapters. At least 6
further publications describing work encompassed in this project are in preparation. We have succeeded in
obtaining significant new insight into human osteoblast biology with respect to their production of osteoclast
activating factors, their response to osteoclast derived factors, and the way in which they differentiate into
mineral producing cells and further, into mature osteocytes. We have established that the skeleton is an
intracrine organ for vitamin D metabolism, effectively describing a paradigm shift in this field. This has
important implications for the interpretation of the diagnostic indicator of vitamin D status, namely, the serum
25-hydroxyvitamin D level. We have characterised a number of pathways whereby osteoblast differentiation is
modulated by proinflammatory signals deriving from both haemopoietic cells and from osteoblasts themselves,
which is likely to be important in bone repair and in diseases of bone inflammation, such as rheumatoid
arthritis and osteoporosis. We have also established an effective model, with which to examine the mechanism
of action of anabolic therapeutics for the treatment of osteoporosis. Our results have direct implications for the
treatment of a number of bone degenerative diseases.
Expected future outcomes:
This project has formed the basis of two further major projects, examining the role in bone of the inflammtory
cytokine TWEAK, and the effect on bone cells of wear particles derived from orthopaedic prostheses. We have
also established important collaborations with international companies to investigate the modes of action of
skeletal therapeutics on human bone cells in vitro.
Name of contact:
Dr. Gerald Atkins
Email/Phone no. of contact:
NHMRC Research Achievements - SUMMARY
gerald.atkins@adelaide.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 299078
CIA Name: Dr Tania Crotti
Admin Inst: University of Adelaide
Main RFCD: Not Allocated
Total funding: $374,520
Start Year: 2004
End Year: 2011
Grant Type: Early Career Fellowships (Overseas)
Title of research award:
Role of the bone matrix and coordinate expressof CTR and Beta 3 in initiating terminal differentiation...Role of
the bone matrix and coordinate expressof CTR and Beta 3 in initiating terminal differentiation...
Lay Description (from application):
Not Available
Research achievements (from final report):
Dr Crotti identified Beta 3 integrin as a gene specifically regulated by an intracellular signalling factor, Nuclear
Factor of Activated T cells (NFATc1). Beta 3 integrin is induced during the later stage of differentiation of the
bone resorptive cell, the osteoclast, and is required for attachment, motility and optimal resorption. NFATc1 is
a factor crucial to differentiation and activity of the osteoclast, and thus central to bone resorption and turnover.
During the candidates period overseas Dr Crotti acquired techniques in molecular biology enabling her to
demonstrate specific binding and regulation of the Beta 3 integrin by NFATc1, further supporting it as a target
for treatment of pathological bone loss. Additional work involved Dr Crotti generating TAT-NFATc1
dominant negative constructs for the generation of proteins. These proteins were used in osteoclast cultures to
see if they could block induction of the endogenous Beta 3 gene. Dr Crotti was awarded 3 Young Investigator
Awards in her field for this work and published 2 first author publications. In conjunction with another postdoctoral researcher in the lab Dr Crotti also characterised a newly identified region of the osteoclast specific
calcitonin receptor gene. Work carried out during the latter part of the post-doctural candidature entailed
characterising late stage osteoclast genes superinduced by contact with bone matrix itself. This work
highlighted the role of Annexin VIII in the osteoclast and has now been accepted for publication in the Journal
of Cellular Physiology (2011).
Expected future outcomes:
Manuscripts are being completed on an extension of these studies where by osteoclasts isolated from B3
integrin knockout mice were cultured on substrates to ascertain substrate specific genes dependent on the B3
integrin. Dr Crotti continues a productive collaboration with Dr McHugh and Professor Goldring.
Name of contact:
Tania Crotti
Email/Phone no. of contact:
tania.crotti@adelaide.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 375170
CIA Name: Dr Claire Jessup
Admin Inst: University of Adelaide
Main RFCD: Cellular Immunology
Total funding: $372,010
Start Year: 2006
End Year: 2010
Grant Type: Early Career Fellowships (Overseas)
Title of research award:
Modulation of T cell surface receptors that are dependent on extrinsic tyrosine kinases.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 23 years.
Name of contact:
Claire Jessup
Email/Phone no. of contact:
claire.jessup@flinders.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 399305
CIA Name: Prof Nicola (Nick) Fazzalari
Admin Inst: University of Adelaide
Main RFCD: Orthopaedics
Total funding: $447,027
Start Year: 2006
End Year: 2008
Grant Type: NHMRC Project Grants
Title of research award:
Intrinsic bone qualities in fragility fracture patients: mass, microarchitecture, mineralization and damage
accumulationIntrinsic bone qualities in fragility fracture patients: mass, microarchitecture, mineralization and
damage accumulation
Lay Description (from application):
Osteoporosis drug therapies have been associated with a significant reduction in fragility fracture. Patients
receiving osteoporosis drugs, which have different effects on BMD, may have similar reductions in fractures.
Furthermore, patients with fragility fractures may have abnormalities in bone structural and material properties.
Changes to the process of bone renewal, due to drug therapy, may explain why fracture risk decreases where no
detectable change to the structure of bone has been detected. It has also been shown that when bone renewal is
suppressed microdamage accumulates in bone tissue, leading to reduced bone toughness. The toughness of
bone is of primary importance in relation to fragility fractures, and it has been shown that the fatigue strength
and fracture toughness (work to fracture) reduce considerably with age. This proposed study would seek to
elucidate the role of bone tissue-level properties in determining bone quality for human subjects: patients with
fragility hip fractures on no osteoporosis drugs therapy, hip fracture patients on osteoporosis drugs therapies,
and normal age- and sex-matched individuals. Our laboratory has extensive experience in the analysis of the
structure of human bone tissue. Recently, we have developed novel and unique techniques to assess bone
quality, using micro-CT, backscatter SEM imaging, confocal microscopy and immunohistochemistry. This
multifaceted study will identify at the bone tissue-level the structural mechanisms (micro-architecture,
mineralisation, and microscopic cracking) that are indicative of the efficacy of fragility fracture drugs. Better
understanding of the mechanisms by which bones are less likely to fracture will enable better targeting of
osteoporosis drug therapy to individuals at risk of fragility fracture.
Research achievements (from final report):
Fragility fracture risk is strongly dependent upon skeletal strength. Low bone mass is not the sole predictor of
loss of bone strength. Bone strength is determined by a number of inter-related structural and material
components, collectively constituting bone quality. We have undertaken complementary investigations of bone
structure (how bone is arranged in 3D space), bone mineralisation (how soft or brittle the bone is), and bone
microdamage accumulation (how many microscopic cracks are present in the bone) on bone specimens from
the femur from patients with fragility hip fractures that were not/were receiving osteoporosis drug therapy and
skeletally normal individuals (non-fracture controls). Measurements of trabecular bone volume (3D bone mass)
and bone microarchitecture do not discriminate hip fracture patients from controls. However, bone from hip
fracture patients is less mineralised and contains more unrepaired microdamage (damage is repaired/removed
by bone turnover) compared to control individuals. Hip fracture patients that were receiving osteoporosis drug
therapies prior to fracture, show a different bone mineralisation profile compared to the fracture patients not on
therapy and controls. Our data demonstrate that the effect on bone of osteoporosis drug therapies, and hence
reduction of secondary fragility fracture, may differ on an individual patient basis. Our finding of altered bone
mineralisation profiles for hip fracture patients that were not/were receiving osteoporosis drug therapies and
non-fracture controls implicates the involvement of bone turnover in determining bone material quality, and
hence bone strength. This project has delivered novel material property data for fragility hip fracture patients
and non-fracture individuals representative of the Australian population. These data together with other bone
quality measures may be of central importance in defining individualised fracture risk assessment and tailorised
treatment efficacy.
Expected future outcomes:
Currently prescribed osteoporosis drug therapies only reduce the risk of fracture by approximately 50%. Novel
bone quality data obtained for fragility fracture patients arising from this project has identified individualised
NHMRC Research Achievements - SUMMARY
responses to osteoporosis drug therapy. Future preventative treatment approaches for primary and secondary
fragility fracture must be considered on an individualised basis.
Name of contact:
Prof Nick Fazzalari
Email/Phone no. of contact:
nick.fazzalari@imvs.sa.gov.au
NHMRC Research Achievements - SUMMARY
Grant ID: 451900
CIA Name: Dr Catherine Hill
Admin Inst: University of Adelaide
Main RFCD: Rheumatology and Arthritis
Total funding: $702,725
Start Year: 2007
End Year: 2009
Grant Type: NHMRC Project Grants
Title of research award:
Fish Oil in the treatment of knee osteoarthritisFish Oil in the treatment of knee osteoarthritis
Lay Description (from application):
Knee osteoarthritis (OA) affects about 30% of Australians over the age of 65, but also at younger ages. It
causes joint pain and stiffness, especially on exercise. The cause is unknown but it results in loss of joint
cartilage. There are few treatments available to stop the progression, which can finally result in need for an
artificial joint. Most treatments such as paracetamol and non-steroid anti-inflammatory drugs (NSAIDs) reduce
pain but have no effect on cartilage. NSAIDs can have serious side effects such as stomach ulcers and
increased cardiovascular events (such as heart attacks). Fish oil has possible benefits in OA as it decreases pain
and inflammation in rheumatoid arthritis (RA, another type of arthritis with joint inflammation and swelling),
less use of NSAID in patients with RA, and in laboratory experiments may reduce cartilage breakdown in OA.
It is likely that fish oil will have few side effects and decrease blood cholesterol. Many people with OA are
already taking fish oil, however, there is no studies to know if it is effective in OA. The aim of this proposal is
to study the effect of fish oil on pain and progression of knee OA, by doing a randomised clinical trial.
Participants with knee OA will be given either high dose fish oil or similar oil with low levels of fish oil. The
study will run for 2 years and during that time, we will measure pain and blood levels of fatty acids (part of the
fish oil) and cholesterol. At the beginning and end of the study, magnetic resonance imaging (MRI) of the
knee, a knee xray, and bone density testing will be done. The outcomes of the study will be to determine if fish
oil affects pain and function (measured by questionnaires) and progression of OA (measured by cartilage
changes on MRI). If fish oil is shown to reduce pain and disability and cartilage loss in OA, it will provide
Australians with OA an alternative treatment that is low in side effects with positive effects on cardiovascular
disease.
Research achievements (from final report):
Fish oil is widely used in the community for the treatment of painful osteoarthritis (OA). However, its effect
has not previously been investigated in a randomised clinical trail. This study was undertaken to determine
whether high dose fish oil was superior to low dose fish oil in the treatment of painful knee OA., The study
recruited 202 people with Knee OA, suffering from regular knee pain and were randomized to (1) high dose
fish oil liquid 15mL/day or (2) low dose fish oil (blend of fish oil and sunola oil) 15mL/day. Each oil was also
flavored with citrus to provide a comparable taste. The primary study outcome was change in pain scale and
change in cartilage volume (measured by MRI) between baseline and 2 years. , Results: There was significantly
greater and earlier dropout in the high dose group (34.6%), compared to the low dose group (19.8%). Both
groups demonstrated a clinically important improvement in pain and disability scores compared to baseline.
There was no difference between the 2 groups for change in pain or function in the first year, however, the low
dose group were superior to the high dose group for both pain and function at month 24. The change in
cartilage volume is still being calculated., Conclusion: , Fish oil in either low dose or high dose improves the
symptoms of knee OA. In contrast to rheumatoid arthritis, however, high dose fish oil was not superior to low
dose particularly in the second year of treatment.
Expected future outcomes:
Over the next 3 months, we will have results to determine whether fish oil improved cartilage volume. , There
are at least 5 publications in preparation regarding this study relating to relationship of fish oil with knee OA
symptoms, MRI changes, lung function, bone density and LFTs This study provides a template for performing
investigator-led multicentre clinical trials in OA.
Name of contact:
Catherine Hill
NHMRC Research Achievements - SUMMARY
Email/Phone no. of contact:
Catherine.Hill@health.sa.gov.au
NHMRC Research Achievements - SUMMARY
Grant ID: 453497
CIA Name: A/Pr Stan Gronthos
Admin Inst: University of Adelaide
Main RFCD: Orthopaedics
Total funding: $485,928
Start Year: 2007
End Year: 2009
Grant Type: NHMRC Project Grants
Title of research award:
The role of TWIST family basic Helix-Loop-Helix transcription Factors in Bone Cell Commitment, Function
and RepairThe role of TWIST family basic Helix-Loop-Helix transcription Factors in Bone Cell Commitment,
Function and Repair
Lay Description (from application):
In developed countries, projected estimates predict an alarming trend of a two to three fold increase in the
number of fractures that require surgical intervention and rehabilitation therapy in the coming decades as a
consequence of an aging population. Fracture healing is a complex physiological process that involves the
coordinated participation of different bone marrow cells, immune cells and skeletal progenitor cells. Multiple
factors regulate interactions between these cell types that influence the capacity of bone cell progenitors to
develop into functional bone forming cells known as osteoblasts. An understanding of the fracture healing is
critical for the future advancement of fracture treatment, and for identifying the mechanisms of skeletal growth
and repair as well as the causes of aging and disease. This proposal seeks to identify critical regulatory
molecules that act to mediate bone cell progenitor recruitment and development during bone fracture repair.
Research achievements (from final report):
, 1. The basic helix-helix-loop (bHLH) transcription factors, Twist-1 and Dermo-1 are known to be important
in normal mesodermal development during embryogenesis. , 2. Our studies showed that Twist-1 and Dermo-1
are highly expressed by human mesenchymal stem cell (MSC) in bone marrow aspirates but are quickly down
regulated folloing ex vivo expansion. , 3. Multiple human bone marrow derived MSC lines were successfully
retrovirally transduced to overexpress either Twist-1 or Dermo-1 in vitro. Functional studies were performed
examining the effect of Twist-1 and Dermo-1 on MSC proliferation, bone gene expression patterns and
differentiation in vitro and in vivo following implantation into NOD/SCID immunocompromised mice., 4.
Enforced expression of Twist-1 and Derrmo-1 was found to maintain the MSC in an undifferentiated state and
greatly increase the growth and lifespan of MSC in vitro., 5. Interestingly, Twist-1 and Dermo-1 inhibited the
capacity of MSC to differentiate into bone and cartilage forming cells , 6. We have established a mouse femoral
bone fracture model for the in vivo analysis of bHLH-transcription factors during bone repair.
Expected future outcomes:
Characterising the role of Twist-1 and Dermo-1 in MSC growth, recruitment and development during fracture
healing may help identify genes that are regulated by Twist-1 and Dermo-1, which can then be used as
therapeutic targets for fracture repair.
Name of contact:
Prof. Stan Gronthos
Email/Phone no. of contact:
stan.gronthos@health.sa.gov.au
NHMRC Research Achievements - SUMMARY
Grant ID: 453510
CIA Name: Prof Howard Morris
Admin Inst: University of Adelaide
Main RFCD: Orthopaedics
Total funding: $543,302
Start Year: 2007
End Year: 2009
Grant Type: NHMRC Project Grants
Title of research award:
Maintenance of bone strength in aged rats: the Vitamin D requirementMaintenance of bone strength in aged
rats: the Vitamin D requirement
Lay Description (from application):
Hip fracture remains the most devastating of the osteoporotic fractures particularly in women in whom the
incidence increases to about 3% per annum by the ninth decade. This incidence is bound to increase as the
population ages with increasing longevity. Supplementation of diets of elderly female nursing home residents
with vitamin D and calcium has been shown to reduce the risk of hip fracture by 30% in two years. However
we do not know how much vitamin D is necessary to maintain optimal bone strength. This project will
determine the level of vitamin D required to maintain optimal bone strength in aged rats using a simple blood
test which could then be used to screen the elderly and identify those at risk of hip fracture from low vitamin D
levels. The project will also investigate the effects of vitamin D on the bone cells that maintain optimal skeletal
architecture. This information is essential for comparison with the current knowledge of other biochemical
bone markets in blood and vitamin D status in the elderly, in order to develop nutritional recommendations to
reduce the incidence of hip fracture.
Research achievements (from final report):
We have described for the first time that the effect of vitamin D depletion is to increase bone resorption and
loss of bone mineral content in this rat model. This study has identified that optimal bone mineral content is not
obtained unless the serum 25D level is greater than 80 nmol/L. Two feeding studies have been completed to
achieve levels above and below the critical values (25D 80 nmol/L) of vitamin D status for bone health as
determined from our first study. Dietary calcium levels have also been varied. Regression analyses
demonstrated significant positive relationships between serum vitamin D levels and bone mineral volume.
Mechanical testing demonstrated that resistance to fracture was positively correlated to vitamin D status.
Furthermore the benefits of high dietary calcium may at least partially be due to the maintenance of higher
serum 25D levels., SIGNIFCANCE: Long-term vitamin D deficiency causes bone loss in both the cortical bone
as well as in trabecular bone resulting in reduced bone strength. Importantly, while vitamin D status is a major
determinant of bone mineral content, both dietary vitamin D and dietary calcium are major determinats of
serum 25D levels. Thus the effect of dietary calcium to protect bone loss appears be due to improvement of
serum 25D levels.
Expected future outcomes:
This dietary model is currently being used to further examine the effects on osteocyte density, apoptosis and
mechanical strength of long bones. Cellular activity in these trabecular and cortical bone regions are being
completed.
Name of contact:
Howard Morris
Email/Phone no. of contact:
howard.morris@health.sa.gov.au
NHMRC Research Achievements - SUMMARY
Grant ID: 453568
CIA Name: Dr David Haynes
Admin Inst: University of Adelaide
Main RFCD: Orthopaedics
Total funding: $439,904
Start Year: 2007
End Year: 2009
Grant Type: NHMRC Project Grants
Title of research award:
Regulation of Osteoclasts in Bone PathologiesRegulation of Osteoclasts in Bone Pathologies
Lay Description (from application):
Destructive bone loss is a serious complication of many common inflammatory diseases. Three important
examples are are, periodontal disease, rheumatoid arthritis and peri-implant osteolysis. The mechanism of
osteoclast formation in these diseases is distinctly different from physiologic osteoclast formation. Despite
the prevalence of these diseases until recently little is known about how bone erosion occurs However, recent
advances in the understanding of these diseases has allow us to better investigate the mechanisms of the bone
loss. Drugs to stop the loss of bone have only recently been available to patients and many new treatments are
being developed. While most of these drugs are proving useful to treat osteoporosis, their suitability for the
treatment of bone loss in diseases such as periodontal disease, rheumatoid arthritis and peri-implant osteolysis
is largely unknown. As the way bone is lost in these inflammatory diseases quite different from osteoporosis
different treatments are needed. This project aims to better understand bone loss in these diseases and identify
new treatments to prevent the debilitating bone loss associated with inflammation in disease.
Research achievements (from final report):
Aim 1. We have defined pathogenic mechanisms that regulate localised bone loss in periodontal disease (PD)
and rheumatoid arthritis (RA). We have demonstrated apoptosis (programmed cell death) is inhibited in
periodontal disease and rheumatoid arthritis. This is through an inhibitor of caspase 3 (xIAP and related
molecules). This shows that drugs which inhibit this molecule may induce remission of bone loss in these
diseases. Our results (in vitro) with inhibitors of xIAP from a commercial collaborator (Aegera) show this to be
the case and futher in vivo work is needed. A nubers of other approches also show similar results that idicate
that OSCAR, TREM-2 and their adaptor molecules are keys to bone los in these diseases. , Aim 2. We have
dentifed suitable treatments of localised inflammatory bone loss in PD and RA. We tested over 30 potential
compounds. Of most interest besides the xIAP inhibitors described above were novel histone deacetylase
inhibitors (HDACi). A novel class I and II HDACi 1179.4b obtained from the Institute of Molecular
Bioscience (IMB) at the University of Queensland resulted in a concentration dependent suppression of
osteoclast formation and activity. We have developed and used a mouse model of periodontal disease. Oral
administration of the dual inhibitor 1179.4b (1mg/kg/day) in the mouse model of PD significantly (p=0.011)
reduced alveolar bone resorption. Of most interest is that these drugs appear to be working through inhibition
of OSCAR, TREM-2 and their adaptor molecules. , Achiving our original aims means that these approches to
bone loss in periodonal disease and rheumatoid arthritis can be developed.
Expected future outcomes:
We have identified several new approches to the reatment and prevention of bone loss in periodontal disease
and rheumatoid arthritis. These are being further investegated and developed with industry to provide new
treatments.
Name of contact:
David R Haynes
Email/Phone no. of contact:
david.haynes@adelaide.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 508041
CIA Name: Prof Antonio Ferrante
Admin Inst: University of Adelaide
Main RFCD: Cellular Immunology
Total funding: $524,559
Start Year: 2008
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
Characterisation of the anti-inflammatory properties of the n-3 fatty acid product, 4-hydroxyhexenal.Characterisation of the anti-inflammatory properties of the n-3 fatty acid product, 4-hydroxy-hexenal.
Lay Description (from application):
A concerted effort is being made by experts in the field of omega 3 fats (fish oils) to make specific
recommendation on their use to improve human health . We have reasoned that the characterisation of a major
oxidation product of these oils could be a key to understanding how these fats benefit us. The project is likely
to influence the formulation of fish oils to enhance their health promoting properties.
Research achievements (from final report):
Achievements and significanceThe objective of this research was to characterize the anti-inflammatory
properties of one of the main products generated from the oxidation of fish oil omega 3 polyunsaturated fatty
acids, hexenal. The action of hexenal was investigated in relation to that of the corresponding omega 6 fatty
acid product, nonenal.Our findings are quite interesting as they have revealed that hexenal targets a white blood
cell (T cell) involved in damaging our bodies during the course of an inflammatory disease such as rheumatoid
arthritis. In the test tube we were able to show the direct inhibitory action of hexenal on white blood cell
responses. Responses and messenger proteins produced by these cells, involved in tissue damage in rheumatoid
arthritis, could be prevented by hexenal. The T cells were particularly sensitive to hexenal. When injected into
mice with experimental inflammation, hexenal significantly decreased inflammation mediated by T cells.
These anti-inflammatory effects were not evident when the omega-6 polyunsaturated product, nonenal, was
used. Thus hexenal may be a significant contributory factor to the immunosuppression and anti-inflammatory
properties of omega 3 fatty acids.The basis of the action of hexenal was examined in T cells and results showed
that hexenal blocked the transmission of signals early in the T cell activation process.We have identified a new
mode of anti-inflammatory activity generated through the oxidation of n-3 polyunsaturated fatty acids. Apart
from this agent being a biomarker in nutrient-induced protection against inflammation, it may form the basis of
new anti-inflammatory agents.
Expected future outcomes:
We have now identified a new category of anti-inflammatory products resulting from the oxidation of omega 3
polyunsaturated fatty acids or fish oil. There may therefore be benefits in measuring the levels of hexenal in
vivo to ascertain the inflammatory state or protective nature of omega 3 supplementation.
Name of contact:
Prof Antonio Ferrante
Email/Phone no. of contact:
antonio.ferrante@adelaide.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 508084
CIA Name: Prof Nicola (Nick) Fazzalari
Admin Inst: University of Adelaide
Main RFCD: Orthopaedics
Total funding: $434,498
Start Year: 2008
End Year: 2010
Grant Type: NHMRC Project Grants
Title of research award:
Vertebral body strength: Contribution of bone mass, bone structure and material propertiesVertebral body
strength: Contribution of bone mass, bone structure and material properties
Lay Description (from application):
This study will determine the contributions to vertebral body strength made by its structural and material
properties. Using state-of-the-art computed-tomography scanners, digitised representations of vertebral bodies
in three-dimensions will be produced, which enable measurement of bone structure. After strength testing of
the vertebral bodies, the structural and material properties, which combine to predict vertebral body strength,
will be identified in an aged population.
Research achievements (from final report):
We have successfully developed and implemented protocols for multi-modal and multi-scale imaging
modalities to achieve the project aims. The unique aspect of this study is that each of the complementary bone
structure and material parameters as well as a measure of whole vertebral body bone strength was obtained
from the same specimen. Using current clinically available DXA to meansure area BMD and pQCT to measure
volumetric BMD we validated these clinical data against high-resolution micro-CT imaging. We have
developed and implemented a sub-regional analysis protocol of bone mass at clinical resolution (DXA and
pQCT imaging) against high-resolution micro-CT imaging of whole vertebral bodies (Aims 1 and 4). This
work was performed in conjunction with our associate investigators at the University of Melbourne and is
ongoing with the aim of making the analysis clinically available for patient assessment of vertebral body
fracture risk. We have also shown that a significant proportion of the variability in bone strength can be
explained by cancellous bone morphology and the validation of these observations is about to be published in
Osteoporosis International (Aims 2 and 3). To date the project data has resulted in three peer-reviewed
publications and thirteen conference presentations both nationally and internationally. In additional,
publications highlighting the clinical applicability of our findings are in preparation. Finally, our unique
regional analysis of data from the clinical imaging modalities will inform the clinical guidelines for fracture
risk assessment that will be necessary with new high resolution X-ray based imaging that is currently being
developed for clinical use.
Expected future outcomes:
This work is ongoing within our research program. We are continuing to correlate high-resolution
morphometry and biomechanics, with clinical imaging modalities, with the aim of implementing new improved
clinical imaging protocols to better predict vertebral body fracture risk.
Name of contact:
Prof Nicola (Nick) Fazzalari
Email/Phone no. of contact:
nick.fazzalari@health.sa.gov.au
NHMRC Research Achievements - SUMMARY
Grant ID: 508087
Start Year: 2008
CIA Name: Prof Stan Gronthos
End Year: 2012
Admin Inst: University of Adelaide
Grant Type: NHMRC Research Fellowships
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $570,218
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
I am a stem cell biologist researching the properties and application of mesenchymal stem cells, with an aim to
develop cellular based therapies for repairing mineralised tissues such as bone, cartilage, dentin, cementum and
other connective-supportive ti
Research achievements (from final report):
N/A
Expected future outcomes:
N/A
Name of contact:
Prof. Stan Gronthos
Email/Phone no. of contact:
stan.gronthos@adelaide.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 519223
CIA Name: Prof Donald Howie
Admin Inst: University of Adelaide
Main RFCD: Orthopaedics
Total funding: $192,187
Start Year: 2008
End Year: 2010
Grant Type: NHMRC Project Grants
Title of research award:
Radiostereometric analysis of the effect of a large articulation on prosthetic wear and migration after hip
replacementRadiostereometric analysis of the effect of a large articulation on prosthetic wear and migration
after hip replacement
Lay Description (from application):
At total hip replacement, there has been a recent trend to use prostheses with a larger ball and liner in the
socket. This may decrease the risk of post-operative dislocation, but may also increase the amount of wear,
leading to bone loss and loosening of prostheses, which may then require replacement. This project will use a
special type of x-ray to determine whether wear and movement of these new prostheses is clinically acceptable,
so that they can be used with confidence in patients.
Research achievements (from final report):
Large articulations in total hip replacement are increasingly being used. We have previously shown in an
NHMRC-funded randomised trial that a large articulation significantly reduces the risk of dislocation following
hip replacement. Although new polyethylene liners have made the use of larger articulations feasible, whether
larger articulations were associated with significant amounts of polyethylene wear was not known. Significant
polyethylene wear results in polyethylene particulate debris being deposited around the hip replacement
prosthesis which can then lead to localised bone loss, requiring costly revision of the total hip replacement with
its associated risks of both death and complications. We used a highly sophisticated radiographic technique,
namely radiostereometric analysis, to measure early polyethylene wear, which can not be seen on plain
radiographs. Our study has shown that the wear between one and two years of the large metal on highly crosslinked polyethylene articulations now commonly used in total hip replacement are similar to those of the
standard-sized articulations and within the clinically acceptable range of wear. Therefore, these articulations
can now be recommended for more general use. However, continued monitoring of wear is required to ensure
that there is no unexpected increase in wear over time.
Expected future outcomes:
Wear of metal on highly cross-linked polyethylene articulations will continue to be examined to determine the
longer term wear associated with these hip replacements.
Name of contact:
Dr Oksana Holubowycz
Email/Phone no. of contact:
oksana.holubowycz@health.sa.gov.au
NHMRC Research Achievements - SUMMARY
Grant ID: 565081
CIA Name: Dr Sharon Byers
Admin Inst: University of Adelaide
Main RFCD: Paediatrics
Total funding: $383,784
Start Year: 2009
End Year: 2011
Grant Type: NHMRC Project Grants
Title of research award:
Gene therapy for skeletal disease in MPS.Gene therapy for skeletal disease in MPS.
Lay Description (from application):
Skeletal disease is a major problem for children with mucopolysaccharidoses (MPS). Patients suffer from early
onset osteoporosis and osteoarthritis, severely affecting their quality of life. We will evaluate a lentiviral gene
therapy vector developed in-house for its capacity to transduce bone, cartilage, synovial and ligament cells in a
mouse model of MPS VI. Our goal is to generate high level, sustained expression of the deficient MPS enzyme
and alter the course of skeletal disease in MPS.
Research achievements (from final report):
We have shown that neonatal gene therapy prevents the development of the high bone mass phenotype
characteristic of MPS VII, via an increase in osteoclast number and attachment to bone. Established bone
disease also responds rapidly in mice treated at an older age. Conversely growth in bone length is unchanged
by gene therapy. Thus this mode of therapy has future application to disorders of high bone mass phenotype
but does influence bone length discrepancies arising from growht plate cartilage dysfunction.
Expected future outcomes:
Oucomes can be developed to provide a gene therapy approach to disorders of high bone mass.
Name of contact:
Sharon Byers
Email/Phone no. of contact:
sharon.byers@adelaide.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 565341
CIA Name: Prof Mark Bartold
Admin Inst: University of Adelaide
Main RFCD: Dentistry not elsewhere classified
Total funding: $520,657
Start Year: 2009
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
Relationship between periodontal disease and rheumatoid arthritisRelationship between periodontal disease and
rheumatoid arthritis
Lay Description (from application):
Periodontal (gum) disease and rheumatoid arthritis are two of the most common chronic inflammatory diseases
affecting humans. These two diseases have remarkably similar patterns of tissue destruction. It is possible that
individuals with chronic periodontitis may prime or predispose individuals prone to developing rheumatoid
arthritis. Treatment of periodontal disease may help reduce the severity of rheumatoid arthritis.
Research achievements (from final report):
This project studied the relationship between rheumatoid arthritis and periodontitis. From small animal studies
we demonstrated that periodontal inflammation can exacerbate the induction and severity of experimental
arthritis. In addition we demonstrated that induction of experimental arthritis can adversely affect the
periodontal tissues. Thus we have shown that the relationship between periodontitis and rheumatoid arthritis is
bi-directional. We have also demonstrated a number of unique molecular mechanisms/pathways which could
explain these relations ships including the citrullination of proteins in inflamed periodontal tissues and the
RANK/RANKL/OPG/TRAIL axis.
Expected future outcomes:
The next phase of these studies is to commence human intervention trials where patients with both rheumatoid
arthritis and periodontitis are treated for their periodontitis to determine whether this has any effect on the
clinical parameters of rheumatoid arthritis.
Name of contact:
Professor Mark Bartold
Email/Phone no. of contact:
mark.bartold@adelaide.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 565372
CIA Name: A/Pr Gerald Atkins
Admin Inst: University of Adelaide
Main RFCD: Orthopaedics
Total funding: $511,295
Start Year: 2009
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
Strategies for healthy osteocytesStrategies for healthy osteocytes
Lay Description (from application):
Osteocytes (OY) are the most abundant cell type in bone whose high density and viability are essential for
healthy bone. We have found that vitamin K, vitamin D & strontium, promote human OY differentiation. We
will test these in novel models of human OY differentiation and survival, and in animal models of bone loss
associated with vitamin D deficiency, menopause and glucocorticoid treatment. Our work will lead to a better
understanding of human OY and give a new approach to treat osteoporosis.
Research achievements (from final report):
The aims of this project were to characterise the effects of a number of key bone-acting compounds on the
behaviour of the osteocyte, an important controlling cell type resident throughout the hard bone tissue. We
have illuminated important effects of the compounds strontium ranelate, vitamin K, vitamin D and calcium.
Also, we identified that wear particles from orthopaedic implants may directly affect osteocytes resulting in
their pro-catabolic (bone degrading) activation. We have succeeded in firmly establishing osteocytes as central
to human bone health. This NHMRC funded study has resulted in the publication of some 10 scientific
manuscripts to date, with 2 more submitted for publication and at least 2 more in preparation.
Expected future outcomes:
My work has led to a significant increase in knowledge concerning human osteocyte biology and my group has
established important research tools, with which to ask future questions. We are now performing exciting
further research into the human osteocyte, which is a major regulator of bone behaviour and of systemic
processes, such as serum phosphate homeostasis and immunity.
Name of contact:
Associate Professor Gerald Atkins
Email/Phone no. of contact:
gerald.atkins@adelaide.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1004871
Start Year: 2011
CIA Name: A/Pr Gerald Atkins
End Year: 2013
Admin Inst: University of Adelaide
Grant Type: NHMRC Project Grants
Main RFCD: Medical and Health Sciences not elsewhere classified
Total funding: $536,654
Title of research award:
Sclerostin: a key regulator of bone mineralisation and bone catabolismSclerostin: a key regulator of bone
mineralisation and bone catabolism
Lay Description (from application):
The regulation of bone mass is critical for many areas of human disease including osteoporosis, osteoarthritis,
inflammatory bone loss conditions, e.g. rheumatoid arthritis, cancers of bone and problems relating to
orthopaedic prosthesis failure. The osteocyte, the most abundant bone cell, plays a central role in normal bone
biology and is likely key to these diseases. Sclerostin is one osteocyte product that may be a key to
understanding how bone’s mass and composition is controlled locally.
Research achievements (from final report):
This study was designed to elucidate the way in which sclerostin, an exciting new therapeutic target for the low
bone mass disease, osteoporosis, exerted its effects. We uncovered several key mechanisms of action of
sclerostin, in keeping with the prospective aims. First, we identified the major cell types that respond to
sclerostin, pre-osteocytes and osteocytes. Second, we disovered that sclerostin functions as a master regulator
of bone mineralisation. Third, we showed that sclersotin is an indirect inducer of bone resorption, via osteocyte
support of osteoclast formation and activitý. Fourthly, we made the highly novel discovery that sclerostin
promotes osteocyte driven bone loss, a process termed osteocytic osteolysis. These major findings have
contributed significantly to our understanding of sclerostin and the cells that produce it, the osteocyte. Peerreviewed scientific manuscripts arising from these studies have been well cited to date. Our work has received
wide recognition including the award of most outstanding basic science abstract at the ANZBMS IBMS joint
scientific meeting, Gold Coast, 2011 and has been the subject of numerous podium presentations at major
international meetings including the ASBMR, ANZBMS/IBMS and ORS annual scientific conferences. This
work provides an informed rationale for the clinical inhibition of sclerostin for the treatment of bone loss
diseases, such as osteoporosis. Importantly, our research highlights the osteocyte as an important bone
therapeutic target.
Expected future outcomes:
This work has provided novel insight into how osteocytes, the major and most long-lived cell type in bone,
control bone homeostasis and contribute to human bone disease. Ongoing research is investigating the
involvement of the above mechanisms in other debilitating conditions associated with osteoarthritis.
Name of contact:
A/Prof. Gerald Atkins
Email/Phone no. of contact:
gerald.atkins@adelaide.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 303404
CIA Name: Prof Suresh Mahalingam
Admin Inst: University of Canberra
Main RFCD: Infectious Diseases
Total funding: $336,000
Start Year: 2004
End Year: 2006
Grant Type: NHMRC Project Grants
Title of research award:
A NOVEL MOUSE MODEL TO INVESTIGATE THE MECHANISMS OF VIRUS-INDUCED
ARTHRITISA NOVEL MOUSE MODEL TO INVESTIGATE THE MECHANISMS OF VIRUS-INDUCED
ARTHRITIS
Lay Description (from application):
We have developed a novel animal model by which to study arthritic disease caused by insect-transmitted
viruses known as arboviruses. The existence of this model and novel reagents provides an excellent
opportunity to further explore the basic mechanisms of infectious disease in a complete functioning animal,
rather than specific cultured cells. The study will use modern approaches in molecular and cellular biology to
achieve this goal. The production by our immune systems of soluble mediators (cytokines/chemokines) and
antibodies is an overwhelming positive aspect of our physiological response to infection by microbes.
Protection from disease by these immune compounds can happen naturally, or the body's ability to produce
these factors can be exploited to our benefit via the administration of vaccines. However, these factors can also
be detrimental to the host contributing to severe disease. For instance, work performed almost 40 years ago
showed for the first time that under particular conditions, antibodies against viruses can enhance infection,
instead of inhibiting infection as normally seen. In the intervening years work by scientists all over the world
has associated "antibody-dependent enhancement" (ADE) of infection to many types of viruses; ADE is even
thought to be a risk factor to serious disease with dengue virus, and has been shown in vitro for the AIDS virus
and Ebola virus. We have recently discovered a molecular mechanism which explains how antibody enhances
viral infection in vitro. In studies on immune cells infected with Ross River Virus (RRV) we found that
infection helped by antibody resulted in the specific disruption to the production of cellular chemicals which
are toxic to viruses. Are these mechanisms of antibody-enhanced infection also found in animals? Will such
mode of infection cause enhanced disease and tissue pathology (arthritis) in animals?
Research achievements (from final report):
Mosquito-borne alphaviruses causing arthritis are found in many parts of the world and include Sindbis virus,
the related Scandinavian Ockelbo virus, the African/Asian chikungunya virus, the African O'nyong-nyong
virus, the South American Mayaro virus, and the Australasian Barmah Forest and Ross River viruses (RRV).
RRV is endemic to Australia and New Guinea and is the aetiological agent of epidemic polyarthritis or RRV
disease (RRVD). There is a substantial gap in our knowledge on how viruses cause arthritis. , Achievements:
We have accumulated a considerable body of evidence describing our model of viral-induced arthritis. In
addition, we have accumulated a considerable body of evidence describing the roles of cells and soluble
mediators in our model. We have unravelled the pathobiology of RRVD. The disease has been shown to be an
infectious arthritis with symptoms probably associated with immunopathological responses to virus persisting
in joint macrophages. We have shown that RRV can establish a persistent productive infection in macrophages
despite the presence of neutralising antibodies, a process probably also requiring modulation of type I IFN and
antiviral responses. Benefit: This study has laid the foundation for the new understanding of viral arthritis. The
project has significantly enhanced our understanding of the pathogenesis of virus-induced rheumatic disease
which can ultimately lead to improved therapies against these diseases.
Expected future outcomes:
The mechanims of disease is poorly understood. We have developed a novel animal model of disease by which
to study arthritic disease caused by viral infections. We will be able to identify and understand the
pathophysiologic mechanisms by which viral arthritis causes acute and chronic arthropathies.
Name of contact:
Suresh Mahalingam
NHMRC Research Achievements - SUMMARY
Email/Phone no. of contact:
Suresh.Mahalingam@canberra.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 303413
CIA Name: Prof Suresh Mahalingam
Admin Inst: University of Canberra
Main RFCD: Medical Virology
Total funding: $444,500
Start Year: 2004
End Year: 2008
Grant Type: Career Development Fellowships
Title of research award:
The Mechanisms and Alphavirus-induced Arthritis using a Novel Animal ModelThe Mechanisms and
Alphavirus-induced Arthritis using a Novel Animal Model
Lay Description (from application):
Media Summary not available
Research achievements (from final report):
Mosquito-borne alphaviruses that cause arthritis are found in many parts of the world and include Sindbis
virus, the Scandinavian Ockelbo virus, the African/Asian Chikungunya virus, the African O'nyong-nyong
virus, the South American Mayaro virus and the Australasian Barmah Forest and Ross River viruses (RRV).
RRV is endemic to Australia and New Guinea and is the aetiological agent of epidemic polyarthritis or RRV
disease (RRVD). There is little known about how these viruses cause arthritis in humans.We have developed a
mouse model of viral-induced arthritis, where the arthritis symptoms observed in human disease are replicated
in young C57Bl/6 mice. We have also accumulated a considerable body of evidence about the roles of specific
cells and soluble mediators in the viral induction of arthritis, such as in RRVD. The disease symptoms are
associated with immunopathological responses in the host to the viral infection. Despite the presence of
neutralising antibodies, RRV establishes a persistent productive infection in macrophages in the joints and
modifies the hosts' type I interferon and other immune responses to the viral infection. Together, these explain
the often prolonged duration of symptoms in humans following infection with RRV.This study has laid the
foundation for understanding the pathogenesis of viral arthritis, which can provide vital information for the
development of agents to treat the disease and its symptoms in humans. The mouse model can also be used to
test possible treatments.
Expected future outcomes:
We have developed a novel animal model of disease to study arthritic disease caused by viral infections. We
are using this model to identify the pathophysiologic mechanisms by which the viral infection causes acute and
chronic arthropathies and to test potential therapies to treat the arthritic symptoms.
Name of contact:
Suresh Mahalingam
Email/Phone no. of contact:
Suresh.Mahalingam@canberra.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 3211
CIA Name: E/Pr T Martin
Admin Inst: University of Melbourne
Main RFCD: Rheumatology and Arthritis
Total funding: $3,307,124
Start Year: 1999
End Year: 2004
Grant Type: Programs
Title of research award:
Humoral and local regulators of bone resorption and formationHumoral and local regulators of bone resorption
and formation
Lay Description (from application):
Not Available
Research achievements (from final report):
Several new discoveries that help explain how hormones and products of the body's immune system work
together to control the formation and breakdown of bone. These findings are relevant to the understanding of
how osteoporosis develops and how treatments can be improved for that condition, aiming at fracture reduction
in the elderly. , The research has identified the fact that treatments used for building new bone make use not
only of the bone-forming cells (osteoblasts), but also of the cells that break bone down (osteoclasts). This is
resulting in critical review of how the new bone-building treatment , using parathyroid hormone, can be
combined with available drug inhibitors of bone breakdown (bisphosphonates, SERM's)., The research has led
to improved understanding of the mechanisms important in the spread of breast cancers to bone, and their
growth there as secondary cancers. In particular, the Program research has highlighted how the bone
environment itself can profoundly change the behaviour of cancer cells once they are located there. This is
focussing attention onto new approaches to the prevention and treatment of metastatic disease in bone.
Expected future outcomes:
The Program will lead to the identification of bone cell products that will change current thinking regarding the
prevention and treatment of osteoporosis, and approaches to drug treatments, particularly in the use of drug
combinations. The cancer metastasis research is likely to result in new ways of preventing and treating bone
metastases in breast cancer.
Name of contact:
T.J.Martin
Email/Phone no. of contact:
jmartin@svi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 145619
CIA Name: A/Pr Amanda Fosang
Admin Inst: University of Melbourne
Main RFCD: Rheumatology and Arthritis
Total funding: $703,180
Start Year: 2001
End Year: 2005
Grant Type: NHMRC Project Grants
Title of research award:
Cartilage destruction in arthritis: Mechanism of aggrecanase and matrix metalloproteinase action in vivo and in
vitroCartilage destruction in arthritis: Mechanism of aggrecanase and matrix metalloproteinase action in vivo
and in vitro
Lay Description (from application):
Arthritis is a disease that causes pain, deformity and disability. The lack of adequate therapies for arthritis is
partly a reflection of our limited understanding of the biochemical events involved in disease progression and
cartilage destruction. Two distinct families of enzymes are present in cartilage. These are the MMP and the
ADAMTS family. These enzyme families are important for cartilage turnover in normal growth and skeletal
development. However unregulated enzyme activity resulting in accelerated cartilage breakdown leads to the
pathology recognised as arthritis. While some activities of the MMP and ADAMTS families have been studied
in the laboratory, there have been no in vivo studies to determine which family is responsible for cartilage
destruction, and which is therefore most appropriate for targeting by drugs. This project will create geneticallymodified mice, resistant to either the MMP or the ADAMTS enzymes. The mice will be used in experimental
arthritis models to determine which enzymes play the major role in initiating disease, which enzymes are
involved in disease progression and which enzymes may be important for repair. In parallel studies, the highly
specialised matrix molecule, keratan sulphate, will be studied for its role in cartilage destruction. There is
preliminary evidence to suggest that keratan sulphate may be involved in the regulation of ADAMTS activity.
The possible direct and indirect modalities of keratan sulphate action will be investigated. The results of this
arthritis project will (a) yield new information on the mechanism of disease action; (b) identify targets for the
rational design of disease-modifying drugs; (c) elucidate biochemical processes involved in normal skeletal
growth and cartilage repair; and (d) provide new in vivo models for testing the efficacy of arthritis therapies.
Research achievements (from final report):
The ability of cartilage to protect the surface of bones from wear and tear is dependent upon the integrity of a
proteoglycan called aggrecan. In the early stages of arthritis, aggrecan is degraded by metalloenzymes and lost
from cartilage. Our laboratory is researching which families of enzymes are important in aggrecan
degradation.We have engineered two strains of genetically-modified mice: one in which the aggrecan is
resistant to degradation by matrix metalloproteinases and one in which aggrecan is resistant to degradation by
aggrecanases at a key site. Our main aim is to challenge these mice with experimental arthritis, to see whether
the genetic modifications confer protection against the onset and progression of arthritis., However, before we
could do this work we needed to make a careful analysis of the growth and development of unchallenged mice.
We predicted that these mice would have some problems with bone growth, because aggrecan remodelling is
part of normal development. We were surprised to find that both strains of mice showed no abnormalities in
skeletal growth. These results indicated that the transition from cartilage to bone that occurs during bone
growth does not involve either of these families of enzymes. Our results lead us to challenge the prevailing
dogma about the mechanism of skeletal growth. Our work also has implications for the design of arthritis
therapies aimed at modulating cartilage metabolism, particularly the use of such therapies in children and
women of child bearing age., Aggrecanase-resistant mice that were challenged with acute inflammatory
arthritis proved to be less susceptible to the early loss of aggrecan from the tissue, suggesting that preventing
aggrecanase action might protect against the onset of disease (manuscript in preparation).
Expected future outcomes:
We will investigate our new hypothesis that aggrecan remodelling during normal skeletal development is via a
non-metalloenzyme-mediated mechanism. The potential outcome from investigating this hypothesis is a new
paradigm for matrix remodelling in skeletal development, From 145619 and its sister project 350487 (CIA
Fosang), we have identified aggrecanase-2 as a potential target for drug design.
NHMRC Research Achievements - SUMMARY
Name of contact:
A/Prof. Amanda Fosang
Email/Phone no. of contact:
amanda.fosang@mcri.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 145813
Start Year: 2001
CIA Name: Prof John Hamilton
End Year: 2005
Admin Inst: University of Melbourne
Grant Type: NHMRC Project Grants
Main RFCD: Protein Targeting and Signal Transduction
Total funding: $470,278
Title of research award:
Control of monocyte/macrophage function by CSF-1Control of monocyte/macrophage function by CSF-1
Lay Description (from application):
The project aims to understand how a factor responsible for the production of a type of white blood cell
interacts with its receptor. If we knew the molecular details of how this factor works then we would be able to
control better diseases, such as osteoporosis and arthritis, where such cells can play havoc by destroying tissue.
The project also has implications for certain leukaemias which lose growth control mechanisms in response to
this factor.
Research achievements (from final report):
I have developed a new cell system to study the influence of cytoplasmic residues of the CSF-1 receptor on the
degree of macrophage differentiation observed in response to CSF-1 and to develop proteomic technologies
including new technologies to enrich for and detect CSF-1R binding partners. By this approach we were able to
identify a new form of myosinXVIIIA243. More recent molecular studies have focussed on a proposed role for
CSF-1-induced changes in cell metabolism and survival as well as the role of integrins and the podosome in
CSF-1-induced survival and migration, respectively. , The project has helped to define at a molecular level how
a particular protein controls the development of a type of white blood cell which is involved in host defence
and inflammation. Blockade of this control by antibodies has been shown in animal models to lead to less
inflammatory disease. By understanding the relevant molecular events governing the function of this molecule
it is possible that orally active drugs could be developed to achieve the same outcome.
Expected future outcomes:
Drugs will be developed to control the number and activation state of a white blood cell important for the
inflammation and tissue destruction observed in a disease such as rheumatoid arthritis. Recent evidence also
suggests that progression of certain tumours may also be slowed down in the same way.
Name of contact:
Professor John Hamilton
Email/Phone no. of contact:
jahami@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 145815
CIA Name: Prof John Hamilton
Admin Inst: University of Melbourne
Main RFCD: Gene Expression
Total funding: $392,037
Start Year: 2001
End Year: 2003
Grant Type: NHMRC Project Grants
Title of research award:
Regulation of macrophage lineage differentiationRegulation of macrophage lineage differentiation
Lay Description (from application):
Macrophages are a key component of the immune system; thier functions include killing of pathogens as well
as cancerous cells. Macrophage lineage cells are derived from stem cells within the bone marrow and thier
differentiation, proliferation and survival is mediated by a particular growth factor termed colony stimulating
factor-1 (CSF-1). The understanding of how macrophage lineage cells develop will help us to treat many
diseases including certain cancers (such as leukemia), arthritis and inflammation, and disorders of the immune
system. The action of CSF-1 is mediated by the CSF-1 receptor (CSF-1R) which, when activated, controls gene
regulation. In this proposal we will study CSF-1R activation and identify the genes regulated by CSF-1 with a
view to characterize genes critical for macrophage development. These genes may provide potential targets
for new pharmacological agents.
Research achievements (from final report):
The research was able to define molecular mechanisma following the activation of a type of white blood cell
with a growth and differentiation factor. A completely new molecule was found which is probably involved in
the maturation of the white blood cell lineage. In addition a new concept was developed whichis proposed to
explain how white blood cells are committed to develop in a certain direction. The findings are relevant to the
control of leukaemia which results from defects in the molecular pathways studied in the research project.
Potential benefits will be means to control the development of white blood cells which is relevant to the control
of leukaemia; also the control of such development is relevant to the suppression of inflammatory diseases
which have a wide impact on the community.
Expected future outcomes:
Drugs that control leukaemia and inflammation could result from this research.
Name of contact:
Prof John Hamilton
Email/Phone no. of contact:
jahami@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 145820
CIA Name: Prof Ego Seeman
Admin Inst: University of Melbourne
Main RFCD: Endocrinology
Total funding: $196,018
Start Year: 2001
End Year: 2003
Grant Type: NHMRC Project Grants
Title of research award:
Apportioning deficits in bone size and density in women with fractures to growth or ageing by studies in their
daughtersApportioning deficits in bone size and density in women with fractures to growth or ageing by studies
in their daughters
Lay Description (from application):
Women fracture their bones because the bones are small and break easily and because the bones are thin or low
in denseness (very porous like a honey comb). This study is aimed at identifying why women with fractures
have small bones and why the bones are so porous. They may have these problems because they lost a lot of
bone as they get older or because growth was abnormal so the size of the bone didn't reach its potential size or
because the denseness of the bones didn't develop properly. The study will be carried out in women with spine
or hip fractures and their daughters. All participants will have bone densitometry, provide a 24 hour urine
sample and a fasting blood sample of 20 ml whole blood. Informed consent will be obtained from all
participants. The bone density scan is associated with radiation exposure of about 4 mSv, about one tenth of a
chest x ray, temporary bruising may follow taking blood. If we can understand the different ways
osteoporosis can occur we can then start to devise specific treatments tailored to the individual. Also if we can
identify the causes of small bones and bone thinness during growth it may be possible to correct some of these
causes before the reduced growth and reduced building of bone occurs. We might also prevent the thinning of
bone by identifying and removing causes of bone thinning.
Research achievements (from final report):
The aim of this study is to determine if the deficits in bone mass and size in women with spine or hip fractures
are growth-related (reduced bone accrual during growth), age-related (excessive bone loss), or a combination
of the two., , Women with spine fractures have low bone density at the spine, which is likely due to reduced
accrual during growth, as the deficits in their daughters' bone density were about half that of their mother's.
However, the lower vertebral size in women with spine fractures is likely to occur during aging, as their
daughters do not have deficits in vertebral size., , Women with hip fractures have larger femoral neck bone
size, lower bone density and a thinner bone. Daughter of women with hip fractures also had larger femoral
neck bone size, but normal bone density and normal bone thickness. Therefore, we infer that the larger bone
size in women with hip fractures is growth-related, but the reduction in bone density and thinning of the bone
occurs during aging. Fragility fractures at the spine and hip have their origins in both growth and aging., , The
results of this study should influence how osteoporosis is viewed and the approach taken to research, prevent
and treat osteoporosis. Approaches need to look beyond just factors influencing bone density during aging, to
also include factors that affect bone density during growth and influence bone size and structure. The major
shift appears to be from treatment in adulthood, to prevention and risk assessment during both growth and
aging.
Expected future outcomes:
The results of this study open new approaches to research into the pathogenesis and prevention of bone
fragility. Drug therapy may need to be different in persons with deficits due to low peak accrual versus those
with excessive bone loss. Approaches to the whole of the population during growth and aging are needed just
as cardiovascular disease prevention is increasingly focussed at children.
Name of contact:
Ego Seeman
Email/Phone no. of contact:
egos@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 145828
CIA Name: A/Pr Thomas Cocks
Admin Inst: University of Melbourne
Main RFCD: Basic Pharmacology
Total funding: $486,943
Start Year: 2001
End Year: 2005
Grant Type: NHMRC Project Grants
Title of research award:
Characterisation of PAR2 knockout and transgenic mice: towards gene therapy for epithelia based
inflammatory diseasesCharacterisation of PAR2 knockout and transgenic mice: towards gene therapy for
epithelia based inflammatory diseases
Lay Description (from application):
Debilitating and sometimes fatal diseases like asthma and rheumatoid arthritis urgently require new approaches
for their effective management and hopefully, cure. We have recently discovered that the airways posses a
powerful and naturally-occuring protective mechanism which is regulated by unique molecules in the
membranes of the lining cells of the air passages. These molecules are called protease-activated receptors, or
PARs, and are also found on cells lining the inner surfaces of blood vessels and joints as well as in skin. We are
fortunate to have strains of mice - a species in which the PAR-mediated protective mechanism is well
developed - in which the gene for the most important of the PARs found in the lung, PAR2, is missing. These
animals are called PAR2 'knock-outs'. We also have another strain of mouse in which the human PAR2 gene
has been inserted back into PAR2 knock-out mice. These animals will allow us to determine the importance of
PAR2 in protection against asthma, arthritis, vascular disease and deficiencies in skin healing, as well as how
PAR2 might be a more effective protective agent in mice rather than humans. Thus, modification of the human
gene to make the protective system work as effectively as in the mouse might provide an effective therapy or
cure for diseases of the lungs, joints and skin as well as in vascular diseases.
Research achievements (from final report):
Under my leadership over the last seven years, my group has contributed substantially to a frontier field of
medical science - protease-activated receptors (PARs) and their role in inflammation. I intend to keep my
laboratory in the forefront of this field by capitalising on discoveries that PARs play central roles in anxiety,
epileptogenesis and immunological defence against allergens and autoimmune diseases.
Expected future outcomes:
My philosophy is to maintain a balance of fundamental and applied research. Research areas to date include (1)
respiratory diseases, (2) allergy and autoimmune disease and (3) central nervous system. Each of these has
significant importance globally.
Name of contact:
Tom Cocks
Email/Phone no. of contact:
thomasmc@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 170207
CIA Name: A/Pr Amanda Fosang
Admin Inst: University of Melbourne
Main RFCD: Not Allocated
Total funding: $473,542
Start Year: 2001
End Year: 2005
Grant Type: Established Career Fellowships
Title of research award:
Cartilage destruction in arthritis: mechanism of aggrecanase & matrix metalloproteinase action in vivo & in
vitroCartilage destruction in arthritis: mechanism of aggrecanase & matrix metalloproteinase action in vivo &
in vitro
Lay Description (from application):
Not Available
Research achievements (from final report):
The ability of cartilage to protect the surface of bones from wear and tear is dependent upon the integrity of a
proteoglycan called aggrecan. In the early stages of arthritis, aggrecan is degraded by metalloenzymes and lost
from cartilage. Two members of the ADAMTS metalloenzyme family, ADAMTS-4 and ADAMTS-5 are
particularly active against aggrecan in vitro, but the extent to which each acts in vivo was previously unknown.
We engineered two strains of mice lacking functional ADAMTS-4 or ADAMTS-5 and showed that deleting
ADAMTS-5 alone is sufficient to halt the progression of inflammatory arthritis in the mouse. This finding was
published back-to-back in Nature with another report from Wyeth, USA, showing that ADAMTS-5 is also the
primary aggrecanase in a mouse model of osteoarthritis. These studies generated much excitement in the field,
highlighting ADAMTS-5 as an important new target for the development of arthritis therapies., , We developed
a further two strains of mice in which we mutated the aggrecan substrate. In one strain, aggrecan was made
resistant to degradation by matrix metalloproteinases and in the other, aggrecan was made resistant to
degradation by aggrecanases. We predicted that these modifications would confer protection against the onset
and progression of arthritis, and indeed this proved to be true for the aggrecanase-resistant mice, in an
inflammatory model of arthritis. Most unexpected, however, was our discovery that the transition from
cartilage to bone that occurs during normal bone growth does not involve either matrix metalloproteinases or
aggrecanases. These results lead us to challenge the prevailing dogma about the mechanism of skeletal growth.
Our work also has implications for the design of arthritis therapies aimed at modulating cartilage metabolism,
particularly the use of such therapies in children and women of child bearing age.
Expected future outcomes:
We will investigate our new hypothesis that aggrecan remodelling during normal skeletal development is via a
non-metalloenzyme-mediated mechanism. The potential outcome from investigating this hypothesis is a new
paradigm for matrix remodelling in skeletal development, From 170207 and its sister project 350487 (CIA
Fosang), we have ADAMTS-5 as a potential target for drug design.
Name of contact:
A/Prof. Amanda Fosang
Email/Phone no. of contact:
amanda.fosang@mcri.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 170208
CIA Name: Prof John Hamilton
Admin Inst: University of Melbourne
Main RFCD: Not Allocated
Total funding: $651,717
Start Year: 2001
End Year: 2005
Grant Type: Established Career Fellowships
Title of research award:
Control of monocyte/macrophage function by CSF-1Control of monocyte/macrophage function by CSF-1
Lay Description (from application):
Not Available
Research achievements (from final report):
I have developed a new cell system to study the influence of cytoplasmic residues of the CSF-1 receptor on the
degree of macrophage differentiation observed in response to CSF-1 and to develop proteomic technologies
including new technologies to enrich for and detect CSF-1R binding partners. By this approach we were able to
identify a new form of myosinXVIIIA243. More recent molecular studies have focussed on a proposed role for
CSF-1-induced changes in cell metabolism and survival as well as the role of integrins and the podosome in
CSF-1-induced survival and migration, respectively. , The project has helped to define at a molecular level how
a particular protein controls the development of a type of white blood cell which is involved in host defence
and inflammation. Blockade of this control by antibodies has been shown in animal models to lead to less
inflammatory disease. By understanding the relevant molecular events governing the function of this molecule
it is possible that orally active drugs could be developed to achieve the same outcome.
Expected future outcomes:
Drugs will be developed to control the number and activation state of a white blood cell important for the
inflammation and tissue destruction observed in a disease such as rheumatoid arthritis. Recent evidence also
suggests that progression of certain tumours may also be slowed down in the same way.
Name of contact:
Professor John Hamilton
Email/Phone no. of contact:
jahami@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 208960
CIA Name: Prof Eleanor Mackie
Admin Inst: University of Melbourne
Main RFCD: Endocrinology
Total funding: $216,100
Start Year: 2002
End Year: 2003
Grant Type: NHMRC Project Grants
Title of research award:
The role of protease-activated receptor-2 in regulation of bone metabolismThe role of protease-activated
receptor-2 in regulation of bone metabolism
Lay Description (from application):
Many diseases of bones, such as osteoporosis and delayed fracture repair, result from the abnormal function of
bone cells. Factors regulating bone cell function are, therefore, important in maintaining a healthy skeleton, as
well as in the skeleton's response to disease. We have recently demonstrated the presence of a receptor called
PAR-2 on bone-forming cells. We have also shown that activation of PAR-2 inhibits the development of boneresorbing cells (osteoclasts) in response to hormones. We plan to investigate the mechanism of this effect, as
well as to identify how PAR-2 activation modulates other responses of bone cells to hormones. Molecules that
activate PAR-2 are present in bone in certain disease situations, but it is not known what activates PAR-2 in
bone under normal conditions. We will identify physiological activators of PAR-2 within bone.
Research achievements (from final report):
Many diseases of bones, such as osteoporosis and delayed fracture repair, result from the abnormal function of
bone cells. Factors regulating bone cell function are, therefore, important in maintaining a healthy skeleton, as
well as in the skeleton's response to disease. We have demonstrated that a receptor called PAR-2 on boneforming cells (osteoblasts) inhibits the development of bone-resorbing cells (osteoclasts) in response to
hormones. Furthermore, we have demonstrated that PAR-2 exerts this effect through inhibition of expression of
a number of factors produced by osteoblasts that are necessary for osteoclast formation. We have shown that a
number of tissue proteases that activate PAR-2 are not expressed in the bone environment, and that one
putative activator of PAR-2 is not capable of activating it. These observations add substantiallyto our
understanding of osteoclast biology, and therefore to bone biology in general.
Expected future outcomes:
The observations made in this grant have led to ongoing studies on regulation of osteoclast function by
proteases. These and our future studies are likely to help in the development of improved therapeutic
approaches to bone disease.
Name of contact:
Professor Eleanor Mackie
Email/Phone no. of contact:
ejmackie@unimelb.edu.auYes
NHMRC Research Achievements - SUMMARY
Grant ID: 208994
CIA Name: Prof Jeffrey Zajac
Admin Inst: University of Melbourne
Main RFCD: Endocrinology
Total funding: $437,640
Start Year: 2002
End Year: 2004
Grant Type: NHMRC Project Grants
Title of research award:
The physiological relevance of calcitonin in osteoclast functionThe physiological relevance of calcitonin in
osteoclast function
Lay Description (from application):
Throughout adult life, bone tissue is continuously remodelled. The two main processes involved in bone
remodelling, are bone formation and bone breakdown. Bone formation is controlled by cells known as
osteoblasts and bone breakdown is controlled by cells known as osteoclasts. Under normal circumstances these
two processes are tightly coupled. Excessive breakdown of bone, causes these two processes to become
unbalanced and results in bone loss. This is the basis of many bone diseases such as osteoporosis, a condition
in which the bones become fragile and therefore more susceptible to fracture. 1 in 2 women and 1 in 5 men
aged 70 years and older suffer from osteoporosis in Australia. Despite this, the mechanisms which control
osteoclast breakdown of bone are not well understood. Our laboratory is interested in how hormones affect
osteoclast action. We plan to examine the role of the hormone calcitonin, thought to be important inhibitor of
osteoclastic bone breakdown. This will be achieved by studying transgenic mice in which the receptor for
calcitonin is specifically removed from osteoclasts. This will allow us to precisely determine the role of
calcitonin in osteoclast function. Current treatment for osteoporosis involves the administration of drugs
which inhibit bone breakdown. This project will increase our understanding of how calcitonin acts to regulate
the function of osteoclasts. We believe that this research is of great importance as osteoporosis is becoming
more prevalent as the population ages.
Research achievements (from final report):
The aim of this research was to investigate the physiological control of bone resorption by calcitonin and
related peptides (amylin). The first component of this research was to investigate the mechanism of amylin
action on bone. Using a global amylin knockout mouse line, we demonstrated that global deletion of amylin
causes increase bone resorption (or breakdown) leading to a late onset loss of bone. This study sheds new light
on the importance of this hormone in the regulation of bone turnover and provides an understanding of the
bone loss observed in patients with type 1 diabetes who are also amylin deficient. The second component of
this research was to investigate the physiological role of calcitonin in controlling bone turnover, that is the
processes of bone breakdown and bone formation. To achieve this we have generated a number of in vivo
model systems. The first model we generated was a calcitonin receptor (CTR) knockdown model, in which
greater than 90% of the CTR is deleted in every tissue. Global knockdown of the CTR results in bone loss in
young female mice due to increased bone breakdown while males are unaffected. This suggests that the role
calcitonin plays in regulating bone turnover is greater in young female mice than in males. In addition, in
collaboration with Prof Karsenty, USA, we demonstrated in an adult mice that have one copy of the CTR
deleted that bone formation was increased, suggesting a potential role for calcitonin in controlling bone
formation. To further characterise the mechanism of calcitonin action in regulating bone turnover, we have
generated a mouse model in which the CTR is specifically deleted in osteoclasts, the bone resorbing cells. The
characterisation of this model is ongoing. These studies have increased our understanding of how calcitonin
acts on bone. This knowledge will allow us to further understand how bone diseases, such as osteoporosis
develop, which is essential for improving the current forms of therapy.
Expected future outcomes:
This research is currently investigating the physiological role of calcitonin in controlling bone turnover. Mouse
models are being used to understand how calcitonin regulates bone turnover and how calcitonin may act to
protect the skeleton in times of calcium stress (eg. hypercalcaemia, pregnancy, lactation). This understanding
will allow the design of new treatments for osteoporosis.
NHMRC Research Achievements - SUMMARY
Name of contact:
Dr Rachel Davey
Email/Phone no. of contact:
r.davey@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 209014
CIA Name: Prof Ego Seeman
Admin Inst: University of Melbourne
Main RFCD: Endocrinology
Total funding: $316,320
Start Year: 2002
End Year: 2004
Grant Type: NHMRC Project Grants
Title of research award:
Is periosteal bone formation responsible for sexual dimorphism in bone fragilityIs periosteal bone formation
responsible for sexual dimorphism in bone fragility
Lay Description (from application):
Men and women sustain fractures as they age because their bones become fragile. Women sustain fractures
more often than men. Bone thinning occurs in both sexes but it is usually believed that this thinning or loss of
bone is greater in women than men. We have evidence to suggest that this may not be correct. In fact, it is
likely that men and women lose a similar amount of bone, about half what they started with, but during ageing,
men lay down more bone on the outside surface of the bone than women compensating for the similar amount
lost on the inside of the bone. We also have evidence to suggest than men and women who get spine fractures
do so because the process of laying down bone may fail to occur normally. We will study these processes of
bone loss inside the bone and bone gain outside the bone to try to better understand why bones become weak.
We will measure the bone size and its density in healthy men and women and patients with fractures to
determine how the increasing size of the bone produced by laying down bone on its outside helps to keep it
strong and to preserve the bone that would otherwise be lost if it didn't occur or if a disease developed that
might reduce the compensatory
Research achievements (from final report):
We studied 1013 healthy subjects (327 men, 686 women), 125 patients with spine fractures (36 men and 89
women), and 307 patients with hip fractures (127 men, 180 women). We made the following observations:, At
the spine (i) reduced bone fromation on the outer surfaces (periosteum) of the verebral body during growth or
agening, may be in part responsible of verebral fragility and spinal fractures. (ii) The biomechanical index fracture risk indes (FRI) - is not a better predictor of spinal fractures than bone density. In addition, we found
that women, not men, with vertebral fractures may come from a population with short stature. The difference
between arm span and standing or sitting height cannot be sued to predict vertebral fracture risk., At the hip, we
reported that, differences in the geomentry between men and women were confined to further displacement of
the cortex (the wall of the bone) from neutral axis in young men compared to young women explaining why
men bones are stronger. Ageing amp;ified these differences shifting the cortex even further from the neutral
axis and maintaining the bending strength of the bone in men, but not in women. This at least partly explained
the lower fracture rate in men compared to women. Also, we observed that compared to their peers women and
men with hip have reduced cortical thickness. Women who fracture have larger bones. Where as men who
fracture have smaller bones.
Expected future outcomes:
target the periosteum as a very effective way of maintaining bone strength and reducing the burden of fracture.,
It is likely that bone size, independently of bone density, could be used in the future to predict fracture. We
plan to test this hypothesis emanating from this grant.
Name of contact:
Ego Seeman
Email/Phone no. of contact:
egos@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 247909
CIA Name: A/Pr Evange Romas
Admin Inst: University of Melbourne
Main RFCD: Rheumatology and Arthritis
Total funding: $443,250
Start Year: 2003
End Year: 2005
Grant Type: NHMRC Project Grants
Title of research award:
Modulation of osteoclast formation and function to prevent joint destruction in rheumatoid arthritisModulation
of osteoclast formation and function to prevent joint destruction in rheumatoid arthritis
Lay Description (from application):
Rheumatoid arthritis is a disease that affects about 200,000 Australians. It is characterised by painful joint
destruction leading to work disability, diminished quality of life and decreased life expectancy. The usual
treatment of arthritis leads to less inflammation however it cannot be relied upon to control bone and joint
destruction. Patients often have long term worsening of joint function despite short and medium term
improvement in joint pain and swelling. One reason for this paradox may be that while research has mainly
focused on inflammation, far less is known about the processes responsible for bone damage. Normally,
specialised bone cells called "osteoclasts" carry out bone breakdown during growth and maintenance of the
skeleton. In rheumatoid arthritis, these cells are responsible for the joint damage; this proposal, therefore,
focuses on inhibiting the activity of these cells as a new therapy. So far, our work using a model of human
rheumatoid arthritis has demonstrated that it is possible to separate joint inflammation from joint damage by
selectively targeting osteoclasts with an inhibitor known as "Osteoprotegerin". Besides Osteoprotegerin, we
have identified two novel molecules named OCIL and sFRP-1 and shown that they are present in the joints of
animals and humans with arthritis. Very recent experiments in our laboratory show that in the test tube, OCIL
and sFRP-1 (like Osteoprotegerin) block osteoclast activity. The sFRP-1 molecule may also block a very
important messenger molecule in arthritis called tumour necrosis factor. We therefore propose to study the
effect of OCIL and sFRP-1 in the joints of mice with arthritis. We expect that these new inhibitors will have
favorable effects on joint damage. If so, they could undergo further testing for use in humans. We believe that
investigations along these lines may provide a rationale for an entirely new treatment approach to improve the
long term outcome for patients with arthritis.
Research achievements (from final report):
Joint damage in rheumatoid arthritis causes pain, disability and loss of function. The research team employed
animal models of rheumatoid arthritis to elucidate the mechanism of arthritic damage. A major discovery was
that the mechanism of bone destruction in arthritis is entirely different to the mechanism of cartilage injury. It
was determined that the cells responsible for bone damage were osteoclasts. The osteoclasts are generated in
the joints by the action of locally produced inflammatory molecules especially TNF-alpha and RANKL, and
when present in large numbers, these cells remove excessive amounts of bone and degrade joint structure. This
process can lead to joint deformity, pain and loss of function. It was shown that reducing the numbers and or
activity of osteoclasts with drugs such as Osteoprotegerin (OPG) or Zoledronic acid could effectively reduce
bone erosion and damage in models of arthritis. These discoveries suggest that regulating the number of
osteoclasts in the skeleton could effectively minimise or even prevent joint destruction in rheumatoid arthritis.
Expected future outcomes:
Treatment for rheumatoid arthritis is often unsatisfactory because joint damage may continue even when
inflammation is controlled. The identification of specific pathways that lead to bone erosion allows for reliable
prevention of joint damage and deformity. New strategies that target osteoclasts, TNF or RANKL are likely to
become important facets of therapy for arthritis.
Name of contact:
Dr. E. Romas
Email/Phone no. of contact:
evange.romas@svhm.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 251575
CIA Name: Prof Eleanor Mackie
Admin Inst: University of Melbourne
Main RFCD: Endocrinology
Total funding: $120,775
Start Year: 2003
End Year: 2003
Grant Type: NHMRC Project Grants
Title of research award:
Cellular responses to thrombin in skeletal pathologyCellular responses to thrombin in skeletal pathology
Lay Description (from application):
Many diseases of bones, such as osteoporosis and delayed fracture repair, result from the abnormal function of
bone cells. Factors regulating bone cell function are, therefore, important in maintaining a healthy skeleton, as
well as in the skeleton's response to disease. The enzyme thrombin is involved in blood coagulation but also
causes bone cells to alter their behaviour. Thrombin stimulates proliferation of bone-forming cells and protects
them from premature death. Thrombin also stimulates the breakdown of bone. We will investigate how
thrombin's effects on bone cell behaviour influence the course of bone healing. We will also determine how
thrombin stimulates bone breakdown and increases survival of bone-forming cells. This study will contribute
to the understanding of how bone cells function in health and disease.
Research achievements (from final report):
Many diseases of bones, such as osteoporosis and delayed fracture repair, result from the abnormal function of
bone cells. Factors regulating bone cell function are, therefore, important in maintaining a healthy skeleton, as
well as in the skeleton's response to disease. The enzyme thrombin is involved in blood coagulation but also
causes bone cells to alter their behaviour. In this project we have demonstrated that the early stages of bone
healing occur abnormally in the absence of the major thrombin receptor found in bone (PAR-1). We have
found that thrombin stimulates formation of osteoclasts (bone-resorbing cells). We have also identified a
signalling pathway through which thrombin prevents the death of osteoblasts (bone-forming cells). These
observations add substantiallyto our understanding of the biology of bone growth, maintenance and repair.
Expected future outcomes:
The observations made in this grant have led to ongoing studies on regulation of osteoclast function by
proteases. These and our future studies are likely to help in the development of improved therapeutic
approaches to bone disease.
Name of contact:
Professor Eleanor Mackie
Email/Phone no. of contact:
ejmackie@unimelb.edu.auYes
NHMRC Research Achievements - SUMMARY
Grant ID: 251638
CIA Name: A/Pr Mark Kotowicz
Admin Inst: University of Melbourne
Main RFCD: Endocrinology
Total funding: $428,225
Start Year: 2003
End Year: 2005
Grant Type: NHMRC Project Grants
Title of research award:
BONE SIZE AND BONE TURNOVER: RELATIONSHIP TO FRACTURE RISK OVER TEN
YEARSBONE SIZE AND BONE TURNOVER: RELATIONSHIP TO FRACTURE RISK OVER TEN
YEARS
Lay Description (from application):
The occurrence of fracture in the ageing population is a major public health problem because these fractures
are responsible for considerable morbidity and mortality. Of women reaching 90 years of age, one third will
fracture their hip and overall, one in every six women will sustain an osteoporotic fracture in her lifetime. The
direct cost to the community is unknown but estimated, conservatively, at 175 million dollars annually. Most
of this is likely to be the result of hip fractures which occupy an estimated 400,000 bed-days annually. This
bed occupancy is fourth next to mental illness, cardiac disease and cancer. The Geelong Osteoporosis Study is
a large population-based epidemiological study currently under way to evaluate the major risk factors for
fracture in women . This present study which will be an extension of the study to date, will provide in total, 810 years of data concerning the processes that result in increased bone fragility and fracture.
Research achievements (from final report):
The present study is an extension of the Geelong Osteoporosis Study, a large population-based epidemiological
study designed to evaluate major fracture risk factors in women, and provides up to 10 years of data about the
development of bone fragility and fracture. We have shown that hip fracture patients have thinning of the outer
shell of the thigh bone that likely compromises bone strength and that there is a compensatory increase in the
diameter of the bone. Additional information about the biomechanical implications of these structural changes
will become available when Hip Structure Analysis of all bone densitometry scans is complete. We have
developed a clinically useful fracture risk (FRISK) score that predicts fracture by combining information from
bone densitometry, previous fracture and falls history. The FRISK score predicts 75% of fractures over a 2 year
period. Systemic inflammation, as assessed by measurement of high sensitive C-reactive protein (hsCRP),
predicts fracture risk over and above information provided by bone densitometry. The role of vitamin D, the
influence of drug exposures, the nervous system, genetic factors, oxidative stress and depression in bone
fragility have been reported. We have demonstrated that the population burden of fracture comes from the large
number of individuals with a modest reduction in bone mass rather than the relatively small number of highrisk individuals with osteoporosis. Reference ranges for bone densitometry have been established, the health
impact of fragility fracture and cost benefit analyses of treating women with osteopenia and osteoporosis have
been published.
Expected future outcomes:
Development of an updated FRISK score incorporating bone turnover markers and hsCRP, pursuit of a
common aetiology for osteoporosis and cardiovascular (CVD) disease based on predictive value of hsCRP in
both disorders and evidence of systemic inflammation in CVD, evaluation of osteoporosis in men using
expertise gain from this study (NHMRC Project 299831)
Name of contact:
Assoc Prof Mark Kotowicz
Email/Phone no. of contact:
markk@BarwonHealth.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 251657
CIA Name: Prof Paul Gleeson
Admin Inst: University of Melbourne
Main RFCD: Autoimmunity
Total funding: $441,000
Start Year: 2003
End Year: 2005
Grant Type: NHMRC Project Grants
Title of research award:
Investigating T cell tolerance and organ-specific auotimmunity using autoantigen deficient miceInvestigating 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/Phone no. of contact:
pgleeson@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 251682
CIA Name: Prof Geoffrey Nicholson
Admin Inst: University of Melbourne
Main RFCD: Primary Health Care
Total funding: $305,750
Start Year: 2003
End Year: 2007
Grant Type: NHMRC Project Grants
Title of research award:
Primary care prevention of falls and fractures in the elderly by annual vitamin D supplementationPrimary care
prevention of falls and fractures in the elderly by annual vitamin D supplementation
Lay Description (from application):
While Australia has one of the highest rates of skin cancer, many of us are not receiving enough sun exposure
to adequately maintain necessary blood levels of vitamin D. For years it was assumed that vitamin D
deficiency was rarely seen in Australia where sunlight abounds for most of the year. Although few foods are
high in vitamin D, it was thought that only certain cultural groups where women are always veiled in public,
very dark-skinned people and the housebound elderly, were at risk of vitamin D deficiency. Lower vitamin D
levels following wintertime have now been reported in many populations including those living near the
Mediterranean and in Geelong, Victoria. Vitamin D insufficiency is associated with an increased risk of
falling through increased body sway and muscle weakness. Low levels of the vitamin also encourage the
removal of calcium from bones and will predispose to bone fracture for two reasons - increased likelihood of
falling and increased bone fragility and osteoporosis. Osteoporotic fractures are amongst the most important
causes of ill-health among elderly people, causing an estimated 65,000 fractures in 2000-01. If nothing is
done, fracture rates are estimated to increase from one every 8.1 minutes in 2001, to one every 3.7 minutes in
2021. Falls among the elderly are also a major health with about a third of people over 70years falling at least
once every year. Almost 90% of all hip fractures result from the impact of a fall. This project will trial an
annual dose of vitamin D to the elderly at high risk of vitamin D deficiency, falls and fractures. Fifteen
hundred women will be supplemented with either vitamin D or a placebo "dummy" pill at the beginning of
winter for five years. The supplementation will take place through their local doctor and researchers will
expect to see fewer falls and bone fractures occurring in those receiving vitamin D than in the group receiving
the placebo.
Research achievements (from final report):
The Vital D study successfully recruited 2,317 women aged at least 70 years and who were assessed as at a
higher risk of fragility fracture or osteoporosis. Although the initial NHMRC 5-year grant funding has finished,
the study has been awarded further NHMRC funding to extend the project's outcomes. All participants will
complete the study during 2008. The findings have been extended to investigate not only the prevention of falls
and fractures, as originally planned but also to investigate if vitamin D supplementation improves mental health
in the elderly and if vitamin D supplementation over a number of years reduces the overall use and cost of
medical and hospital services. Since commencing this project in 2003 the many potential benefits of an
adequate to high vitamin D status has received much scientific attention. The project's pragmatic design
continues to have much appeal. The concept of a once-a-year dose of vitamin D tablets holds promise as
several international studies on vitamin D supplementation have reported low compliance of the study tablets
when participants were required to take calcium and vitamin D tablets on a daily basis. The results of these
other studies generally show that vitamin D prevents falls and fractures when targeted to participants likely to
have a low vitamin D status. Not surprisingly when the analysis of results includes both those participants who
took the daily supplementation and those participants who were asked to but didn't take the tablets on a regular
basis, the evidence that vitamin D prevents falls and fractures is weaker. The results of other studies has also
shown that the dose of vitamin D needs to be sufficiently large to increase the levels of the vitamin in the blood
and to show benefits to bone health. Participants in our study -Vital D randomised to vitamin D have been
given an annual dose of 500,000 IU of vitamin D3 (cholecalciferol). This dose continues to be regarded as
sufficiently high.
Expected future outcomes:
NHMRC Research Achievements - SUMMARY
The main analysis comparing falls and fractures in participants taking the vitamin D tablets with those taking
placebo will commence later this year when all participants have finished the study and the research team are
no longer 'blinded' as to their active or placebo status.
Name of contact:
Dr Kerrie Sanders
Email/Phone no. of contact:
kerrie@barwonhealth.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 299831
CIA Name: Prof Geoffrey Nicholson
Admin Inst: University of Melbourne
Main RFCD: Endocrinology
Total funding: $432,645
Start Year: 2004
End Year: 2006
Grant Type: NHMRC Project Grants
Title of research award:
MALE OSTEOPOROSIS: A POPULATION-BASED STUDY IN GEELONGMALE OSTEOPOROSIS: A
POPULATION-BASED STUDY IN GEELONG
Lay Description (from application):
Osteoporosis is a term used to indicate that bones have become thin and fragile. During the ageing process
bone fragility increases and fractures occur more easily and more often. Fractures may also occur during
normal daily activities, with fractures of the spine, forearm and hip being common. However, many other sites
may fracture. This is a serious problem because fractures cause pain, disability and, sometimes, death.
Although previously overshadowed by its effect in women, osteoporosis is increasingly being recognised in
men. In Australia, 39% of all fractures occur in men and prognosis for fracture in men is worse than in women.
A consequence of increasing male longevity is that osteoporosis will affect a growing number of Australian
men. It is anticipated that between 1996 and 2051, the number of men with fracture will double, with a 4-fold
increase in the number of male hip fractures. Unless the problem of osteoporosis in men is addressed and
effective interventions are implemented, the substantial health burden imposed by age-related fractures will
continue to escalate. In this case-control study of fracture risk in men, men with fractures (cases) will be
identified prospectively for 3 years from radiological reports. Controls will be selected concurrently, at
random from electoral rolls. Anticipated number of cases and controls are 800 and 1400, respectively. Cases
and controls will be characterised for risk factors for fracture: bone density and bone geometry will be
measured, serum samples collected, and diet, lifestyle and medical history documented by questionnaire. The
advantage of this type of data is that information from patients with fracture will be used to tell us about the
risk of fracture in healthy, unaffected men and about the characteristics of the Australian male population at
risk for fracture. The information can be used in decision making for the individual and in policy making for
the whole population.
Research achievements (from final report):
This large population-based epidemiological study enrolled 1,540 men (aged 20-97 years) to evaluate major
fracture risk factors. Assessments included bone mineral density (BMD), demographic, anthropometric and
clinical data; diet; osteoporosis risk factors; medical, falls and fracture history; drug exposures; muscle strength
and gait; and fasting blood samples for biochemical, hormonal and genetic analysis. , BMD reference ranges
will be made available for use on all densitometers across Australia, once finalised. Using bone densitometry,
measurement of vertebral height identified alterations in vertebral dimensions that define fracture. We have
determined age distribution of newly recognised vertebral fractures for ambulatory men and shown that these
fractures remain largely undiagnosed, are associated with poor quality of life, compromised mobility, balance
and physical activity. Relatively few high trauma fractures occur among elderly men whereas they predominate
in younger men., Among men with depression, BMD is reduced, suggesting that depression may be an
osteoporosis risk factor. Metabolic syndrome, a combination of features realted to obesity associated with
increased risk cardiovascular was identified in nearly 1/3 of middle-aged and elderly men. These men have
increased BMD, possibly related to skeletal loading. We have also reported that men with prostate cancer have
reduced BMD. Magnetic resonance imaging was explored as a promising technique for identifying structural
parameters of bone associated with ageing and bone fragility.
Expected future outcomes:
Development of a clinically useful fracture risk score incorporating multi-site bone mineral density, clinical
risk factors, biomarkers and structural parameters of bone, investigation of a common aetiology for
osteoporosis and depression based on predictive value of markers of inflammation and inflammatory cytokines,
further evaluation of the metabolic syndrome in men.
NHMRC Research Achievements - SUMMARY
Name of contact:
Assoc Prof Julie Pasco
Email/Phone no. of contact:
juliep@barwonhealth.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 299944
CIA Name: Dr Andrew Cook
Admin Inst: University of Melbourne
Main RFCD: Rheumatology and Arthritis
Total funding: $481,500
Start Year: 2004
End Year: 2006
Grant Type: NHMRC Project Grants
Title of research award:
The role of the plasminogen activators (PAs), urokinase-PA and tissue-type PA in arthritisThe role of the
plasminogen activators (PAs), urokinase-PA and tissue-type PA in arthritis
Lay Description (from application):
Many diseases, such as rheumatoid arthritis (RA), are inflammatory by nature. Intra-articular fibrin deposition
is an early and persistent hallmark of inflammatory responses, resulting from an altered balance between
coagulation (the production of fibrin) and fibrinolysis (the breakdown of fibrin). This fibrin accumulation can
have adverse effects in RA, including mediating and/or enhancing inflammation, and contributing to
subsequent joint damage. The plasminogen activators (PA), urokinase PA (u-PA) and tissue-type PA (t-PA)
convert plasminogen into plasmin which can then breakdown the accumulated fibrin. Their presence in RA
patients would therefore be beneficial. However, u-PA is also implicated in cell migration leading to
inflammatory cells accumulating in the joint, and cartilage destruction, both of which are detrimental to disease
outcome. In the joints of RA patients there are high levels of u-PA and low levels of t-PA. We, and our
collaborators, have found that in the absence of t-PA, disease is exacerbated, whilst in the absence of u-PA, the
outcome depends on the type of disease, either exacerbating or ameliorating disease. This highlights the
different roles u-PA can have. The current proposal aims to determine the role of u-PA in inflammation and
arthritis, and whether enhancing t-PA can have beneficial outcomes with respect to disease severity. In
addition, we will also study whether intra-articular fibrin deposition can, in fact, drive the inflammatory
reaction and cartilage destruction seen in RA. The findings will be important for our understanding of the role
of fibrin accumulation in the inflammatory and destructive processes that occur in RA, and the roles of u-PA
and t-PA in enhancing and preventing them respectively. Information gained will provide clues for useful
strategies for the treatment of human inflammatory diseases, including RA.
Research achievements (from final report):
Many diseases, such as rheumatoid arthritis (RA), are inflammatory by nature. Fibrin deposition within the
joint is an early and persistant hallmark of inflammatory responses, resulting from an altered balance between
coagulation (the production of fibrin to form a clot) and fibrinolysis (the breakdown of fibrin). This fibrin
accumulation can have adverse effects in RA, including mediating and/or enhancing inflammation, and
contributing to subsequent joint damage. The plasminogen activators (PA), tissue-type PA (t-PA) and
urokinase PA (u-PA), convert plasminogen to plasmin which can breakdown fibrin. The presence these PAs in
RA would therefore be beneficial. However, u-PA is also implicated in cell migration leading to inflammatory
cells accumulating in the joint, and cartilage destruction, both of which are detrimental to disease outcome. We
have found that t-PA and u-PA do indeed have differing roles during inflammatory responses and arthritis
development, with the main action of t-PA being in fibrin breakdown, whereas u-PA has several roles and its
main action differs depending on the type of inflammatory response. u-PA appears to play a role in ther
activation of the complement system which forms part of our immune system destroying pathogens, and which
is implicated in RA. Chronic inflammatory diseases, such as RA, are a vast burden to the community and
represent unmet medical needs. The benefits of understanding the differing roles of the PAs in inflammation
and disease means more specific therapies can be developed. A therapy that targets u-PA, but not t-PA, is
likely to be beneficial for the treatment of RA.
Expected future outcomes:
Future outcomes will include a better understanding of the role urokinase plasminogen activator (u-PA) plays
in complement activation, which will have implications not only for rheumatoid arthritis (RA), but many other
diseases. More targetted treatments specific for u-PA or tissue-type PA are also likely given our better
understanding of their differing roles in inflammation and disease.
NHMRC Research Achievements - SUMMARY
Name of contact:
Andrew Cook
Email/Phone no. of contact:
adcook@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 299968
CIA Name: Prof John Wark
Admin Inst: University of Melbourne
Main RFCD: Endocrinology
Total funding: $639,050
Start Year: 2004
End Year: 2006
Grant Type: NHMRC Project Grants
Title of research award:
Smoking cessation and bone health: observational and intervention studies in twins and a Quitline
populationSmoking cessation and bone health: observational and intervention studies in twins and a Quitline
population
Lay Description (from application):
Osteoporosis is a major health problem that causes bones to break (fracture) easily. Many bones are
susceptible, with hip fractures being the worst outcome of osteoporosis. They cause pain, disability, require
major health interventions (surgery and rehabilitation), lead to death in about 20% of cases, and the overall care
of hip fracture patients is very expensive. Osteoporosis is treated to reduce the risk of fractures. The prevention
and treatment of osteoporosis should include avoidance of factors known to bring on or worsen the condition.
Smokers are known to have an increased risk of osteoporosis and fractures. However, it is not known how
smoking brings on osteoporosis. Importantly, neither is it clear whether quitting smoking leads to improved
bone health (and a reduced risk of fractures). These are important questions for the community in general and
for smokers with osteoporosis in particular. We will endeavour to answer these questions by studying twins
who do and do not smoke and by observing what happens to measures of bone health (bone mineral density
and other factors) in people attempting to quit smoking. New information gained from these studies may lead
to better ways of avoiding or treating the damage that smoking does to bone. We may also become able to
predict the benefit to bone when people quit smoking.
Research achievements (from final report):
Study 1: we have recruited and evaluated 84 smoking-discordant twin pairs. This approaches the
conservatively estimated required sample of 86 pairs. 34 of these pairs were seen at the RMH site, 50 at
RNSH., Study 2: recruitment of smoking-concordant twin pairs, both willing to cease smoking, has proven
difficult. To date, 7 pairs have been recruited and completed visits at the RMH site, 1 twin pair at RNSH;
conservatively, 28 pairs were required and recruitment is ongoing. We have also completed a controlled, shortterm smoking cessation trial in 48 subjects (32 smokers, 16 non-smokers) to augment the data to be obtained in
the smoking-concordant twin smoking cessation study. Samples are ready for analysis in this study. , Study 3: a
long-term smoking cessation study in Quitline callers; we have recruited 419 subjects to date. This is at our
recruitment target, which appears very conservative given a very high retention rate in this group. The quitting
rate at 2 weeks is 63%, at 6 months 37% and at 12 months 33%. These figures are a little greater than reported
in the literature and are re-assuring regarding the adequacy of our sample size. To date, 113 subjects have
completed 1 year visits.
Expected future outcomes:
(i)
to improve understanding of the
mechanisms underlying the bone deficits and increased fracture risk observed in smokers compared with nonsmokers, , (ii)
to examine the reversibility of
smoking-associated bone and mineral abnormalities.
Name of contact:
Professor John D Wark
Email/Phone no. of contact:
jdwark@unimelb.edu.eu
NHMRC Research Achievements - SUMMARY
Grant ID: 350297
Start Year: 2005
CIA Name: Prof Kim Bennell
End Year: 2008
Admin Inst: University of Melbourne
Grant Type: NHMRC Project Grants
Main RFCD: Rehabilitation and Therapy: Occupational and Physical
Total funding: $480,850
Title of research award:
Effects of laterally wedged insoles on symptoms and disease progression in knee osteoarthritisEffects of
laterally wedged insoles on symptoms and disease progression in knee osteoarthritis
Lay Description (from application):
Knee arthritis is a painful, disabling, costly condition particularly affecting the elderly. As there is presently no
cure for knee arthritis, strategies that slow progression of the disease will reduce the personal and societal
burden of arthritis. Most research has focussed on drug therapies, which are effective in reducing pain and
disability but have side effects and are expensive. Insoles worn inside the shoes are a simple, cheap, selfadministered intervention with the potential to slow disease progression in certain patients, in addition to
managing symptoms. However, to date there has been little quality research investigating the effectiveness of
insoles in knee arthritis. This study aims to see whether 12 months of wearing insoles can lead to
improvements in knee pain and function and slow disease progression in 200 people with knee arthritis. It will
use state-of-the-art technology, magnetic resonance imaging, to measure changes in the amount of knee
cartilage. This research is timely and the findings will be of major significance as there is increasing worldwide attention on slowing progression of knee arthritis. Insoles are one of the few non-drug therapies with the
potential to influence both symptoms and disease progression. If the results show that insoles are beneficial,
then this research will: 1. Better inform clinical guidelines to firmly recommend insoles to manage knee
arthritis 2. Provide the basis for developing education strategies for health care practitioners and patients about
the benefits of insoles 3. Provide the impetus to make insoles more readily available directly to patients 4.
Ultimately lead to better patient outcomes
Research achievements (from final report):
The majority of clinical guidelines recommend lateral wedge shoe insoles for medial knee osteoarthritis (OA),
despite limited and equivocal evidence of efficacy. The primary aim of this randomised controlled trial was to
assess the efficacy of lateral wedge insoles for improving symptoms and slowing structural disease progression
compared with control insoles in medial knee OA. 200 people with knee OA and aged 50 or more were
recruited from the community in Melbourne, Australia. Participants wore either full-length 5 degree lateral
wedged insoles or flat control insoles inside their shoes daily for 12 months. Measurements were taken at
baseline and 12 months later and included measures of pain, physical function, quality of life and knee joint
structure (from magnetic resonance imaging). Ninety percent of participants completed the study. The results
showed that there were no significant differences between the lateral wedge insole and the control insole
groups for any of the measures. This suggests that lateral wedge insoles worn for 12 months provide no
symptomatic or structural benefits compared to a flat control insole.
Expected future outcomes:
This study does not support the use of lateral wedge insoles in the management of people with medial knee
osteoarthritis. This is likely to alter future recommendations of clinical guidelines.
Name of contact:
Kim Bennell
Email/Phone no. of contact:
k.bennell@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 350346
CIA Name: Dr Rachel Davey
Admin Inst: University of Melbourne
Main RFCD: Orthopaedics
Total funding: $487,500
Start Year: 2005
End Year: 2007
Grant Type: NHMRC Project Grants
Title of research award:
The role of androgens in osteoblast development and bone metabolism.The role of androgens in osteoblast
development and bone metabolism.
Lay Description (from application):
Maintenance of the skeleton involves the processes of bone formation by cells known as osteoblasts and bone
breakdown by cells known as osteoclasts. When these processes become unbalanced, bone loss results, which
is the basis of osteoporosis. The reduced bone mass found in osteoporosis leads to an increased susceptibility to
bone fracture. 1 in 2 women and 1 in 3 men over the age of 60 will suffer a fracture due to osteoporosis. The
increasing incidence of osteoporotic fractures has lead to renewed efforts to understand the actions of
hormones on bone. Androgens, the male sex hormones, have beneficial effects on skeletal growth and bone
maintenance in both males and females by stimulating osteoblasts. It is believed that androgens act by binding
to a specific protein known as the androgen receptor (AR), which is only found in androgen-responsive cells.
Although it is well documented in human and animal models that androgens stimulate osteoblasts to increase
the formation of bone, the way in which they act on osteoblasts remains poorly understood. The aim of this
project is to investigate the effects of androgens at different stages of the developing osteoblast. This will be
achieved by making transgenic mice in which the androgen receptor has been inactivated only in osteoblasts at
specific stages of their development. We hypothesise that the inactivation of the androgen receptor will have
dramatic effects on the development and function of osteoblasts.This project will help clarify the role
androgens play in bone formation and will give fundamental insights into the basic biology of bone in both
normal and disease processes. As androgens are one of the few agents that act to increase bone formation,
understanding the way in which they act is important for the treatment of osteoporosis in males and females.
We believe that this research is of great importance as osteoporosis becomes more prevalent in our aging
population.
Research achievements (from final report):
The aim of this research was to investigate the role of the male sex hormones, androgens, in the development
and function of the bone forming cells (osteoblasts), in males. To achieve this we generated and characterised a
number of in vivo mouse model systems in which the target for androgens, the androgen receptor (AR), was
inactivated either a) in all tissues (Global-ARKOs) or b) specifically in osteoblasts (OBL-ARKOs). The first
aim was to determine the effect of inactivating the AR in all tissues by generating Global-ARKO mice. GlobalARKO males had female external genitalia and decreased bone due to increased bone resorption (breakdown).
These data clearly show that the actions of androgens via the AR are indispensable for male sexual
differentiation and bone maintenance. The second aim was to determine the effect of inactivating the AR only
in mature osteoblasts. This led to vertebral bone loss due to increased bone resorption, thereby demonstrating
that androgens acting directly via the AR in mature osteoblasts to maintain bone by regulating bone resorption.
The final aim of this project was to determine the effect of inactivating the AR only in mineralising osteoblasts.
This resulted in trabecular and cortical bone loss due to increased bone resorption and abnormalities in the
mineralisation of bone matrix. Our findings demonstrate that androgens act via the AR in mineralising
osteoblasts to maintain bone by regulating bone resorption and the coupling of bone matrix synthesis to
mineralization. This action is most important during times of bone accrual and high rates of bone remodelling.
These studies have further advanced our understanding of how the male sex steroids act on bone. This
knowledge will allow us to further understand how bone diseases such as osteoporosis develop, which in turn,
will provide avenues for the prevention and reversal of bone fragility in both men and women.
Expected future outcomes:
This research is currently further investigating the mechanism of androgen action on bone by identifying target
genes that are directly regulated by the androgen receptor in osteoblasts.
NHMRC Research Achievements - SUMMARY
Name of contact:
Dr Rachel Davey
Email/Phone no. of contact:
r.davey@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 350487
CIA Name: A/Pr Amanda Fosang
Admin Inst: University of Melbourne
Main RFCD: Orthopaedics
Total funding: $540,600
Start Year: 2005
End Year: 2007
Grant Type: NHMRC Project Grants
Title of research award:
Cartilage destruction in joint disease: studies with ADAMTS-4 and ADAMTS-5 deficient miceCartilage
destruction in joint disease: studies with ADAMTS-4 and ADAMTS-5 deficient mice
Lay Description (from application):
In healthy joints the proteoglycan, aggrecan, gives cartilage compressive resilience to permit weight bearing,
but in disease aggrecan is degraded by ADAMTS enzymes. The challenges to the field are to determine which
ADAMTS is involved, when these enzymes are active and precisely where they come from. We hypothesise
that ADAMTS-4 and/or ADAMTS-5 is involved in cartilage pathology. To test this hypothesis we aim to [1]
Generate mice containing mutant ADAMTS-4 and/or -5 in all cells, or [2] in cartilage cells only. [3] Analyse
mutant mice for changes in skeletal architecture, changes in ADAMTS mRNA and protein, and changes in
aggrecan breakdown products. [4] Assess disease severity in mutant mice in in vivo models of joint disease.
We already have mice with ADAMTS-4, or -5, mutated in all tissues and we are generating the double mutants
now. We will also generate single and double mutants with dysfunctional enzymes in cartilage only. We will
examine skeletal structure by histology and X-ray at all ages and monitor for expression of ADAMTS-1 and -9
to detect any compensatory over-production of other potential 'aggrecanases'. We will also do co-culture
experiments in which cartilage and synovial cells from combinations of mutant and control mice will be
incubated together to determine whether synovial ADAMTS can penetrate and degrade aggrecan in cartilage.
Finally we will induce arthritis in mutant and control mice and monitor them to detect differences in the time of
disease onset, the rate of disease progression and overall disease severity. A comparison of whole-mouse with
cartilage only mutants in the in vivo models will complement the in vitro co-culture studies and determine
whether other joint tissues such as synovium and joint capsule can also produce ADAMTS enzymes that
destroy cartilage. This is not known. Together these experiments will reveal if, where and when ADAMTS-4
and/or -5 are active, and whether indeed they are the best targets for drug development.
Research achievements (from final report):
The ability of cartilage to protect the surface of bones from wear and tear is dependent upon the integrity of a
proteoglycan called aggrecan. In the early stages of arthritis, aggrecan is degraded by metalloenzymes and lost
from cartilage. Our laboratory is researching which families of enzymes are important in aggrecan degradation.
We have engineered mutant mice that lack active 'aggrecanases' and studied these mice in experimentallyinduced arthritis. We discovered that an enzyme called ADAMTS-5 is the major aggrecanase in mice; we
published this work in the world-premier journal, Nature in 2005. The attention of arthritis researchers and the
pharmaceutical industry has since focussed on ADAMTS-5, for further study and for the design of arthritis
therapies.
Expected future outcomes:
ADAMTS-5 inhibitors will join the list of compounds being tested for potential as arthritis therapies.
Name of contact:
A/Prof. Amanda Fosang
Email/Phone no. of contact:
amanda.fosang@mcri.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 384370
Start Year: 2006
CIA Name: Dr Catherine van Vliet
End Year: 2011
Admin Inst: University of Melbourne
Grant Type: Early Career Fellowships (Australia)
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $342,498
Title of research award:
The role of T-cell protein tyrosine phosphatase in TNF signallingThe role of T-cell protein tyrosine
phosphatase in TNF signalling
Lay Description (from application):
Not Available
Research achievements (from final report):
This project examined the role of a population of specialist immune cells, called T cells, in infection and
disease. Studies undertaken at Monash University established an important role for T cell tyrosine phosphatase
(TCPTP) in preventing autoimmune diseases. Mutations in TCPTP have been found to be associated with a
number of human autoimmune diseases. Using a system where we could delete this protein exclusively from T
cells in mice, we identified TCPTP as a negative regulator of T cell receptor (TCR) signalling. We found that
TCPTP dephosphorylates and inactivates Src family kinases downstream of the TCR to regulate T cell
responses. We showed that conditional deletion of TCPTP leads to enhanced TCR-driven selection in the
thymus and accumulation of memory T cells in the periphery. This research has provided important insights
into the role of TCPTP in autoimmune diseases in humans. , Research at the University of Melbourne has
examined the immune response of a population of tissue resident immune memory T cells (Trm) following
secondary infection with herpes simplex virus (HSV). HSV infects the skin and persists in a latent form in the
dorsal root ganglia, along with Trm that help maintain viral latency. Using a ganglion transplantation model of
HSV reactivation and a panel of recipient mice deficient for various immune cell types or signaling pathways,
we have established that monocytes from the host play an important role in activating the Trm during a
secondary immune response. Significantly, we have demonstrated that these Trm are not terminally
differentiated but are capable of renewed virus-specific proliferation.
Expected future outcomes:
Future outcomes of research into the role of TCPTP in autoimmune diseases could lead to novel therapeutics
for diseases such as type 1 diabetes and rheumatoid arthritis. While a greater understanding of tissue resident
memory T cells should provide impetus for a new generation of vaccines targeting these cells for enhanced
protective immunity.
Name of contact:
Catherine Van Vliet
Email/Phone no. of contact:
cjvv@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 400056
CIA Name: A/Pr Amanda Fosang
Admin Inst: University of Melbourne
Main RFCD: Rheumatology and Arthritis
Total funding: $529,723
Start Year: 2006
End Year: 2008
Grant Type: NHMRC Project Grants
Title of research award:
How important is collagen destruction in arthritis? A study with collagenase-resistant knockin miceHow
important is collagen destruction in arthritis? A study with collagenase-resistant knockin mice
Lay Description (from application):
Aggecan and collagen are important structural molecules in cartilage. Together they allow cartilage to bear
weight and resist compression. In arthritis, collagen is degraded by collagenases and aggrecan is degraded by
aggrecanases. Aggrecan loss is a feature of cartilage disease. Early aggrecan loss is well documented and
usually precedes clinical symptoms, suggesting that it is the initiating step in cartilage pathology. Aggrecan
loss precedes collagen damage in explant culture, however it is not known whether inhibiting aggrecanases is
sufficient to block cartilage damage long-term. In contrast, other studies suggest that aggrecan is only lost after
damage to the collagen scaffold. These studies propose that clipping of the collagen scaffold may initiate
aggrecan release; with progressive degeneration and collagen clipping, more aggrecan is lost, until ultimately
the scaffold is severely damaged and aggrecan is severely depleted. Cartilage can only withstand a limited
degree of collagen degradation and any significant damage to the network is widely considered to be
irreparable. It is unclear what role aggrecanases and collagenases have in initiating and perpetuating cartilage
damage. We have mice with aggrecan resistant to aggrecanases and mice with inactive aggrecanase. We will
also create mice with collagen resistant to collagenase. We will use these mice to determine the contribution of
collagenases and aggrecanases to the initiation and progression of cartilage damage, in three models of joint
disease. We will identify differences in time of disease onset, rate of disease progression and disease severity.
The results will show whether one or both activities is important for the initiation & progression of joint
disease. This will reveal whether single or combination therapies are required for the management of arthritis.
The research will inform the pharmaceutical industry on directions for the development of new drugs to
prevent joint disease.
Research achievements (from final report):
The ability of cartilage to protect the surface of bones from wear and tear is dependent upon the integrity of the
molecules collagen and aggrecan. In arthritis, the collagen scaffold is degraded by collagenases and aggrecan is
degraded by aggrecanases. , Aggrecan loss is a feature of cartilage disease. Early aggrecan loss is well
documented and usually precedes clinical symptoms, suggesting that it is the initiating step in cartilage
pathology. Aggrecan loss precedes collagen damage in in vitro cultures, however it is not known whether
inhibiting aggrecanases is sufficient to block cartilage damage long-term. , In contrast, other studies suggest
that aggrecan is only lost after damage to the collagen scaffold. These studies propose that clipping of the
collagen scaffold by collagenases may initiate aggrecan release; with progressive degeneration and collagen
clipping, more aggrecan is lost, until ultimately the scaffold is severely damaged and aggrecan is severely
depleted. Cartilage can only withstand a limited degree of collagen degradation and any significant damage to
the network is irreparable. , Because it is unclear what role aggrecanases and collagenases have in initiating
and perpetuating cartilage damage, we engineered mutant mice in which the collagen scaffold is resistant to
collagenases and/or the aggrecan is resistant to aggrecanases. We are using these mice to determine the
contribution of collagenases and aggrecanases to the initiation and progression of cartilage damage, in three
models of joint disease. Early comparisons of the mice indicate that protecting the collagen scaffold is more
likely to prevent cartilage erosion than protecting aggrecan. The research will help prioritise strategies for
blocking cartilage erosion in arthritic disease.,
Expected future outcomes:
Although it is early days, we expect that the pharmaceutical companies will give greater consideration to
therapies that protect the collagen scaffold (collagenase inhibitors), rather than therapies that protect against
aggrecan degradation alone.
NHMRC Research Achievements - SUMMARY
Name of contact:
A/Prof Amanda Fosang
Email/Phone no. of contact:
amanda.fosang@mcri.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 400057
CIA Name: A/Pr Amanda Fosang
Admin Inst: University of Melbourne
Main RFCD: Rheumatology and Arthritis
Total funding: $664,574
Start Year: 2006
End Year: 2010
Grant Type: Established Career Fellowships
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
Arthritis is a major cause of disability in Australia. There are no treatments for the cartilage destruction seen in
osteoarthritis and other arthritides. The big questions in the cartilage field are, how is cartilage degraded, what
are the key destructive enzymes, and how can we block their activity? My lab has tackled these questions headon during the past 5 years. Using mice with cartilage aggrecan resistant to either ADAMTS enzymes or MMP
enzymes, we showed that ADAMTS, but not MMP-resistant mice were protected from cartilage erosion in
experimental arthritis, identifying ADAMTS activity as a target for arthritis therapies. We made the startling
discovery that MMP-resistant mice developed worse disease, and we discovered a new ADAMTS activity in
cartilage. We next showed that ADAMTS-5, not ADAMTS-4, drives cartilage erosion in the mouse;
ADAMTS-5 is now a key target for the development of osteoarthritis therapies. Surprisingly, our enzymeresistant and enzyme-deficient mice have no skeletal phenotype, suggesting that contrary to the paradigm,
neither MMP nor ADAMTS activities are required for skeletal remodelling in growth and development. To
explain this paradox, we proposed an entirely new mechanism of cartilage degradation and confirmed a role for
lysosomal exocytosis in this process. Whether collagen loss or aggrecan loss is most detrimental for cartilage
integrity is unknown. Our newly-developed collagenase-resistant mouse now makes it possible to address this
question directly. This exciting mouse has a striking and unanticipated skeletal phenotype, which shows we
have targeted a key regulatory process, not previously recognised in skeletal development.
Expected future outcomes:
Our data will inform the research community and the pharmaceutical industry about the enzymes that remodel
aggrecan and collagen during arthritic diseases and during the transition from cartilage to bone.This
information is essential for identifying suitable targets for drug discovery.
Name of contact:
A/Prof. Amanda Fosang
Email/Phone no. of contact:
amanda.fosang@mcri.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 400089
CIA Name: Prof John Wark
Admin Inst: University of Melbourne
Main RFCD: Endocrinology
Total funding: $469,605
Start Year: 2006
End Year: 2008
Grant Type: NHMRC Project Grants
Title of research award:
The effect of antiepileptic medication on indices of bone health and risk factors for falls and fracturesThe effect
of antiepileptic medication on indices of bone health and risk factors for falls and fractures
Lay Description (from application):
Epilepsy is a common brain disorder and most patients with epilepsy take anti-epileptic drugs (AEDs) for many
years. These patients have high rates of bone fractures, but the reasons are uncertain. Earlier studies identifying
an association between AED use and bone disease were performed on institutionalised patients, and more
recent studies on outpatient populations have been conflicting. A better understanding of this problem is critical
for designing potential preventive measures and treatments. One important additional mechanism by which
AEDs may increase fracture risk is impairment of gait and balance, leading to a high risk of falls. We have
novel data demonstrating the power of a Twin and Matched Sibling approach to study this important problem.
This study showed that chronic AED use was associated with significant deficits in bone mineral density
(BMD), a key predictor of the risk of fractures. The proposed project will ask the following questions: 1. Is
BMD and estimated bone strength lower in the bones most at risk for fracture in women and men chronically
taking AEDs? 2. Is the loss of bone in measurements over time greater in patients continuing to take AEDs? 3.
Is the risk of bone loss greater for certain types of AEDs, and is the risk influenced by length of exposure, age
and menopausal status? 4. How does AED treatment lead to reductions in BMD and bone strength? 5. Are
measures of muscle strength, gait and balance impaired in patients taking AEDs compared with matched
people not taking AEDs? The proposed study will utilise twins and pairs of siblings to investigate the effects of
the long-term use of AEDs for epilepsy on measures of bone mass and strength, indices of bone turnover,
vitamin D status, calcium regulating hormones, mineral levels, sex hormone levels, and measures of muscle
strength, gait and balance function. In addition, a group of patients newly commencing AED treatment for
epilepsy will be studied over 2 years.
Research achievements (from final report):
, Anti-epileptic drugs (AEDs) are required long-term for patients with epilepsy and several other disorders.
Fractures are a major adverse outcome in people taking AEDs. , This project explored the causes of AEDassociated bone fractures using several approaches. One was the powerful exposure-discordant twin/ sibling
pair model, where one member of each pair used AEDs and the other did not. We found significant deficits in
bone mineral density (a key indicator of bone fragility) in people taking AEDs; a person's age and duration of
treatment added to their risk. , The second approach was a cohort study in newly-diagnosed epileptic patients
and non-treated subjects, following indices of bone health for 2 years. This study demonstrated accelerated
bone loss (e.g., at the hip) in newly-treated patients. Further observations may identify specific AEDs that
cause bone loss and fractures. , We also conducted a comprehensive assessment of falls risk in AED-treated
subjects and their non-treated twins and siblings, identifying multiple balance impairments in the AED-treated
subjects. Poor balance and bone fragility are therefore key determinants of the increase in fractures associated
with AED use. A survey of 150 epilepsy patients identified many with high falls risk, confirming the need for
intervention in this population. , This research is unique and important, improving understanding of AEDassociated fracture risk. We are now launching the first specific treatment trial for AED-associated bone loss
and plan a physcial activity intervention trial seeking to reduce AED-associated falls. Our ultimate aim is to
improved bone health in people taking AED therapy.
Expected future outcomes:
Over the next ive years we expect to complete the first RCT of treatment for AED-induced bone loss, to
conduct the first physical activity RCT in prevention of falls during AED therapy and to have translated the
findings into improved clinical care and outcomes for AED-treated patients.
NHMRC Research Achievements - SUMMARY
Name of contact:
Professor John D Wark
Email/Phone no. of contact:
jdwark@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 400139
CIA Name: Prof Ego Seeman
Admin Inst: University of Melbourne
Main RFCD: Endocrinology
Total funding: $751,823
Start Year: 2006
End Year: 2008
Grant Type: NHMRC Project Grants
Title of research award:
Structural Basis of Femoral Neck StrengthStructural Basis of Femoral Neck Strength
Lay Description (from application):
Fractures, in particular femoral neck (FN) fractures, are a huge public health problem resulting in disabilities,
mortality and financial cost to the community. The prevention of these fractures is based on estimation of bone
strength. The decision whether someone needs treatment, or the effectiveness of a treatment can only be judged
by estimating bone strength. The bottom line is that currently we cannot correctly estimate bone strength.
Present methods such as bone mineral density (BMD) perform poorly. Most people who fracture are not
detected by BMD because their BMD is either normal or high, and many people with low BMD never fracture.
The main aim of this grant application is to develop new tools to allow doctors and scientists worldwide to
better estimate FN strength. To develop new methods to replace BMD, scientists need to make use of the 3D
aspects of the bone such as size, shape and internal architecture. Presently, these 3D aspects (structure) have
not been adequately studied and scientists incorrectly approximate them. As a result new methods are not any
better. A good quantification of structure is needed. Another reason for the failure to accurately estimate the
strength of bones is that estimates are based on a single parameter whereas the bone, like any architectural
structure (e.g. building), comprises many components acting together to maintain its strength. To determine the
strength based on density alone is incorrect; the size, the shape and things inside the structure need to be
considered as a whole. After quantifying correctly the structure and components of bone strength, we will
determine how they can be used individually and together to better estimate the strength of the FN in men and
women. Tools generated will be used to better determine people likely to fracture and needing treatment; to
better tailor and monitor treatments. A better understanding of the causes and epidemiology of fractures will
ensue.
Research achievements (from final report):
Research in osteoporosis has focused in the role of trabecular bone (the spongy bone inside the cortical shell)
loss as the cause of osteoporosis because it was commonly believed that bone loss with advancing age is
largely trabecular. In this project we demonstrate that bone loss and fragility in old age originates not from the
trabecular compartment, but from the cortical compartment (outer shell of bone). This work received an award
from the American Society for Bone and Mineral Research., Furthermore, we identified the mechanism
through which the cortical bone becomes fragile - that is, by enlargement and fusions of the holes inside the
cortex, in particularly next to the marrow cavity. The end result of this process is the transformation of a
previously compact cortex in young age into a spongy-like structure in old age leading to fragility., We showed
that this process is poorly detected by bone densitometry ( the currently used diagnosis tool) and this may
explain why most people with fragile bones are missed when the bone density test is used. Understanding of
the process has led us to develop a new diagnostic test. This test is currently subject to a patent application and
its ability to improve fracture prediction will be tested soon., Insights into how bone size, shape and bone
quality interact to make bone strong were have also being studied.
Expected future outcomes:
It is expected that quantification of porosity in clinical settings will allow better identification of individuals at
risk for fracture. Funds have been requested to test this hypothesis.
Name of contact:
Ego Seemna
Email/Phone no. of contact:
egos@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 400144
Start Year: 2007
CIA Name: Prof John Hamilton
End Year: 2007
Admin Inst: University of Melbourne
Grant Type: NHMRC Development Grants
Main RFCD: Clinical Sciences not elsewhere classified
Total funding: $334,000
Title of research award:
Development of a highly potent, fully human anti-GM-CSF monoclonal antibodyDevelopment of a highly
potent, fully human anti-GM-CSF monoclonal antibody
Lay Description (from application):
Many diseases, such as arthritis, have unwanted inflammatory reactions. Better drugs are needed to control
inflammation. A powerful antibody to a significant pro-inflammatory cytokine will be generated; this antibody
will be especially designed so that it will not be rejected by patients. Because of its properties it will cost the
community less than similar therapeutics. Because inflammatory diseases are common many patients will
benefit from our therapeutic.
Research achievements (from final report):
The generation of a truly human neutralizing anti-GM-CSF antibody.
Expected future outcomes:
The development of such an antibody for clinical trials.
Name of contact:
Professor John Hamilton
Email/Phone no. of contact:
jahami@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 400145
Start Year: 2006
CIA Name: Prof John Hamilton
End Year: 2010
Admin Inst: University of Melbourne
Grant Type: Established Career Fellowships
Main RFCD: Clinical Sciences not elsewhere classified
Total funding: $826,161
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
Several achievements in the areas of macrophage and CSF biology were made. Some of these are as follows: ,
Low dose joint implant particles induce monocyte/macrophage survival. Hypoxia prolongs
monocyte/macrophage survival. Glucose metabolism is required for oxidized LDL-induced macrophage
survival., Detection and properties of the human proliferative monocyte subpopulation. The generation and
properties of human macrophage populations from hemopoietic stem cells. The proliferative human monocyte
subpopulation contains osteoclast precursors., GM-CSF and M-CSF (CSF-1)-dependent macrophage
phenotypes display differences in cytokine profiles and transcription factor activities - implications for CSF
blockade in inflammation. GM-CSF- and M-CSF-dependent macrophage phenotypes display differential
dependence on type I interferon signaling. Macrophage lineage phenotypes and osteoclastogenesis complexity in the control by GM-CSF and TGF-beta., The significance and potential benefits of these
achievements will lie in the development of therapeutics to control macrophage and CSF function particularly
in chronic inflammatory/autoimmune conditions such as rheumatoid arthritis, multiple sclerosis, lung
inflammation, psoriasis, nephritis, atherosclerosis etc.
Expected future outcomes:
Drugs will be developed to control the number and activation state of a white blood cell important for the
inflammation and tissue destruction observed in a disease such as rheumatoid arthritis. Recent evidence also
suggests that progression of certain tumours may also be slowed down in the same way.
Name of contact:
Professor John Hamilton
Email/Phone no. of contact:
jahami@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 400210
CIA Name: Dr Richard Osborne
Admin Inst: University of Melbourne
Main RFCD: Health Promotion
Total funding: $343,875
Start Year: 2006
End Year: 2008
Grant Type: NHMRC Project Grants
Title of research award:
Can self-management education programs improve outcomes of people with osteoarthritis?Can selfmanagement education programs improve outcomes of people with osteoarthritis?
Lay Description (from application):
Arthritis is a very common disease associated with pain, disability and poor quality of life. An important way
that people with arthritis can deal with the disease is through using a variety of self-management behaviours
and coping strategies as well as becoming well informed about the best available treatments. A specific course
was developed in he US to help people self-manage. It has been available in Australia for 20 years through
Arthritis Foundations and has become their core business. Treatment guidelines used by doctors to treat people
with arthritis regularly recommend that patients should be referred to such courses. Although the course is
widely distributed, the evidence scientific evidence regarding its effectiveness is patchy, and some overviews
suggest it is not useful at all. Confusion exists regarding the value of the course. While treatment guidelines
advise doctors to refer patients to the program by very few GPs, Rheumatologist or Orthopaedic surgeons do
refer. The proposed study is a large controlled trial which will provide essential evidence to inform patients,
doctors and policy makers on the benefits of the course. It will involve people with well defined moderate to
severe arthritis who have consulted a surgeon or rheumatologist. People will be randomised to receive the
intervention (two hours per week, six session course including an 'arthritis self-help' book) will be compared
with people in a control group (who only receive the book without instruction). People will be followed for 1
year to see if the course improves quality of life, health behaviours, and whether less health care resources (ie
attendance at doctors or less medication use) are used. The results of this study will be influential in
determining government policy as the number of people with chronic diseases like arthritis is rapidly growing
and the acute healthcare system, including hospitals, are poorly equipped to deal with this growing problem.
Research achievements (from final report):
Group-based patient education programs such as the Arthritis Self-Management Program (ASMP) are widely
applied and aim to impart skills for managing arthritis. Clinical guidelines indicate that people with
osteoarthritis (OA) should be referred to ASMPs as part of routine management, however the effectiveness of
the program is unknown. , Previous research has mostly been conducted in the community setting among
people with mild OA; this project focused on people with moderate to severe OA who may be expected to
benefit most from an effective self-management intervention. , We screened large numbers (n=1,123) of
potentially eligible people across 7 public and private Victorian hospitals. Of those screened, 208 declared they
were not interested in such a course, 213 said they were unable to attend, 144 had insufficient English
language, 117 were not contactable, and 254 were ineligible for other reasons. Participation barriers included
course format (group-based/6 weeks), scheduling, location, family responsibilities or work commitments.
Overall, the nature or structure of the course deterred 565 (50%) of those approached and only relatively well
patients took part. Of the 187 eligible, only 120 were randomized. While data analysis is continuing,
preliminary analyses show that the ASMP had limited or no effect on patient outcomes across many domains. ,
This research provides insights into why people with arthritis do not participate in ASMPs, with implications
for the redesigning and planning of future programs. The ASMP may only be suitable for some people in the
outpatient setting and telephone, internet and multi-lingual programs are likely to better reach patients.
Expected future outcomes:
This study will inform the development of new arthritis programs. We are currently developing a patientfocused training program for health professionals to deliver self-management education and plan to develop an
internet-based intervention based on international protocols. Arthritis Foundations currently delivering
education programs will be encouraged to diversify their programs.
NHMRC Research Achievements - SUMMARY
Name of contact:
Richard Osborne
Email/Phone no. of contact:
richard.osborne@deakin.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 454435
CIA Name: A/Pr Amanda Fosang
Admin Inst: University of Melbourne
Main RFCD: Rheumatology and Arthritis
Total funding: $213,343
Start Year: 2007
End Year: 2008
Grant Type: NHMRC Project Grants
Title of research award:
Regulation of ADAMTS-5 activity by keratan sulphate-binding exositesRegulation of ADAMTS-5 activity by
keratan sulphate-binding exosites
Lay Description (from application):
Arthritis and musculoskeletal conditions are the predominant cause of disability in Australia. The burden of
arthritis is felt not only by patients, their families and carers, but also the labour market and the national
economy. There is a pressing need to identify new targets for design of inexpensive arthritis therapies. The
TNF antagonists have proved effective in managing rheumatoid arthritis (RA), but they are expensive,
administered by injection, and in general, only prescribed in Australia for patients who respond poorly to
DMARDs. Their long-term efficacy and safety is not yet determined. There are no treatments for osteoarthritis
(OA), the disease that occurs more frequently with age and is characterised by destruction of cartilage and
aggrecan. New drugs that protect against aggrecan breakdown are urgently needed for OA and they would also
be valuable adjunct therapies to the DMARDs for treatment of RA. We have discovered that the major
aggrecan-degrading enzyme is ADAMTS-5. ADAMTS-5 is, therefore, a potential target for arthritis therapies.
Unfortunately, drugs targeting the active site of ADAMTS-5 are predicted to fail, given the wide tissue
distribution of ADAMTS-5, the high level of homology between the active site of ADAMTS enzymes and
matrix metalloproteinases (MMPs), and the notorious failure of MMP active site inhibitors in clinical trials.
The aim of this project is to determine whether ancillary domains of ADAMTS-5 are a viable alternative target
to the active site. We have evidence to suggest that keratan sulphate, which is covalently attached to the
aggrecan core protein, can modulate aggrecan cleavage by ADAMTS enzymes. We aim to identify
opportunities for developing antagonists that block keratan sulphate binding, or keratan sulphate analogues that
block enzyme binding to its substrate. The data will inform the pharmaceutical industry on new directions for
modulating aggrecanolysis by ADAMTS-5.
Research achievements (from final report):
The ability of cartilage to protect the surface of bones from wear and tear is dependent upon the integrity of a
proteoglycan called aggrecan. In the early stages of arthritis, aggrecan is degraded by metalloenzymes and lost
from cartilage. In 2005 we discovered that the metalloenzyme ADAMTS-5 is the major aggrecan-degrading
enzyme in mouse (Stanton et al, Nature, 2005). ADAMTS-5 is now a target for arthritis therapies.
Unfortunately, drugs targeting the active site of ADAMTS-5 are predicted to fail, given the wide tissue
distribution of ADAMTS-5, the high level of homology between the active site of ADAMTS enzymes and
matrix metalloproteinases (MMPs), and the notorious failure of MMP active site inhibitors in clinical trials.
The aim of this project is to determine whether ancillary domains of ADAMTS-5 are a viable alternative target
to the active site. These domains are implicated in enzyme-substrate binding. We have evidence to suggest that
aggrecanase activity is modulated by keratan sulphate (KS), which is covalently attached to the aggrecan core
protein. To investigate whether ADAMTS-5 ancillary domains bind KS, and whether this binding modulates
activity, we expressed mutant ADAMTS-5 proteins with progressive deletion of the C-terminal ancillary
domains. The expression work is complete, but the KS interaction studies are ongoing.
Expected future outcomes:
We expect to identify opportunities for developing ADAMTS-5 antagonists that block keratan sulphate
binding, or keratan sulphate analogues that block ADAMTS-5 binding to its substrate. This information will
inform the pharmaceutical industry on alternative approaches to ADAMTS-5 catalytic inhibitors.
Name of contact:
A/Prof Amanda Fosang
NHMRC Research Achievements - SUMMARY
Email/Phone no. of contact:
amanda.fosang@mcri.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 454484
CIA Name: Dr Rachel Davey
Admin Inst: University of Melbourne
Main RFCD: Endocrinology
Total funding: $496,447
Start Year: 2007
End Year: 2009
Grant Type: NHMRC Project Grants
Title of research award:
The physiological role of calcitonin and its receptor in bone cell metabolism.The physiological role of
calcitonin and its receptor in bone cell metabolism.
Lay Description (from application):
Throughout adult life, bone tissue is continuously remodelled. The two main processes involved in bone
remodelling, are bone formation and bone breakdown. Bone formation is controlled by cells known as
osteoblasts and bone breakdown is controlled by cells known as osteoclasts. Under normal circumstances these
two processes are tightly coupled. Excessive breakdown of bone, causes these two processes to become
unbalanced and results in bone loss. This is the basis of many bone diseases such as osteoporosis, a condition
in which the bones become fragile and therefore more susceptible to fracture. 1 in 2 women and 1 in 3 men
aged 70 years and older suffer from osteoporosis in Australia. Despite this, the mechanisms which control
osteoclast breakdown of bone are not well understood. Our laboratory is interested in how hormones affect
osteoclast action. We plan to examine the role of the hormone calcitonin, an important inhibitor of osteoclastic
bone breakdown. This will be achieved by studying transgenic mice in which the receptor, or target, for
calcitonin is specifically removed from osteoclasts. This will allow us to precisely determine the role of
calcitonin in osteoclast function. Data generated by our research group indicates that calcitonin is also
involved in controlling bone formation, however, the way in which calcitonin acts on osteoblasts remains
poorly understood. Therefore, studying our transgenic mice will also help clarify the role calcitonin plays in
bone formation. Current treatment for osteoporosis involves the administration of drugs which inhibit bone
breakdown. This project will increase our understanding of how calcitonin acts to regulate bone breakdown
and bone formation and may assist in the design of new therapies for osteoporosis. We believe that this
research is of great importance as osteoporosis is becoming more prevalent as the population ages.
Research achievements (from final report):
The aim of this project was to investigate the physiological control of bone resporption and formation by the
calcitonin receptor (CTR)., To achieve this, we generated a viable global CTR knockout (global-CTRKO)
mouse model using the Cre/loxP system, in which the CTR is globally deleted by greater than 94%, but less
than 100%. Using this model, our data demonstrate that the CTR plays a modest physiological role in the
regulation of bone and calcium homeostasis in the basal state in mice. , To further characterise the
physiological role of calcitonin via the CTR in bone, we generated a mouse line in which the CTR is
specifically deleted in osteoclasts, the bone resorbing cells (OCL-CTRKOs). Our data indicate that the
inhibitory role of the calcitonin receptor on bone formation is not mediated via its actions in osteoclasts., We
have utilised our unique CTR deletion models to address the physiological role of the CTR in times of calcium
stress and showed that the calcitonin receptor protects against induced hypercalcaemia via its inhibitory action
on osteoclasts., Our data has provided insight into the physiological role of the calcitonin receptor. Our
findings demonstrating that the calcitonin receptor protects against induced hypercalcemia has clinical
implications for the management of thyroidectomized patients in times of calcium stress, such as during
pregnancy.
Expected future outcomes:
Whilst the current model specifically investigated the role of the CTR in osteoclasts in protecting against
induced hypercalcemia, the importance of CTR expression in other tissues remains unclear. The contribution of
the renal CTR in protecting against induced hypercalcemia will be determined in future studies by generating a
mouse model, in which the CTR is specifically deleted in renal cells.
Name of contact:
Dr Rachel Davey
NHMRC Research Achievements - SUMMARY
Email/Phone no. of contact:
r.davey@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 454686
Start Year: 2007
CIA Name: Prof Kim Bennell
End Year: 2008
Admin Inst: University of Melbourne
Grant Type: NHMRC Project Grants
Main RFCD: Rehabilitation and Therapy: Occupational and Physical
Total funding: $271,503
Title of research award:
Reducing knee load and slowing disease progression with conservative interventions in knee
osteoarthritisReducing knee load and slowing disease progression with conservative interventions in knee
osteoarthritis
Lay Description (from application):
Knee arthritis is a painful, disabling, costly condition particularly affecting the elderly. As there is presently no
cure for arthritis, interventions that slow progression of the disease will reduce the personal and societal burden
of arthritis. Recently it has been postulated that specific exercise that targets how the muscles are controlled by
the nervous system may have greater disease-modifying effects than exercise aimed at strengthening the
muscles. Data are beginning to highlight the complexity of muscle strategies adopted by the nervous system to
compensate for joint derangement in knee arthritis. It is our contention that there may be specific strategies that
provide more optimal knee joint loading in relation to slowing disease progression. The first part of this project
is to investigate knee control in people with knee arthritis and to evaluate whether this influences disease
progression. This will provide the basis for refinement and optimisation of rehabilitation interventions for this
patient group. The second part of this project will investigate whether strengthening the hip muscles in patients
with knee arthritis influences knee load and hence disease progression. Hip muscle strengthening is currently
not routinely included as part of the management of knee arthritis. If the results of this project find it to be
effective, then hip muscle strengthening can be recommended for treating knee arthritis.
Research achievements (from final report):
This research investigated factors influencing knee load during walking and ways to reduce knee load in people
with knee osteoarthritis. This is important as knee load is a predictor of the risk of structural disease
progression - those who walk with higher knee load are more likely to progress to more serious disease. The
research showed that muscles around the hip are weaker in people with knee osteoathritis but that strengthening
the hip muscles does not change knee load although it leads to a significant reduction in knee pain and
improvement in knee function. This suggests that hip muscle strengthening is not a disease-modifying
treatment as has been postulated in the literature. The research also showed that neuroumuscular and
biomechanical factors can influence knee load and hence disease progression. This will impact upon the design
of more effective rehabilitation programs for knee osteoarthritis.
Expected future outcomes:
The research provides information that will influence rehabilitation programs for people with knee
osteoarthritis that will be of use to clinicians
Name of contact:
Kim Bennell
Email/Phone no. of contact:
k.bennell@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 508923
CIA Name: A/Pr Amanda Fosang
Admin Inst: University of Melbourne
Main RFCD: Orthopaedics
Total funding: $563,044
Start Year: 2008
End Year: 2011
Grant Type: NHMRC Project Grants
Title of research award:
Understanding skeletal development: A non-proteolytic mechanism of aggrecan resorption in the growth
plateUnderstanding skeletal development: A non-proteolytic mechanism of aggrecan resorption in the growth
plate
Lay Description (from application):
Bone formation requires resorption of a cartilage template. We challenge the dogma that cartilage resorption is
only by PROTEASES, and propose instead that GLYCOSIDASES might also be involved. Aims:
Demonstrate that chondrocytes release glycosidases that are important for bone formation. Significance: New
information for the design of reconstructive therapies for people with congenital and acquired limb deficiencies
or inherited disorders such as arthritis and chondrodysplasias may be gained.
Research achievements (from final report):
Cartilage is abundant in a proteoglycan called aggrecan. During skeletal growth, the cartilage template is
remodelled to bone; this process involves the resorption of aggrecan. According to dogma, aggrecanase
enzymes degrade aggrecan during skeletal growth. Yet mice with genetically ablated aggrecanase activity have
normal skeletal development with no defects in bone formation. We challenged the dogma, and for this project
we hypothesised that intracellular organelles called lysosomes release hydrolases at the cell surface which
degrade aggrecan aggregates in the cartilage matrix. Furthermore, we hypothesised that cartilage cells
(chondrocytes) release hydrolases via a mechanism that is common to many cell types: lysosomal exocytosis.
No-one has demonstrated lysosomal exocytosis in chondrocytes previously. In this study we confirmed that
hypertrophic chondrocytes release hydrolases via lysosomal exocytosis in vitro and we showed for the first
time, direct in vivo evidence for lysosomal exocytosis in hypertrophic chondrocytes during skeletal
development. We propose that lysosomal exocytosis has a role in resorbing growth plate cartilage via release of
destructive hydrolases from hypertrophic chondrocytes.
Expected future outcomes:
The potential outcome from investigating our hypothesis is a new paradigm for cartilage remodelling in
skeletal development.
Name of contact:
A/Prof. Amanda Fosang
Email/Phone no. of contact:
amanda.fosang@mcri.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 508927
CIA Name: Prof Anthony Purcell
Admin Inst: University of Melbourne
Main RFCD: Autoimmunity
Total funding: $609,535
Start Year: 2008
End Year: 2010
Grant Type: NHMRC Project Grants
Title of research award:
The role of post-translationally modified antigen in rheumatoid arthritisThe role of post-translationally
modified antigen in rheumatoid arthritis
Lay Description (from application):
Rheumatoid arthritis (RA) is an inflammatory disease of joints. People who get RA often develop antibodies
which react against proteins found in inflamed joints. We will investigate why cells of the immune system react
against these proteins in RA, and identify which joint proteins, especially abnormal proteins, are targeted. This
will allow us to design new approaches to treat RA in a way that just targets the response to these abnormal
proteins, rather than the entire immune system.
Research achievements (from final report):
This project investigated the role of a common modification of proteins in the joint and its role in immune
responses in the joints of individuals with rheumatoid arhtritis (RA). Using proteomics we idneitfied a number
of modified joint proteins. We identified a complex immune response to a variety of modified proteins that
indicated that T cells from RA patients respond frequently to multiple citrullinated peptide antigens through
production of cytokines associated with RA pathogenesis.
Expected future outcomes:
Further publication of this work will ensue as well as a new application for funding to continue our work on
this immune response and potential therapeutic interventions based on antigen specific immunotherapy.
Name of contact:
Anthony Purcell
Email/Phone no. of contact:
apurcell@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 508966
Start Year: 2008
CIA Name: A/Pr Kay Crossley
End Year: 2011
Admin Inst: University of Melbourne
Grant Type: NHMRC Project Grants
Main RFCD: Rehabilitation and Therapy: Occupational and Physical
Total funding: $616,431
Title of research award:
Patellofemoral arthritis: Efficacy of physiotherapy and understanding the role of joint stressPatellofemoral
arthritis: Efficacy of physiotherapy and understanding the role of joint stress
Lay Description (from application):
Arthritis of the kneecap leads to considerable pain and difficulty with daily activities. This project is testing
whether a physiotherapy treatment (8 sessions over 12 weeks) designed specifically for people with kneecap
arthritis is effective. In order to understand more about kneecap arthritis, this project will calculate the force on
the kneecap and its relationship to pain and other factors, including thigh and hip muscle strength, knee
alignments and knee movements.
Research achievements (from final report):
, The patellofemoral joint (PFJ), or kneecap, is one compartment of the knee that is frequently affected by
osteoarthritis (OA) and is a potent source of symptoms. However, there are few treatments for PFJOA.
Therefore, this project aimed to evaluate whether a physiotherapy treatment, targeted to the PFJ, resulted in
greater improvements in pain and physical function than a physiotherapy education treatment., We conducted a
clinical trial in 92 people with PFJ OA. We observed that the targeted physiotherapy resulted in greater
improvements than the education group for perceived pain and function at 3 months. , We also determined the
force in the PFJ, on a patient-specific basis using computer modelling. We observed that people with PFJ walk
up and down stairs with lower PFJ forces, muscle size and forces than people with no OA., Significance:, Our
physiotherapy treatment, targeted to the PFJ, resulted in superior outcomes than a physiotherapy-led education
treatment for PFJOA. Therefore, treatments for knee OA may be enhanced by targeting treatments to the
compartment most affected by the disease. The project's outcome will influence knee OA rehabilitation, thus
reducing the personal and societal burden of this increasing public health problem. Our findings also have the
potential to foster development of interventions that may prevent PFJ OA, .
Expected future outcomes:
The results of these studies should increase the awareness of the importance of PFJ OA. The results may lead
to improved treatment options for people with PFJ OA. We will also use the results of these studies to evaluate
treatments with potential to reduce development, or progression of PFJ OA.
Name of contact:
Associate Professor Kay Crossley
Email/Phone no. of contact:
k.crossley@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 508995
Start Year: 2008
CIA Name: Prof John Wade
End Year: 2010
Admin Inst: University of Melbourne
Grant Type: NHMRC Project Grants
Main RFCD: Medical Biochemistry: Proteins and Peptides
Total funding: $573,807
Title of research award:
The structural basis of the interaction of human relaxins with their receptors.The structural basis of the
interaction of human relaxins with their receptors.
Lay Description (from application):
Relaxin is a peptide that is involved in the regulation of the birth process. It has considerable promise as an
anti-fibrotic agent. Recently, another relaxin-like peptide, relaxin-3, was identified and shown to be brainspecific. It modulates the stress response and appetite. Both relaxins act upon different receptors to elicit their
biological effects. To exploit their clinical potential, we will determine how these peptides selectively bind and
ativate their individual receptors.
Research achievements (from final report):
Our studies led to the further elucidation of the structural features and broader domains of each of relaxin-2 and
relaxin-3 for their selctive receptor binding. The results led to the rational design of smaller analogues of each
ot the two peptides that retained significant receptor binding and activation capability. In the case of relaxin-2,
it was concluded that the whole, two-chain molecule is required for such activity whereas for relaxin-3, it could
be minimized such that a truncated two-chain analogue retained agonist activity but a single B-chain analogue
was a potent antagonist. These findings have important implications for the production of new generation
relaxins, particularly relaxin-2 which is currently in Phase III clinical trials for the treatment of congestive heart
failure.
Expected future outcomes:
The results of our work will lead to further investigations into the suitability of our relaxin analogues as clinical
therapeutics. In particular, the domain-minimized peptides have great potential as lead molecules for further
modifications into more drug-like compounds which may be used to treat, for example, cardiovascular disease.
Name of contact:
Professor John D. Wade
Email/Phone no. of contact:
john.wade@florey.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 509103
CIA Name: Prof Julie Pasco
Admin Inst: University of Melbourne
Main RFCD: Psychiatry
Total funding: $291,230
Start Year: 2008
End Year: 2010
Grant Type: NHMRC Project Grants
Title of research award:
A prospective study of inflammatory cytokines as common factors in the aetiology of both depression and
osteoporosis.A prospective study of inflammatory cytokines as common factors in the aetiology of both
depression and osteoporosis.
Lay Description (from application):
Both depression and osteoporosis are common, debilitating and expensive diseases and there is research to
suggest that these conditions are related. This study will examine a potential common mechanism,
inflammation, which may underlie both diseases. It will focus on circulating proteins which are associated with
both depression and fragility fractures, and examine the role they play in both disorders.
Research achievements (from final report):
We report that bone mineral density is lower among individuals with depression. Our study has also shown that
imbalances in the immune system increase the risk for developing depression. Specifically, raised levels of
inflammatory cytokines are associated with increased risk for developing de novo major depression; smoking,
which increases free radicals, increases the risk for major depression; and the use of aspirin and statins, both of
which have anti-inflammatory properties, protect against the onset of depression. We have also demonstrated
that an inflammatory marker is associated with increased risk of sustaining a fragility fracture, and that statins
are protective against fracture. These findings support the notion that systemic inflammation increases the risk
for both depression and osteoporosis and may provide evidence of a role for inflammatory cytokines as
potential mediators between the two disorders.
Expected future outcomes:
Anti-inflammatory treatment may have the potential to prevent the onset and treat existing mood disorders and
associated bone fragility.
Name of contact:
A/Prof Julie Pasco
Email/Phone no. of contact:
juliep@barwonhealth.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 509218
CIA Name: Prof John Hamilton
Admin Inst: University of Melbourne
Main RFCD: Rheumatology and Arthritis
Total funding: $638,526
Start Year: 2008
End Year: 2010
Grant Type: NHMRC Project Grants
Title of research award:
Macrophage lineage phenotypesMacrophage lineage phenotypes
Lay Description (from application):
A type of white blood cell, the macrophage, is a key player in determining the chronicity of inflammatory
conditions such as rheumatoid arthritis, atherosclerosis, psoriasis, nephritis, multiple sclerosis etc. Two
particular proteins can control macrophage development and functions, both under normal conditions and
during inflammation. The project aims to understand this control. More rational ways to suppress
inflammation due to aberrant macrophage function should result.
Research achievements (from final report):
We have been able to specifically deplete a subpopulation of blood monocytes. This is potentially an important
finding as it means that we do not necessarily have to rely on removal of all monocyte/macrophages during an
inflammatory response which can be a risky approach. We also have found a way to manipulate macrophages
at sites of inflammation which has implications for their control as drivers of chronic inflammatory diseases. ,
The relevance of GM-CSF as a target in inflammatory disease has been enhanced by showing that its depletion
in two additional experimental arthritis models is beneficial. , A method has been developed for generating a
large number of replicating human macrophages making signalling mechanisms and gene targetting strategies
amenable., A novel concept has evolved whereby a state of "CSF-1 resistance" must be attained in
macrophages before they can express a profinflammatory phenotype.
Expected future outcomes:
Better means of manipulating macrophage populations for benefit in chronic inflammation.
Name of contact:
Professor John Hamilton
Email/Phone no. of contact:
jahami@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 509310
Start Year: 2008
CIA Name: Dr Kerrie Sanders
End Year: 2008
Admin Inst: University of Melbourne
Grant Type: NHMRC Project Grants
Main RFCD: Medical and Health Sciences not elsewhere classified
Total funding: $104,995
Title of research award:
Does An Annual High Dose Vitamin D Supplement Decrease Healthcare Utilisation in Older Women?Does An
Annual High Dose Vitamin D Supplement Decrease Healthcare Utilisation in Older Women?
Lay Description (from application):
The shorter bleaker days of winter can cause a vitamin D deficiency in Australian women, increasing their risk
of osteoporosis and broken bones including hip fracture. New research suggests that the low winter levels of
the vitamin may not be good for us in many ways and the NHMRC is funding a Geelong-based study to
determine if Austrlia's elderly can improve their overall health by taking a once-a-year dose of vitamin D
tablets.
Research achievements (from final report):
Recent research suggests that higher levels of vitamin D in your blood may provide protection from many
disorders such as diabetes, osteoporosis, depression and certain types of cancer. This project represents the first
international study to investigate this hypothesis using a randomised, placebo-controlled clinical trial. The
hypothesis was that older women supplemented annually for 3 to 5 years with a high oral dose of vitamin D3
(500,000 IU) would use fewer healthcare services than those given placebo (dummy) tablets. The preliminary
analysis using data from Medicare Australia suggests there is no difference between the groups and that the
women randomised to vitamin D used the same number of Medicare services as women receiving placebo
(vitamin D group: 28.5 and placebo group: 28.0 Medicare services per person per year). The age of participants
did not differ between the groups (vitamin D: 76.8 years and placebo: 76.7 years). In the year prior to
commencing the study medication the women used an average of 18.5 services per person (vitamin D group:
18.6 and placebo group: 18.5). These results also suggest that women aged 70+ years had a 1.5 fold increase in
the average number of healthcare service/visits they used each year over a 2 to 3 year period and that this
increase did not differ between those given vitamin D and placebo.
Expected future outcomes:
Further analysis of the data will determine the cost of healthcare services between the vitamin D and placebo
groups to determine if there is a significant difference in the type of health services used and the total cost of
health service utilisation between the two groups. The data will be analysed by age group using 70-74; 75-79;
and 80+ years and stratified by fracture (yes/no).
Name of contact:
A/Prof Kerrie Sanders
Email/Phone no. of contact:
kerrie@barwonhealth.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 509328
CIA Name: Dr Helen MacLean
Admin Inst: University of Melbourne
Main RFCD: Cell Physiology
Total funding: $703,665
Start Year: 2008
End Year: 2010
Grant Type: NHMRC Project Grants
Title of research award:
Role of non-classical actions of androgens in musculoskeletal physiologyRole of non-classical actions of
androgens in musculoskeletal physiology
Lay Description (from application):
Androgens (male sex hormones) are important for growth/maintenance of muscle and bone. The classical
action of androgens is to bind the androgen receptor (AR) and regulate target genes. They can also act via nonclassical AR mechanisms through other cellular pathways. To understand the role of non-classical actions in
the musculoskeletal system we will study mice in which androgens can only act via this pathway. This
knowledge is important for the treatment of osteoporosis and muscle wasting.
Research achievements (from final report):
This study investigated the mechanisms through which male sex hormones (androgens) act. Androgens
normally act through the androgen receptor, a key-lock mechanism required to make particular cells responsive
to androgens, which controls other genes to be switched on or off. Our study used a mouse line in which we
created a mutant version of the androgen receptor that cannot directly regulate other genes. We showed that
mutant male mice have alterations in body weight and weight of the kidney, spleen and muscle and decreased
bone mass. In contrast, mutant female mice had altered kidney, spleen and heart weight and reduced bone
growth. This proves that androgens act in males via the direct gene regulation pathway to control kidney,
spleen, muscle and bone development. This also shows that male sex hormones also play an important role in
females to control kidney, spleen, heart and bone development. We also showed that treatment of mutant male
mice with male sex hormones decreased their bone size, proving that male sex hormones also act through other
mechanisms that do not involve direct gene regulation, to modify bone development. This research has
identified new pathways for male sex hormone action in both males and females. Understanding these actions
completely will open up new pathways for drug design to target these actions. This may allow the development
of more effective and specific therapies for the treatment of osteoporosis, a highly prevalent disease of the
aging population, and a number of conditions associated with reduced muscle mass, including chronic disease
and age-related frailty.
Expected future outcomes:
Results from continued research in this area will identify further actions of male sex hormones that occur via
novel mechanisms that do not involve direct gene regulation, including studying bone, muscle, fat and brain in
further detail. This knowledge may contribute to the development of novel treatments for osteoporosis, muscle
wasting and obesity.
Name of contact:
Helen Maclean
Email/Phone no. of contact:
hmaclean@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 509331
Start Year: 2008
CIA Name: Prof David Bowtell
End Year: 2010
Admin Inst: University of Melbourne
Grant Type: NHMRC Project Grants
Main RFCD: Protein Targeting and Signal Transduction
Total funding: $568,452
Title of research award:
Inhibitors of Siah ubiquitin ligaseInhibitors of Siah ubiquitin ligase
Lay Description (from application):
Recent evidence suggests that the Siah proteins are involved in sensing low oxygen levels in cells, and
subsequently activating processes to help the cell survive under these conditions. Low oxygen conditions occur
in cancer and sites of inflammation, suggesting that inhibiting Siah may improve patient outcomes in diseases
such as cancer and arthritis. We aim to perform a high throughput screen for drugs that inhibit Siah protein
function and to test these in cancer cells.
Research achievements (from final report):
With respect to the aims of the grant:, 1. Over 250 drug-like compounds that we discovered using an in silico
approach to drug screening were assessed as inhibitors of Siah ubiquitin ligase. These compounds were
assessed in both biophysical and biochemical assays to establish the validity of their binding and inhibitory
properties. Whilst individual compounds showed promise in some assays, none were active by all of our
specific criteria and were thus not pursued., 2. In collaboration with the group of Prof. Paul Workman at the
Centre for Cancer Therapeutics, Cancer Research UK, we screened a library of 79,000 compounds for
inhibition of the interaction between Siah and its substrates. Ten of these compounds were eventually
shortlisted and interrogated for Siah binding and Siah inhibition. Despite effects on HIF-1alpha stabilisation (a
Siah-dependent event), and some variable effects on other Siah-dependent readouts, none of the compounds
convincingly bound to Siah and were not developed., 3. To validate hits from aims 1 and 2, we utilised binding
assays (ELISA), and functional assays including HIF-1alpha stabilisation and substrate degradation in
overexpression experiments, as well as in vitro ubiquitination assays. , 4. Whilst no hits came from the earlier
aims, crystallisation has been pursued in order to improve crystal quality and resolution of diffraction data. We
have been able to improve the resolution to 2.0 Angstroms, which will allow us to readily detect binding of any
compounds to the Siah molecule.
Expected future outcomes:
Our results suggest that the site of substrate interaction on the Siah molecule may be difficult to target with
conventional high throughput screening. We have instigated a fragment screen for this site, as well as a screen
for inhibitors of Siah ubiquitination activity.
Name of contact:
David Bowtell
Email/Phone no. of contact:
david.bowtell@petermac.org
NHMRC Research Achievements - SUMMARY
Grant ID: 566503
CIA Name: Dr Rachel Davey
Admin Inst: University of Melbourne
Main RFCD: Endocrinology
Total funding: $470,960
Start Year: 2009
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
The mechanisms of the anabolic actions of androgens in bone.The mechanisms of the anabolic actions of
androgens in bone.
Lay Description (from application):
Androgens (male sex hormones) are one of the few agents that increase bone formation. Androgens act by
binding to a specific protein, the androgen receptor (AR). To understand exactly how androgens increase bone
formation, we will study mice in which the AR is inactivated only in bone forming cells at specific stages of
their development. Understanding the way in which androgens act on bone to increase size and strength will be
of great benefit in the design of new treatments for osteoporosis.
Research achievements (from final report):
Our goal was to gain a better understanding of how the male sex hormones, androgens, act to control both the
formation of new bone and the breakdown of old bone. More specifically, our aim was to understand how
androgens control the bone forming cells (osteoblasts) at different stages of their development to increase bone
formation during growth and maintain bone in adulthood. To achieve this, we generated two different mice
models in which the target for androgens, the androgen receptor (AR) was deleted in osteoblasts at the matrix
synthesis and mineralisation stages of their development: osteoblast-specific ARKOs. We showed that
androgens act on osteoblasts at both the matrix synthesis and mineralisation stages of their development to
maintain the inner trabecular bone by regulating the breakdown of bone. Androgens also act via the AR at the
mineralisation stage to regulate the matrix mineralisation process. In contrast to our previous findings in the
global ARKOs, the bone size of these osteoblast-specific ARKOs was not affected, suggesting that androgens
act on osteoblasts at different stages of their development to exert different effects., Understanding the precise
mechanisms by which androgens exert their effects on bone may provide new avenues for therapies that target
the specific actions of androgens via the AR, within specific bone cell types that lead to increased bone size
and volume, thereby improving bone health. It is also hoped that these results may assist in increasing public
awareness of male osteoporosis and the importance of undertaking research in this area.
Expected future outcomes:
The next stage of our research will determine the relative contribution of androgens acting via the androgen
receptor to increase bone size and to maintain bone volume in the proliferation stage of the osteoblast cycle, as
compared to the mineralising stage.
Name of contact:
Dr Rachel A Davey
Email/Phone no. of contact:
r.davey@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 566776
Start Year: 2009
CIA Name: Prof Alastair Stewart
End Year: 2011
Admin Inst: University of Melbourne
Grant Type: NHMRC Project Grants
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $369,690
Title of research award:
2-Methoxyestradiol analogues: prototype modulators of annexin II-dependent plasminogen activation2Methoxyestradiol analogues: prototype modulators of annexin II-dependent plasminogen activation
Lay Description (from application):
The enzyme system that enables us to dissolve blood clots is similar to the system that enables cancer cells to
escape from the primary tumour and travel in the blood to another organ to form a secondary cancer growth.
We have new results showing that some drug candidates can distinguish between these two closely related
enzyme systems. We are now working to develop inhibitors that will stop cancer cells from spreading without
compromising the ability to dissolve blood clots.
Research achievements (from final report):
We set out to investigate a family of proteins called annexins for their roles in regulating the plasminogen
activation system. Our particular initial focus was on annexin-2. Early on in the project we made the
unexpected finding that annexin-1 regulated tumour cell division. This finding was consolidated by showing
that annexin-1 stimulated cells to divide by engaging with a receptor molecule on the surface of the tumour
cells called FPR. These findings were published in the prestigious FASEB journal and add to growing evidence
from several other research groups worldwide that supports a role for FPR in the devlelopment of tumours and
the spread of tumour cells to create secondary tumours (metastases). we further evaluated the effects of the
annexins on the anti-cancer and other actions of 2-methoxyestradiol. This work used annexin-1 and annexin-2
gene-deleted mice, implicating annexin-2 but not -1 in the actions of anti-inflammatory actions of 2methoxyestradiol. Radioligand binding studies indicated that the role of annexin-2 was not as a primary
binding site for 2-methoxyestradiol.
Expected future outcomes:
Based on our findings we created a new research grouping involving a breast cancer physician, molecular and
stem cell biologists. The team secured further funding to investigate the roles of annexins and FPR in breast
and other types of cancer. Upon completion of this research, will be able to make recommendations as to the
value targeting the FPR with drugs in cancer treatment.
Name of contact:
Professor Alastair Stewart
Email/Phone no. of contact:
astew@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 566783
Start Year: 2009
CIA Name: A/Pr Paul McCrory
End Year: 2013
Admin Inst: University of Melbourne
Grant Type: NHMRC Project Grants
Main RFCD: Complementary-Alternative Medicine not elsewhere classified
Total funding: $701,120
Title of research award:
Laser acupuncture in patients with chronic knee pain: a randomised placebo-controlled trialLaser acupuncture
in patients with chronic knee pain: a randomised placebo-controlled trial
Lay Description (from application):
Chronic knee pain is a common and disabling musculoskeletal condition that causes a loss of functional
independence and results in significant health care costs. In the majority of patients the most common cause is
osteoarthritis. Acupuncture is a form of non-surgical treatment commonly sought by patients and often
recommended by GP's. The main outcomes from our project are to establish the role, clinical effectiveness and
cost benefit of laser and needle acupuncture in knee pain patients.
Research achievements (from final report):
Knee pain is a common, chronic musculoskeletal condition or which arthritis is the major cause in older adults.
'Arthritis' has been identified by the Government as one of its priority health areas. Acupuncture may be
effective in relieving knee pain, and laser acupuncture has the potential to be as effective or superior to needle
acupuncture. Our project compared the efficacy of needle acupuncture, laser acupuncture, and sham laser
acupuncture to a natural history cohort who did not receive acupuncture. We have completed a large Zelendesign randomised controlled trial in order to answer this question. We have published the protocol for this
clinical trial and are about to commence analysing the data to determine the study findings. This work has
potential to be published in the highest impact literature in the field. The findings will contribute to the
formulation of evidence-based clinical guidelines for rehabilitation of knee OA and will impact the clinical
practice of healthcare professionals (particularly physiotherapists) who manage patients with knee pain.
Expected future outcomes:
We are about to analyse the data from our completed clinical trial. We expect to publish the findings in a major
medical journal, as well as present at multidisciplinary conferences. Our results will influence future clinical
guidelines and clinical practice.
Name of contact:
A/Prof Paul Mccrory
Email/Phone no. of contact:
paulmccrory@icloud.com
NHMRC Research Achievements - SUMMARY
Grant ID: 566834
CIA Name: Prof Peter McIntyre
Admin Inst: University of Melbourne
Main RFCD: Basic Pharmacology
Total funding: $480,127
Start Year: 2009
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
Targeting Post-translational Modifications in TRPV Pain ChannelsTargeting Post-translational Modifications
in TRPV Pain Channels
Lay Description (from application):
The same nerve receptor that binds the pungent component of chilli peppers (TRPV1) is an important part of
our pain pathway. TRPV1 also responds to painful heat and acids. Chronic pain is an important unmet medical
need and it uses the TRPV1 pathway. After activation by chilli, a feedback system in nerves inactivates TRPV1
and stops pain signalling. This feedback changes in chronic pain. This project aims to understand and exploit
this feedback mechanism to find new approaches to pain therapy.
Research achievements (from final report):
We discovered new postranslational modulation mechanisms for both TRPV1 and TRPV4 ion channels. We
also discovered new mutations of TRPV4 that cause an inherited arthitic condition., We identified a new
mechanism of activation of TRPV4 which may be the target of new painkilling drugs. We went on to identify
drug that is in clinical trials for another indication tha may be a useful analgesic. This compound blockes the
opening of TRPV4 by intracellular signalling from protease-activaed receptors and hypotonic salt solutions
(painful stimuli). We took out a provisional patent on this compound but we had to let the patent lapse because
we could not get enough drug to perform a pain assay in rodents in time to support it. We now have the
compound in sufficient quantity and are planning to follow-up on this.
Expected future outcomes:
We hope to define a new thereapeutic target for chronic pain that is in the pathway for activation of TRPV4, a
known pain-sensing ion channel. The phenomenon of TRPV channels being opened by intracellular signalling
may be a genreral and physiologically relevant one and we think it is likely to be of great importance to the
field.
Name of contact:
Peter Mcintyre
Email/Phone no. of contact:
pmci@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 566916
CIA Name: Prof Ego Seeman
Admin Inst: University of Melbourne
Main RFCD: Endocrinology
Total funding: $620,381
Start Year: 2009
End Year: 2011
Grant Type: NHMRC Project Grants
Title of research award:
Bone Fragility: The Neglected Role of Cortical PorosityBone Fragility: The Neglected Role of Cortical
Porosity
Lay Description (from application):
Cortical (outer shell) or compact bone constitutes 80% of the skeleton. It is not solid as implied by its name
but made of inter-connected canals resembling a network of roads. We recently discovered that most of the
bone loss with age occurs from these canals, not from t rabecular bone as currently believed. This suggests to
know why and how bone breaks requires the study of the morphology of these canals and how they change
with age. This is what we propose to do. It has never been done.
Research achievements (from final report):
, About 75% of all fractures in the community occur in women with bone density values above the osteoporosis
range. These individuals will not be offered treatment and so will go on to sustain fractures. There is therefore
an urgent need to develop tests that allow better identification of individuals at risk for fracture. Measurement
of porosity (i.e., holes in the bone) is a prime candidate because the higher the porosity, the more fragile the
bone independent of its density. The aim of this grant was to(i.) define the 3D morphology of pores (ii.) define
changes in tporosity associated with ageing . (iii.) Use the information obtained to build a software that
measures this porosity in clinical settings; and can be used a diagnosis test., , We reported that increase in
porosity was responsible for 70% of the total bone loss during ageing and this was poorly captured by the bone
density test. This work was published in The Lancet. It is highly cited and has played a key role in driving the
bone medical community interested in cortical porosity. , , Knowledge of the morphology network of pores has
led to discovery of a method and system for quantification of porosity in clinical settings. The method is
patented and reached the national phase in key countries including the USA, EU, Australia, Japan, China, and
India. The software implementing the method has been developed and is now used to quantify porosity in
individuals worldwide including USA and Australia, .
Expected future outcomes:
We expect that the porosity measurement develop with the support of this grant will become a routine clinical
test for bone diseases; allowing to better identify individuals at risk for fracture in clinics, better monitor the
effect of diseases and treatment on bone. This will reduce disease burden with major social and economic
benefits.
Name of contact:
Roger Zebaze
Email/Phone no. of contact:
zebaze @unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 628422
CIA Name: A/Pr Kerrie Sanders
Admin Inst: University of Melbourne
Main RFCD: Orthopaedics
Total funding: $411,628
Start Year: 2010
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
The Australian Study of Cost and Utilities Related to Osteoporotic FracturesThe Australian Study of Cost and
Utilities Related to Osteoporotic Fractures
Lay Description (from application):
The research will quantify the cost and quality of life impact of fragility fractures in Australia. The study
design is based on an international study - International Costs and Utilities Related to Osteoporotic Fracutres
Study (ICUORS) that aims to investigate the impact of osteoporosis-related fractures of the hip, spine and
wrist. Results can be used to compare cost-effectiveness of different drugs and lifestyle interventions aiming to
decrease the burden of osteoporosis in Australia.
Research achievements (from final report):
This project is a health economics study on fragility fractures in Australia. Using uniform methodology this
study, being conducted at eight teaching hospitals across Australia, will establish both 'quality of life' loss and
monetary cost of low trauma fractures in older adults. The study design is based on an international Swedish
study. This standardised methodology will facilitate international comparisons. The results will be used to
establish the true burden of osteoporosis in Australia and in future cost-effectiveness analysis. Future
researchers will be able to access this data to demonstrate that new interventions improve the quality of life and
minimize cost in the prevention and treatment of fragility fracture patients. The results to date are already being
used by Osteoporosis Australia to identify and highlight the under-recognised burden of fragility fractures in
this country.
Expected future outcomes:
Results are generating data on the type of services patients use when they sustain a low trauma fracture
including medical and inpatient services, use of allied health as well as comunity and family assistance.
Participants also complete quality of life questionnaires at intervals up to 18 months following the fracture. The
major fractures are hip, vertebral and wrist..
Name of contact:
A/Prof Kerrie Sanders
Email/Phone no. of contact:
ksanders@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 628475
CIA Name: A/Pr Amanda Fosang
Admin Inst: University of Melbourne
Main RFCD: Rheumatology and Arthritis
Total funding: $407,635
Start Year: 2010
End Year: 2013
Grant Type: NHMRC Project Grants
Title of research award:
Detecting bioactivity in a naturally-occurring aggrecan fragmentDetecting bioactivity in a naturally-occurring
aggrecan fragment
Lay Description (from application):
The dynamic balance of anabolic and catabolic processes in healthy cartilage is disturbed in arthritis, with
increased catabolism leading to irreparable cartilage damage. We will study the ability of a naturally-occuring
aggrecan fragment to modulate cartilage catabolism. Our in vitro and in vivo experiments suggest that the
aggrecan fragment limits cartilage destruction. This study tests our hypothesis that the aggrecan fragment
antagonises cartilage damage and promote cartilage repair.
Research achievements (from final report):
Osteoarthritis is a degenerative disease of the joints that affects approximately 20% of Australians. More basic
research on the molecular drivers of osteoarthritis is urgently needed to identify new targets for drug
development. The integrity of joint cartilage is dependent on the matrix molecule aggrecan, which is
fragmented during the initial stage of osteoarthritis. We have discovered that a naturally occurring fragment of
aggrecan, the 32mer, signals joint cells to mount a pro-inflammatory and pro-catabolic response. We found that
the 32mer is a 'DAMP', a Damage Associated Molecular Pattern that acts as a renewable danger signal.
DAMPs trigger ongoing and escalating cycles of inflammation that are unregulated and non-resolving; their
action is mediated via toll-like receptors. Our studies showed that the 32mer signals gene expression in joint
cells via toll-like receptor-2. These novel findings represent the first evidence of a mechanistic link between
aggrecan degradation and inflammation in joint disease. We predict that this project, and our ongoing studies,
will stimulate new ways of thinking about potential treatment modalities for what is currently an untreatable
degenerative disease.
Expected future outcomes:
Ongoing work will identify new, evidence-based directions for pursuing the aggrecan 32mer as a novel target
for disease modifying osteoarthritis drugs. Our hypothesis-driven research will lead naturally into the
translational studies needed to better manage osteoarthritis.
Name of contact:
A/Prof Amanda Fosang
Email/Phone no. of contact:
amanda.fosang@mcri.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 628556
CIA Name: Prof Kim Bennell
Admin Inst: University of Melbourne
Main RFCD: Physiotherapy
Total funding: $629,509
Start Year: 2010
End Year: 2013
Grant Type: NHMRC Project Grants
Title of research award:
Is physiotherapy beneficial for people with hip osteoarthritis?Is physiotherapy beneficial for people with hip
osteoarthritis?
Lay Description (from application):
Hip osteoarthritis (OA) is a chronic joint disease that causes pain and reduced function. There is currently no
cure so safe, effective treatments are needed. Physiotherapy plays a role in the management of hip OA but there
is little evidence of its effectiveness. This project will determine the effects of a 12 week physiotherapy
program on pain and function in 148 people with hip OA. The results will help with recommendations as to the
best ways to treat this chronic condition.
Research achievements (from final report):
The main achievement was completion of the first randomised placebo-controlled trial investigating the
efficacy of a physiotherapy program comprising exercise, manual therapy and education for the management of
hip osteoarthritis. Hip OA is a common, chronic musculoskeletal condition and 'Arthritis' has been identified
by the Government as one of its priority health areas. Physiotherapy (including exercise) is a recommended
first line treatment for hip OA but unlike knee OA there is little evidence of its efficacy. Major international
rheumatology bodies have identified this gap in knowledge and have placed clinical trials of conservative nondrug interventions for hip OA as a research priority. The study included 102 people with hip OA randomised
into an active physiotherapy group or a sham physiotherapy group. Both groups attended 10 physiotherapy
visits over 12 weeks. Outcome measures were assessed at baseline, 12 weeks and 36 weeks. The findings will
contribute to the formulation of evidence-based clinical guidelines for rehabilitation of hip OA. Our project
also provides the impetus for a series of research questions regarding the role of physiotherapy for hip OA,
which include head-to-head comparisons with other treatment alternatives as well as strategies to maximize
self-management for this chronic condition.
Expected future outcomes:
We will complete the statistical analysis and expect to publish the results in a major rheumatology journal as
well as present at multidisciplinary conferences. The results will influence clinical guidelines and clinical
practice.
Name of contact:
Prof Kim Bennell
Email/Phone no. of contact:
k.bennell@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 628644
CIA Name: Prof Kim Bennell
Admin Inst: University of Melbourne
Main RFCD: Physiotherapy
Total funding: $719,199
Start Year: 2010
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
Neuromuscular exercise : a novel treatment to reduce symptoms and joint load in medial knee
osteoarthritisNeuromuscular exercise : a novel treatment to reduce symptoms and joint load in medial knee
osteoarthritis
Lay Description (from application):
There is currently no cure for knee osteoarthritis (OA). Thus treatments are needed that not only reduce
symptoms but also slow disease progression. Exercise is recommended for knee OA but traditional thigh
muscle strengthening exercises do not appear to be effective in all cases and may not slow the disease. This
project will compare novel 'neuromuscular exercise' and compare it to traditional strengthening exercise. The
results have the potential to alter current exercise prescription
Research achievements (from final report):
Knee OA is a common, chronic musculoskeletal condition and 'Arthritis' has been identified by the
Government as one of its priority health areas. Exercise is a recommended first line treatment for knee OA and
can alleviate symptoms associated with the disease. Excessive knee joint loads are pivotal in the disease
pathogenesis and generation of symptoms of knee OA. Accordingly, there is much research interest in
developing treatment strategies that can lower knee joint load. Neuromuscular exercise, which is the focus of
our research, has potential to both reduce knee joint loads and alleviate symptoms. Our proposed project is
therefore of international relevance. It will be the first to establish the efficacy of a neuromuscular exercise
program for the treatment of knee OA. We have completed a randomised controlled trial in order to answer this
question. We have published the protocol for this clinical trial and are now analysing the data to determine the
study findings. This work has potential to be published in the highest impact literature in the field. The findings
will contribute to the formulation of evidence-based clinical guidelines for rehabilitation of knee OA and will
impact the clinical practice of healthcare professionals (particularly physiotherapists) who manage patients
with knee OA.
Expected future outcomes:
We are currently analysing the data from our completed clinical trial. We expect to publish the findings in a
major rheumatology journal, as well as present at multidisciplinary conferences. Our results will influence
future clinical guidelines and clinical practice.
Name of contact:
A/Prof Rana Hinman
Email/Phone no. of contact:
ranash@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 628691
CIA Name: Prof Alastair Stewart
Admin Inst: University of Melbourne
Main RFCD: Basic Pharmacology
Total funding: $453,288
Start Year: 2010
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
Glucocorticoid resistance: identifying new anti-inflammatory drug targetsGlucocorticoid resistance: identifying
new anti-inflammatory drug targets
Lay Description (from application):
The control of chronic inflammatory diseases such as asthma involve use of drugs related to the steroid
hormone cortisol. Up to 40% of patients with more severe disease respond poorly or not at all to these drugs.
The remaining non-steroid treatments are only partially effective. Poor disease control is a great health and
economic burden. We have identified a molecular mechanism for steroid resistance and propose new studies to
identify novel drugs that act to reverse steroid resistance.
Research achievements (from final report):
Treatment of chronic diseases that affect the airways and lungs, like asthma and COPD involves the use of
drugs which widen the airways and descrease the instensity of inflammation. In severe forms of asthma and
COPD the effectiveness of the major class of anti-inflammatory drugs, the glucococortcoids, is very limited.
Our research has identified an important mechanism for the development of this resistance. A protein that
causes scarring, called TGFbeta, dramatically reduces the ability of glucocorticoids to increase the expression
of anti-inflammatory proteins. We are now working on new drugs that can inhibit some aspects of the action of
TGFbeta to see whether they can reverse the limitations in glucocorticoid effectiveness.
Expected future outcomes:
We have commenced studies of tranilast and pirfenidone in human airway cell culture to establish a proof-ofconcept for their use as clinical therapies to reverse steroid resistance. If successful, a rapid translation impact
on chronicairway disease could be expected.
Name of contact:
Prof Alastair Stewart
Email/Phone no. of contact:
astew@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 628701
CIA Name: Prof Ego Seeman
Admin Inst: University of Melbourne
Main RFCD: Endocrinology
Total funding: $865,474
Start Year: 2010
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
Fragility Fractures: The Neglected Role of Cortical PorosityFragility 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/Phone no. of contact:
zebaze@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 987029
CIA Name: Dr Helen MacLean
Admin Inst: University of Melbourne
Main RFCD: Reproduction
Total funding: $259,673
Start Year: 1998
End Year: 2004
Grant Type: Early Career Fellowships (Overseas)
Title of research award:
The hormonal regulation of cell proliferation and differentiation in muscle and bone.The hormonal regulation
of cell proliferation and differentiation in muscle and bone.
Lay Description (from application):
Not Available
Research achievements (from final report):
The aim of this research was to investigate the fundamental mechanisms through which hormones control the
growth and specialisation of cells in tissues including muscle and bone. This first component of this research
investigated how hormones and intracellular proteins (transcription factors and cell cycle regulators) interact
during bone formation, using the mouse as a model to study bone development. The main focus of this study
examined how parathyroid hormone related protein (PTHrP) controls cartilage cells during early bone
formation. This study used genetically modified mouse models to demonstrate for the first time that PTHrP
stimulates cartilage growth by controlling one of the basic proteins that is required for cell division. This
research sheds new light into the basic mechanism of action of PTHrP in cartilage, which may be useful in
understanding how disorders of cartilage growth occur in genetic diseases and during arthritis. The second
component of this research investigated the actions of male sex hormones (androgens), in reproductive and
non-reproductive tissues. Androgen receptor gene mutations were identified in Australian patients with
disorders of sexual development, which helps us understand how the androgen receptor protein functions
during normal development. In addition, a genetic variation of the androgen receptor was identified that
increases the risk and severity of breast cancer in men. These studies increase our understanding of how male
sex hormones act through the androgen receptor. This knowledge will allow us to understand how disease
conditions including prostate cancer, breast cancer and spinal and bulbar muscular atrophy develop, all of
which can be caused by mutations in the androgen receptor. A complete understanding of these disease
processes is required in order to develop more effective therapies.
Expected future outcomes:
This research is currently investigating the role of androgens in controlling cell growth in muscle. Mouse
models are being used to understand how androgen treatment increases muscle size and strength; and how
decreased androgen levels, as occurs during normal ageing, causes muscle weakness. This research will
ultimately be used to develop more targeted treatments for patients with muscle wasting.
Name of contact:
Helen Maclean
Email/Phone no. of contact:
hmaclean@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1002914
Start Year: 2011
CIA Name: Prof John Hamilton
End Year: 2013
Admin Inst: University of Melbourne
Grant Type: NHMRC Project Grants
Main RFCD: Medical and Health Sciences not elsewhere classified
Total funding: $565,215
Title of research award:
Macrophage lineage phenotypesMacrophage lineage phenotypes
Lay Description (from application):
A type of white blood cell, the macrophage, is a key player in determining the chronicity of inflammatory
conditions such as rheumatoid arthritis, atherosclerosis, psoriasis, nephritis, multiple sclerosis etc. Two
particular proteins can control macrophage development and functions, both under normal conditions and
during inflammation. The project aims to understand this control. More rational ways to suppress
inflammation due to aberrant macrophage function should result.
Research achievements (from final report):
The effects of two protein mediators on the development and function of a particular white blood cell lineage
have begun to be defined both in the steady state and during inflammatory reactions. Surprisingly the
development of this lineage (macrophage lineage) by one of these mediators (CSF-1 or M-CSF) only occurs
late in the lineage which goes against current dogma. When cells of the macrophage lineage are exposed to
CSF-1 and the other meidator (GM-CSF) quite different responses were found which were influenced by
several parameters such as time of exposure; it was also found that endogenous mediators could influence the
interpretation of the data. What was striking from these experiments was that the cellular responses (global
gene expression) were quite different for the two CSFs with some evidence of their competition. These
findings have particular implications for the respective roles of the CSFs at sites of inflammation and during
the development of inflammatory diseases.
Expected future outcomes:
These studies will assist in defining which patient groups should be treated with therapies designed to suppress
the function of the CSFs in clinical trials as well as lead to further insights into the basic biology of the CSFs
and the macrophage lineage.
Name of contact:
John A Hamilton
Email/Phone no. of contact:
jahami@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1004938
CIA Name: Prof Ego Seeman
Admin Inst: University of Melbourne
Main RFCD: Endocrinology
Total funding: $873,951
Start Year: 2011
End Year: 2013
Grant Type: NHMRC Project Grants
Title of research award:
The micro-structural basis of bone loss and fragility after menopause: a longitudinal co-twin control studyThe
micro-structural basis of bone loss and fragility after menopause: a longitudinal co-twin control study
Lay Description (from application):
Every woman becomes postmenopausal. Not all lose bone or sustain fractures after menopause. We will
identify women who lose bone and those who don't and so identify women at risk for fracture so that they can
be targeted for treatment and identify those who do not need to be treated. This will be done by measuring
bone structure and how strong the bone is using a new, safe, quick technology that can be used in clinical
practice
Research achievements (from final report):
Bone loss is a most important cause of bone fragility. To identify women who lose bone after menopause and
those who do not, in a prospective cotwin control study, we have (i) assessed genetic and environmental
contributions to variance in bone microstructure (ii) determined causes of bone loss by comparing cotwin
differences in structure vs cotwin differences in remodelling markers (iii) examined the contribution of
differences in cortical porosity, area and tissue mineral density, trabecular architectural decay to fracture risk in
a case-control study. Bone structure, remodelling and strength at baseline and their relationship have been
quantified during 3 years (changes in cortical porosity, trabecular number and thickness, loss of strength) using
high-resolution 3-D pQCT in 320 female twin pairs aged 25 to 75 years old in Melbourne area. Analysis
followed the classical twin model, using a generalised estimating equation and logistic regression. Our
prospective data demonstrated that cortical porosity increased and trabecular BV/TV decreased confirming the
accelerated loss of bone during menopause. Women enter menopause with high cortical porosity and bone
remodelling markers would be at high risk to lose bone and also sustain fractures.
Expected future outcomes:
To provide a clinical tool to accurately identify those at risk who lose bone and those who don't to correctly
target treatment to individuals who need it and avoid unnecessary treatment of individuals unlikely to sustain
fractures.
Name of contact:
Ego Seeman
Email/Phone no. of contact:
egos@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 157031
CIA Name: Prof Samuel Breit
Admin Inst: University of New South Wales
Main RFCD: Rheumatology and Arthritis
Total funding: $309,537
Start Year: 2001
End Year: 2003
Grant Type: NHMRC Project Grants
Title of research award:
Role of the novel TGF-b superfamily cytokine MIC-1 in the pathogenesis and treatment of rheumatoid
arthritisRole of the novel TGF-b superfamily cytokine MIC-1 in the pathogenesis and treatment of rheumatoid
arthritis
Lay Description (from application):
Cytokines are hormone like messengers that mediate the interactions between cells. We have discovered a new
cytokine that we have named macrophage inhibitory cytokine 1 (MIC-1). It belongs to a very important family
of proteins that are involved in wound healing, development and inflammation. Our data thus far suggests that
MIC-1 is an anti-inflammatory factor that is of particular relevance in rheumatoid arthritis. We wish to
determine the relationship between the amount of this cytokine in the joint and the blood and the activity of
rheumatoid arthritis. To better understand the actions of this molecule, we also want to study the factors that
regulate the production of MIC-1 from human blood cells. Finally, to assess whether MIC-1 is useful for the
treatment of rheumatoid arthritis, we will use gene therapy approaches to develop animals that produce
increased amounts of MIC-1 and determine whether this prevents or mitigates the development of rheumatoid
arthritis.
Research achievements (from final report):
N/A
Expected future outcomes:
N/A
Name of contact:
N/A
Email/Phone no. of contact:
N/A
NHMRC Research Achievements - SUMMARY
Grant ID: 157059
Start Year: 2001
CIA Name: Prof Samuel Breit
End Year: 2003
Admin Inst: University of New South Wales
Grant Type: NHMRC Project Grants
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $241,528
Title of research award:
The structure - function relationship of NCC27, a novel nuclear chloride ion channel proteinThe structure function relationship of NCC27, a novel nuclear chloride ion channel protein
Lay Description (from application):
Ion channels (IC) are complex proteins that regulate the transport of salts, an essential cell function. We have
recently cloned a new IC, NCC27, unique in its location on the nuclear membrane, a site where they were
previously thought to be unnecessary. The function of nuclear membrane ICs is unknown but our studies
suggest that NCC27 is involved in regulating cell division. Because NCC27 has unique functional and
structural characteristics, it will be particularly useful for answering fundamental questions relevant to the
biology of animal cells: the role of nuclear membrane ICs in cell division; the way the structure of NCC27
allows it to carry out its function.
Research achievements (from final report):
N/A
Expected future outcomes:
N/A
Name of contact:
N/A
Email/Phone no. of contact:
N/A
NHMRC Research Achievements - SUMMARY
Grant ID: 157067
CIA Name: Prof Carolyn Geczy
Admin Inst: University of New South Wales
Main RFCD: Pathology
Total funding: $392,037
Start Year: 2001
End Year: 2003
Grant Type: NHMRC Project Grants
Title of research award:
Mechanisms of inflammation by S100A12Mechanisms of inflammation by S100A12
Lay Description (from application):
This project will characterise the biological and functional properties of a novel human pro-inflammatory S100
protein. The protein is a natural component of the innate immune system and is regulated in cells by mediators
of inflammation and infection. Our preliminary experiments indicate that this protein can activate mast cells.
These cells reside in almost all body tissue and are located close to blood vessels and nerves. This location
makes them prime targets to trigger vascular and inflammatory events. They are known to be important in
allergy and infection and have a proposed role in chronic inflammatory processes. Although the mechanisms
of mast cell activation contributing to acute responses in allergic reactions are well accepted, ways in which
they are activated in asthma and other chronic inflammatory disease are virtually unknown. We will use lung
biopsies from patients with asthma to detect patterns of expression of the protein and determine its effects on
lung mast cells. A murine model will be used to define the characteristics of inflammation induced by the S100
protein and the role of mast cells in this process. Structural studies will define the parts of the protein necessary
for mast cell activation. We will attempt to identify its receptor on mast cells to enable future studies to define
how the protein triggers the cells to produce mediators such as histamine and those causing blood vessel
changes. This knowledge could lead to design of novel drugs that could regulate this process. Results from this
project will provide new knowledge of chronic inflammatory processes and could result in designing novel
strategies to regulate these. Studies are relevant to infectious diseases and many other conditions with a chronic
inflammatory basis, including asthma, rheumatoid arthritis, cardiovascular disease, cystic fibrosis and
infection.
Research achievements (from final report):
We discovered a novel activator of mast cells, important cells that, when stimulated, generate mediators that
cause asthma and allergy. This protein is a natural constituent of white blood cells that migrate to sites of
inflammation, paarticularly in response to infection. Upon release from these cells, the novel activator caused
mast cells to release histamine and other molecules that cause inflammation. It also amplified the response to
allergens. We identified a possible receptor on mast cells and were able to partially antagonise responses to the
protein. Administration of the protein caused inflammation and swelling and mice and provoked an
inflammation of the gut. We prepared antibodies against the activator, but these did not neutralise the
response., Mast cells are pivotal to the initiation of hbost responses to infection but the mechanisms whereby
activation occurs in these circumstances are undescribed. The significance of this work is the discovery of a
key mechanism that may regulate mobilisation of white blood cells to sites of infection. However when these
cells migrate to the lung in an episode of actute asthma, the severity of the attack may be exacerbated.
Indetification of a putative receptor for the novel activator may allow the design of new therapies that may
reduce severity. , We also studied the gene regulation of 3 new inflammation-associated proteins and found that
one of these, S100A8, that may be a novel anti-oxidant, is upregulated in the skin by UV light and by oxidants.
In addition, the gene is upregulated selectively in several cell types by corticosteroids, that are normally
immunosuppressive and we postulate that S100A8 plays an important protective role in preventing tissue
damage as a result of inflammation.
Expected future outcomes:
The project recieved continuing funding from the NHMRC aimed at characterising the receptor for the novel
mast cell activator. This will allow us to characterise the responses and may lead to design of new drugs that
would be more effective in treating patients with asthma.
Name of contact:
NHMRC Research Achievements - SUMMARY
Carolyn Geczy
Email/Phone no. of contact:
c.geczy@unsw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 157080
Start Year: 2001
CIA Name: Dr Judith Walker
End Year: 2003
Admin Inst: University of New South Wales
Grant Type: NHMRC Project Grants
Main RFCD: Pharmacology not elsewhere classified
Total funding: $406,528
Title of research award:
Opioids as a new therapy for inflammatory arthritis: Immunopharmacological mechanismsOpioids as a new
therapy for inflammatory arthritis: Immunopharmacological mechanisms
Lay Description (from application):
Arthritis is a chronic inflammatory disorder characterized by joint pain, swelling and stiffness. In fact, 69% of
patients present with radiographic erosions and joint space narrowing during the first three years of the disease
and it is insufficiently appreciated that patients with rheumatoid arthritis may have a 5-year mortality similar to
patients with cardiovascular or neoplastic disease. Prevention of disability and death is the ultimate goal of
treatment. However, no cure is yet available. Instead, current treatment is aimed at relieving symptoms and
improving functional performance. There is now a growing recognition that patients with rheumatoid arthritis
require more agressive treatment early in the disease, before the development of erosions and deformity. My
work has shown for the first time that opioid drugs that act via kappa (k) receptors in the periphery are able to
ameliorate the incidence and severity of disease symptoms in rat adjuvant arthritis. Histological and
radiological analysis reveals a significant, beneficial effect on joint pathology. The present proposal seeks to
build upon this basic information gained in rats into the anti-inflammatory mechanisms of opioid action. I will
now apply my expertise to extend this research in animals to human tissues. I am able to combine multiple
techniques to carry out a systematic and rigorous study on human synovium from arthritis patients. This work
aims to find out why opioids have anti-arthritic actions and might potentially lead to potent, less toxic and less
expensive new therapies for arthritis and increase our understanding of the pathogenesis of arthritis.
Research achievements (from final report):
The aim of these studies was to assess the therapeutic potential of opioids in the treatment of adjuvant arthritis
in rats, and to investigate the immunopharmacological mechanisms by which opioids mediate their antiinflammatory effects. The antinociceptive and anti-inflammatory properties of the novel peripherally selective
k-opioid ADL 10-0116 were examined in the adjuvant arthritis model and compared to asimadoline. Treatment
with ADL 10-0116 significantly reduced the pooled severity index - paw swelling, radiography and histology by as much as 69%. The anti-inflammatory effect of ADL 10-0116 was similar to that obtained with
asimadoline. Antinociceptive effects showed a dose-dependant increase in paw pressure threshold compared to
control animals. The optimum anti-inflammatory dose (10 mg/kg/day) was much lower then the optimum
analgesic dose (40 mg/kg/day). The readily clinically available opioid oxycodone was also found to attenuate
adjuvant induced arthritis in rats by as much as 50%. These anti-inflammatory effects were significantly
enhanced when oxycodone was administered locally (i.pl) in comparison to distant administration (i.p),
indicating a peripheral site of action. This was confirmed by administration of the opioid antagonist naloxone
- antagonist MR2266 dose-dependently inhibited the anti-inflammatory
effects of oxycodone (5 mg/kg; i.pl). These results indicate that oxycodone mediates its anti- inflammatory
- receptors in the periphery. Histomorphometry showed significantly fewer cells positive for the
-treated rats., Our findings suggest that
peripherally acting opioid agonists may lead to improved anti-inflammatory activity compared to standard nonsteroidal anti-inflammatory drugs, partly by inhibiting chemokines. This raises the possibility of novel
combination therapies incorporating anti-inflammatory opioids in arthritis.
Expected future outcomes:
Further experiments aimed at addressing the role of opioids in attenuation of chemokine-dependent
inflammatory cell migration to inflamed joints need to be pursued. In addition, examination of novel
peripherally active k opioid agonists needs to be initiated in the human disease setting.
Name of contact:
NHMRC Research Achievements - SUMMARY
Michael Grimm
Email/Phone no. of contact:
M.Grimm@unsw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 209540
Start Year: 2002
CIA Name: Prof Paul Curmi
End Year: 2004
Admin Inst: University of New South Wales
Grant Type: NHMRC Project Grants
Main RFCD: Medical Biochemistry: Proteins and Peptides
Total funding: $271,320
Title of research award:
Probing the control and action of CLIC1/NCC27, an unusual chloride ion channel, by x-ray
crystallographyProbing the control and action of CLIC1/NCC27, an unusual chloride ion channel, by x-ray
crystallography
Lay Description (from application):
Cells must regulate the flow of ions and water across their membranes in order to survive and function
normally. The balance of ions and water is controlled by ion channels - proteins that control the permeability
of the cell membrane. Of the ion channels, chloride channels are the most abundant in cells. They are central
to the functioning of normal cells as well as playing a key role in many disease states. Our group was the first
to identify and characterise a new class of chloride channel which plays a key roles in the regulation of the
immune system. These channels are unusual in that they can move between two states: a soluble state and a
state that resides in the cell membrane. We have determined the first structure of this class of channel in the
soluble state. In this project, we will determine: how the protein makes the transition into the membrane state;
which factors control this transition; and the structure of the protein in the membrane state. We will also
determine how several drugs control the activity of this channel. The results of our work will have specific
implications for our channel and will serve as a paradigm for other members of this new class of chloride
channel. Understanding how this channel functions and how the current drugs control it will lead to the
development of a new class of therapeutic agents that will control these channels by preventing the transition
from the soluble to the membrane state.
Research achievements (from final report):
Ion channel proteins are essential in that they allow cells to communicate with each other. As such, they are
central to controlling cellular activity and a key route for therapeutic intervention. The work on the CLIC ion
channel has mapped out atomic detail on a protein that can form an ion channel. In future, we will map out the
structure of the active channel state of this protein. As CLIC proteins play a key role in immune system cells,
the structure of the CLIC channel will provide avenues for drug and therapeutic strategies that will modulate
inflammation and immune responses.
Expected future outcomes:
A complete understanding of the function of the CLIC proteins by solving structures of the integral membrane
form and complexes with partner proteins. This will open many avenues for therapeutic intervention.
Name of contact:
Paul Curmi
Email/Phone no. of contact:
p.curmi@unsw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 222870
Start Year: 2003
CIA Name: Dr Kieran Scott
End Year: 2005
Admin Inst: University of New South Wales
Grant Type: NHMRC Project Grants
Main RFCD: Medical Biochemistry: Proteins and Peptides
Total funding: $554,400
Title of research award:
The mechanism of action of secreted phospholipase A2 and its inhibition in inflammationThe mechanism of
action of secreted phospholipase A2 and its inhibition in inflammation
Lay Description (from application):
Secretory phospholipase A2 (sPLA2) is an important mediator of inflammation and is clinically associated with
the onset and severity of several immune-mediated diseases including arthritis, asthma, atherosclerosis,
psoriasis and recently prostate cancer. These are complex diseases which are poorly understood. We have
shown that sPLA2 can by itself and in combination with inflammatory cytokines modulate signalling pathways
in cells derived from the joints of patients with arthritis to upregulate inflammatory molecules. How this
happens is completely unknown. We plan to work out how this enzyme does this. We have also developed
small cyclic peptide inhibitors of sPLA2 which potently block the function of the enzyme in these cells. We
plan to determine how this happens and if these inhibitors are effective at blocking inflammation and arthritis.
The proposal may identify new mechanisms by which secreted factors upregulate inflammation in human cells
and may lead to the discovery of new ways to intervene to block these pathways.
Research achievements (from final report):
Four key findings from this grant provide insights into how secreted phospholipase A2 (sPLA2) proteins may
be usefully targeted to treat certain inflammatory conditions such as rheumatoid arthritis (RA) and some
cancers. First, we have found that sPLA2 amplifies proinflammatory pathways in cells from the joints of
patients with RA by new mechanisms that do not need the enzyme activity of the protein. Blocking these new
pathways may be better than blocking enzyme activity. Second, we have learned more about how sPLA2 gets
into cells and generated new ideas about how sPLA2 might be working. Third, our new inhibitors are orally
absorbed and well tolerated, suggesting they have the chemical properties that may make them useful oral
medicines. Fourth we have worked out how several sPLA2 inhibitors bind to sPLA2.This information will help
us design more potent and selective inibitors. Together these findings suggest our efforts to develop new
treatments for inflammation and cancer are worth continuing.
Expected future outcomes:
These findings are encouraging because they strengthten the evidence that our approach to developing a new
treatment approach to immune-mediated inflammation and certain cancers based on inhibition of secreted
phospholipase A2 continue to valid and therefore should be pursued.
Name of contact:
Dr Kieran Scott
Email/Phone no. of contact:
kieran.scott@unsw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 300452
Start Year: 2004
CIA Name: Dr Nicodemus Tedla
End Year: 2006
Admin Inst: University of New South Wales
Grant Type: NHMRC Project Grants
Main RFCD: Immunology not elsewhere classified
Total funding: $254,250
Title of research award:
Leukocyte immunoglobulin-like receptors regulate the function of the major cells involved in allergic
inflammation.Leukocyte immunoglobulin-like receptors regulate the function of the major cells involved in
allergic inflammation.
Lay Description (from application):
An important aspect of the immune system is its ability to maintain a delicate equilibrium between the
extremes of reactivity and quiescence. A break in this equilibrium can lead to unchecked activation of immune
cells or inability of these cells to mount an effective defence. Potential outcomes of the unchecked activation
of cells are autoimmune diseases such as rheumatoid arthritis or allergic diseases such as asthma. A new
family of cell surface proteins termed leukocyte immunoglobulin-like receptors (LIRs) has been shown to
regulate immune cells by either increasing or decreasing their activity. In this project we will study the role of
LIRs in regulating the activity of the major cells involved in allergy and asthma. This study would provide
important insights to mechanism(s) of regulation of immune cell activation during protective immune
responses such as the fight against infections and cancers and during pathological inflammations such as
asthma and rheumatoid arthritis. Understanding the role of the LIRs in the regulation of immune cell activation
might lead to new therapeutic strategies aimed at restoring the balance between the inhibitory and activating
LIRs.
Research achievements (from final report):
The objectives of this project were to understand how activating and inhibitory LIRs regulate the balance
between protective and pathologic inflammation in vivo with special emphasis on allergic inflammation. , We
completed all the intended aims of the project and also extended aspects of our studies beyond the initial aims.
We determined the functions of activating and inhibitory LIRs on basophils was determined and published in
Blood (Blood. 2004: 104:2832-2839). We observed differential expression of LIRs between immature and
mature mast cells indicating developmental regulation of these molecules in mast cells. A manuscript was
published in Journal of leukocyte Biology reporting the above findings. , We recently published in
Rheumatology showing the effects of disease modifying anti-rheumatoid drugs on in vivo expression of LIRs
in rheumatoid synovium and in vitro function of LIR s on macrophages. We have also recruited 10 rheumatoid
patients and 10 age and sex matched controls and investigated the expression of LIRs in their peripheral blood
leukocytes. Our data shows that significantly higher proportions of lymphocytes from patients with rheumatoid
arthritis have an activating molecule LIR-6 as compared to controls suggesting that this molecule might play
important role in the activation of lymphocytes in RA. We obtained a new NHMRC Project grant (2008-2010)
to investigate the functions of LIR-6 and LIR-4 in RA and identify novel LIR ligands. We identified a potential
high affinity ligand for LIR-4 on the surface of monocytes with dissociation constant of 2.4x10-8M and
approximately 5000 ligand molecules per cell.
Expected future outcomes:
Determining the immune regulatory functions of LIRs in the pathogensis of allergic inflammation and
inflammatory arthritis may provide new theraputic approaches.
Name of contact:
Nicodemus Tedla
Email/Phone no. of contact:
N.Tedla@unsw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 300499
CIA Name: Prof Samuel Breit
Admin Inst: University of New South Wales
Main RFCD: Basic Pharmacology
Total funding: $432,750
Start Year: 2004
End Year: 2006
Grant Type: NHMRC Project Grants
Title of research award:
The in vivo and in vitro biology of the novel intracellular ion channel CLIC1 (NCC27)The in vivo and in vitro
biology of the novel intracellular ion channel CLIC1 (NCC27)
Lay Description (from application):
Ion channels are complex proteins that regulate the transports of salts, and essential cell function. We have
recently cloned a new ion channel, CLIC1, unique in its location on the nuclear membrane as well as other
sites. The function of this channel is uncertain, although we have suggested its association with cell growth
and inflammation. We propose to investigate the function of CLIC1, dominantly based on gene knockout
animals, in which the CLIC1 gene has been deleted.
Research achievements (from final report):
CLIC1 rapidly translocates to the plasma membrane of activated macrophages where it forms chloride ion
channels. We observed that CLIC1 is localised in vesicular structures present in macrophages and other cells,
the identity of which is yet to be characterised. On PMA activation, CLIC1 rapidly translocates to plasma
membrane, perhaps by fusion of the CLIC1 containing vesicles with plasma membrane. We further
demonstrated by patch clamping that the plasma membrane CLIC1 in macrophages is correlated to chloride
currents which can be partially blocked by IAA94, a CLIC blocker, or CLIC1 antibody. Our data show, for the
first time and undoubtedly, CLIC1 is a chloride channel protein which requires oxidation to become membrane
integrated and function in macrophages. , Role of CLIC1 in platelet function. CLIC1-/- mice have abnormal
platelet function with increased bleeding time and decreased platelet aggregation, that is mediated by patways
associated with P2Y12, the major ADP receptor, Role of CLIC1 in experimental allergic encephalomyelitis
(EAE). We have examined the role of CLIC1 in EAE, a widely used model of the common, debilitating brain
inflammatorydisease, multiple sclerosis. We have been able to demonstrate that the CLIC1 -/- mice have
markedly diminished EAE disease severity. , Effect of R29A mutations on ion channel activity of CLIC1 . By
mutating a charged arginine at position 29 (in TM region of CLIC1) to a neutral alanine and observing the
chloride current, we are able to show an altered single channel close probability in response to the membrane
potential.
Expected future outcomes:
demonstration of the mechanisms underlying the effect of CLIC1 on macrophages and patelets, identificaion of
the intracellular vesicles in/on which CLIC1 resides and determine mechanism for membrane translocation
Name of contact:
Samuel Breit
Email/Phone no. of contact:
s.breit@cfi.unsw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 350844
Start Year: 2005
CIA Name: Prof Paul Curmi
End Year: 2007
Admin Inst: University of New South Wales
Grant Type: NHMRC Project Grants
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $505,500
Title of research award:
Crystallographic studies of CLIC family proteinsCrystallographic studies of CLIC family proteins
Lay Description (from application):
Cells must regulate the flow of ions and water across their membranes in order to survive and function
normally. The balance of ions and water is controlled by ion channels - proteins that control the permeability
of the cell membrane. Of the ion channels, chloride channels are the most abundant in cells. They are central
to the functioning of normal cells as well as playing a key role in many disease states. Our group was the first
to identify and characterise a new class of chloride channel which plays a key roles in the regulation of the
immune system. These channels are unusual in that they can move between two states: a soluble state and a
state that resides in the cell membrane. We have determined the first structures of this class of channel in both
the soluble state and what is believed to be the membrane docking state. This has given us the first atomic
picture of how this channel protein can alter its structure so as to carry out its function. In this project, we will
determine: how the protein completes the transition into the membrane state; the structures of other key
members of this class of channel protein; complexes between channel proteins and other cellular proteins; and
the structure of the protein in the membrane state. We will also determine how several drugs control the
activity of this channel. The results of our work will have specific implications for our channel and will serve
as a paradigm other members of this new class of chloride channel. Understanding how this channel functions
and how the current drugs control it will lead to the development of a new class of therapeutic agents that will
control these channels by preventing the transition from the soluble to the membrane state.
Research achievements (from final report):
CLIC proteins are unusual chloride ion channel proteins in that they have both a soluble form and an integral
membrane form. These proteins have the ability to transit between these two states. We have determined
atomic structures for several human CLIC proteins as well as CLIC proteins from model organisms. This data
provides a detailed view of these proteins and allows one to correlate experimental findings based on model
organism studies to human health and physiology. Additionally, we have determined how CLIC proteins
interact with other protein molecules, specifically the nuclear transport protein importin alpha and the
membrane scaffolding protein ezrin. The nuclear transport of human CLIC4 is implicated in both cancer and
programmed cell death. The interaction of CLIC4 with importin alpha controls the physiological mechanisms
by which it is involved in these processes. We have also determined factors that control the transition of CLIC
proteins from the cell cytoplasm to the membrane. These include stress states such as oxidation. These studies
provide a clearer understanding of how CLIC protein participate in stress responses in vitro. We have also
examined the cellular response of CLIC proteins in microglial cells which have been challenged with the
Alzheimer's disease A-beta peptide.
Expected future outcomes:
We expect to determine the atomic structure of CLIC proteins in the membrane. This will show how the
proteins function as ion channels and how this process participates in cellular processes. This will give a better
understanding of how CLIC proteins participate in the activation of immune cells such as macorphages and
microglial cells.
Name of contact:
Paul Curmi
Email/Phone no. of contact:
p.curmi@unsw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 350916
Start Year: 2005
CIA Name: Dr Shane Thomas
End Year: 2007
Admin Inst: University of New South Wales
Grant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $271,500
Title of research award:
Role of indoleamine 2,3-dioxygenase in vascular diseaseRole of indoleamine 2,3-dioxygenase in vascular
disease
Lay Description (from application):
Atherosclerosis and its clinical presentation including heart attack and stroke represent a major source of
morbidity and mortality in the developed world, including Australia. Atherosclerosis involves the
accumulation of lipid-laden cells in the wall of arteries that generates plaques resulting in a decrease in the
lumen of the affected vessel that can impede or block blood flow resulting in clinical complications. The
cellular events involved in atherosclerosis are complex. However, increasing information indicates that
atherosclerosis involves an inappropriate response of the immune and inflammatory systems. This proposal
plans to investigate the role of a protein, indoleamine 2,3-dioxygenase (IDO) that is increased during
inflammation and is important for the regulation of the host's immune system. We propose that increasing IDO
activity in inflammatory cells will attenuate the degree of vascular disease by decreasing the overall level of
immune activation and inflammation in the blood vessels. We will test this by modulating the expression and
activity of this protein in animal models of vascular disease, measure the extent of disease and then elucidate
the mechanisms by which the protein acts. The significance of these studies is that they will provide useful
information on the inflammatory and immune processes involved in the progression of atherosclerosis and may
identify a potential novel target for therapeutic intervention.
Research achievements (from final report):
The project investigated the role and regulation of a protein that controls the immune system in vascular
disease. The study showed that this protein is present in increased levels in human diseased blood vessels
where it is expressed in immune cells. In diseased vessels the protein appears to be modified such that its
activity may be reduced during vascular disease. In detailed biochemical studies employing purified protein we
established that such modification inhibits the proteins activity and defined the mechanism through which this
occured. In the final period of the grant we have performed studies examining the effect of an inhibitor of the
protein on vascular disease in mice. To date, the data support that the protein represents an inhibitor of disease
progression. Together, these studies support that the activity of this immune control protein may, to a certain
extent, be defective during vascular disease and that agents that increase the proteins activity may represent
novel means for treating vascular disease.
Expected future outcomes:
We expect to perform new studies examining the effect of immunotherapuetic agents that increase the activity
of the protein in question to determine the extent to which these treatements can reduce vascular disease. We
will also contiue to study novel mechanisms through which this protein is controlled that may highlight novel
strategies to control the enzymes activity.
Name of contact:
Dr Shane Thomas
Email/Phone no. of contact:
shane.thomas@unsw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 455306
CIA Name: Prof Carolyn Geczy
Admin Inst: University of New South Wales
Main RFCD: Rheumatology and Arthritis
Total funding: $454,692
Start Year: 2007
End Year: 2009
Grant Type: NHMRC Project Grants
Title of research award:
Inflammation-associated S100 proteins: links between arthritis and atherosclerosisInflammation-associated
S100 proteins: links between arthritis and atherosclerosis
Lay Description (from application):
Deeper understanding of the basic contributions of inflammation to cardiovascular disease can lead to better
strategies for treatment and diagnosis. There are shared mechanisms in rheumatoid arthritis and these patients
are at significantly higher risk of myocardial infarction and heart failure than the healthy normal population.
This project will improve heart health because it will address how newly-recognised proteins, called S100
proteins, mediate pathogenesis and how they are regulated in cells by various therapeutic drugs. We
developed a potential diagnostic test that distinguishes patients with angina from those with arthritis and this
could be useful in improving diagnosis and following treatment of patients with cardiovascular disease or
arthritis. We find that some anti-inflammatory drugs enhance S100 gene expression whereas our preliminary
data indicates that some cholesterol-lowering drugs (statins) reduce it. Results of treating patients with
arthritis with statins will add to understanding of why cholesterol-lowering drugs commonly used in
management of CVD patients may be effective in treating symptoms in arthritis sufferers and could contribute
to changes in clinical management of these patients.
Research achievements (from final report):
The work from this grant is important because it questions the current dogma regarding roles of S100 proteins
in inflammation., We find that the inflammation-associated S100 proteins S100A8, S100A9 and S100A12 are
elevated in lesions from patients with coronary artery disease (CAD), as others showed for rheumatoid arthritis
(RA). We proposed that S100A8 played a protective role by scavenging oxidants and that statin treatment may
reduce the risk of cardiovascular disease in RA patients because of increased production of the S100s. Oxidised
S100A8 did not induce proinflammatory genes, but reduced a gene important in monocyte recruitment., We
showed that S100A8 and S100A9 preferentially scavenge different oxidants and these adducts may suppress
transmigration of phagocytes from blood vessels. We propose a pleiotropic effect for S100A12 because it
inhibited enzymes important in cell migration and plaque rupture and thus may be protective role in CAD. Our
work in asthma (NHMRC#455307) proved that S100A8 acts as an anti-oxidant in inflammation and we find a
novel complex in human atheroma. , A clinical study showed that S100 proteins were associated with RA
inflammation (138 patients) and autoantibody production, and with classical vascular risk factors for end-organ
damage. However methatrexate, a drug used to treat RA, induced the S100 proteins, in blood monocytes in
vitro, as did statin treatment. Normal donors on statins confirmed levels in blood monocytes increased over 12
weeks.
S100A8 and S100A12 bound
proteins in HDL; S100A12 inhibited proinflammatory actions of SAA; S100A8 may protects ApoA1 from
oxidation., Thus the increased levels of S100s in the circulation of patients may contribute to protection.
Expected future outcomes:
We expect to prove that S100s have important protective functions in chronic human inflammatory diseases.
Name of contact:
Carolyn Geczy.
Email/Phone no. of contact:
029385 2777
NHMRC Research Achievements - SUMMARY
Grant ID: 456438
Start Year: 2007
CIA Name: Dr Christine Lu
End Year: 2012
Admin Inst: University of New South Wales
Grant Type: Early Career Fellowships (Australia)
Main RFCD: Public Health and Health Services not elsewhere classified
Total funding: $177,449
Title of research award:
Safer and more effective use of medicines in patients with diabetes and rheumatoid arthritis.Safer and more
effective use of medicines in patients with diabetes and rheumatoid arthritis.
Lay Description (from application):
Not Available
Research achievements (from final report):
Little is known about how specific co-existing medical conditions affect patients' patterns of drug treatments,
medical services or outcomes. My research generated new evidence by considering how the overall
comorbidity burden and specific co-existing condition(s) affect the use and outcomes of medications in the
real-world setting in Australia via a series of observational studies. Results of my work identified vulnerable
populations to whom interventions or educational efforts should be targeted for improving quality of care. Two
major contributions published are:, To measure comorbidity reliably, I conducted the first study in Australia to
compare two existing instruments using administrative data. I found both the Charlson (based on inpatient
diagnoses) and Rx-Risk scores (based on prescription medicine dispensings) predicted mortality. Due to the
lack of systematic recording of diagnostic information in outpatient settings in Australia, researchers can
consider using medication-based comorbidity index where appropriate because it broaden the ability to adjust
for comorbidity to individuals in the outpatient setting., Chronic conditions are frequently associated with
psychological distress partly due to functional incapacitation. If left untreated or inappropriately treated,
depression may lead to significant personal and social costs because of the increased risk of suicide, social
impairment and the increased use of health services. Clinical guidelines recommend that antidepressant
treatment should be continued for at least 6 months. My research indicates persistence with antidepressant in
the Australian veteran patients is inconsistent with clinical guidelines, with the majority of initiating patients
provided with insufficient duration. Enhanced management of elderly patients with characteristics associated
with shorter persistence, including cancer and multi-morbidities, may improve antidepressant use.
Expected future outcomes:
The safety and effectiveness of cancer medicines in patients with comorbidities are largely unknown because
they are significantly under-represented in most randomised controlled trials, the gold standard for evaluating
new medicines. My studies also addressed how and which specific non-cancer illnesses affect the use and
effectiveness of cancer medicines (to be completed and published).
Name of contact:
Dr Christine Lu
Email/Phone no. of contact:
christine_lu@harvardpilgrim.org
NHMRC Research Achievements - SUMMARY
Grant ID: 510236
CIA Name: A/Pr Nicodemus Tedla
Admin Inst: University of New South Wales
Main RFCD: Autoimmunity
Total funding: $292,217
Start Year: 2008
End Year: 2011
Grant Type: NHMRC Project Grants
Title of research award:
Expression and functions of leukocyte Immunoglobulin-like Receptor (LIR)-6 and LIR-4 in inflammatory
arthritis (IA).Expression and functions of leukocyte Immunoglobulin-like Receptor (LIR)-6 and LIR-4 in
inflammatory arthritis (IA).
Lay Description (from application):
Rheumatoid arthritis (RA) that affects millions worldwide is characterised by uncontrolled activation of
immune cells destroying ones own joints. The reasons for this excessive activation of cells are not known and
existing treatments are limited to easing symptoms. We will study the role of new proteins named as Leucocyte
Ig-like Receptors in regulating immune cell activation. Understanding mechanisms that control unwanted
activation of immune cells is critical in preventing and treating RA.
Research achievements (from final report):
The objectives of this project were to understand how activating and inhibitory LILRs regulate the balance
between protective and pathologic inflammation in vivo. The specific aims were to determine expression
patterns of activating LILRA1and LIRA3 in patients with IA, to identify their ligands and determine their
functions in context of inflammatory arthritis IA). We have achieved all stated aims including identification of
novel ligands for LILRA3 (LAMR1 and HLA-B27) that potentially play key role in the pathogenesis IA,
response to anti-TNF treatment and clinical outcomes.
Expected future outcomes:
We expect to publish our key findings related to the novel LILRA3 ligands and effects of LILRA1 on T
lympocytes in at least two peer-reviewed high impact journals. We are in early stage of discussions with the
university regarding patenting LILRA3 as potential anti-inflammatory agent in IA.
Name of contact:
Nicodemus Tedla
Email/Phone no. of contact:
N.Tedla@unsw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 510724
CIA Name: Prof Julie Byles
Admin Inst: University of Newcastle
Main RFCD: Epidemiology
Total funding: $439,324
Start Year: 2008
End Year: 2011
Grant Type: NHMRC Project Grants
Title of research award:
Tracking the impact of drug regulatory actions: consumer health outcomes, risk-benefit issues and policy
framework.Tracking the impact of drug regulatory actions: consumer health outcomes, risk-benefit issues and
policy framework.
Lay Description (from application):
This study will explore what happens in the community when a medicine is withdrawn from the market or
discredited due to safety concerns. It will examine the impacts of two recent cases of medicine withdrawal or
serious long-term safety concern, on a large cohort of women with high utilisation rates who were monitored
during the time the medicines were discredited. The study will be an important guide to future regulatory,
media and provider responses when medicines are discredited.
Research achievements (from final report):
In 2004, a prescribed medicine for the relief of arthritis pain and inflammation (Vioxx) was taken off the
market due to safety concerns. Caution in the use of other related medicines was also advised. When a
medicine such as Vioxx is withdrawn (or a whole class of medicines discredited), follow-up of impacts at
consumer level can be difficult and costly. The Australian Longitudinal Study on Women's Health provided a
rare opportunity to examine medicine use by individuals following this major discrediting event. When first
marketed, Vioxx was expected to reduce the health problems related to arthritis medicine use; however, it was
later found that this medicine could actually increase the risk of heart and kidney problems for some people.
This study found that women who had frequently used Vioxx often switched to medicines related to Vioxx for
their arthritis pain, once Vioxx was no longer available. This conflicted with public health advice at the time.
Whether this choice was mostly made by women or by their prescribers depended upon their age group.
Overall, we found little evidence that discrediting Vioxx resulted in harm for this group of Australian women,
in terms of health outcomes and quality of life, and effect on perceptions of safety of medicines overall.
Expected future outcomes:
These findings contribute to our understanding of how public safety concerns with medicines should be
managed and communicated in future events, and provides important information for improvements in
regulatory and provider responses when other medicines are discredited in the future.
Name of contact:
A/Professor Lynne Parkinson
Email/Phone no. of contact:
lynne.parkinson@newcastle.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 142958
CIA Name: Prof Mark Forwood
Admin Inst: University of Queensland
Main RFCD: Orthopaedics
Total funding: $301,018
Start Year: 2001
End Year: 2003
Grant Type: NHMRC Project Grants
Title of research award:
Prostaglandin G/H synthase-2 (PGHS-2) is a key regulator of skeletal adaptation and remodellingProstaglandin
G/H synthase-2 (PGHS-2) is a key regulator of skeletal adaptation and remodelling
Lay Description (from application):
Knowledge of the biology underlying bone formation is important for developing novel approaches to
stimulate new bone formation in skeletal diseases associated with ageing or disability, or for maintenance of
new bone around orthopaedic or dental implants. The discovery that a prostaglandin enzyme (PGHS-2) is a key
factor in activity-related bone formation and normal bone turnover, as well as a pharmacological target for
reducing inflammation, has considerable clinical significance. Specific inhibition of PGHS-2 by recent antiinflammatory drugs avoids formation of gastric ulcers, but their influence on normal bone remodelling and
fracture repair is not known and must be investigated. Many such inhibitors are in advanced clinical trials, but
their effect on bone metabolism has not been published. This project is important because it employs novel
experimental models to advance our knowledge of prostaglandin biology in skeletal adaptation, and elucidates
important clinical consequences for specific inhibition of PGHS-2 in the skeleton. This project will investigate
the regulation of prostaglandin production by PGHS enzymes following mechanical loading in vivo. It will use
cell, molecular and histochemical techniques to determine if the genes that regulate the enzymes are influenced
by mechanical stimuli, and if they are dependent on other molecules, associated with structural proteins (stress
fibres) within the cell. It will investigate if inhibition of PGHS-2 by antiinflammatory drugs or stress-fibre
inhibitors, depresses normal bone turnover and healing responses. The outcome of these experiments could
indicate new approaches to stimulate bone formation, preserve bone mass, or minimise adverse skeletal effects
of anti-inflammatory treatments related to orthopaedic or dental procedures.
Research achievements (from final report):
The experiments showed that PGHS-2 (or COX-2) gene expression (normally related to inflammation) is
increased in bone tissue following loading. It also provided experimental evidence that PGHS-2 inhibition
reduces bone turnover which can prevent menopause related bone loss. This was shown to be related to
decreases in osteoclast surface and activity - the cells that remove bone. PGHS-2 inhibitors (anti-inflammatory
drugs) also slowed the remodelling and consolidation of woven bone on the periosteal surface following
loading. This would lead to increased healing time for fractures, but would not jeopardise the strength of those
healing fractures. The findings above suggest that there is a clinical implication for COX-2 inhibition in terms
of regulating bone turnover, but this has not yet been translated into a direct clinical outcome.
Expected future outcomes:
Evidence that new antinflammatory drugs not only reduce inflammation, but may have a role in managing and
regulating bone diseases associated with rapid bone loss, will be investigated. The role of COX-2 in bone
biology is being pursued in mice producing excess levels of this enzyme to study whether this exacerbates
conditions of bone loss or enhances adaptive mechanisms associated with loading
Name of contact:
Mark Forwood
Email/Phone no. of contact:
m.forwood@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 143049
Start Year: 2001
CIA Name: Prof Stephen Taylor
End Year: 2003
Admin Inst: University of Queensland
Grant Type: NHMRC Project Grants
Main RFCD: Pharmacology not elsewhere classified
Total funding: $317,546
Title of research award:
Design and Evaluation of Inhibitors of Phospholipases A2 as Anti-Inflammatory DrugsDesign and Evaluation
of Inhibitors of Phospholipases A2 as Anti-Inflammatory Drugs
Lay Description (from application):
There are at least 16 types of enzymes called phospholipases A2 (PLA2). They are found in venoms of snakes,
bees, lizards, cone snails, etc and act as toxic and digestive agents. PLA2 enzymes are also found in cells and
tissues of mammals where they carry out a wide range of digestive, maintenance, immune defence, and cell
signalling functions. The human pancreas secretes one form of PLA2 into the gut to aid digestion. Human
immune cells (macrophages, thymocytes, spleen leukocytes, platelets) use other forms of PLA2 in the
inflammatory immune response to kill infectious foreign agents like viruses and bacteria. One form of PLA2,
known as type IIa, is the main bacteria-killing ingredient of human tears and it is also a chief component of
fluid from the joints of patients with arthritis. Type IIa PLA2 is present in abnormally high levels in blood from
humans with arthritis, burns, sepsis, ARDS, atherosclerosis, Crohn's disease, malaria, cancer and other chronic
illnesses. These high levels can cause injury, tissue damage and pain due to too much inflammation and
treatments are needed to stop or decrease effects of this enzyme . For these reasons this and related enzymes
are thought to be potential targets for drugs which would act by blocking the functions of such an enzyme. Our
group has been using computers to design new chemicals that can selectively fit into this enzyme and stick
very tightly. We are determining the three dimensional structures of these chemicals in the enzyme to learn
how to make them bind even more tightly. This information is allowing us to synthesize new selective drugs
that stop PLA2 from promoting the development of disease. We propose to continue these studies towards
developing powerful new antiinflammatory drugs that block the enzyme, and to demonstrate possible benefits
of these drugs by testing them in animal models of arthritis, sepsis, adult respiratory distress syndrome
(ARDS), period pain, malaria, and cancer.
Research achievements (from final report):
Inflammatory diseases are often poorly treated by current drugs, and new agents targeting specific disease
mechanisms are required. Our work on a new target enzyme, believed to be involved in numerous
inflammatory diseases suggests that a new class of medicine can be developed that may provide benefits that
are not yet available clinically.
Expected future outcomes:
N/A
Name of contact:
N/A
Email/Phone no. of contact:
N/A
NHMRC Research Achievements - SUMMARY
Grant ID: 143109
Start Year: 2001
CIA Name: Dr Allison Pettit
End Year: 2005
Admin Inst: University of Queensland
Grant Type: Early Career Fellowships (Overseas)
Main RFCD: Cell Development (incl. Cell Division and Apoptosis)
Total funding: $235,026
Title of research award:
The role of T cell expression of receptor-activator NFkB ligand (RANKL) in the pathogenesis of rheuatoid
arthritis boneThe role of T cell expression of receptor-activator NFkB ligand (RANKL) in the pathogenesis of
rheuatoid arthritis bone
Lay Description (from application):
Not Available
Research achievements (from final report):
Research undertaken during the tenure of this Fellowship prominently contributed to the delineation of the
cellular and molecular mechanisms of bone destruction in inflammatory arthritis. Bone destruction is a
detrimental outcome in many diseases, including rheumatoid arthritis and osteoporosis. It is associated with
poor prognosis and significantly contributes to morbidity. We definitively demonstrated that osteoclasts (cells
that remove bone in normal bone remodelling) are primarily responsible for bone destruction in inflammatory
arthritis. Additionally, we provided compelling evidence supporting that the regulatory factor RANKL
(receptor activator of NF-κB ligand) is the critical and potentially rate limiting signal driving the aberrant
formation of osteoclasts and subsequently bone destruction in inflammatory arthritis. These studies provided
compelling evidence to support that RANKL is a promising therapeutic target for the prevention of bone
destruction in inflammatory arthritis and many other diseases that have associated-bone destruction. To better
understand how RANKL expression is controlled, we examined regulation of RANKL gene expression in T
cells, a relevant source of RANKL in inflammation. The data indicated that NFAT (nuclear factor of activated
T cell) gene regulatory factors may be important regulators of RANKL expression in T cells. Importantly,
NFAT factors have also been shown to be important regulators of osteoclast development. Therefore,
considering that NFATs potentially contribute to osteoclast formation at mutliple points in the pathyway,
strategic blockade of the NFAT gene regulatory factors may provide a powerful strategy for preventing
inflammation-associate bone destruction.
Expected future outcomes:
Clinical trials are currently underway to determine the safety and efficacy of therapies that block that action of
RANKL. Successful therapies will significantly reduce the economic and social impact of musculoskeletal
diseases such as rheumatoid arthritis and osteoporosis.
Name of contact:
Allison Pettit
Email/Phone no. of contact:
a.pettit@imb.uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 210237
CIA Name: Prof Ranjeny Thomas
Admin Inst: University of Queensland
Main RFCD: Autoimmunity
Total funding: $421,980
Start Year: 2002
End Year: 2004
Grant Type: NHMRC Project Grants
Title of research award:
Induction of antigen-specific tolerance through inhibition of RelB function in dendritic cellsInduction of
antigen-specific tolerance through inhibition of RelB function in dendritic cells
Lay Description (from application):
This proposal builds on preliminary data showing the possibility that responses of the immune system to
antigens can be suppressed by modifying cells known as dendritic cells using an inhibitory drug. The drug
appears to be able to control the ability of dendritic cells to educate the immune system about antigens. When
antigens presented continuously are harmful to the immune system, they produce diseases such as rheumatoid
arthritis and allergies. The experiments to be undertaken specifically look at means to prevent and reverse
diseases like rheumatoid arthritis through the use of dendritic cells.
Research achievements (from final report):
Dendritic cells (DC) are a key component of the immune system and are involved in regulation of innate and
acquired immunity. These cells capture, process and present antigens to T cells, and have been implicated in
autoimmune disease as well as other diseases of the immune system such as allergy, immunodeficiency,
transplant rejection, persistent viral infection and cancer. We have carried out in vitro and in vivo experiments
that provide evidence in mice of the capacity of DC modified with an inhibitor of NFkB activation, to suppress
existing immune responses in an antigen-specific way. Data indicate that the ability of DC to induce T cell
activation or tolerance can be controlled by manipulation of a protein known as RelB in DC. Thus, mouse DC,
generated in the presence of a soluble inhibitor of NFkB (modified DC) and exposed to antigen, prevent
priming, and also suppress a previously primed immune response and arthritis in mouse models. This tolerance
is antigen-specific, and dependent on the dose of administered DC. In vitro studies of modified human blood
DC demonstrate that the cells have a similar phenotype and in vitro functional capacity as the modified mouse
DC. These results suggest that future treatment of autoimmune disease with modified dendritic cells may
provide an effective, and antigen specific solution to controlling the disease in affected individuals. This
modified DC platform technology has potential application in a number of diseases where tolerance is broken,
including autoimmune disease, allergy, transplantation and graft vs. host disease (GVHD).
Expected future outcomes:
Modified DC are in development for tolerising immunotherapy in a phase I clinical trial. If successful they will
be further developed for applications in autoimmune disease.
Name of contact:
Rthomas@Cicr.Uq.Edu.Au
Email/Phone no. of contact:
agautam@cicr.uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 210261
CIA Name: Dr Alan Cassady
Admin Inst: University of Queensland
Main RFCD: Gene Expression
Total funding: $226,650
Start Year: 2002
End Year: 2004
Grant Type: NHMRC Project Grants
Title of research award:
Osteoclast- specific gene regulationOsteoclast- specific gene regulation
Lay Description (from application):
Osteoporosis is a pathological loss of bone that affects many Australians. It occurs because of an excessive
release of calcium from bone that is caused by the overactivity of the cells that break down bone, osteoclasts.
We have studied two genes that are involved in the way these cells work and by a close examination of the the
way they are regulated we hope to understand how osteoclasts are derived and how their activity is controlled.
In particular we will look at two newly dicovered osteoclast regulators called PPAR-gamma and PPAR-delta.
These offer the opportunity for the development in the future of new, alternative drugs for the treatment of
osteoporosis.
Research achievements (from final report):
Osteoclasts are the cells responsible for the normal processes of damaged bone removal and bone remodelling
but in diseases such as osteoporosis the over-activity of osteoclasts results in weak bones. We have been
studying the control of osteoclast genes in order to understand the mechanisms that govern their activity. In this
project we studied a characteristic osteoclast marker gene called "TRAP" and have identified DNA structures
within the gene that govern the operation of the gene. This pattern of regulation may apply more generally to
other osteoclast genes. In addition we have characterized previously unreported mouse and human gene
structures that will govern the sites at which this gene is expressed. , We have found that the steroid hormone
receptor PPARup-regulated by the pathological bacterial product LPS. The stimulator of PPARcarbaprostacyclin, also up-regulates the expression of the osteoclast marker genes including the calcitonin
receptor and MMP-9, implicating PPARmouse lines to be used to knockout genes of interest specifically in osteoclasts. These utilize the control regions
of the osteoclast-expressed TRAP and cathepsin K genes to drive expression of the Cre enzyme. When these
mice are crossed with transgenic mice in which the target gene of interest is marked by "loxP" sites then the
gene will be excised. This will permit us to examine the biology of gene knockout of the PPARosteoclasts without generalized effects on mouse development which are known to occur with a standard
knockout strategy. Using this approach we can make a more comprehensive assessment of the role of PPAR-
Expected future outcomes:
The characterization of PPAR-responsive elements in osteoclast-expressed genes will proceed to determine if
PPAR-delta in particular has direct or indirect effects on osteoclastogenesis. The PPAR-delta conditional
knockout mouse is under investigation for phenotypic effects on bone development, structure and turnover.
Name of contact:
Alan Cassady
Email/Phone no. of contact:
I.Cassady@imb.uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 210308
Start Year: 2002
CIA Name: Prof Ross Smith
End Year: 2004
Admin Inst: University of Queensland
Grant Type: NHMRC Project Grants
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $346,650
Title of research award:
Heterogeneous nuclear ribonucleoprotein A2-dependent mRNA trafficking in the cytoplasm of
cells.Heterogeneous nuclear ribonucleoprotein A2-dependent mRNA trafficking in the cytoplasm of cells.
Lay Description (from application):
Control of the use of DNA, gene expression, is vital to all living organisms, especially in development and
disease. The information in the genes of DNA is transferred to an intermediate molecule, mRNA, in a process
called transcription. The genetic information in the mRNA is subsequently used to make the protein encoded
by the original gene. The switching on and off of DNA appears to be most frequently controlled at the
transcription step but recently it has become apparent that there are many post-transcriptional events that
govern how efficiently the genetic information is ultimately converted to protein molecules. The RNA
molecules may be confined to a small region of the cell, resulting in the localization of the protein produced
from it; the RNA may be rapidly degraded or stabilized; and the efficiency of production of the protein from its
RNA precursor may be modulated by other molecules. It had previously been shown that the mRNA encoding
a protein that is an essential structural component of central nervous system myelin is selectively transported to
the regions in the cell where the myelin is made. We have identified the molecule that recognises this RNA as a
protein called hnRNP A2 and shown how it selects the RNA molecules that have to be transported from the
myriad of RNA moleclues in the cell at any given time. hnRNP A2 was previously thought to be confined to
the nuclei of cells, but we have shown that it is also present outside the nucleus and is involved in RNA
transport in a variety of cell types. hnRNP A2 appears to be directly involved in rheumatoid arthritis, lung
cancer and other cancers. It has been proposed as a diagnostic test for cancer as elevated intracellular levels and
circulating antibodies against this protein appear before the cancerous cells are visible under the microscope.
The major aim of the proposed project is to explore the molecular mechanism by which hnRNP A2 transports
RNA molecules in cells.
Research achievements (from final report):
These studies have contributed to our knowledge of the biology of two of the main types of cells in the brain,
oligodendrocytes and neurons. Cells have elaborate mechanisms for localization of proteins to specific
subcelluar destinations and this protein localization plays an essential role in the ways in which cells function.
For example, the communication between neurons and consequently memory formation is dependent on the
localization of several proteins, and the mRNA molecules that encode them, close to the junctions between the
cells.
Expected future outcomes:
The major outcome is expected to be a fuller understanding of the means by which some mRNA molecules are
targeted for transport to specific destinations in cells and how these proteins affect development and
functioning in humans and other mammals.
Name of contact:
Ross Smith
Email/Phone no. of contact:
ross.s@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 252811
CIA Name: Prof David Fairlie
Admin Inst: University of Queensland
Main RFCD: Enzymes
Total funding: $439,500
Start Year: 2003
End Year: 2005
Grant Type: NHMRC Project Grants
Title of research award:
Design and Development Of Small Molecules To Regulate Protease Activated Receptor Type 2Design and
Development Of Small Molecules To Regulate Protease Activated Receptor Type 2
Lay Description (from application):
A new class of proteins have been discovered on the surface of cells. These are activated by enzymes known as
proteases and are therefore called Protease Activated Receptors (PARs). PARs appear to be very important
'sensors' of proteases outside cells, becoming activated in response to very low concentrations of proteases.
This suggest that proteases may exert some of their biological effects through these receptors, which are now
implicated in a growing number of diseases (e.g. thrombosis, cardiovascular disorders, asthma, inflammatory
bowel disease, Crohn's disease, pancreatitis, stomach and colon cancer, arthritis, and there may also be a role in
wound healing). We are working towards dissecting the roles for one of these receptors (PAR2) in disease by
developing small molecules for selective binding to this receptor. We will particularly distinguish between
compounds that can activate (agonists) or deactivate (antagonists) the receptor. These experiments will involve
computer-assisted compound design, structural comparisons between small molecules with activity and those
without, and cellular studies designed to measure affinity, activation and deactivation of PAR2. The outcome
will be a series of small molecules that bind tightly to the PAR2 receptor and have a well defined function
(antagonist, agonist, partial agonist). While the above studies are in progress some peptides that are known to
activate this receptor will be examined in rodent models of human disease (airways inflammation, pancreatitis,
stomach and colon cancer, arthritis). Studies like this have been very revealing for us in the past (Nature 1999,
398, 156-160 "A protective role for protease-activated receptors in the airways"). Then the designed and
developed compounds will also be examined for signs of therapeutic potential. The work will provide a better
understanding of how this receptor works and a clearer picture of the role of this receptor in human disease.
Research achievements (from final report):
PAR2 has been idntified and investigated on 30 epithelial and endothelial cell types, and a potent agonist has
been examined for effects on gene expression in two cell types. Structure-activity relationships for several
hundred peptidic agonists provided information used to create the first PAR2 antagonists as well as the first
nonpeptidic agonists. The structures of these compounds were determined, a model was created for their
interaction with the transmembrane region of PAR2, and mechanisms of agonismwere investigated.
Preliminary in vivo studies were also conducted to begin documenting the role of PAR2 in inflammatory
diseases.
Expected future outcomes:
The research results pave the way for a new class of antiinflammatory and antiproliferative drugs to be
developed. The information gathered in this project provides new insights to the role of PAR2 in proliferative
and inflammatory processes and disorders and new probes for analysing this novel type of GPCR.
Name of contact:
David Fairlie
Email/Phone no. of contact:
d.fairlie@imb.uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 252812
Start Year: 2003
CIA Name: Prof David Fairlie
End Year: 2005
Admin Inst: University of Queensland
Grant Type: NHMRC Project Grants
Main RFCD: Pharmacology not elsewhere classified
Total funding: $473,250
Title of research award:
Agonists and Antagonists Of The Human Complement C3a ReceptorAgonists and Antagonists Of The Human
Complement C3a Receptor
Lay Description (from application):
Many serious inflammatory diseases, such as arthritis, septic shock, lung shock, heart disease, atherosclerosis,
multiple sclerosis, are poorly controlled with currently available drugs. There is a great deal of evidence that
naturally occuring "Complement" proteins in human blood are involved in exacerbating these and many other
human diseases, yet there are no good drugs available to counteract their effects. One of the most important
complement proteins is known as C3a. It is called an anaphylatoxin and is thought to be a pivotal component of
the complement system synthesized by the human body early on in the development of inflammatory and
immune diseases. New compounds that could stimulate or block the activity of C3a are expected : (a) To
lead us to a better understanding of how C3a binds to its receptors on immune cells and its role in the immune
response to infection and injury, and (b) To enable the rapid development of an entirely new class of drugs for
treating autoimmune and inflammatory diseases. No Complement-based drugs are yet available. It is not yet
possible to examine detailed structures of the receptors on cells that interact with complement proteins.
However it is possible to determine and analyse three dimensional structures of small molecules that can bind
to human immune cells, and mimic or block effects of human C3a on cells, rat tissues, and in whole rats. We
will identify and improve such small molecules by optimising their binding to immune cells, by tailoring them
to selectively block or mimic just the effects of C3a, and by making them pharmacologically stable for
administration (preferably by mouth) to rats (and humans). We will then test them in rats for potential future
development into a completely new type of anti-inflammatory drug, one that treats inflammatory disease
processes rather than just the symptoms like most current antiinflammatory drugs.
Research achievements (from final report):
Potent and selective new regulators of the human complement receptor known as C3aR have been created,
their structures determined, and their mechanisms of action investigated on human immune cells. This research
should enable the development of new drugs for the treatment of inflammatory diseases and immune disorders
and provides new insights to natural immune defence mechanisms in human blood.
Expected future outcomes:
We expect that a new class of orally bioavailable antiinflammatory drugs can be developed from the
information and lead compounds generated in this research project. The results will also contribute to piecing
the jigsaw puzzle together on how the surfaces of immune cells trigger physiological responses that protect
humans from infection.
Name of contact:
David Fairlie
Email/Phone no. of contact:
d.fairlie@imb.uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 252879
CIA Name: Prof Ranjeny Thomas
Admin Inst: University of Queensland
Main RFCD: Autoimmunity
Total funding: $280,000
Start Year: 2003
End Year: 2004
Grant Type: NHMRC Project Grants
Title of research award:
Migration and differentiation of dendritic cells and monocytes in inflammatory arthritis.Migration and
differentiation of dendritic cells and monocytes in inflammatory arthritis.
Lay Description (from application):
Dendritic cells and monocytes are of critical importance to the development and persistence of inflammatory
disease in rheumatoid arthritis. Blocking this process at key strategic intervention points is a major focus of
research to improve disease treatment. These studies examine the critical processes and molecules that control
the entry of these cells to the joint in mice, and the derivation of cells that contribute directly to bone damage in
the disease.
Research achievements (from final report):
Given the importance of cells of the mononuclear phagocyte system in the pathogenesis of RA through antigen
presentation, inflammatory cytokine and chemokine production, and bone erosion, these studies were designed
to contribute information on the basic mechanism of their recruitment and homing and contribution to the
inflammatory process in vivo. Such work is essential for development of therapeutics targeting these migratory
pathways. Furthermore, the novel model systems developed for this project provide the first opportunity to
perform detailed cDNA expression profiling on DC populations. The array infrastructure provided by associate
investigator David Hume, is the most extensive available for the study of mononuclear phagocyte biology.
During the granting period we examined recruitment and homing of dendritic cells, monocytes and neutrophils
to inflamed joints and lymphoid organs in mice. We used mice transgenic for the green fluorescent protein
expressed by the c-fms promoter to examine the differentiation and expansion DC in vivo. Finally we carried
out cDNA expression profiling on immunogenic and tolerogenic DC, generating much novel information on
genes impacting on tolerance induced by antigen presenting cells.
Expected future outcomes:
We aim to demonstrate mechanisms of recruitment of DC and neutrophils to lymphoid organs under conditions
of immunity and tolerance, and we aim to understand the contribution of various genes induced or suppressed
under conditions of tolerance to the mechanisms of tolerance.
Name of contact:
Rthomas@Cicr.Uq.Edu.Au
Email/Phone no. of contact:
N/A
NHMRC Research Achievements - SUMMARY
Grant ID: 276415
CIA Name: A/Pr Edith Gardiner
Admin Inst: University of Queensland
Main RFCD: Endocrinology
Total funding: $496,500
Start Year: 2004
End Year: 2006
Grant Type: NHMRC Project Grants
Title of research award:
Anabolic Bone Gene PathwaysAnabolic Bone Gene Pathways
Lay Description (from application):
Osteoporosis is a major health burden resulting from bone fractures in older men and women due to
progressive loss of bone and weakening of the skeleton. Although there are currently therapies to reduce bone
loss, no current treatment effectively reconstructs lost bone. In this project, which is designed to identify new
genes that may in the future be targeted by drugs to reverse osteoporosis, we have identified specific sets of
genes that appear to work together to increase bone formation. This proposal is aimed at characterising these
genes and the ways in which they work to determine whether they may be good targets for new osteoporosis
treatments. We will examine the patterns of these genes in bone. We will also use cell cultures in which bone
forming cells develop and function, to determine when the genes are expressed and how they function. We will
test the ability of the candidate genes to cause an increase in the amount of bone forming activity in these cell
cultures. An increase in bone formation may be caused by an increase in the number bone-forming cells, an
increase in the activity of the cells, a decrease in cell death, or a combination of these changes. Each possibility
will be tested. This research is important because of the need for new osteoporosis therapies to repair
weakened bones. The knowledge resulting from this proposal has the potential to provide an important
contribution to skeletal health and thus aged health worldwide.
Research achievements (from final report):
Osteoporosis is a condition in which bones are fragile, at least in part because of a decrease in bone mass. In
osteoporosis research, the Wnt regulatory pathway is being studied because it can increase bone mass by
increasing the activity of osteoblasts, which are the bone forming cells. How the Wnt pathway stimulates
osteoblast activity is not well understood, however, and in this project we have unexpectedly discovered that
under some circumstances, Wnt pathway activation can inhibit the bone forming activity of osteoblasts. In
experiments designed to explain how this unusual observation could occur, we have demonstrated that Wnt can
alter the expression of key genes that control the development and maturation of osteoblasts. We have also
discovered a novel mechanism of interaction between the Wnt pathway and another major regulator of
osteoblasts, the vitamin D response pathway. The knowledge gained in these experiments is important because
any future osteoporosis therapies based on Wnt pathway activation must take into account the potential
negative as well as positive effects of such interventions. Better understanding of the range of consequences of
Wnt activation including the effects on the osteoblastic vitamin D response will aid in the development of
effective strategies for both Wnt and vitamin D based therapies.
Expected future outcomes:
Future studies will determine why the negative effects of Wnt activation on bone formation occur under some
circumstances but not others.
Name of contact:
Edith Gardiner
Email/Phone no. of contact:
e.gardiner2@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 290519
CIA Name: A/Pr Elizabeth Eakin
Admin Inst: University of Queensland
Main RFCD: Preventive Medicine
Total funding: $765,984
Start Year: 2004
End Year: 2007
Grant Type: NHMRC Project Grants
Title of research award:
Addressing Multiple Risk Factors in Primary Health and Community Care settings: A Cluster-Randomised
TrialAddressing Multiple Risk Factors in Primary Health and Community Care settings: A ClusterRandomised 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 national-level 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 Non-Governmental Telephone Information services.
Name of contact:
A/Prof Elizabeth Eakin
Email/Phone no. of contact:
e.eakin@sph.uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 301137
Start Year: 2004
CIA Name: Prof Jennifer Stow
End Year: 2006
Admin Inst: University of Queensland
Grant Type: NHMRC Project Grants
Main RFCD: Protein Targeting and Signal Transduction
Total funding: $470,750
Title of research award:
LPS-regulated SNAREs and control of cytokine secretion in macrophages.LPS-regulated SNAREs and control
of cytokine secretion in macrophages.
Lay Description (from application):
TNF(tumour necrosis factor alpha) is a potent proinflammatory cytokine secreted by immune activated
macrophages. TNF has essential roles in host defense, tumour killing and energy metabolism. Excessive
secretion of TNF in acute and chronic inflammatory conditions, such as septic shock, Crohn s disease,
rheumatoid arthritis and in cancer has many severe, even fatal, consequences. Improved anti-TNF therapeutics
are needed for clinical management in all of these conditions. Our studies are focused on investigating how
macrophages synthesize and secrete TNF, with the ultimate goal of characterizing the molecules and vesicles in
the TNF secretory pathway. Our recent findings show the expression of SNARE proteins, part of the vesicle
docking and fusion machinery, is regulated in concert with cytokine secretion and other trafficking changes in
activated macrophages. We identified the proteins Syntaxin4, Munc-18c and SNAP-23 as the specific tSNARE complex that regulates TNF delivery to the cell surface. In the proposed studies we will investigate
how SNAREs are regulated during macrophage activation by studying their gene expression and protein
modifications. We have developed a single-cell assay to measure TNF trafficking in macrophages; this allows
the identification of molecules with roles in TNF secretion and it will be used in a series of experiments to
identify the specific v-SNARE proteins that partner the t-SNARE for TNF delivery. Finally we will use live
cell imaging to investigate how and where TNF is delivered to the macrophage cell surface and membrane
fractionation to examine a role for membrane microdomains in organizing SNARE-mediated TNF secretion.
Manipulation of SNAREs, using data generated by these studies, holds potential for the development of new
anti-TNF therapies.
Research achievements (from final report):
We have discovered new and unexpected cellular pathways that lead to the releae of cytokines or chemical
messengers from immune cells. These cytokines have necessary roles in inflammation and describing their
pathways for release generates a new level of understanding in this area. However the excess secretion of these
cytokines, TNF and IL-6, causes the chronic symptoms of inflammatory dieases like IBD and arthritis. Our
findngs identify, for the first time, molecules important for cytokine secretion that can potentiallly be targeted
by drugs for alternative and improved approaches to treating inflammation.
Expected future outcomes:
Our findings uncover potentially drug targets and strategies for blocking TNF secretion that could lead, in the
future, to new medicines for inflammatory disease.
Name of contact:
Jennifer Stow
Email/Phone no. of contact:
j.stow@imb.uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 301143
CIA Name: Prof Mark Forwood
Admin Inst: University of Queensland
Main RFCD: Endocrinology
Total funding: $440,750
Start Year: 2004
End Year: 2006
Grant Type: NHMRC Project Grants
Title of research award:
Investigation Of COX-2 Regulation Of Bone Turnover And Mechanically Induced Bone Formation By Genetic
overexpression.Investigation Of COX-2 Regulation Of Bone Turnover And Mechanically Induced Bone
Formation By Genetic overexpression.
Lay Description (from application):
This project is important because it uses novel experimental models to advance our knowledge of prostaglandin
biology in normal and pathological bone remodelling, and the response of the skeleton to increased physical
activity. We expect that a genetic modification in mice to increase the normal production of key prostaglandin
enzymes, cyclooxygenase-2 (COX-2), in bone cells will increase the number of cells that remove bone
(osteoclasts), and increase bone loss and the rate of bone turnover when compared to normal mice. We believe
this will occur via the effect of prostaglandins on expression of genes that control osteoclast formation. This
will be tested by examining the structure of the skeleton, and the expression of certain genes, in transgenic
mice at different ages from 2-8 months. These effects may be exacerbated in conditions of increased bone
turnover, such as postmenopausal bone loss. This will be tested by examining the bone structure and gene
expression in adult mice following removal of their ovaries. Due to the role of COX-2 in adaptation of bone to
mechanical loading, we also expect the load-bearing skeleton to be more sensitive to increased weight-bearing
activity. We will investigate this hypothesis by applying mechanical loads to the tibiae of mice in a controlled
manner and then analysing the bone structure. Knowledge of specific pathways by which bone formation can
be stimulated is important for developing novel approaches to induction and augmentation of osteogenesis in
skeletal diseases associated with ageing or disability, or for maintenance of new bone around implants. The
discovery that COX-2 is a key enzyme in mechanotransduction and osteoclastogenesis in bone, and a
pharmacological target for modulating inflammation, has considerable clinical significance. Exploiting this
knowledge requires precise knowledge of the role of this enzyme in bone remodelling and adaptation and our
experiments will contribute significantly to that knowledge
Research achievements (from final report):
This project used novel experimental models to advance our knowledge of prostaglandin biology in bone
health and disease. We used a genetic modification in mice that allowed us to increase the normal production
of prostaglandins in bone cells, alone. This was done by increasing the synthesis of an important enzyme in
bone resorbing cells called osteoclasts. The enzyme, cyclooxygenase-2 (COX-2) is normally found during
inflammation, but is also crucial for bone cell function. We observed that osteoclasts from these mice did
indeed express high levels of COX-2 when cultured in vitro. Importantly, using micro-computed tomography,
preliminary analysis of bone architecture of these mice revealed an osteoporotic phenotype compared to control
mice, suggesting the importance of this enzyme in such diseases. We believe this is mediated via the effect of
activated osteoclasts to increase bone turnover. This is now being tested. Generated in this project, COX-2
over-expressing mouse models could also be extremely valuable for evaluation of the in vivo effects and
efficacy of new, as well as existing, inhibitors of COX-2 activity. It is also possible that overexpression of
COX-2 in either or both cell types of bone can become a useful model(s) of disorders of bone turnover and
remodelling, e.g. osteoporosis.
Expected future outcomes:
We will use these mice to test the physiological role of COX-2 in the skeleton in these conditions where it is
being overexpressed. These experiments will examine the response of bone to mechanical loading, the loss of
bone following ovariectomy, and the role of COX-2 during fracture healing.
Name of contact:
Mark Forwood
NHMRC Research Achievements - SUMMARY
Email/Phone no. of contact:
m.forwood@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 301178
Start Year: 2004
CIA Name: Prof David Fairlie
End Year: 2006
Admin Inst: University of Queensland
Grant Type: NHMRC Project Grants
Main RFCD: Pharmacology not elsewhere classified
Total funding: $465,750
Title of research award:
C3/C5 Convertase Inhibitors As A New Class Of Anti-Inflammatory DrugsC3/C5 Convertase Inhibitors As A
New Class Of Anti-Inflammatory Drugs
Lay Description (from application):
Many serious inflammatory diseases, such as arthritis, septic shock, lung shock, heart disease, atherosclerosis,
multiple sclerosis, are poorly controlled with currently available drugs. There is a great deal of evidence that
naturally occuring "Complement" proteins in human blood are involved in exacerbating these and many other
human diseases, yet there are no good drugs available to counteract their effects. Three complement proteins
known as C3a, C5a and MAC (membrane attack complex) are thought to be particularly pivotal components of
the complement system synthesized by the human body early in the development of inflammatory and immune
diseases. New compounds that could block the formation of human C3a, C5a and MAC are expected : (a) To
lead us to a better understanding of how these proteins act on immune cells and of their respective roles in the
immune response to infection and injury, and (b) To enable the rapid development of an entirely new class of
drugs for treating autoimmune and inflammatory diseases. No Complement-based drugs are yet available in
man. In other NHMRC funded work we have developed compounds ("antagonists") that selectively block the
actions of human C3a or C5a, and shown that they are effective antiinflammatory agents in rat models of a
number of inflammatory diseases. In this project we will design and develop small molecules that block the
enzymes ("C3/C5 convertases") that make C3a, C5a and other complement proteins including MAC. We
expect that such inhibitors will be even more effective antinflammatory drugs because they will block
formation of multiple complement proteins that each have proinflammatory activity. We will demonstrate
selective effects of the new compounds on components of complement, and test them in rat models of
inflammatory diseases. We expect C3/C5 convertase inhibitors to be a completely new type of antiinflammatory drug, treating disease processes rather than symptoms like current drugs.
Research achievements (from final report):
In this project we have studied some very important enzymes from human blood (the serine proteases known as
Complement factor B, C2, and C3 convertase) that are known to contribute to both immune defence and
inflammatory diseases. We have : (a) profiled their biochemical functions, (b) identified conditions that
allowed the first observation of catalytically active factor B and C2, (c) successfully created the first assay
protocols for efficient screening of inhibitors, (d) designed and developed the first potent small molecules to
block the functions of these enzymes, and (e) shown blockade of the formation of downstream products of
complement activation (namely C3a, C5a and membrane attack complex). These enzymes are not affected by
other serine protease inhibitors that we have tested. These studies are facilitating the development in our
laboratories of an entirely new class of antiinflammatory drug that intervenes directly in disease development
rather than targetting symptoms of inflammatory disease.
Expected future outcomes:
Our discovery of potent inhibitors of human complement enzymes has potential to be developed into human
pharmaceuticals with antiinflammatory properties and to be used to gain further insights to different paths of
complement activation in humans. Our focus on human enzymes, cells and inflammation in rodents is expected
to extend to more animal studies and ultimately a clinical trial.
Name of contact:
Professor David Fairlie
Email/Phone no. of contact:
d.fairlie@imb.uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 301244
CIA Name: Prof Ranjeny Thomas
Admin Inst: University of Queensland
Main RFCD: Cellular Immunology
Total funding: $165,125
Start Year: 2004
End Year: 2004
Grant Type: NHMRC Development Grants
Title of research award:
Phase 1 clinical trial of autologous dendritic cells to induce antigen-specific tolerancePhase 1 clinical trial of
autologous dendritic cells to induce antigen-specific tolerance
Lay Description (from application):
We have previously generated modified dendritic cells in mice with the ability to suppress immune responses
once they have started. This project will develop the dendritic cell vaccine as a platform technology for human
clinical use. We aim to demonstrate, in a phase I clinical trial, the capacity of modified human autologous
dendritic cells to suppress the immune response to a model antigen in a group of healthy volunteers and a
group of patients with rheumatoid arthritis taking drugs for their disease
Research achievements (from final report):
Dendritic cells (DC) are a key component of the immune system and are involved in regulation of innate and
acquired immunity. These cells capture, process and present antigens to T cells, and have been implicated in
autoimmune disease as well as other diseases of the immune system such as allergy, immunodeficiency,
transplant rejection, persistent viral infection and cancer. We have carried out in vitro and in vivo experiments
that provide evidence in mice of the capacity of DC modified with an inhibitor of NFkB activation, to suppress
existing immune responses in an antigen-specific way. Data indicate that the ability of DC to induce T cell
activation or tolerance can be controlled by manipulation of a protein known as RelB in DC. Thus, mouse DC,
generated in the presence of a soluble inhibitor of NFkB (modified DC) and exposed to antigen, prevent
priming, and also suppress a previously primed immune response and arthritis in mouse models. This tolerance
is antigen-specific, and dependent on the dose of administered DC. In vitro studies of modified human blood
DC demonstrate that the cells have a similar phenotype and in vitro functional capacity as the modified mouse
DC. This project will developed human modified DC as a platform technology for human clinical use. During
the granting period we produced modified human dendritic cells (DC) to GLP standard, developed in vitro
assays and specific operating procedures for QA and antigen loading of the modified DC, tested toxicity of
modified DC in mice and wrote and submitted a clinical trial protocol to our institutional ethics committee.
Expected future outcomes:
We aim to demonstrate, in a phase I clinical trial, the capacity of modified human autologous dendritic cells to
suppress the immune response to a model antigen in a group of healthy volunteers and a group of patients with
rheumatoid arthritis taking drugs for their disease.
Name of contact:
Rthomas@Cicr.Uq.Edu.Au
Email/Phone no. of contact:
agautam@cicr.uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 351439
CIA Name: Prof Ian Frazer
Admin Inst: University of Queensland
Main RFCD: Transplantation Immunology
Total funding: $4,928,324
Start Year: 2005
End Year: 2009
Grant Type: Programs
Title of research award:
Immunological therapies for cancer and autoimmunityImmunological therapies for cancer and autoimmunity
Lay Description (from application):
The programme team comprises a group of leading scientists with a history of successful investigation into the
mechanisms and treatment of diseases in which the immune system plays a role in their development. These
include cancers of the cervix
and blood system, and autoimmune diseases such as rheumatoid arthritis and type 1 diabetes. Working
together, the team have made discoveries that have led to testing and clinical development of new treatments
for these diseases. In this programme, the team aims to discover mechanisms regulating the immune response,
and to exploit this knowledge to define new ways of switching on or off, specific immune responses. We will
particularly seek to develop novel vaccines for chronic infections and autoimmune diseases, and to improve the
safety of bone marrow transplantation.
Research achievements (from final report):
The research led to a better understanding of why the body's defences against infection are sometimes able to
attack the body itself, and sometimes fail to defend it against chronic infection and cancer. Specifically, key
control mechanisms that determine whether a response is initiated or not were identified, and it was shown that
this information could be used to alter the course of disease in animal models, and, in preliminary studies, in
patients
Expected future outcomes:
Better vaccines to help prevent cancer and chronic viral infection, and better treatments for autoimmune
diseases including rheumatoid arthritis, diabetes, and the complications of bone marrow transplantation
Name of contact:
Ian Frazer
Email/Phone no. of contact:
i.frazer@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 351441
Start Year: 2005
CIA Name: Prof Robert Parton
End Year: 2008
Admin Inst: University of Queensland
Grant Type: Established Career Fellowships
Main RFCD: Protein Targeting and Signal Transduction
Total funding: $516,250
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
This fellowship has allowed me to investigate how the cell is able to process information from the outside
world and translate this information into a biological signal inside the cell. This work has provided insights into
the properties of the plasma membrane which are disrupted in diseases such as cancer and muscular dystrophy.
My research has contributed to the understanding of the compartmentalization of the plasma membrane into
microdomains and has provided insights into how these microdomains are generated and how they function.
My research has focussed on caveolae and Ras signalling domains. Caveolae have been implicated in
regulation of cell growth and in maintaining the balance of lipids in the cell. In addition, caveolae and
caveolins, the major proteins of caveolae, have been implicated in a number of disease states including tumour
formation, atherosclerosis, and muscular dystrophy. We have provided new insights into the formation of
caveolae, we have described how caveolae dysfunction can lead to muscle disease, and we have shown that
caveolae are essential for lipid regulation and for liver regeneration.
Expected future outcomes:
This research has provided fundamental insights into the way that abnormal formaion or function of surface
microdomain leads to diseases such as cancer and muscular dystrophy. These findings will provide the
fundamental molecular understanding required to combat these diseases in the future.
Name of contact:
Robert Parton
Email/Phone no. of contact:
R.Parton@imb.uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 410002
CIA Name: Prof Stephen Duckett
Admin Inst: University of Queensland
Main RFCD: Health Economics
Total funding: $656,029
Start Year: 2006
End Year: 2009
Grant Type: NHMRC Strategic Awards
Title of research award:
Assessment to Service Outcomes - Care pathways for older Australians with Dementia, CVD and
ArthritisAssessment to Service Outcomes - Care pathways for older Australians with Dementia, CVD and
Arthritis
Lay Description (from application):
The project aims to use existing data source to answer questions similar to ‘What happens to people after they
have been assessed and recommended for aged care?’ in respect of service delivery for people with one of the
three chronic conditions dementia, arthritis or cardiovascular disease. The project is to provide information
about issues such as ‘bed blockers’ and determine if the outcomes are different for people who have been
assessed for aged care while they are in hospital. It is to chart changes in service use over time and examine
factors that affect the type of care used by older people.
Research achievements (from final report):
As in other ageing populations, dementia, musculoskeletal conditions and cardiovascular disease affect a high
proportion of Australians aged over 65 years, and the prevalence of these conditions increases significantly
with age. People with these conditions may need to access a range of care services over time to enable them to
remain living in their homes. Many eventually need to move into a nursing home. , In contrast to the
considerable recent literature on the funding of long-term care systems for population ageing, studies on the
care pathways followed by individuals are much less common. This project identified the effect of disease on
use of community care services and nursing homes over time, focusing on people with dementia,
cardiovascular disease and musculoskeletal conditions. , The different symptoms and courses of diseases meant
that the patterns of aged care service use, both in terms of care services accessed and the timing of this access,
varied considerably for people with different health conditions. These differences persisted across a range of
client characteristics. In particular, people with dementia or cerebrovascular disease as their main health
condition were more likely to enter nursing home care than those with heart disease or musculoskeletal
conditions. , The variation in use of aged care services according to disease group need to be taken into account
in any projections of demand for aged care. Such projections must allow for predictions of disease prevalence,
or else they will yield inaccurate predictions of demand for both community and residential care.
Expected future outcomes:
This project was the first to link aged care data succesfully. This is now done routinely by the Australian
Institute of Health and Welfare
Name of contact:
Stephen Duckett
Email/Phone no. of contact:
stephen.duckett@grattan.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 455836
CIA Name: Prof Matthew Brown
Admin Inst: University of Queensland
Main RFCD: Quantitative Genetics
Total funding: $677,383
Start Year: 2007
End Year: 2011
Grant Type: Established Career Fellowships
Title of research award:
Uncoupled Research FellowsUncoupled Research Fellows
Lay Description (from application):
I am a clinican-scientist and rheumatologist studying genetic determinants of common chronic human
musculoskeletal diseases. My research aims are to define for key genes how specific genotypes promote diease
phenotypes, using in vitro and in vivo approac
Research achievements (from final report):
I have developed human gene mapping approaches using genomewide association studies and next generation
sequencing. In doing so I have identified genetic loci associated with a wide variety of common and rare
diseases including ankylosing spondylitis, rheumatoid arthritis, osteoporosis, multiple sclerosis, psoriasis, and
ocular diseases. I have contributed to the development of study designs for genetic studies, and pioneered the
use of sequencing based approaches in human genetics. My group has also determined mechanisms underlying
genetic associations with disease, notably in ankylosing spondylitis investigating the mechanisms of
association of the genes IL23R and ERAP1, from which therapies are either in use or in development
respectively.
Expected future outcomes:
I expect my research will lead to the development of curative therapies for the common autoimmune disease
ankylosing spondylitis, and likely psoriasis and inflammatory bowel disease.
Name of contact:
Matthew Brown
Email/Phone no. of contact:
matt.brown@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 455863
Start Year: 2007
CIA Name: Prof Paul Hodges
End Year: 2012
Admin Inst: University of Queensland
Grant Type: Centre of Clinical Research
Excellence
Main RFCD: Rehabilitation and Therapy: Occupational and Physical
Total funding: $2,007,200
Title of research award:
CCRE in Spinal Pain, Injury and HealthCCRE in Spinal Pain, Injury and Health
Lay Description (from application):
Spinal complaints present the greatest social and economic burden of musculoskeletal conditions in Australia.
This reflects current realities: the cause remains unknown; 80% of the population is affected; and isolated
professions perform a staggering array of interventions. The CCRE aims to target these realities and improve
Australia's capacity to prevent and manage spinal disorders by supporting innovative interdisciplinary research
and training. This community- and university-based centre will align highly successful clinical and basic
researchers in collaboration with a national network of spine scientists to foster interdisciplinary clinical
researcher training, develop new diagnostics and therapeutics, and translate findings to the community.
Through clinical research the centre aims to: (i) Advance understanding of physiology and pathophysiology of
spinal pain (ii) Translate findings from basic research to clinical practice (iii) Establish coordinated
multidisciplinary research to reduce the burden of spinal pain (iv) Predict and prevent the transition from acute
to chronic states (v) Train a new generation of transdisciplinary clinical scientists (vi) Rapidly assess new
treatment possibilities in pre-clinical studies (vii) Develop innovative technologies for diagnostics and
therapeutics (viii) Encourage Australian commercialisation opportunities for new discoveries (ix) Encourage
community-user participation in direction of research programs (x) Disseminate new findings and information
of evidence-based practice to patients, clinicians, insurers, government and the scientific and wider community
Research achievements (from final report):
The Centre of Clinical Research Excellence in Spinal Pain, Injury and Health (CCRE SPINE) aimed to
improve the outcomes for people with spinal pain through research, research training, and translation of
research findings to practice. Highlights include the following. Major research outcomes include identification
of novel brain changes in spinal pain (awarded the major international back pain prize), identification of
mechanisms for transition from acute to chronic pain, and evaluation of efficacy of treatments. A key research
achievement involved organisation of two "Summit" meetings of world experts to establish consensus opinion,
a research agenda and new collaborations to address; (i) mechanisms of transition from acute to chronic pain,
and (ii) relationships between spine control, spine pain and rehabilitation. Outcomes were published as a major
text (Elsevier) and a special issue of the leading journal (Spine). Multiple papers, grants and new initiatives
evolved from new collaborations. Training not only supported doctoral students and post-doctoral researchers,
but also a unique program to involve clinicians in research. Twelve clinicians were supported to undertake
research. Outcomes include published papers, conference presentations, and enrollment of clinicians in
doctoral programs (three completions to date).Translation of research findings to patients and clinicians was a
major focus. Major achievements include completion of a patient-focused website to enable people with
whiplash associated disorders to compare evidence for treatments in a clear understandable manner, extensive
research regarding the information needs of patients with low back pain, and patient forums and clinician
training in Australia, Europe and North America.
Expected future outcomes:
New collaborations arising from "Summit" meetings have produced novel multidisciplinary research
paradigms and grants. Training programs enhanced clinician involvement in research as a foundation to narrow
the gap between clinical practice and research. Extensive qualitative research laid the foundation for
development of a patient centered web resource for back pain.
Name of contact:
Paul Hodges
NHMRC Research Achievements - SUMMARY
Email/Phone no. of contact:
p.hodges@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 455907
CIA Name: A/Pr Jonathan Whitehead
Admin Inst: University of Queensland
Main RFCD: Endocrinology
Total funding: $731,312
Start Year: 2007
End Year: 2009
Grant Type: NHMRC Project Grants
Title of research award:
Interaction between PTH and Y2 bone anabolic pathwaysInteraction between PTH and Y2 bone anabolic
pathways
Lay Description (from application):
Osteoporosis is a costly condition that affects more than 150 million people worldwide and fills more hospital
beds than any other disease*. People who have osteoporotic fractures experience a diminished quality of life
and a reduced life expectancy. Although there are currently a number of therapies in use to reduce further loss
of bone in osteoporotic patients, there is only one to replace lost bone, parathyroid hormone. For clinical and
economic reasons, there is a need for additional bone-building therapies. Like all tissues, the nervous system
affects skeletal function. We recently discovered a powerful control pathway by which the nervous system
regulates bone formation. This project will test whether altering the function of this neural pathway can
increase bone formation and whether it can work together with parathyroid hormone therapy to produce an
enhanced bone formation response greater than either therapy alone. This research is important because of the
need for new osteoporosis therapies to repair weakened bones. The knowledge gained from this study has the
potential to provide a very important and useful contribution to skeletal health and thus aged health worldwide.
*The Burden of Brittle Bones: Costing Osteoporosis in Australia. A report prepared by Access Economics Pty.
Ltd. September 2001
Research achievements (from final report):
The major finding from this project is the novel, and potentially paradigm shifting, finding that bone tissue is
actively involved in renal regulation of circulating phosphate levels. More specifically, the project produced
evidence of a direct role for neuropeptide Y in this regulatory process. This new understanding may result in
the identification of novel therapeutic targets and or strategies for diseases including chronic kidney disease
and bone diasease.
Expected future outcomes:
We anticipate that further work will lead to increased understanding of this regulatory process and that this
will, in turn, provide a foundation to construct new therapeutic strategies to maintain or restore healthy mineral
homeostasis.
Name of contact:
Jon Whitehead
Email/Phone no. of contact:
jwhitehead@mmri.mater.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 455941
CIA Name: Dr Allison Pettit
Admin Inst: University of Queensland
Main RFCD: Orthopaedics
Total funding: $564,964
Start Year: 2007
End Year: 2009
Grant Type: NHMRC Project Grants
Title of research award:
Role of bone-associated macrophages in bone remodelling and bone diseaseRole of bone-associated
macrophages in bone remodelling and bone disease
Lay Description (from application):
Musculoskeletal diseases, including osteoporosis and osteoarthritis, are a national and international health and
research priorities. Over 3 million Australians suffer from arthritis and musculoskeletal conditions and their
social and economic impact is expected to dramatically increase in the next 20 years as a result of the aging
population. Early diagnosis, prevention and treatment of many musculoskeletal diseases are currently
inadequate. Consequently, there is a high demand for effective treatment options. This project grant application
proposes a novel line of scientific investigation that will provide greater understanding of the contribution of
macrophages (a cell type that has important roles in normal tissue maintenance and defense against infection)
in bone remodelling and disease. Bone is continuously remodelled and replaced to maintain skeletal strength
and mineral metabolism. We have shown that a population of macrophages is intimately associated with bone
and propose that these cells play an important part in regulating bone remodelling. Macrophages have been
implicated in many diseases that have damaging consequences on bone, including osteoporosis and several
forms of arthritis, linking aberrant macrophage function to disease-associated bone damage. This project aims
to characterize this population of bone-associated macrophages and determine their ability to influence the
function of other cells integrally involved in bone remodelling. We will also undertake studies in animal
models to determine whether these cells are required for bone remodelling and/or damage. Detailed description
of the novel role of macrophages in bone biology will facilitate the development of superior therapeutics,
preventatives and cures for bone diseases.
Research achievements (from final report):
Bone diseases and injury have substantial social and economic impact both nationally and internationally.
Osteoporotic hip fractures alone are predicted to cost $240 billion annually by 2045 in the USA. These
statistics clearly indicate the importane of maintaining lifelong bone health and preventing and/or improving
fracture repair. There are few effective bone building treatments available and their development is a clear
research priority. Research undertaken during this project grant showed that a discreet population of
macrophages (traditionally an immune cell) reside in the specilized tissues associated with bones. We
designated this macrophage population 'osteomacs'. Data indicated that osteomacs are unlikely to be a
precursor population for the related osteoclast cell (specilized cell that removes bone). Strikingly, osteomacs
were stratigically located at sites of new bone formation. Presence of osteomacs in both mouse and human
tissues was confirmed using a combination of macrophage specific marker molecules and cell location. Using
multiple approaches molecular markers that distinguished osteomacs from other closely related macrophage
populations were not yet discovered. However, specific cell culture conditions were developed to generate an
osteomac-like population that promoted bone generation by osteoblast (specialized bone building cells).
Subsequently osteomac-expressed factors that potentially induce this bone formation outcome were identified.
In a bone injury model, osteomacs were required for optimal bone formation during healing. Notably, treatment
with a factor that increased osteomacs within bone injury sites also increased bone formation and accelerated
bone repair. This study demonstrated that osteomacs are an unexpected and important cell participant in bone
formation.
Expected future outcomes:
Osteomacs are prime cellular targets for promoting bone repair and development of treatments that either
enhance or replicate osteomac function will improve outcomes in bone diseases and fracture repair.
Identification of osteomacs reveals greater links between the immune and bone systems and the potential for
both benefit and detriment of immune contributions to bone disease/injury.
NHMRC Research Achievements - SUMMARY
Name of contact:
Allison Pettit
Email/Phone no. of contact:
a.pettit@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 511169
CIA Name: Prof Joseph Lynch
Admin Inst: University of Queensland
Main RFCD: Central Nervous System
Total funding: $542,018
Start Year: 2008
End Year: 2010
Grant Type: NHMRC Project Grants
Title of research award:
Identification of novel therapeutic binding sites on glycine receptors by high throughput screeningIdentification
of novel therapeutic binding sites on glycine receptors by high throughput screening
Lay Description (from application):
Glycine receptors mediate inhibitory neurotransmission in the nervous system. They provide fresh therapeutic
targets for chronic inflammatory pain and muscle spasticity. Here we identify 5 compounds that may be
appropriate as leads for discovering novel therapies for these disorders. We will use automated high throughput
screening methods to discover how these drugs interact with the receptor. This will narrow down the search for
the next generation of analgesic and muscle relaxant drugs.
Research achievements (from final report):
First, we implemented several technologies that resulted in four methods papers. The first described optimising
expression of recombinant trimeric receptors for high-throughput screening. The second described a novel
FACS-based approach to screen up to 12 different mutant GlyRs simultaneously. The third detailed the
methods we have developed to create and screen large libraries of random mutant GlyR clones and includes
preliminary discoveries made using these techniques. A fourth methods paper described a method of easily and
reliably creating chimeric receptors. , We developed an improved 'neuronal silencing receptor' to inhibit
electrical activity in defined populations of neurons in behaving animals. This receptor is based on a glycine
receptor that is mutated to make it highly sensitive to activation by orally-ingested ivermectin but insensitive to
glycine. Our plan is to express this receptor in neurons of interest in vivo. The neurons are inhibited by oral
inestion of ivermectin, a safe FDA-approved drug. In addition to allowing the researcher to understand the
relationship between electrical activity in defined neuronal circuits and behaviour, this technology holds
promise for treating human neurological disorders caused by aberrant levels of neuronal activity. Such
disorders potentially include motor neuron disease, Parkinson's disease, addiction, anxiety, epilepsy,
depression, chronic pain states and cardiac arrhythmias., We also developed a simple means of determining
whether a Cys-loop receptor is likely to be a high affinity ivermectin anthelmintic target. We also defined the
ivermectin therapeutic binding site on these receptors. Together, These results will inform
the development
of novel anthelmintics that exhibit an improved therapeutic index and bypass emerging ivermectin resistance.
Expected future outcomes:
The technology we developed holds promise for treating human neurological disorders caused by aberrant
levels of neuronal activity, and will help inform the development of the next generation of anthelmintic drugs.
Name of contact:
Joe Lynch
Email/Phone no. of contact:
j.lynch@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 519744
CIA Name: Dr Allison Pettit
Admin Inst: University of Queensland
Main RFCD: Orthopaedics
Total funding: $406,125
Start Year: 2008
End Year: 2013
Grant Type: Career Development Fellowships
Title of research award:
Osteal macrophages: novel regulators of osteoblast function and the endosteal stem cell nicheOsteal
macrophages: novel regulators of osteoblast function and the endosteal stem cell niche
Lay Description (from application):
Bone diseases are a major health problem and current treatments are inadequate. We are investigating a novel
role for macrophages (cells important in tissue maintenance and immune responses) in bone growth, repair and
disease. Greater understanding of this will provide new ways to treat bone disease. We will also determine if
these macrophages help support stem cells that reside near bone surfaces, which may provide new treatment
strategies to improve bone marrow transplantation in cancer.
Research achievements (from final report):
Bone and blood diseases are a substantial and increasing burdens on health systems and individuals. The
research undertaken during this Fellowship examined the symbiotic relationship between blood and bone. It
discovered that a specialized type of white blood cell, called osteal tissue macrophages or osteomacs for short,
plays an important role in: 1) maintenance of healing bone and aiding successful bone repair; and 2) generation
of specialized environments within bone marrow that house blood stem cells (cells responsible for repopulating
red and while blood cells throughout life). This suggests, and we are continuing to accumate data to support,
that alterations in the function of these osteomacs may contribute to bone diseases such as osteoporosis and
blood disease including anemia and leukemia. Importantly, the research showed that a treatment that increased
osteomacs was able to accelerate bone repair. Overall this research established that the osteomac plays an
important role in coordinating the functions of both the bone marrow and the bone in which is it housed. This
has important implications regarding the potential role of osteomacs in bone marrow transplantation, blood
cancers and tumours metastases that thrive in bone.
Expected future outcomes:
We will continue to accumulate pre-clinical data to support macrophage targeting therapies are a viable
approach to improving bone health, bone marrow transplantation outcomes and treatment approaches for bone
and blood cancer. This information will provide appropriate foundation for novel therapuetic design and drug
development for this broad range of medical conditions that have treatment gaps.
Name of contact:
Allison Pettit
Email/Phone no. of contact:
apettit@mmri.mater.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 519776
CIA Name: Prof Matthew Brown
Admin Inst: University of Queensland
Main RFCD: Geriatrics and Gerontology
Total funding: $810,661
Start Year: 2009
End Year: 2012
Grant Type: International Collaborations
Title of research award:
Genetic Factors for OsteoporosisGenetic Factors for Osteoporosis
Lay Description (from application):
Osteoporosis is a common condition in which bone strength is reduced due to reduced amount and quality of
bone. Reduced bone strength means an increased risk of fracture. Osteoporotic fractures occur in 1 in 2 women
and 1 in 3 men in their lifetime, and the likelihood of suffering osteoporotic fracture increases with age. Most
of the risk of developing osteoporosis is genetic, but few of the genes involved have been identified. Our goal
is to identify those genes. We will complete recruitment and assessment of a cohort of 1500 postmenopausal
women with either low or high bone mineral density from pre-existing population cohorts in Australia. A
genomewide association study will then be performed on these cases. Associated genes in different datasets
will then be investigated further in our cohort, and high-density SNP mapping performed to identify true
associated variants. These studies should identify most genetic variants associated with BMD variation and low
trauma fracture in the general community, allowing development of diagnostic-disease predictive genetic tests,
and informing development of novel therapeutic agents for osteoporosis.
Research achievements (from final report):
This funding enabled us to complete a genomewide association study of Australian, New Zealand and British
postmenopausal women with high or low bone mineral density. The data from this study was then tested in a
large cohort from the general population, and combined with data from other similar general population
cohorts. This lead to the identification of 56 novel loci associated with bone density and 14 loci associated with
fracture risk. The findings were published in a landmark report in the journal Nature Genetics in 2012 (see
below). These findings highlight new pathways that are involved in osteoporosis and osteoporotic fracture risk
and point to novel therapeutic targets. The potential of these findings in the identification of therapeutic targets
is highlighted by the fact that all bar one current osteoporosis treatment with a known mechanism of action
targets a gene identified by the genetic studies.
Expected future outcomes:
We have obtained further NHMRC funding to exome sequence the high and low bone mineral density cohort
to investigate less common genetic variants and their impact on osteoporosis risk. This study is ongoing both
within Australia and as part of the GEFOS consortium internationally.
Name of contact:
Matthew Brown
Email/Phone no. of contact:
matt.brown@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 569595
Start Year: 2009
CIA Name: Prof David Fairlie
End Year: 2012
Admin Inst: University of Queensland
Grant Type: NHMRC Project Grants
Main RFCD: Pharmacology not elsewhere classified
Total funding: $739,435
Title of research award:
Protease Activated Receptor 2 : A New Drug Target For Inflammatory Diseases and CancerProtease Activated
Receptor 2 : A New Drug Target For Inflammatory Diseases and Cancer
Lay Description (from application):
A new class of proteins (Protease Activated Receptors) has been found on the surfaces of many different types
of cells. They are believed to be natural sensors that respond to traces of degradative enzymes called proteases.
This project will create and evaluate new drugs for one of these receptors thought to regulate inflammatory
diseases (e.g. arthritis, inflammatory bowel disease, asthma, pancreatitis) and cancers, while providing a better
understanding of a new mechanism of immune defence.
Research achievements (from final report):
This research was directed at understanding how proteins on the surfaces of cancer cells and inflammatory cells
are activated by human enzymes in the blood called proteases, how they can be blocked by chemical agents,
how drugs can be developed and what promise do they have for treating human diseases. The research created
the first compounds shown to be able to block the action of these cell surface proteins involved in the
development of inflammatory diseases and cancers. The structures and actions of these compounds were
investigated in human cells, effects on human gene expression evaluated, and preliminary evidence obtained on
their capacity to affect many different types of human cells involved in normal physiology versus disease
development. The results reveal a new drug target for the treatment of inflammatory diseases and cancer and
some new drug leads that could be potentially developed into novel human therapies of the future.
Expected future outcomes:
We expect that the new ideas, new compounds and new information obtained from this project can be
harnessed in the development of new drugs that act on human cells to control cancer, inflammatory and
metabolic diseases.
Name of contact:
David Fairlie
Email/Phone no. of contact:
d.fairlie@imb.uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 569735
CIA Name: A/Pr Matthew Sweet
Admin Inst: University of Queensland
Main RFCD: Cellular Immunology
Total funding: $581,893
Start Year: 2009
End Year: 2011
Grant Type: NHMRC Project Grants
Title of research award:
Towards selective targeting of HDACs for anti-inflammatory applicationsTowards selective targeting of
HDACs for anti-inflammatory applications
Lay Description (from application):
HDAC inhibitors are anti-cancer drugs that kill rapidly growing cells (like cancer cells). These drugs also have
anti-inflammatory properties and so may be beneficial in chronic inflammatory diseases such as as Rheumatoid
Arthritis. However, it is unknown how they reduce inflammation. In this project we aim to understand how
HDAC inhibitors act as anti-inflammatory agents and to design new HDAC inhibitors with reduced side effects
for the treatment of inflammatory diseases.
Research achievements (from final report):
Many chronic diseases such as rheumatoid arthritis, inflammatory bowel disease and atherosclerosis are linked
to inappropriate inflammatory responses. New anti-inflammatory agents are urgently required to treat these
diseases and others. This project grant investigated the anti-inflammatory activities of a class of drugs known
as histone deacetylase (HDAC) inhibitors. These drugs block the action of HDACs, a family of enzymes that
regulate many functions in cells. A small number of HDAC inhibitors are used clinically for the treatment of
certain cancers, but also show therapeutic effects in some inflammatory disease models in animals. The
mechanisms by which these compounds exert these effects are not clear. Furthermore, HDAC inhibitors block
the action of a large family of HDAC enzymes and this leads to unwanted side effects of these drugs, which
limits their potential applications in inflammation-related diseases. This project investigated pro-inflammatory
functions of specific HDAC enzymes in immune cells and developed inhibitors that selectively target
individual HDAC enzymes. Some preliminary in vivo studies of HDAC inhibitors in inflammatory disease
models were also performed., , Ultimately, the findings from this project aid our understanding of the specific
HDAC enzymes that drive inappropriate inflammation, and thus how HDAC inhibitors exert anti-inflammatory
effects. Such information is essential for the future clinical development of HDAC inhibitors as therapeutic
agents. By developing chemical reagents that block the action of only specific HDACs, this project has also
generated tools that will help us to understand the functions of HDACs in health and disease.
Expected future outcomes:
Our findings will enable us and others to further explore the roles of specific HDAC enzymes in inflammation.
They will also enable the development of more potent and selective inhibitors of individual HDAC enzymes,
which we anticipate will retain anti-inflammatory activity, but will be associated with fewer side effects.
Name of contact:
Matthew Sweet
Email/Phone no. of contact:
m.sweet@imb.uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 569807
CIA Name: A/Pr Emma Duncan
Admin Inst: University of Queensland
Main RFCD: Genetics not elsewhere classified
Total funding: $107,366
Start Year: 2009
End Year: 2010
Grant Type: Career Development Fellowships
Title of research award:
Genetic Determinants of Bone MassGenetic Determinants of Bone Mass
Lay Description (from application):
I am a clinician-scientist and endocrinologist most interested in clinical problems associated with bone, in
particular the highly heritable disease of osteoporosis. I hope by studying genetic determinants of bone mass to
determine the key genes involved, with the long term aim of informing the development of novel therapies for
this common, painful and disabling disease.
Research achievements (from final report):
I was awarded this grant to investigate the genetics of osteoporosis, through genome-wide association studies
and investigation of unusual bone phenotypes such as high bone mass and skeletal dysplasias. In the course of
the last two years, I have finished in entirity a genome-wide assoication study (GWAS) in extremes of bone
mass (published in PLoS Genetics), finding new genes associated with osteoporosis and confirming many
others. In individuals and families with high bone mass, I searched for the genetic cause with both conventional
and next generation sequencing, and linkage and association studies. I established a genetics programme in
patients and families with skeletal dysplasia (with a further publication in PLoS Genetics). I have also
published a clinical paper in management of osteogenesis imperfecta; two pharmacoepidemiological studies;
and two invited reviews of osteoporosis genetics and future strategies for gene mapping. All these studies aim
to unravel the genetic determination of bone mass, so that this can be translated into new treatment approaches
for management of common bone diseases, such as osteoporosis.
Expected future outcomes:
These projects have already demonstrated new genes and pathways determining bone mass, increasing our
understanding of what causes bone diseases such as osteoporosis. This then raises new possibilities for
different therapeutic approaches for common and devastating bone diseases such as osteoporosis.
Name of contact:
Emma Duncan
Email/Phone no. of contact:
e.duncan@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 569829
CIA Name: Prof Matthew Brown
Admin Inst: University of Queensland
Main RFCD: Immunogenetics
Total funding: $568,612
Start Year: 2009
End Year: 2011
Grant Type: NHMRC Project Grants
Title of research award:
Major Histocompatibility Complex (MHC) Genetics of Ankylosing SpondylitisMajor Histocompatibility
Complex (MHC) Genetics of Ankylosing Spondylitis
Lay Description (from application):
Ankylosing spondylitis (AS) is the prototypic condition of a group of types of inflammatory arthritis called
'seronegative spondyloarthropathies'. These conditions are the most common form of inflammatory arthritis in
white populations and occur worldwide. One third of the risk of developing AS is determined by genes within
a region called the 'major histocompatibility complex' (MHC), in addition to the gene HLA-B27, the main gene
causing AS. We aim to identify the remaining MHC genes.
Research achievements (from final report):
o
The identification of an HLA-B27
tagSNP, rs4349859, which acts as a nearly perfect surrogate of HLA-B27 (within the level of HLA-B27
genotyping accuracy). This SNP can be genotyped for <1% of the cost of current HLA-B27 typing methods; as
HLA-B27 typing is one of the most widely used genetic screening tests performed worldwide, this will have a
major impact on reducing costs. A patent application has been lodged regarding this finding (Australian
Provisional Patent Application No. 2009905817)., o
Using this finding, we demonstrated
that there were no other common variants with significant MHC associations in AS. This was published in
Nature Genetics (P001085096)., o
We used this finding to investigate
differences between HLA-B27 positive and -negative disease, thereby identifying the restriction of the
association of ERAP1 with AS, the first confirmed example of gene-gene interaction in any common human
disease. This was published in Nature Genetics (P001085096). The finding is of major importance in AS
research as it indicates that the mechanism by which HLA-B27 induces AS must involve aberrant peptide
handling, with increased presentation of peptides by ERAP1 to HLA-B27 increasing the risk of disease. This
narrows the potential mechanisms by which HLA-B27 induces AS substantially., o
Having
identified that interaction, we hypothesized and then confirmed that HLA-Cw6 interacted with ERAP1 in a
similar way. This was published in Nature Genetics (P000790258). This indicates that HLA-Cw6 likely
operates in psoriasis by a similar mechanism to which HLA-B27 operates in AS.
Expected future outcomes:
This will enable cheap population screening for AS, and inform development of AS and psoriasis therapies.
Name of contact:
Matthew Brown
Email/Phone no. of contact:
matt.brown@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 569830
CIA Name: Prof Matthew Brown
Admin Inst: University of Queensland
Main RFCD: Immunogenetics
Total funding: $536,680
Start Year: 2009
End Year: 2011
Grant Type: NHMRC Project Grants
Title of research award:
The immunogenetics of ankylosing spondylitis: a genetic and functional investigation of IL23R and related
genesThe immunogenetics of ankylosing spondylitis: a genetic and functional investigation of IL23R and
related genes
Lay Description (from application):
Ankylosing spondylitis (AS) is a common inflammatory arthritis which causes primarily back pain and
stiffness, and affects 1/250 individuals. Our group identified association between tagging genetic markers in
the gene IL23R and AS, and our preliminary data suggests some related genes are involved as well. This study
aims to identify the key genetic variants involved and determine the mechanism by which they cause AS.
Research achievements (from final report):
Ankylosing spondylitis (AS) is a common form of inflammatory arthritis affecting over 20,000 Australians
with an annual cost upto $500 million which targets the spine and pelvis. In a major breakthrough we
demonstrated that mutations in the gene IL23R were associated with AS. IL-23R is a key factor in the
regulation of the proinflammatory cytokine IL-17 which is thought to play a role in a number of inflammatory
diseases. The exact mechanism underlying the association between IL23R and AS is unknown so this grant
undertook to elucidate those mechanisms., To date IL23R has only been associated with AS in white European
patients. To establish that IL23R plays a role in different ethnic populations that also suffer from AS we looked
in Han Chinese which suffer similarly to white Europeans from AS. Although the same IL23R mutations did
not play a role in white Europeans as in Han Chinese, we discovered different mutations in IL23R in Han
Chinese associated with AS further emphasising the importance of the IL23 pathway in AS., We also looked at
the functional role of IL23R in AS. We looked at immune cells from AS patients and controls and investigated
whether there were differences in the cells that utilise IL23 signalling. We discovered that there is a subset of
immune cells that are more responsive to IL23 and produce more IL17 that are more prevalent in AS patients.
These cells were IL23R+ IL17+ gamma delta T cells and we hypothesise these play a key role in AS.
Expected future outcomes:
Confirming a role for the IL23R pathway in non-Caucasian populations further supports development of
therapeutics based on targeting IL23 signalling
Name of contact:
Dr Gethin Thomas
Email/Phone no. of contact:
gethin.thomas@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 631363
CIA Name: Dr Gethin Thomas
Admin Inst: University of Queensland
Main RFCD: Genomics
Total funding: $431,201
Start Year: 2010
End Year: 2013
Grant Type: NHMRC Project Grants
Title of research award:
Regulatory RNAs Underlying Genetic Associations With Ankylosing SpondylitisRegulatory RNAs Underlying
Genetic Associations With Ankylosing Spondylitis
Lay Description (from application):
Ankylosing spondylitis is a chronic inflammatory disease affecting the spine and causing back pain. The
diagnosis of the disease is delayed by up to 10 years due to lack of accurate tests. We aim to identify molecular
signatures of the disease that might be used to distinguish inflammatory processes typical of the disease and
other causes of back pain. This would allow earlier and more accurate diagnosis of the disease and result earlier
patient treatment and better health outcomes.
Research achievements (from final report):
Ankylosing spondylitis (AS) is a chronic inflammatory disease affecting the spine and causing back pain. The
diagnosis of the disease is delayed by up to 10 years due to lack of accurate tests. We aim to identify molecular
signatures of the disease that might be used to distinguish inflammatory processes typical of the disease and
other causes of back pain. This would allow identification of novel molecules and mechanisms controlling
disease which can lead to new therapeutic approaches and also earlier and more accurate diagnosis of the
disease and result earlier patient treatment and better health outcomes., We have identified a novel molecule
that is produced from a genetic region previously associated with ankylosing spondylitis. This region was
termed a "gene desert" due to the fact that no known genes that might mediate disease were identified in this
region. Using cutting edge next-generation RNA sequencing technology we comprehensively identified all
forms of RNA produced from this region. From these studies we have identified a novel RNA that is highly
expressed in immune cells and is overexpressed in AS patients. This novel RNA may identify a new regulatory
pathway in AS.
Expected future outcomes:
This novel transcript will likely be part of a novel pathway regulating development or severity of AS. We will
now undertake further studies characterising the mode of action of this RNA and identify new therapeutic dn
diagnostic targets.
Name of contact:
Gethin Thomas
Email/Phone no. of contact:
gethin.thomas@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 631448
CIA Name: Prof Rob Capon
Admin Inst: University of Queensland
Main RFCD: Central Nervous System
Total funding: $552,647
Start Year: 2010
End Year: 2013
Grant Type: NHMRC Project Grants
Title of research award:
Developing novel selective glycine receptor potentiators as a means to control pain.Developing novel selective
glycine receptor potentiators as a means to control pain.
Lay Description (from application):
It has been estimated that >3M Australians suffer from pain at a cost to the economy of >$34B, with chronic
pain (persisting beyond 1-6 mths) accounting for ~half this burden. There is an urgent and compelling social
and economic case for the development of safer and more effective pain therapeutics. This project takes
inspiration from a new class of Australian marine natural products that selectively regulate a key pain pathway,
and will optimize and develop these as a new class of pain drug.
Research achievements (from final report):
This project significantly advanced our knowledge of, and improved our ability to exploit, a rare class of
Australian marine natural product as a means to control chronic inflammatory pain. Inspired by a lead natural
product, we synthesized and explored the chemistry and pharmacology of >150 structure analogues, to arrive at
a new optimized lead compound (CMB-C28-H01) that is >20,000 times more potent, exhibiting picomolar in
vitro activity against specific GlyRs, and nanomolar in vivo analgesia in a rat behavioural model of chronic
pain.
Expected future outcomes:
In silico modelling has informed our understanding of the binding of CMB-C28-H01 to GlyR, and based on
this we believe that future research has the potential to deliver even better analogues. Investment for future
development is dependent on a pending NHMRC Project application, and presentations/applications to
potential industry partners (ie Pfizer).
Name of contact:
Rob Capon
Email/Phone no. of contact:
r.capon@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 631484
CIA Name: Dr Allison Pettit
Admin Inst: University of Queensland
Main RFCD: Orthopaedics
Total funding: $741,095
Start Year: 2010
End Year: 2013
Grant Type: NHMRC Project Grants
Title of research award:
Regulation of Bone Dynamics by Osteal Tissue Macrophages (Osteomacs)Regulation of Bone Dynamics by
Osteal Tissue Macrophages (Osteomacs)
Lay Description (from application):
There is a high demand for effective treatments to rebuild and replace lost bone in fracture repair and
osteoporosis. We have described a discrete population of macrophages (classically immune defense cells)
within the specialized tissues that line bones. We have shown that these bone tissue macrophages have a novel
role in promoting the formation of new bone. This project grant will extend these observations and identify the
clinical potential of bone tissue macrophages to treat bone disease.
Research achievements (from final report):
Bone disease and fracture are a substantial and increasing burden on health systems and individuals. There is
clinical need for better therapies that rebuild bones and overcome compromised fracture repair. The research
undertaken during this grant expanded on our earlier discovery demonstrating the bone supportive functions of
a particular type of white blood cells, called osteal tissue macrophages or osteomacs for short. We showed that
osteomacs are required for bones to repair after fracture healing irrespective mode of healing (bones can heal
by 2 different mechanisms). Most importantly, a treatment that increased osteomacs was able to accelerate
bone repair. This provides proof-of-principle that enhancing the function of these cells is a viable treatment
approach for improving fracture outcomes. We generated data showing the osteomacs achieve this function
through influencing the maturation and/or function of the cells that make bone as well as the cells that degrade
bone. During the funding period the research rapidly evolved to demonstrate that osteomacs also play an
integral role in creating the specialized environments within bone marrow that house blood stem cells (cells
responsible for repopulating red and while blood cells throughout life). Overall we establish that the osteomac
plays an important role in coordinating the functions of both the bone marrow and the bone in which is it
housed. This has important implications regarding the potential role of osteomacs in bone marrow
transplantation, blood cancers and tumours metastases that thrive in bone.
Expected future outcomes:
We will continue to accumulate pre-clinical data to support macrophage targeting therapies are a viable
approach to improving bone health, bone marrow transplantation outcomes and treatment approaches for bone
and blood cancer. This information will provide appropriate foundation for novel therapuetic design and drug
development for this broad range of medical conditions that have treatment gaps.
Name of contact:
Allison Pettit
Email/Phone no. of contact:
apettit@mmri.mater.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 631621
Start Year: 2010
CIA Name: Dr Amanda Stanley
End Year: 2013
Admin Inst: University of Queensland
Grant Type: NHMRC Project Grants
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $558,442
Title of research award:
Regulating the secretion of inflammatory cytokinesRegulating the secretion of inflammatory cytokines
Lay Description (from application):
Cytokines or chemical messengers released by cells are essential for controlling immune responses but, in
excess, they cause Crohn's disease and arthritis. Our research aims to block cytokine release as a novel way to
ameliorate disease. We have identified specific cellular proteins, called golgins, that can be targeted to reduce
cytokines. Here, characterization of golgin mediated cytokine transport in cells and in a mouse disease model is
necessary to translate these findings for human benefit
Research achievements (from final report):
Cytokines or chemical messengers released by cells are essential for controlling immune responses but, in
excess, they cause inflammatory conditions such as Crohn's disease and arthritis. Multiple secretory pathways
for cytokines exist in individual immune cells, primarily to confer selective control over the release of
cytokines in the tissue microenvironment and thus their subsequent immune or physiological response., We
have identified trafficking pathways and machinery required for several key cytokines in macrophages - the
proinflammatory cytokines TNF and IL-6, and now the anti-inflammatory mediator, IL-10. Building on
previous work, this project demonstrated that soluble cytokines IL-10 and IL-6 are not actively sorted for exit
from the Golgi, and can exit in multiple tubular carriers. This is in stark contrast to TNF, a transmembrane
cytokine that is specifically sorted into carriers for secretion via recycling endosomes. IL-10 is transported both
in membrane-bound carriers in a pathway coincident with the release of the pro-inflammatory cytokines TNF
and IL-6, but also in an additional independent route., , This work demonstrates that multiple pathways exist
for the release of IL-10 to ensure its timely and appropriate secretion during the development of an immune
response, and in doing so, has important implications for therapeutics/strategies targeting the release of
cytokines to limit inflammation. Our results indicate that targeting the regulators of post-Golgi trafficking
could potentially limit pro-inflammatory TNF without completely blocking the release of desirable antiinflammatory mediators such as IL-10.
Expected future outcomes:
The work funded by this grant laid the foundation for our current research to define how inflammatory
cytokines are secreted during an immune response, in vitro and in disease models. These findings will underpin
future efforts to identify drug targets for controlling the inflamatory response during disease.
Name of contact:
Professor Jennifer Stow
Email/Phone no. of contact:
j.stow@imb.uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 631629
Start Year: 2010
CIA Name: Prof Justin Cooper-White
End Year: 2011
Admin Inst: University of Queensland
Grant Type: NHMRC Project Grants
Main RFCD: Regenerative Medicine (incl. Stem Cells and Tissue Engineering)
Total funding: $296,867
Title of research award:
TAKING THE LIMP OUT OF CARTILAGE REPAIRTAKING THE LIMP OUT OF CARTILAGE REPAIR
Lay Description (from application):
In Australia osteoarthritis is the leading cause of pain and disability with the majority of individuals displaying
radiographic evidence of this condition by age 65. We are developing two novel technologies which use
patients' own stem cells to repair damaged cartilage. This project involves both the advancement of these
technologies as well as their evaluation using a sheep cartilage repair model. These technologies offer
significant promise for those suffering joint pain.
Research achievements (from final report):
, This project aimed to produce highly functional cartilage cells (chondrocytes) from mesenchymal stem cells
(MSCs) using our novel low oxygen micropellet (LOM) differentiation process and a novel in vitro culture
system, which prevents matrix loss to the bulk medium, to generate fully functional ex vivo cartilage tissue
plugs. We have successfully demonstrated that LOMs can be readily assembled into larger tissue constructs
suitable for cartilage defect repair. Further, we have optimized MSC chondro-induction medium, to enhance
early chondrogenic differentiation, and subsequently enhance the matrix output of mature cells. The effects of
the presence/presentation of extracellular matrix (ECM) molecules on the conversation of MSCs to
chondrocytes have been thoroughly investgated and these insights have been translated to the formulation
design of novel hydrogel scaffolds. This scaffold system is capable of displaying ECM molecules and can be
optimised to match cartilage tissue mechanics. MSCs have been successfully encapsulated within the hydrogels
and cultured under inductive conditions. These outputs confirm the utility of our novel in vitro protocols for
functional cartilage tissue formation, in readiness for in vivo assessment.
Expected future outcomes:
, The ultimate aim of our work into cartilage tissue engineering is to generate functional ex vivo cartilage tissue
from MSCs and test its suitability for cartilage repair in humans. The results obtained from this in vitro
investigation have provided the necessary proof-of-concept data to permit this novel approach to move into in
vivo assessment within appropriate small animal models.
Name of contact:
Justin Cooper-White
Email/Phone no. of contact:
j.cooperwhite@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1000745
CIA Name: Prof David Fairlie
Admin Inst: University of Queensland
Main RFCD: Molecular Medicine
Total funding: $621,348
Start Year: 2010
End Year: 2012
Grant Type: NHMRC Development Grants
Title of research award:
Protease Activated Receptor 2 Antagonist In Inflammatory DiseaseProtease Activated Receptor 2 Antagonist
In Inflammatory Disease
Lay Description (from application):
The immune response to infection involves a network of proteins that produce an inflammatory response.
Sometimes this response is prolonged or uncontrolled and can lead to a large number of inflammatory and
other diseases. We have discovered a class of drugs that can bind to a particular protein on the surface of
human cells and control this inflammatory response. This property has the potential to treat a wide range of
inflammatory and other diseases in humans.
Research achievements (from final report):
We have created a new drug lead that binds to a particular protein on the surfaces of human cells. We have
shown that this drug candidate is unique in blocking certain deterimental inflammatory processes activated by
this cell surface protein, while not blocking other beneficial proceeses (such as wound healing and repair) that
are also activated by this protein. The beneficial effects of the drug have been tested for proof of concept in rat
models of acute inflammation (paw swelling that occurs in minutes to hours after injury) as well as in chronic
inflammation (arthritis and inflammatory bowel disease that occur in days to weeks; and diet-induced obesity
and cardiovascular disease that occur over several months exposure to high fat high sugar diets). All of these
disease indications in rats are inflammatory conditions that are prevented and treated by administration of the
drug to rats. The project also enabled us to improve the chemical structure of the drug, begin to examine effects
of long term exposure to the drug and its derivatives in rats, and to study its effects on a wide variety of human
cells (monocytes, macrophages, adipocytes, kidney etc.). The positive results obtained suggest that the benefits
observed in rats may also translate to humans and encourage further preclinical studies aimed towards enabling
human clinical trials.
Expected future outcomes:
We have created a strong and commercially attractive data package showing proof of concept for a potent new
type of antiinflammatory drug administered to rats. The data has given us an improved negotiating position for
commercialising development of a new drug for inflammatory disease. We are now marketing the R&D to
venture capitalists and pharma companies for preclinical & clinical development.
Name of contact:
David Fairlie
Email/Phone no. of contact:
d.fairlie@imb.uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 508046
CIA Name: Prof Cory Xian
Admin Inst: University of South Australia
Main RFCD: Orthopaedics
Total funding: $622,598
Start Year: 2008
End Year: 2011
Grant Type: NHMRC Project Grants
Title of research award:
Pathophysiology and prevention of methotrexate chemotherapy-induced bone growth defectsPathophysiology
and prevention of methotrexate chemotherapy-induced bone growth defects
Lay Description (from application):
Childhood chemotherapy often causes growth arrest, osteoporosis, and fractures in cancer patients and
survivors. Using a rat model, this project will study how the most commonly used chemotherapy drug
methotrexate causes bone growth defects and examine any protective effects of two natural-derived substances.
This work will increase our knowledge on chemotherapy-induced bone growth defects, and will be useful for
developing a preventative treatment.
Research achievements (from final report):
Work in this grant has shown that bone growth defects in young rats caused by treatment with the commonly
used anti-metabolite methotrexate (MTX) are associated with dysfunctions in both growth plate and
metaphyseal bone, resulting from (1) arrest of cell growth, induction of apoptosis, reduction in synthesis of
cartilaginous template for bone formation, (2) an increase in osteoclast formation and aggravated resorption of
newly formed trabecular bone, (3) a decrease in osteogenic potential but an increase in adipogenesis in the
bone marrow, and (4) alterations in NF-kB, Wnt/b-catenin and CXCR4 signalling pathways. In addition,
supplementary treatments with folinic acid or genistein can potentially protect bone growth during MTX
chemotherapy.
Expected future outcomes:
Our increased mechanistic understanding for cancer chemotherapy-induced bone defects will open new
windows and opportunities to explore novel therapeutic preventative treatments. Effectiveness of bone
protection with supplementary treatments of folinic acid or genistein could lead to potential therapies in clinical
practice.
Name of contact:
Prof Cory Xian
Email/Phone no. of contact:
cory.xian@unisa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 508047
CIA Name: Prof Cory Xian
Admin Inst: University of South Australia
Main RFCD: Orthopaedics
Total funding: $617,879
Start Year: 2008
End Year: 2012
Grant Type: NHMRC Research Fellowships
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
“I am a biomedical scientist undertaking basic and clinical research on the pathophysiology of growth plate
injury and repair, which critically impacts on children’s bone growth and growth disorders. I aim to investigate
the underlying mechanisms and deve
Research achievements (from final report):
Musculoskeletal conditions including skeletal fractures are major burdens on individuals and health systems.
Childhood bone health is critical for ensuring healthy development, and the peak bone mass achieved in
adolescence and early adulthood also profoundly influences adult bone health. During 2008-2012 with
NHMRC SRF support, I have made following research achievements in three major areas. Injured growth plate
is often "faultily" repaired leading to bone growth defects. My laboratory has identified a sequential injury
repair response and potential targets which could lead to development of a biological treatment. Cancer
chemotherapy unfortunately causes significant bone defects (osteoporosis, marrow adiposity and fractures). My
laboratory has identified that these defects result from reduced bone formation, increased bone resorption, and
increased marrow fat formation, as well as involvement of major signalling pathways (Wnt/b-catenin and NF¿B). Our work also showed that supplementation with folinic acid (a folate analogue) or genistein (a soy
isoflavone) preserved bone mass in MTX-treated rats, and that anti-inflammatory fish oil and emu oil inhibited
bone loss during chemotherapy. Apart from genetics, bone growth is also influenced by nutrition and physical
activity, which are major influences that can be modified to optimise bone mass in childhood. We observed
that maternal fish oil supplementation during pregnancy and lactation improved offspring bone growth. We
demonstrated that soy isoflavone genistein promotes formation of bone forming cells (osteoblasts) and inhibits
formation of bone degrading cells (osteoclasts), and that icariin (a flavonol glycoside from the herb
Epimedium) is more potent than genistein in promoting osteoblast formation.
Expected future outcomes:
oPotential development of the first in situ biological regenerative therapy for children's growth plate trauma
injury-induced bone growth defects;oPotential identification of novel preventative strategies for bone and bone
marrow damage caused by chemotherapy;oPotential identification of dietary interventions for optimising bone
growth and bone mass accrual in early life.
Name of contact:
Prof Cory Xian
Email/Phone no. of contact:
cory.xian@unisa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 571090
CIA Name: Prof G. Lorimer Moseley
Admin Inst: University of South Australia
Main RFCD: Central Nervous System
Total funding: $600,559
Start Year: 2009
End Year: 2013
Grant Type: NHMRC Research Fellowships
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
I am a clinical scientist translating basic science findings into clinical science questions and answers that impart
better understanding and management of pain and painful disease.
Research achievements (from final report):
In the 5 years of this fellowship, I have built an interdisciplinary research team of 28+ members, been
appointed Professor of Clinical Neurosciences and Inaugural Chair in Physiotherapy at UniSA, the youngest
Chair in Medical or Allied Health at an Australian University; was made Fellow of the Australian College of
Physiotherapy; was runner-up for the 2012 Science Minister's Prize for Life Sciences; won the 2012 NHMRC
Marshall & Warren Award for the best innovative and potentially transformative project grant; have been
awarded 3 out of 4 NHMRC project grant submissions as CIA, two scoring '6- top quartile' scores; have given
the most prestigious plenary lecture in world physiotherapy and the keynote address at the American Pain
Congress; have conceived and established the PainAdelaide Stakeholders' Consortium, with a scientific
meeting, public lectures and the annual Ride for Pain (>550 community participants); have been the only nonEuropean invited to the European Union's Societal Impact of Pain Government/Industry forum; and established
the world's most influential pain-related web and social media presence - bodyinmind.org.
Expected future outcomes:
I commenced a PRF this year and my research group is testing three broad hypotheses, each with clear and
important implications for the management or treatment of people in pain. We are funded by NHMRC project
grants and fellowship support.
Name of contact:
Professor Lorimer Moseley
Email/Phone no. of contact:
Lorimer.moseley@unisa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1003433
CIA Name: A/Pr Paul Anderson
Admin Inst: University of South Australia
Main RFCD: Receptors and Membrane Biology
Total funding: $497,001
Start Year: 2011
End Year: 2013
Grant Type: NHMRC Project Grants
Title of research award:
Vitamin D Activity to Regulate Bone Remodelling and Promote Bone StrengthVitamin D Activity to Regulate
Bone Remodelling and Promote Bone Strength
Lay Description (from application):
While vitamin D and calcium supplementation is well known to protect against osteoporosis and hip fracture,
the mechanisms by which this occur are not fully understood. Thus, this project aims to establish the cellular
basis for the importance of direct action of vitamin D and calcium within the bone. This information is
necessary to develop public health nutritional recommendations for improving skeletal health and reducing the
incidence of hip factures in the elderly.
Research achievements (from final report):
This project was set to determine the mechanisms by which vitamin D directly regulates processes of bone
remodelling.We have demonstarted that mature osteoblast-specific deletion of VDR abrogates the regulation of
bone resorption by reducing RANKL-mediated signalling from osteoblasts. In addtion there was a significant
downturn in osteoblast-mediated bone formation with the absence of VDR. The net result of this change in
bone turnover was a profound increased bone volume particularly during periods of rapid growth where bone
turnover is typically high. However, osteocyte-specific VDR deletion did not result in decreased RANKL
signalling or change to bone volume. Thus, these studies demonstarte that mature osteoblasts in the preosteocyte phase are responsible for the regulating bone turnover. , A second aim was to identify whether overexpression of VDR within osteoblasts in a transgenic model is capable of enhancing vitamin D activities to
regulate bone turnover. The original hypothesis, based on intial findings, was that enhanced VDR-mediated
siganlling leads to net imcrease in bone volume due to increased bone formation. However, we demonstrated
that while enhanced VDR-mediated siganlling in osteoblasts always leads in increased bone formation, in the
presence of high circulating active vitamin D (1,25D) levels, enhanced RANKL-mediated bone resoprtion
occurs due to incressed VDR levels and results in a overall loss in bone volume. Thus, only under
circumstances of low circulating 1,25D levels, does processes of bone formation lead to increased bone mineral
volume and stength. , The clinical benefits of this knowledge are that while most people would refer to serum
pre-cursor for vitamin D (25D) as a indicator of bone health, determining serum 1,25D levels and ensuring that
these levels are not raised, partucualrly during rapid growth, may benefit bone mieral accrual during
adolescence which is key to prevention of osteoporosis later in life.
Expected future outcomes:
We are now regulating the synthesis and/or catabolism of active vitamin D within osteoblasts themselves.
Current data suggest that enhancing local synthesis of 1,25D is pro-anabolic. Secondly, we are using analogues
to active vitamin D to determine whether we can illicit a bone formation response without activating bone
resoprtion. Both approches have clinical applications.
Name of contact:
A/Prof Paul Anderson
Email/Phone no. of contact:
paul.anderson@unisa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1010752
CIA Name: Prof Cory Xian
Admin Inst: University of South Australia
Main RFCD: Chemotherapy
Total funding: $540,357
Start Year: 2011
End Year: 2013
Grant Type: NHMRC Project Grants
Title of research award:
Pathophysiology and alternative preventative strategy for breast cancer chemotherapy-induced bone
lossPathophysiology and alternative preventative strategy for breast cancer chemotherapy-induced bone loss
Lay Description (from application):
Combination cytotoxic chemotherapy is the current optimal approach for treating breast cancer in
premenopausal women. However, long-term skeletal defects (osteoporosis and fractures) caused by the
chemotherapy have become an increasingly serious problem due to its intensified use and improved patient
survival rate. This project seeks to elucidate the mechanisms for chemotherapy-induced bone defects and to
initiate development of a preventative treatment using natural bioactive micronutrients.
Research achievements (from final report):
Cytotoxic chemotherapy is currently commonly used for treating breast cancer . However, associaed skeletal
defects have become an increasingly serious problem due to its intensified use of chemotherapy and improved
patient survival rate. This project aimed to elucidate the mechanisms for chemotherapy-induced bone defects
and to initiate development of a preventative treatment using natural bioactive micronutrients. We established
"CEF" (Cyclophosphamide+Epirubicin+5-Fluorouracil) breast cancer combination chemo in adult female rats
and found that CEF caused signficant reduction in bone marrow cellularity and bone mass, but an increse in
bone marrow fat content, which were associated with increased expression in some inflammatory cytokines.
We also saw similar changes in "AC" (Adriamycin+Cyclophosphamide) combination model. In our rat model
of combination treatment with lapatinib (EGFR/HER2 kinase inhibitor) and cytotoxic drug paclitaxel, there
were significant reductions in bone volume and bone cell formation potential, but a significant increase in
osteoclastic bone resorption. In rat models of chemo with 5-fluorouracil or methotrexate (MTX) (used as a
component in breast cancer chemo), there is bone loss due to increased inflammation in the bone, increased
osteoclsatic bone resorption and bone marrow fat formation, but reduced bone formation. Oral delivery of antiinflammatory fish oil or emu oil and osteotrophic phytoestrogenic compound genistein was found to conserve
the bone marrow and prevent chemo-induced bone loss and cellular changes. These studies suggest that
individual or combination of chemo drugs can signficantly damage bone marrow and cause bone loss in rats,
and some bioactive nutraceuticals can help to protect the bone during chemotherapy.
Expected future outcomes:
We had also conducted one animal trial with our "AC" model aiming to examine potential protective effects of
anti-inflammatory oils including fish oil and emu oil and we are currently doing analyses with the specimens
collected. More publications will be derived from these CEF and AC model studies.
Name of contact:
Professor Cory Xian
Email/Phone no. of contact:
Cory.xian@unisa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1017556
CIA Name: Dr Susan Semple
Admin Inst: University of South Australia
Main RFCD: Pharmaceutical Sciences
Total funding: $276,598
Start Year: 2011
End Year: 2013
Grant Type: NHMRC Development Grants
Title of research award:
Development and evaluation of novel anti-inflammatory products derived from an Indigenous medicinal
plantDevelopment and evaluation of novel anti-inflammatory products derived from an Indigenous medicinal
plant
Lay Description (from application):
This collaborative project between researchers at the University of South Australia and Indigenous traditional
owners from Northern Kaanju homelands (Cape York Peninsula, Qld) will develop and evaluate products
derived from the Northern Kaanju medicinal plant Dodonaea polyandra. Extracts of the plant and novel
compounds isolated from it have anti-inflammatory activity. These have the potential to be used in
inflammatory diseases such as dermatitis, arthritis and inflammatory bowel disease.
Research achievements (from final report):
This collaborative study between Chuulangun Aboriginal Corporation and UniSA examined the actions of antiinflammatory extracts and active diterpenoid compounds from the Northern Kaanju medicinal plant Dodonaea
polyandra. Prototype formulations of extracts for use on the skin were produced and optimisation of
diterpenoid extraction from the plant was explored. Diterpenoid compounds from the plant were found to
reduce the production of inflammatory mediators called interleukins (IL) and tumour necrosis factor in human
skin cells and in a mouse model of skin inflammation. Over 60 skin formulations were trialled with the best
performing formulations assessed for stability and release of the two most active diterpenoid compounds. A
final prototype formulation was able to reduce skin inflammation and inflammatory mediator release the mouse
skin inflammation model. Testing of the formulated plant extract product in a laboratory human skin model
suggested it is non-toxic and non-irritant. Mutagenicity testing of the plant resin containing defined quantities
of the active clerodane compounds gave a negative (non-mutagenic) result. In a chronic model of skin
inflammation in mice (used to assess potentially useful agents for psoriasis) the activity of one of the
diterpenoids was comparable with the known anti-inflammatory glucocorticoid betamethasone in terms of
reducing tissue swelling and inflammatory cell infiltration. Plant extraction procedures were able to simplified
and optimised. Profiles of active diterpenoids in individual plants growing on Northern Kaanju homelands
showed substantial inter-individual variation - this is important for future harvesting of plant material on
Indigenous homelands as selection of higher yielding plants may be possible.
Expected future outcomes:
Future research will examine the effectiveness of plant extracts in disease-specific models of inflammatory
disease including skin conditions (psoriasis) and arthritis, with the view of developing medicinal products for
these conditions. Commercialisation will be a partnership between Indigenous traditional owners, ITEK
Ventures and pharmaceutical/skin care companies.
Name of contact:
Dr Susan Semple
Email/Phone no. of contact:
susan.semple@unisa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 107215
CIA Name: Dr Michael Booth
Admin Inst: University of Sydney
Main RFCD: Health Promotion
Total funding: $280,352
Start Year: 2000
End Year: 2002
Grant Type: NHMRC Project Grants
Title of research award:
The development of overweight and bone density among adolescent girls: A 3-year prospective cohort
studyThe development of overweight and bone density among adolescent girls: A 3-year prospective cohort
study
Lay Description (from application):
Being overweight as an adolescent is associated with many health problems, both during adolescence and
throughout the rest of the life span. The proportion of Australian adults who are overweight is increasing
rapidly and it appears that overweight is also increasing among Australian adolescents. Unfortunately, little is
known about the relative influences of physical activity, sedentary activity and dietary fat intake on the
development of overweight among adolescents. Understanding this issue will inform our efforts to prevent the
development of overweight and to maintain healthy weight among Australian adolescents. Bone fractures
among older adults have a major impact on their overall health, quality of life and capacity for independent and
satisfying living. Peak bone strength is reached during adolescence and, although bone strength can be largely
maintained though adult life with appropriate diet and physical activity, little can be done to further strengthen
bones during adulthood. The goal of public health is to foster the development of maximum bone strength
among adolescents in order to reduce the severity of osteoporosis among the older adults of the future. Our
understanding of the factors which influence the development of maximum bone strength is inadequate to the
task of designing programs and interventions intended maximise bone strength among the current generation of
adolescents. This proposed study is intended to make a significant contribution to our understanding of the
development of overweight and bone strength among adolescents. As our understanding of these health issues
improves we will be able to make more effective contributions to the health of the Australian population, both
during adolescence and across the lifespan.
Research achievements (from final report):
N/A
Expected future outcomes:
There are two main directions for this research. First, with better measures of the foods and drinks young
people consume we can repeat this research and work out which aspects of physical activity and food intake
contribute most to the development of overweight among young people. Second, the research needs to include
boys of the same age and younger boys and girls so we can understand the process of fat development right
across the key period of puberty. Armed with this information, we can develop more effective interventions to
prevent the development of overweight
Name of contact:
Michael Booth
Email/Phone no. of contact:
N/A
NHMRC Research Achievements - SUMMARY
Grant ID: 153712
CIA Name: Prof Stephen MacMahon
Admin Inst: University of Sydney
Main RFCD: Orthopaedics
Total funding: $364,218
Start Year: 2001
End Year: 2003
Grant Type: NHMRC Project Grants
Title of research award:
Randomised trial of ibuprofen for the prevention of ectopic bone-related pain and disability after hip
replacementRandomised trial of ibuprofen for the prevention of ectopic bone-related pain and disability after
hip replacement
Lay Description (from application):
Joint replacement is a well-established treatment for severe osteoarthritis of the hip. While most patients
benefit substantially from the procedure, many still experience some pain and disability after surgery. New
evidence suggests that one important cause of this pain and disability may be abnormal bone deposits that form
in the muscles around the hip (ectopic bone formation) during the first few months after surgery. Ectopic bone
formation is seen in about 40% of all patients with hip replacements. If the formation is extensive, all
movement of the hip is lost and revision surgery is necessary. However, even when the formation is less
severe, movement at the hip can be restricted resulting in pain and disability. There is growing evidence that
treatment with a non-steroidal anti-inflammatory drug at the time of surgery may halve the risk of ectopic bone
formation. While this would be expected to decrease the risk and severity of post-operative pain and disability,
there is little evidence available about the long-term effects of these drugs after hip replacement. For this
reason, together with concerns about possible side-effect of these drugs, orthopaedic surgeons have generally
been reluctant to prescribe these drugs routinely for the prevention of ectopic bone formation. Ibuprofen
appears to be the non-steroidal anti-inflammatory drug with the lowest risk of side effects. If it was shown to
be effective in reducing the incidence of pain and disability associated with ectopic bone formation after hip
replacement, it may well be considered worthwhile by doctors and patients alike. If such benefits were
realised, this preventive strategy is likely to be a highly cost-effective way to improve long-term outcome
among the rapidly growing numbers of patients that receive hip replacements. This study will provide reliable
evidence about the short and long-term effects of ibuprofen among 1,000 patients receiving hip replacements in
Australia.
Research achievements (from final report):
Worldwide, HIPAID is the largest randomised clinical trial conducted to date investigating the risks and overall
benefits of a perioperative course of a non-steroidal anti-inflammatory drug (ibuprofen) amongst people
undergoing elective hip replacement surgery. 902 patients were randomised from more than 20 orthopaedic
surgery centres throughout Australia and New Zealand. Bleeding and adverse events were closely monitored
during the study treatment period. Benefits were assessed 6 to 12 months after surgery and included a wide
range of both well-validated patient self-reported outcomes (pain, physical function, general health status and
global assessments of treatment effectiveness) as well as objective measures of physical performance (range of
hip flexion, walking speed). Loss to followup was minimal: less than 6% for the main outcome: self-reported
physical function. HIPAID confirmed that hip replacement surgery is extremely beneficial for most patients
with osteoarthritis, resulting in greatly reduced pain and improved physical function and mobility. HIPAID also
confirmed that more than 40% of patients will develop ectopic bone after elective hip replacement surgery and
that a short perioperative course of ibuprofen (1200mg for 14 days) will significantly reduce the risk of
developing ectopic bone without significantly increasing bleeding or the rate of adverse events. However, the
periooperative anti-inflammatory treatment did not appear to markedly improve the considerable long-term
benefits already achieved by the hip replacement surgery.
Expected future outcomes:
This unique data set will be further explored to analyse how closely ectopic bone is associated to poor outcome
and if any patient characteristics or peri-operative events increase the risk of developing ectopic bone or poor
outcomes to surgery (approximately 15% of this sample did not report that their hip was 'much better' after
surgery.
NHMRC Research Achievements - SUMMARY
Name of contact:
Dr Marlene Fransen
Email/Phone no. of contact:
mfransen@thegeorgeinstitute.org
NHMRC Research Achievements - SUMMARY
Grant ID: 211124
CIA Name: Prof Rebecca Mason
Admin Inst: University of Sydney
Main RFCD: Endocrinology
Total funding: $226,650
Start Year: 2002
End Year: 2004
Grant Type: NHMRC Project Grants
Title of research award:
Nutrient dependent signalling in bone via calcium sensing receptorsNutrient dependent signalling in bone via
calcium sensing receptors
Lay Description (from application):
Osteoporosis is a major health problem that affects as many as 10% of the Australian Community and costs the
health budget millions of dollars each year. A number of key nutritional factors including calcium and dietary
protein intake are known to be important in the development of osteoporosis. This proposal will test the
hypothesis that human bone cells express a protein which senses calcium and amino acids, the calcium-sensing
receptor, and thereby respond to nuritional signals arising from the presence of calcium ions and amino acids in
plasma. Furthermore, we propose that by promoting osteoblast proliferation, maturation and survival, the
calcium sensing receptor acts as the key molecular mechanism by which dietary calcium and protein promotes
bone formation.These studies have potential to explain relationships between bpne resorptive activity, which
raises local calcium concentrations, and bone formation activity and the coupling of bone forming and
resorbing activity. These studies have the potential to explain the positive effects of calcium and protein
intake on bone mass and may also shed light on the regulation of the coupling between osteoblastic and
osteoclastic activity
Research achievements (from final report):
The studies examined whether the sensor which detects extracellular calcium concentrations and also responds
to amino acid concentrations is present and functional in human bone cells. Both the calcium sensing receptor
protein and messenger RNA were detected in bone cells. Furthermore, stimulation of bone cells with calcium
or other agents like calcium, including gadolinium and strontium stimulated bone forming cell proliferation and
turned off signals that would lead to bone resorption. Strontium is currently used in the treatment of
osteoporosis, though its molecular and cellular mechansims of action are unknown. Further studies indicated
that bone cells responded to specific calcium-receptor active agents, though the nature of the response was not
always stimulatory. These studies provide evidence to support the proposal that the calcium sensing receptor is
present and functional in bone cells, although with unusual characteristics. The data also show that calcium in
this system acts like a bone coupling agent and strontium, a newly released bone active agent, may act via a
similar sensing mechanism, though strontium is 10-fold more potent in bone cells than in other cell types so far
described.
Expected future outcomes:
These results are important, because they provide an explanation for the selective anabolic action of strontium
in bone. Further functional effects, not yet tested for may also be present. They also identify the bone calciumsensing receptor as a therapeutic target for the design of even more potent and specific agents which could have
a positive effect on bone mass.
Name of contact:
R S Mason
Email/Phone no. of contact:
rebeccam@physiol.usyd.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 211151
Start Year: 2002
CIA Name: A/Pr Ann Sharpe
End Year: 2004
Admin Inst: University of Sydney
Grant Type: NHMRC Project Grants
Main RFCD: Health, Clinical and Counselling Psychology
Total funding: $195,660
Title of research award:
Selective attention and fear avoidance in the maintenance and management of pain associated with rheumatoid
arthritisSelective attention and fear avoidance in the maintenance and management of pain associated with
rheumatoid arthritis
Lay Description (from application):
Despite advances in the treatment of RA, the condition continues to have a chronic course for the majority of
patients. Research has established that the way in which people think about pain and illness influences their
responses to symptoms. In turn, these factors can impinge on quality of life and disability. For people with
chronic pain problems, those who are fearful of pain and concentrate on symptoms have a poorer outcome in
the long-term. In RA, striking a balance between rest and exercise is thought to be crucial. As such, ignoring
the pain can lead to overactivity and subsequent joint damage and may be as unhelpful as underactivity. This
project aims to investigate the relationship between people's fear of pain and the degree to which they attend to
pain. It is suggested that those with very high or very low levels of fear towards the pain will either over-attend
or under-attend to pain in comparison to healthy controls and patients with a moderate level of fear. Optimum
levels of fear avoidance are expected to be associated with less disability and improved joint function. These
findings have implications for the management of RA. Psychological treatments for patients with RA have
been found to be effective in reducing pain, disability and improving mood. Treatments usually focus on a
combination of changing people's attitudes and behaviours. However, whether strategies that aim to change
attitudes or those targeting behaviour are more successful or have specific treatment effects is unknown. The
present project will compare a treatment targeting behaviours associated with RA and encouraging a balanace
between rest and exercise, with a treatment targeting patient's beliefs about the illness. It is expected that the
treatments will have specific effects, which may better allow tailoring of psychological management to
patient's individual needs.
Research achievements (from final report):
Background: There are over 60 trials that confirm the efficacy of broad-based cognitive-behavioural treatments
(CBT) for patients with rheumatoid arthritis. However, these treatments include a variety of cognitive and
behavioural strategies and it is unclear which treatment components are effective. Aims: The present study
aimed to compare the effectiveness of a well-established CBT program in comparison to a purely cognitive
(CT) and a purely behavioural intervention (BT). Method: One-hundred and twenty-four patients with classic
rheumatoid arthritis were approached to take part in the study and 104 volunteered (84% recruitment rate).
Participants were randomly allocated to one of four groups: CBT, CT, BT or wait-list controls (WLC). Results:
Those receiving either CT or CBT had better outcomes than BT or WLC for number of tender joints and a
measure of immunological functioning. However, there were no differences at six month follow-up between
CT and CBT. Those receiving BT only improved more than the WLC on anxiety, with comparable
improvements observed for CT. Conclusions: This study suggests that cognitive therapy demonstrates some
superiority over BT and (at least in the short-term) CBT for patients with rheumatoid arthritis.
Expected future outcomes:
We have data on hypervigilance and its relationship with baseline disability and treatment-related changes.
These data will have importance in terms of whether hypervigilance is seen as a factor that contributes to
maintaining disability in patients with RA. Moreover, it will allow us to understand whether changes in
hypervigilance are associated with treatment outcome.
Name of contact:
Louise Sharpe
NHMRC Research Achievements - SUMMARY
Email/Phone no. of contact:
louises@psych.usyd.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 211226
Start Year: 2002
CIA Name: Prof Maria Fiatarone Singh
End Year: 2006
Admin Inst: University of Sydney
Grant Type: NHMRC Project Grants
Main RFCD: Rehabilitation and Therapy: Occupational and Physical
Total funding: $819,180
Title of research award:
Hip Fracture Intervention Trial (HIPFIT)Hip Fracture Intervention Trial (HIPFIT)
Lay Description (from application):
Hip fracture secondary to falling in the elderly represents a large and rising health care problem in Australia. At
least 12,000 such hip fractures occur in the elderly in Australia each year and this number is expected to
increase substantially over the next several decades. Long term disability, nursing home placement, reduced
quality of life, and excess mortality are known sequelae of hip fracture despite successful surgical repair.
Factors have been previous identified in epidemiological research which predict poor recovery of function and
the most prominent of these are advanced age, pre-exiting mental or functional impairment, malnutrition,
depression, poor social support networks, and poor gait, balance and muscle function. Current treatment
paradigms for hip fracture do not uniformly screen for or appropriately address potentially reversible factors
such as poor nutrition, neuromuscular dysfunction, depression, strength of social supports, or risk factors for
recurrent injurious falls. It is unlikely that a unidimensional treatment will ever optimize long term functional
independence in such a multifactorial syndrome. Therefore, we propose to apply a multifaceted targeted
experimental treatment package (HIPFIT) to elderly patients admitted to hospital for repair of a fractured hip
secondary to a fall. HIPFIT would begin in hospital and continue throughout the 12 months of follow up, using
individualized treatment strategies based on periodic reassessments in these vital domains over time. The goal
of the study is to reduce the number of patients requiring nursing home care at the end of 12 months, as well as
to improve independence in a range of activities of daily living among experimental subjects. This would have
significance not only in terms of large economic savings for the health care system but reduced personal
suffering and dependency on the part of the affected individuals.
Research achievements (from final report):
Between February 2003 & April 2007 we identified 1748 individuals (60% women) admitted to RPA Hospital
with potential hip fractures (median age 80 y). A total of 262 patients were found eligible for the study and
approached for their consent which was obtained from 124 patients (47% of eligible). Three assessments were
completed per participant: a total of 111 post hip fracture, 98 after 4 months & 87 after 12 months. The 12
months intervention was implemented for 85% of the participants randomised to intervention. Drop-out rate
was 10%, lower than we conservatively anticipated, and death rate was also 10%. , This is the first study to
target all major remediable contributions to recovery of function after hip fracture, including a multicomponent intervention directed at fall risk in the home, bone health, sarcopenia, muscle weakness, gait and
balance impairment, depression, cognitive impairment, nutritional deficiencies, low self-efficacy, low social
support, polypharmacy, and visual impairment. The robust RCT design, supervised 12 month intervention, and
long-term followup of functional status and place of residence/death over 5 years make this study completely
unique internationally, and a critical addition to clinical practice in this area. If the intervention proves
successful as we complete our analyses of primary and secondary outcomes, we will have demonstrated an
approach that can be implemented directly into existing health care infrastructure in Australia, as this study was
carried out in the outpatient clinic of a hospital using a variety of health care professionals who typically work
in such a setting. However, the approach we took to proactively identifying and aggressively treating
etiological factors in hip fracture-related incidence and recovery is not currently the standard of care in
Australia or elsewhere, and translation of this approach to the community will require substantive and vitallyneeded educational and implementation strategies.
Expected future outcomes:
Training of health care professionals to implement this intervention in health care settings throughout Australia
and internationally., Development of multi-medial training materials to allow translational research and
dissemination into community settings.
NHMRC Research Achievements - SUMMARY
Name of contact:
Maria A. Fiatarone Singh
Email/Phone no. of contact:
m.singh@usyd.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 211266
CIA Name: Dr James Melrose
Admin Inst: University of Sydney
Main RFCD: Orthopaedics
Total funding: $331,320
Start Year: 2002
End Year: 2004
Grant Type: NHMRC Project Grants
Title of research award:
INVESTIGATIONS ON THE REGULATION OF INTERVERTEBRAL DISC CELL MATRIX
METALLOPROTEINASESINVESTIGATIONS ON THE REGULATION OF INTERVERTEBRAL DISC
CELL MATRIX METALLOPROTEINASES
Lay Description (from application):
Degeneration of the intervertebral disc is a painful disabling condition with major socioeconomic
consequences. Medical problems associated with disc degeneration and back-pain, of sufficient severity to
warrant consultation with a physician, are experienced by 90% of the population some time during their lives.
In man, back pain increases in incidence in the third and fourth decades of life, peaks in the fifties and declines
thereafter. Changes in population demographics indicate this problem will increase in severity over the next
few decades. American Bureau of Census data indicate that between 1990 to 2010 the number of people >45
years will increase from 82 to 124 million, the number of elderly in emerging countries will also increase
between 200 to 400% in the next 30 years. In the United States, back-pain is the second most common reason
that people visit a physician and medical conditions related to back-pain account for more hospitalisations than
any other musculoskeletal disorder. Despite its high incidence, associated problems of incapacity and economic
implications, costed at $100 million per annum in Australia in 1992, and US$100 billion globally in 1999-2000
(Dorland Data Networks, PA, USA) the causes of low back-pain are still poorly understood. Disc disease is
responsible for 23-40% of all cases of low back-pain. The management of discogenic low back-pain is
currently empirical, directed either toward life-style changes to minimise symptomatology or to surgical
resection or spinal arthrodesis to restrict articulation. Based on our recent findings and those of colleagues over
the last 16 years, it is our strong conviction that it should be possible with a better understanding of disease
mechanisms and with the use of modern technologies to inhibit, reverse or ideally prevent disc degeneration.
Without such basic research there will be no scientific foundation upon which prospective therapies may be
based.
Research achievements (from final report):
Defects in the intervertebral disc are difficult to treat clinically and may be a source of intense low back pain,
furthermore overloading of a biomechanically compromised disc may exacerbate this condition and lead to
propogation of the defect to other neurological structures which may also be a source of intense pain. In dense
avascular connective tissues such as the intervertebral disc the normal healing response to a traumatic insult
leading to formation of a defect in this important weight bearing structure is to lay down a stabilising
collagenous scar tissue in the defect site. Unfortunately, such scar tissue is generally less compliant and less
capable of acting as a weight bearing structure than the native connective tissue of the disc. Replacement of
scar tissue with new functional weight bearing connective tissue is only possible if the endogenous connective
tissue cells remodel the scar tissue and replace it with new functional tissue. Intervertebral disc cells are not a
particularly active metabolic cell type thus agents have been sought which can increase their cellular
metabolism to encourage them to remodel connective tissue and reconstruct mechanically damaged regions of
the disc. Such an approach has provided encouraging results in-vitro with regard to the remodelling of major
structural components of scar tissue, namely collagen and its proteoglycans. On-going studies in animal models
in which intervertebral disc defects are reproduced surgically may provide significant insights as to how dense
avascular connective tissues may be remobilised to provide new functional weight bearing connective tissues.
Expected future outcomes:
Improvement in the recovery of trauma defects in dense avascular connective tissues such as intervertebral disc
and tendon would be expected to improve their functional status and aid in the rehabilitation of affected
individuals and the mobility of the general population.,
NHMRC Research Achievements - SUMMARY
Name of contact:
James
Email/Phone no. of contact:
jmelrose@med.usyd.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 211278
CIA Name: Prof Philip Sambrook
Admin Inst: University of Sydney
Main RFCD: Geriatrics and Gerontology
Total funding: $340,550
Start Year: 2002
End Year: 2004
Grant Type: NHMRC Project Grants
Title of research award:
Epidemiology of Osteoporotic Fractures in the Very Frail Elderly: Risk factors, Quality of Life and
MortalityEpidemiology of Osteoporotic Fractures in the Very Frail Elderly: Risk factors, Quality of Life and
Mortality
Lay Description (from application):
Osteoporosis, a disease characterised by skeletal fragility, is a major public health problem. The direct costs
alone of treating osteoporotic fractures have been estimated at more than $800 million in Australia. Hip
fractures are the most costly to treat and are due to a fall or injury in over 90% of cases. The frail elderly are at
particular risk of osteoporotic fractures but little is known about risk fractures in this 'at risk' group or the effect
of fracture on quality of life. This study is examining risk factors for fractures in the frail and institutionalised
older person by asessment of quantitative bone ultrasound, falls risk, vitamin D status and other biochemical
markers of bone in an attempt to identify predictors that can be modified to reduce fractures, improve quality of
life and reduce mortality due to osteoporotic fractures.
Research achievements (from final report):
In 1999, the NHMRC funded a 3 year Project Grant to assess the role of calcaneal ultrasound combined with
falls risk factors as a screening tool in a high risk population (the frail older person) for identifying those at risk
of osteoporotic fractures. This funding was extended between 2002 and 2004. Nursing homes and hostels in
northern Sydney were randomly selected from all such institutions within the Northern Sydney Area Health
Service and all residents over the age of 65 were asked to participate. The study, which recruited 2005 subjects.
, Findings from the FREE Study include a very high prevalence of vitamin D deficiency as noted above, a very
high falls rate and a high fracture incidence. We observed 181 hip fractures with a rate of 367 per 10,000
person years or 8.6 % over median 2.4 years followup. For total fractures, we observed 402 fractures during
3240 years of follow-up with an overall rate of 1241 per 10,000 (compared with 295 per 10,000 for community
dwelling women in the Dubbo Osteoporosis Epidemiology Study) or 16.8% after 19.4 months of follow-up.
Our study identfied tools that can be used to predict future falls and fractures.
Expected future outcomes:
Further publications will refine these tools to allow prediction of those at high risk of fracture and falls and
allow preventive measures.
Name of contact:
Philip Sambrook
Email/Phone no. of contact:
sambrook@med..usyd.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 211279
CIA Name: A/Pr Lyn March
Admin Inst: University of Sydney
Main RFCD: Orthopaedics
Total funding: $360,660
Start Year: 2002
End Year: 2006
Grant Type: NHMRC Project Grants
Title of research award:
Economic Evaluation and Health Outcomes of Arthritis and its TreatmentsEconomic Evaluation and Health
Outcomes of Arthritis and its Treatments
Lay Description (from application):
Musculoskeletal diseases are the most common single cause of chronic disability in Australia and total joint
replacement is rapidly becoming one of the most commonly performed operations. This burden of illness is
likely to increase with our ageing population and there is an urgent need to obtain data relating to the costs and
outcomes in the Australian context so that appropriate planning of health services and resources can be carried
out. The WHO (World Health Organisation) has declared 2000 to 2010 the Bone and Joint Decade,
recommending that research into musculoskeletal disorders be a priority. We have been recruiting and
following a unique cohort of osteoarthritis and rheumatoid arthritis patients, from both the public and private
health sectors, who have been carefully documenting their health outcomes, health care costs (including
primary, revision and bilateral hip and knee joint replacement surgery), out-of-pocket and indirect costs related
to their arthritis. Long-term follow-up is now essential to obtain a clear picture of the impact of living with
arthritis over time and the cost-effectiveness and predictors of good and bad outcomes of joint replacement
surgery. The information derived from this study will be useful for patients and doctors in making their
decisions about treatments, as well as for health care providers in planning of health services for arthritis
sufferers. Given that the cohorts are already established, the study is in a unique position to provide ongoing
important longer-term data for relatively low cost.
Research achievements (from final report):
We have established a unique cohort of over 900 arthritis subjects (244 non-surgical and 687 surgical including revision and bilateral arthroplasty). A relatively high proportion of the cohort has been maintained
considering the age of the participants and the amount of commitment required from participants. This was
done using regular telephone contact, quarterly newsletters, birthday cards, certificates of appreciation and
decorative magnets., Analysis of costs and health outcomes over 9 years for the non-surgical cohort showed
that disease progression in the OA group was slow, with slight non-significant deterioration in health status
measures. The health status of the RA group deteriorated significantly over the 9 years. Out-of-pocket
expenditure increased significantly for OA subjects from $247 to $548 per 3 months, but remained relatively
stable for the RA subjects, increasing from $367 to $397 for each 3 month period., Significant improvement
from pre-surgery to 12 months post-surgery was shown. The OA group then showed no deterioration in
function or increase in pain over the following eight years, despite a worsening in general health status which
may be attributed to aging of the cohort. No increase was seen in out-of-pocket expenditure over the eight year
period. It appears that joint replacement sugery amongst this cohort is showing a sustained beneficial impact in
terms of costs and outcomes at 8 years post-surgery.
Expected future outcomes:
An assessment of pre-operative self-efficacy amongst the recently recruited patients has shown that higher selfefficacy was associated with better health status & lower costs to both the respondent & health system. Selfefficacy is amenable to change, so these preliminary cross-sectional results suggest that increasing patients'
self-efficacy may improve post-operative outcome and reduce costs.
Name of contact:
A/Prof Lyn March
Email/Phone no. of contact:
lynmar@med.usyd.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 219282
CIA Name: Prof Geoffrey Farrell
Admin Inst: University of Sydney
Main RFCD: Gastroenterology and Hepatology
Total funding: $2,000,000
Start Year: 2003
End Year: 2007
Grant Type: Centre of Clinical Excellence
Title of research award:
Centre for Clinical Research Excellence to improve outcomes in chronic liver diseaseCentre for Clinical
Research Excellence to improve outcomes in chronic liver disease
Lay Description (from application):
This Centre will provide new information to improve clinical outcomes for people with chronic liver disease.
Among people referred by GPs with abnormal liver tests, two thirds have hepatitis C or non-alcoholic
steatohepatitis. The Centre aims to develop non-invasive ways to identify those with progressive liver disease,
and will assess whether lifestyle adjustments (diet and exercise) improve liver injury and fibrosis progression.
They hope to improve the health and survival of people with advanced stage cirrhosis who are waiting for a
liver transplant by correcting nutritional problems, osteoporosis and earlier detection and treatment of liver
cancer. The program forms the basis for clinical research training for GPs, specialists, nurses, dieticians, sports
medicine and other health care professionals.
Research achievements (from final report):
A Lifestyle Intervention RCT in 152 patients with NAFLD and HCV found that face to face counselling
targeting physical activity and nutritional behaviours and modest weight loss is an effective method for
improving the health of patients with elevated liver enzymes and metabolic risk factors. The case for even low
intensity Lifestyle measures is strengthened by this study. A reliable clinical index of hepatic fibrosis
developed that uses routinely assessed markers to predict the probability of significant hepatic fibrosis in most
patients with chronic HCV infection. A useful to guide decisions regarding the need for liver biopsy, and
potentially for avoiding or deferring biopsy in patients with mild liver disease. Despite the high prevalence of
zinc deficiency in the cirrhotic population, it was found that therapeutic supplementation does not improve
serum IGF-I levels, markers of liver disease severity or subclinical encephalopathy. A randomised clinical trial
of zoledronic acid therapy following liver transplant is now complete. A review of Vitamin D replacement for
cirrhosis-related bone disease has been published. The results from a study of the presence of ascites on the
accuracy of bone density measurement in the spine suggest that ascites causes a fluid artifact in the soft tissue
and bone interface that can falsely lower BMD measurements, particularly in the spine. HCC can be diagnosed
earlier and managed better in high-risk patients who have regular screening but this may reflect Lead-time bias.
A comparison of risk factors, demographic features, tumour stage and cirrhosis severity of patients with HCC
detected at screening with those diagnosed clinically was conducted for patients diagnosed between 1997 and
2003 A review of HCC diagnosis and management revealed that both surgical resection and liver
transplantation improve survival of patients with HCC, but improvements in the delivery of locoregional
therapy are needed to improve its effectiveness
Expected future outcomes:
Studies nearing completion are the effect of a nocturnal cornflour-based supplement on fuel utilisation in
cirrhosis and effect of gender and impact of cirrhosis on fuel utilisation.
Name of contact:
Professor Geoffrey Mccaughan
Email/Phone no. of contact:
g.mccaughan@centenary.usyd.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 253775
CIA Name: Prof David Handelsman
Admin Inst: University of Sydney
Main RFCD: Reproduction
Total funding: $378,750
Start Year: 2003
End Year: 2005
Grant Type: NHMRC Project Grants
Title of research award:
The Role of Androgens In Female PhysiologyThe Role of Androgens In Female Physiology
Lay Description (from application):
This study is aiming to develop an unique mouse model in which to study the question whether testosterone
plays an essential role in female reproductive and general health. It will develop a genetic mouse model for a
biological state of complete resistance to the effects of androgens. Such mice and humans are well known
among genetic males but this cannot occur naturally among genetic female mammals. By creating such a
mouse line, this project will be able to test for the first time indetail whether testosterone has an impotant role
in the development and function of the ovary and of other female tissues such as bone, muscle and the brain.
Research achievements (from final report):
This study developed a new model suitable for experimental study of the role of androgens, like the male
hormone testosterone, in women's reproductive and geneal health. To do this we aimed to create female mice
that would be unable to respond to testosterone, the male sex hormone. However such mice cannot arise
naturally because the males necessary to father tham are always sterile. Using the genetic tools to modify the
DNA of mice, we produced female mice that lacked either one or both copies of the androgen receptor, a
protein that is specified by a gene on the X chromosome and which is the necessary for androgens like
testosterone to act on any of the body's tissues. These studies have focussed mostly on the ovary and we found
that such mice were subfertile with defects in the way ooccytes (eggs) were recruited for ovulation.
Expected future outcomes:
These studies have elucidated findings that are relevant to female fertility, the timing of menopause and allow
for further studies on whether androgens have a role in normal female development of the non-reproductive
organs and tissues which are underway
Name of contact:
Prof Dj Handelsman
Email/Phone no. of contact:
djh@anzac.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 300457
CIA Name: Prof Des Richardson
Admin Inst: University of Sydney
Main RFCD: Cell Metabolism
Total funding: $513,438
Start Year: 2004
End Year: 2006
Grant Type: NHMRC Project Grants
Title of research award:
The Physiological and Pathophysiological Roles of MelanotransferrinThe Physiological and
Pathophysiological Roles of Melanotransferrin
Lay Description (from application):
Melanotransferrin (MTf) is a membrane-bound molecule that was originally identified at very high levels in
malignant melanoma cells and other tumours. To our surprise, our recent studies showed that MTf was also
widely expressed in normal tissues (DR EJB 2000). MTf has many similarities to the iron (Fe)-binding
protein, transferrin (Tf), and initially, MTf was thought to play a critical role in Fe uptake that is crucial for
DNA synthesis. However, we demonstrated that MTf did not play a major role in Fe uptake by melanoma cells
(DR 1990, 1991a,b, 2000). We also showed that the tissue distribution of MTf was very different to Tf and the
Tf-receptor 1 (TfR1) that are well known to be involved in Fe transport. For instance, TfR1 is highly expressed
in tissues with large Fe needs (e.g., placenta), while MTf is not expressed at high levels in these tissues and is
found in unexpected locations (i.e., salivary gland). In contrast to expectations, MTf was also found at higher
levels in normal than foetal tissue. Also interesting was the finding that MTf is found in the serum and brain of
Alzheimer's disease patients. Over the last 2 years under our current NHMRC grant on MTf we have
significantly extended our knowledge on this molecule. As proposed in this grant, we generated a MTf
knockout mouse. This is a very exciting model that is the best way of determining the function of MTf.
Furthermore, we used recombinant MTf to show that soluble MTf that is found in the plasma is not an effective
Fe donor to cells (DR EJB 2002). Our results over the last 12 years indicate that MTf may play unexpected
biological roles (see DR FEBS Lett 2000). For the first time, generation of our MTf knockout mouse will
provide the exciting opportunity of characterising its role(s). This will be important in understanding the
function of MTf in cancer cells, Alzheimer's disease and in other tissues (eg., salivary gland and kidney) where
it is expressed at high levels.
Research achievements (from final report):
Melanotransferrin (MTf) is a homologue of the serum iron (Fe) transport protein, transferrin. Traditionally,
MTf is associated with malignant melanoma and other tumours. Due to the high Fe requirement of cancer cells
and the fact that MTf: (i) is highly expressed in melanoma; (ii) has high homology with transferrin (Tf); and
(iii) has the ability to bind Fe, it potentially could play a role in Fe uptake by melanoma cells. Despite very
high MTf expression on melanoma cells, in this study, we demonstrated that it does not play a marked role in
Fe uptake in this cell type. However, excitingly, our study also demonstrated that MTf plays roles in cellular
proliferation, migration and tumourigenesis. , In this study, we also developed five, in vivo and in vitro, models
of MTf down- and up-regulation. Assessing these five models, we identified three genes modulated by MTf.
These included ATP-binding cassette subfamily B member 5, thiamine triphosphatase and transcription factor
4. Hence, this study identifies novel molecular targets directly or indirectly regulated by MTf and the potential
pathways involved in its function, including modulation of proliferation
Expected future outcomes:
Possible understanding of the rapid growth and metastasis of melanoma and other cancer
Name of contact:
Des Richardson
Email/Phone no. of contact:
d.richardson@med.usyd.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 300487
CIA Name: Dr Hala Zreiqat
Admin Inst: University of Sydney
Main RFCD: Orthopaedics
Total funding: $489,375
Start Year: 2004
End Year: 2006
Grant Type: NHMRC Project Grants
Title of research award:
Mechanisms of bone formation at the device/tissue interface: Role of Biomaterial Surface chemistry
modificationMechanisms of bone formation at the device/tissue interface: Role of Biomaterial Surface
chemistry modification
Lay Description (from application):
In 1992 300,000 prosthetic devices, artificial hips and knees were implanted into patients in a global market
worth $2.1 billion. Growth in this field of medicine has been exceptional with now more than 1 million
implants carried out each year. In 1998/99, 38,512 artificial hips and knees were implanted in Australia alone,
with approximately 10% of these replacing older, failed implants. Since joint replacements provide great
benefits for the patient considerable health funding is required for joint replacements. However, failure of the
implants is a major concern to the patient and financially to our health system, especially with the ever
increasing life expectancy of our population. The long-and short-term success of an implant depends on the
healthy support of the surrounding bone. This study aims to find ways of improving the attachment of healthy
bone to the implant by modifying the surface characteristics of the implant. We will modify the surface
chemistry of biomaterials with divalent cations, such as magnesium, which is known to play a critical role in
bone remodelling and skeletal development. Our goal is to improve the formation of healthy bone that will
promote a rapid and permanent fixation of implant into skeletons. This study goes further to study the factors,
inside the cell, on the cell surface and secreted by the cell, which promote this attachment. Once these factors
are identified, it should be possible to alter implant surfaces in ways to improve stability. In this proposal we
will use novel bioceramic coatings and ion beam technologies. This study will not only improve our
understanding of the interactions of bone and implant but also identify ways of improving implants to benefit
the patient's quality of life and reduce costs in this important heath area
Research achievements (from final report):
This project has provided new important information on the role surface chemistry modification of commonly
used orthopaedic implants on bone remodelling. The major finding of this study is that we describe for the first
time the development of plasma sprayed novel calcium silicate materials coated onto commonly used
orthopaedic implants (titanium alloy-Ti-6Al-4V). We found that the developed coatings possess significantly
improved bonding strength, chemical stability and cellular bioactivity compared to the currently clinically used
hydroxyapatite (HAp) coating. The chemical stability of the ceramic is an important factor influencing the
long-term stability of the coating. In this study, we found that our novel ceramics when plasma-sprayed coated
has a decreased dissolution rate compared to HAp coating, indicating that our developed novel material
possesses an improved chemical stability, compared to clinically available coatings (HAp). A major finding of
our research was that our developed material is highly bioactive inducing bone cells proliferation and
differentiation, compared to plasma-sprayed HAp coating and uncoated Ti-6Al-4V. Moreover, in vivo we
demonstrated that the novel coating induce bone formation at the skeletal tissue device interface indicating its
potential application as a coating for orthopaedic implants. , This project has the potential of developing new
implant materials with improved osseous integration. With the current rate of prosthetic failures in orthopaedic
patients unacceptably high, and with implant use growing at ~10% per annum, our new biocompatible coating
for implants will make a timely contribution to reducing patient morbidity, benefiting quality of life, and
making significant health care savings.
Expected future outcomes:
With the current rate of prosthetic failures in orthopaedic patients unacceptably high, and with implant use
growing at ~10% per annum, our new biocompatible coating for implants will make a timely contribution to
reducing patient morbidity, benefiting quality of life, and making significant health care savings.
NHMRC Research Achievements - SUMMARY
Name of contact:
Hala Zreiqat
Email/Phone no. of contact:
hzreiqat@usyd.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 301916
CIA Name: Prof Robert Cumming
Admin Inst: University of Sydney
Main RFCD: Epidemiology
Total funding: $1,780,888
Start Year: 2004
End Year: 2008
Grant Type: NHMRC Project Grants
Title of research award:
Concord Hormones and Ageing in Men Project (CHAMP)Concord Hormones and Ageing in Men Project
(CHAMP)
Lay Description (from application):
Throughout life men have poorer health than women, a health difference that extends into old age. In Australia
in 2001, life expectancy for a 65 year old man was 20% less than for a 65 year old woman (81.6 years for men
and 85.2 years for women). The study proposed here will fill major gaps in knowledge about key health
problems in older men. The study will be called CHAMP: Concord Hormones and Ageing in Men Project. As
people grow older, health problems that cause loss of independence and reduced quality of life become
increasingly important. The term 'geriatric giants' is sometimes used to describe these disabling syndromes:
falls and fractures, cognitive impairment and dementia, urinary incontinence, and poor mobility and functional
dependence. CHAMP has been designed to investigate the causes of, and inter-relationships between, these
geriatric syndromes in men. Reproductive hormones are responsible for the fundamental biological differences
between men and women. Underpinning CHAMP is the idea that age-related changes in reproductive
hormones play an important role in the development of the geriatric syndromes in older men. There have been
numerous studies of oestrogen and health in older women but only limited research on testosterone and other
reproductive hormones in older men. CHAMP will be the largest study of the geriatric syndromes in older men
ever conducted. The study will inlvolve 2800 men aged 65 years and over recruited from the community
around Concord Hospital in Sydney. These men will each spend 3 hours at the study centre, where they will
have a comprehensive physical examination and tests for osteoporosis, muscle weakness, dementia and urinary
problems, as well as blood tests. This will all be repeated 2 years later.
Research achievements (from final report):
We successfully recruited 1705 men aged 70 years and over from the local community in the area around
Concord Hospital in Sydney. The participation rate was about 50%. All subjects had detailed clinical
examinations and completed a detailed questionnaire. Over 1300 subjects were re-examined after 2 years. We
are currently extracting DNA from blood samples and testing blood for levels of reproductive hormones and
vitamin D. This is one of the most comprehensive studies of the health of older men evr conducted anywhere in
the world., , The study has provided important information on the prevalence in older men of chronic pain,
dementia, disability, falls, fraility, osteoporosis and urinary incontinence. Data on risk factors for these
conditions are currently being analysed. A key analysis in the next few months will be to study the reaktiosnhip
between changes in testosterin and oestradiol levels and mortality. Over 300 of the men in CHAMP were born
in Italy, providing a wonderful opportunity to study the heralth of this migrant group.
Expected future outcomes:
Epidemiological cohort studies only achieve their full potential after long-term follow-up of subjects. To date,
follow-up has only been for two years. Numerous publications are expected in the next few years as we
continue follow-up of the cohort.
Name of contact:
Robert Cumming
Email/Phone no. of contact:
bobc@health.usyd.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 352391
CIA Name: A/Pr David Little
Admin Inst: University of Sydney
Main RFCD: Orthopaedics
Total funding: $329,750
Start Year: 2005
End Year: 2007
Grant Type: NHMRC Project Grants
Title of research award:
Relationship of the anabolic and catabolic responses in healing a critical sized defect in ratsRelationship of the
anabolic and catabolic responses in healing a critical sized defect in rats
Lay Description (from application):
Delayed bone healing after trauma is a large clinical problem. Figures suggest up to 60,000 fractures result in a
delay in healing in Australia per year. Bone healing can also fail to occur in other circumstances, such as after
an operation. Research effort into new approaches to solving these problems is clearly justified. We believe
that in some situations, bone healing fails due to the body's healing response, the anabolic response, being
insufficient. In some other situations, the body's bone resorbing response, the catabolic response, may be too
high and prevent healing from occurring. In normal bone healing, there is a balance between the anabolic and
catabolic response. In disordered bone healing, these responses are out of balance. Several reasonably new
treatments are available which can increase the anabolic response or decrease the catabolic response. We have
preliminary results showing that with these agents we can bring these elements into better control, and thus
drive bone healing. We have optimised an animal model where both the anabolic and catabolic responses can
be controlled. In this project, we explore the optimisation of the timing and magnitude of anabolic and
catabolic responses in bone healing.
Research achievements (from final report):
This study investigated the potential for the use of existing therapeutic agents to modulate bone repair. Many
therapies for bone diseases such as osteoporosis offer avenues for pharmaceutical promotion of bone healing in
siuations where intervention is needed. The relationship of the anabolic (bone forming) and catabolic (bone
resorbing) responses is key to this objective. We have shown that treatment with bone morphogenic proteins
(BMP's) stimulates bone healing in a complete non-union bone repair model. This healing response was further
enhanced when the BMP was combined with systemic Bisphosphonate treatment, the most common antiresorptive treatment for osteoporosis. The healing bones treated with these agents in combiniation were not
only larger but also more resistant to applied mechanical forces. When these agents were examined alone and
in combination in a delayed union model with reduced but not absent healing capacity, the combination therapy
again surpassed all other treatment groups, producing enhanced repair rates, size of the callus produced and its
overall mechanical strength. , Parathyroid hormone (PTH) was also examined as a potential enhancer of bone
repair in both normal bone healing and our delayed union model. Even though in fractures that normally heal
PTH treatment enhanced the fracture callus size and strenght, unlike BMP's this agent was unable to enhance
repair rates in the delayed union model. The outcomes of this study highlight BMP's as superior to PTH in the
treatment of delayed or non-unions following skeletal injury. We have elucidated the different mechanisms
through which these two enhancers of bone formation act in skeletal repair environments. This study has
impacted highly on the clinical treatment of dealyed or non-union fractures.
Expected future outcomes:
These outcoms have been and will continue to be applied in clinical orthopaedics to successfully treat cases of
delayed and non-unions. Although BMP's offer the most successful treatment strategies for these cases, their
application is expensive and requires surgical intervention. Our continuing research aims to unveil a nonsurgical, systemic treatment strategy for these situations.
Name of contact:
Associate Professor David Little
Email/Phone no. of contact:
davidl3@chw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 352562
CIA Name: Dr James Melrose
Admin Inst: University of Sydney
Main RFCD: Orthopaedics
Total funding: $516,625
Start Year: 2005
End Year: 2007
Grant Type: NHMRC Project Grants
Title of research award:
Pathobiology of the small leucine rich repeat proteoglycans in cartilage, intervertebral disc and tendon
degenerationPathobiology of the small leucine rich repeat proteoglycans in cartilage, intervertebral disc and
tendon degeneration
Lay Description (from application):
Back problems (M$700), OA (M$600), muscle and tendon disorders (M$500) accounted for 60% of
musculoskeletal (MSK) health care expenditure in Australia in 1993-1994, were the second most common
cause of presentations to a general practitioner, the third leading contributor to health system expenditure (>$3
billion) and accounted for ~300,000 hospital admissions, ~15 million medical services and over 13 million
prescriptions. Significant disability due to MSK disease were noted in ~50% of people aged 65 years.
Australian census data indicates that ageing trends will result in an increased incidence of MSK conditions as
the longevity of the Australian population rises, exerting an ever increasing burden on the healthcare budget.
Extreme levels of sporting or physical activity from traumatic loading of joints can lead to excessive loading of
collagen fibres in MSK tissues leading to their failure and loss of tissue function. Common end stages of
collagen fibre breakdown are preceded by matrix changes which may predispose MSK tissues to enzymatic
and mechanical damage. One such change is an increased degradation of a family of small leucine-rich
proteoglycans (SLRPs) which modulate the diameter, strength and assembly of collagen fibrils and bind and
modify the effects of reparative growth factors and degradative cytokines within connective tissues. Altered
synthesis of SLRPs and SLRP fragments have been identified in abnormal intervertebral disc, cartilage and
tendon. Very little is known however about how these fragments are generated within these tissues and how
they affect growth factor binding or collagen fibril formation. This deficiency will be addressed in our
proposed study which will provide novel information on mechanisms of cartilage, intervertebral disc and
tendon degeneration and potential therapeutic and diagnostic targets which may be exploited in future studies
on the treatment of these musculoskeletal conditions.
Research achievements (from final report):
Musculoskeletal disorders affecting the knee and hip represent a major cause of disability and morbidity in
Western societies, exert a severe socio-economic impact on the afflicted individuals and cause a heavy burden
on healthcare resources. Disruption of collagen fibres in musculoskletal tissues through the action of
collagenolytic matrix metalloproteinases (MMPs) and mechanical forces represent a common end stage of
disease. Identifying changes in these tissues that not only precede collagen destruction, but also predispose
them to disease progression, may provide important targets for diagnosis, disease monitoring and facilitate
early intervention strategies when the likelihood of therapeutic repair is enhanced. The small leucine rich
proteoglycans (SLRPs) including biglycan, decorin, fibromodulin, lumican and keratocan, have important
linking, shape determining and matrix organising roles which are essential for the correct functioning of
musculoskeletal tissues. In the present study we demonstrated in two publications that the SLRPs were
extensively fragmented in a number of pathological human connective tissues and in an ovine model of IVD
degeneration. A further manuscript which is currently under review showed that fragmentation of fibromodulin
was dissimilar to other SLRP members in that it was more extensively C-terminally processed. Two define
MMPs (MMP-13 and ADAMTS-4) could reproduce similar fragmentation patterns for fibromodulin to that
evident in pathological cartilages. A final mauscript which we are currently writing has determined a novel
cleavage site in lumican duye to the action of ADAMTS-4 . We have also developed and validated an ovine
model to determine the changes in shoulder tendons which was published in the top clinical arthritis journal
Arthrits Rheum. This model will allow us to determine therapeutic intervention strategies to prevent further
degenerative changes in the tendon and improve tendon repair.
Expected future outcomes:
NHMRC Research Achievements - SUMMARY
Improvements in tendon repair/prevention of further degeneration. Improvements in post surgical rehabilitation
for tendon injuries. Identification/characterisation of SLRP core protein fragments may identify them as
valuable biomarkers of joint disease progression. Identification of the enzymes responsible for their generation
may uncover useful therapeutic targets.
Name of contact:
James Melrose
Email/Phone no. of contact:
jmelrose@med.usyd.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 402462
CIA Name: Prof Markus Seibel
Admin Inst: University of Sydney
Main RFCD: Endocrinology
Total funding: $464,521
Start Year: 2006
End Year: 2008
Grant Type: NHMRC Project Grants
Title of research award:
GLUCOCORTICOID EFFECTS ON BONE: THE ROLE OF THE OSTEOBLASTGLUCOCORTICOID
EFFECTS ON BONE: THE ROLE OF THE OSTEOBLAST
Lay Description (from application):
Glucocorticoids (usually referred to as "cortisone") are used as therapeutic agents in almost all fields of
medicine, where they have been proven to be of great benefit to countless patients suffering from diseases such
as rheumatoid arthritis, asthma, inflammatory bowel disease and malignancies. Glucocorticoids are also of live
saving benefit to patients who have undergone organ transplantation. It is, however, well known that
glucocorticoids may also exert deleterious effects on bone, muscle, cartilage and skin, causing osteoporosis,
muscle wasting and skin damage. As a matter of fact, cortisone-induced muscle and bone disease is one of the
most frequent and serious side effects associated with glucocorticoid treatment, and substantially affects quality
of life and co-morbidity in many patients. In the present project, we aim to develop new strategies for the
understanding and prevention of costisone-induced bone disease. The first step is to investigate the
mechanisms of actions of glucocorticoids in bone. To this aim, we have generated a model in which a
cortisone- inactivating enzyme is produced in excess in the bone forming cells ("osteoblasts"). Previous studies
have shown that these cells are protected against the effects on cortisone, while other cells not producing this
enzyme remained vulnerable. We now intend to use this model to study the mechanisms of glucocorticoid
action on bone and muscle under normal and diseased conditions (e.g. in a model of glucocorticoid excess and
in a model of rheumatoid arthritis). We also intend to study how internal glucocorticoids affect the
development of bone forming cells. Our long-term aim is to uncover new ways to target drug action to the
desired tissues and cells, while protecting other tissues and cells from deleterious side effects.
Research achievements (from final report):
Our research has resulted in a novel paradigm about the role of glucocorticoids (GC; commonly referred to as
"cortisone") in the skeleton. , We discovered that endogenous (i.e. internal, low level) GC control, the fate of
immature precursor cells and the development of the cranial skeleton in mice. These effects are mediated
through specific signalling molecules secreted by the cells that form bone (the osteoblasts)., We further
discovered that the interaction between endogenous GC and osteoblasts plays an important role in autoimmune
arthritis. Using a well established mouse model of arthritis (K/BxN serum-induced arthritis) we found the
inflammatory response was significantly blunted in animals in which GC action on and in the osteoblast was
blocked. As a result, the bones of these latter mice were protected, while animals with intact osteoblastic GC
signalling showed sever arthritis and bone loss. These exciting and unexpected findings suggest that osteoblasts
are able to modulate the immune-mediated inflammatory response of the joint via a GC-dependent pathway. ,
Finally, we discovered that the effects of exogenous (i.e. external, high level) GC on energy metabolism are
mediated, at leats in part, through the skeleton and here again, the osteoblast. Using a genetically modified
mouse model, in which GC are inactivated in osteoblasts only, we demonstrated that animals with intact GC
signalling gained significantly in total and site specific fat mass, whereas mice with osteoblast-targeted
disruption of GC-signalling did not. These results show that the osteoblast plays a role in the regulation of
energy metabolism. , In summary, our research has revealed hitherto unknown and exciting functions of GC,
bone and its cells that affect not only bone health and development, but also point to a central role of the
osteoblast in mediating auto-immune inflammation and GC-induced effects on bone energy metabolism.
Expected future outcomes:
Our future research will establish the mechanisms that govern GC action in osteoblasts, and how this
interaction determines how osteoblasts comntrol mesenchymal progenitor lineage commitment, immunemediated inflammatory responses, and effects of GC on bone, fat and energy metabolism.
NHMRC Research Achievements - SUMMARY
Name of contact:
Markus Seibel
Email/Phone no. of contact:
mjs@med.usyd.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 402496
CIA Name: Prof Michael Murray
Admin Inst: University of Sydney
Main RFCD: Basic Pharmacology
Total funding: $457,268
Start Year: 2006
End Year: 2008
Grant Type: NHMRC Project Grants
Title of research award:
Novel omega-3 fatty acid epoxides and the activation of cellular survival pathwaysNovel omega-3 fatty acid
epoxides and the activation of cellular survival pathways
Lay Description (from application):
Recent studies have reported that foods and oils containing high levels of omega-3 fatty acids have beneficial
effects in patients with arthritis and cardiovascular disease. The mechanisms by which these dietary changes
produce health benefits are unclear but it is known that omega-3 fatty acids can replace omega-6 and other fatty
acids in cells; these omega-6 acids are more common in western diets. A number of enzymes in cells convert
fatty acids to oxygenated derivatives and some of these have potent protective effects that allow cells to survive
in the presence of toxic stimuli. We have found that epoxides formed from the omega-3 fatty acid stearidonic
acid are extremely potent protective agents in cells - more so that epoxides from omega-6 acids like
arachidonic acid. The present project seeks to identify omega-3 fatty acid epoxides with potent and long-lived
beneficial effects in cells, relate these properties to those of omega-6 fatty acid epoxides and then understand
how the omega-3 epoxides enhance cell survival. The findings will provide a rational basis from which to
understand the beneficial effects of dietary modification already seen in clinical studies. By understanding the
biochemical and molecular events in cells that are activated by omega-3 fatty acid epoxides we may be able to
design therapies, most likely involving changes in dietary fat intake, that could benefit individuals with
arthritic, cardiovascular and other conditions. Given the high incidence of these conditions in this country the
potential impact of the findings from this project could be highly significant and are consistent with the
national research priority "healthy ageing."
Research achievements (from final report):
In humans omega-3 polyunsaturated fatty acids (PUFAs) appear to have beneficial anticancer, cardiovascular
and anti-arthritic effects, but there is a deficiency of mechanistic data underpinning the epidemiological
evidence. This project defined the mechanisms by which epoxides formed from omega-3 fatty acid PUFA, by
an important group of enzymes known as cytochromes P450, regulate cell growth and survival. , During the
tenure of this grant we:, * Found that the unique omega-3 epoxide formed from omega-3 PUFAs inhibits the
growth of endothelial and breast cancer cells, in contrast to the alternate epoxide isomers of PUFA. These
properties of the omega-3 epoxide are also in contrast to epoxides of omega-6 PUFA (which are prevalent in
western diets) that stimulate cell growth and accelerate the spread of cancers., * To establish these properties
we synthesised and characterised all of the stable epoxides that can be formed from the omega-3 PUFA
eicosapentaenoic acid. , * We identified the key pathways in cells by which the omega-3 PUFA epoxide stops
cell growth., * We establiched that omega-3 PUFAs inhibit cell migration and the growth of tubular structures
that could also deliver nutrients to tumours, whereas omega-6 epoxides are stimulators of these processes. , * In
cells we identified the enzymes that convert PUFAs to metabolites the mediate increased migration. These
findings aid understanding of PUFA effects on metastasis (spreading of tumours around the body to establish
secondary tumours).
Expected future outcomes:
We have information on the chemical features responsible for some of the beneficial effects of omega-3 PUFA
in cells. We are now utilising these findings to prepare model compounds as potential drugs to minimise
tumour spread. By identifying the enzymes and signalling pathways that mediate the effects of these epoxides
there are additional opportunities for drug development.
Name of contact:
Michael Murray
NHMRC Research Achievements - SUMMARY
Email/Phone no. of contact:
michaelm@pharm.usyd.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 402511
CIA Name: A/Pr Marlene Fransen
Admin Inst: University of Sydney
Main RFCD: Primary Health Care
Total funding: $1,250,215
Start Year: 2006
End Year: 2011
Grant Type: NHMRC Project Grants
Title of research award:
The effect of glucosamine sulphate on structural disease progression in knee osteoarthritisThe effect of
glucosamine sulphate on structural disease progression in knee osteoarthritis
Lay Description (from application):
Osteoarthritis (OA) is a joint disease characterized by a progressive loss of cartilage and joint space resulting in
increasing pain and difficulty performing usual daily activities. OA is the leading health problem amongst older
Australians and a National Health Priority area. There is no known cure for OA and no intervention
demonstrated to slow disease progression or delay time to joint replacement surgery. Currently patients are
managed symptomatically with all clinical guidelines recommending paracetamol as 'the preferred long term
oral analgesic'. This recommendation is based on the increased risk of serious gastrointestinal, cardiovascular
and renal diseases with long-term NSAIDs use in older people. However, NSAIDs appear to provide better
pain relief for patients with more than mild joint pain. Amongst patients with OA, there is much demand for
the dietary supplement glucosamine sulphate. Product marketing has led to the belief that glucosamine is able
to slow the rate of joint destruction and cartilage loss and help ease joint pain with, in contrast to NSAIDs, little
risk of side effects. However, the few trials conducted to date have been inconclusive. If the marketing claims
are unjustified, many older people are wasting limited financial resources and due to unrealistic expectations of
the benefit of glucosamine, placing a lower priority on lifestyle changes of proven effectiveness, such as
regular exercise and weight loss. A total of 900 patients with knee OA will be randomly allocated to
glucosamine sulphate or matching placebo capsules for two years. The main outcomes will be the rate of joint
space narrowing, use of NSAIDs and physical disability. If glucosamine results in slowing disease progression
or in reducing NSAIDs consumption, the widespread use of this product would effectively decrease pain,
disability and NSAIDs-related illnesses amongst the increasing number of people with OA.
Research achievements (from final report):
Completed the two year followup of 605 randomised study participants in November 2011., Data entry and
auditing completed in January 2012., Clinic-based assessments: Achieved a 92% followup at one year, 81%
followup at two years., Bimonthly Participant Diary: Achieved >85% return rate over first 12 months followup.
Expected future outcomes:
Data lock, unblinding of study treatment allocation and statistical analysis will take place in the week
commencing February 13, 2012. The main results paper will be submitted to a highly ranked international
journal in April 2012.
Name of contact:
Marlene Fransen
Email/Phone no. of contact:
marlene.fransen@sydney.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 402587
CIA Name: Prof Arthur Conigrave
Admin Inst: University of Sydney
Main RFCD: Endocrinology
Total funding: $566,035
Start Year: 2006
End Year: 2008
Grant Type: NHMRC Project Grants
Title of research award:
Molecular determinants of amino acid-dependent signalling by the calcium-sensing receptorMolecular
determinants of amino acid-dependent signalling by the calcium-sensing receptor
Lay Description (from application):
Amino acids are the building blocks of proteins and an alternative energy source to carbohydrate and fat.
Proteins are major structural components of our bodies. They also fulfil an amazing diversity of cellular and
bodily functions acting, for example, as enzymes (biological catalysts), receptors, molecular chaperones and
biological machines. Thus, amino acids are key nutrients and the human body has developed mechanisms for
tightly regulating cellular responses depending upon their levels in blood. Identifying amino acid sensing
molecules and identifying the mechanisms they use to control cellular responses is thus a key issue in human
biology. The applicant identified the calcium-sensing receptor as an amino acid sensor and has shown that this
receptor provides a means by which fluctuations in amino acid levels regulate the secretion of the key calciumregulating hormone, PTH. In the current proposal, the mechanisms that link amino acid activation of the
calcium-sensing receptor to its key cellular responses will be determined.
Research achievements (from final report):
This grant had the following overall goals:, o
To determine whether the CaR's
amino acid sensitivity is regulated by receptor density and thus varies in different cellular settings;, o
To
determine whether amino acids regulate the secretion of calcitonin as well as parathyroid hormone; , o
To
determine, how the amino acid-activated CaR activates intracellular signalling pathways and how regulation of
these pathways induces inhibition of parathyroid hormone secretion. , , The first goal has been satisfied by
demonstrating that cells prepared from the parathyroid glands of patients with primary hyperparathyroidism
have reduced calcium and amino acid sensitivity when compared with normal parathyroid cells. , , The second
goal has been satisfied by the demonstration that amino acids that activate the calcium sensing receptor
stimulate cellular responses incuding secretion of the calcium-regulating hormone, calcitonin from human
thyroid medullary TT carcinoma cells. , , The third goal has led us to demonstrate that amino acids have
powerful actions on two key intracellular signalling pathways: one for intracellular calcium ion mobilization
and the other for the accumulation of the key second messenger cyclic AMP. Remarkably, amino acids appear
to be positive allosteric modulators of the first pathway and agonists of the second. In addition, amino acids
appear to have much smaller effects on other signalling pathways., , During this work CIA authored two
seminal contributions to the theory of molecular endocrinology as well as calcium and bone metabolism: one
demonstrating that a subgroup of class 3 G-protein coupled receptors are receptors with broad spectrum
sensitivity for amino acids, and the other demonstrating that amino acids sensing receptors have multiple roles
in modulating calcium metabolism and bone health.
Expected future outcomes:
We are performing a detailed analysis of receptor expression on ligand-dependent activation of intracellular
signalling pathways and animal experiments to test whether amino acid infusions acutely stimulate calcitonin
secretion. Finally, the effect of amino acids on cAMP accumulation has led to new hypotheses regarding the
mechanism that underlies the control of PTH secretion.
Name of contact:
Prof Arthur Conigrave
Email/Phone no. of contact:
a.conigrave@usyd.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 402714
CIA Name: A/Pr David Little
Admin Inst: University of Sydney
Main RFCD: Orthopaedics
Total funding: $310,137
Start Year: 2006
End Year: 2008
Grant Type: NHMRC Project Grants
Title of research award:
Role of the Osteoclast in Endochondral Fracture RepairRole of the Osteoclast in Endochondral Fracture Repair
Lay Description (from application):
Failure of bone healing leads to significant pain and disability, such that augmentation of fracture repair is a
dynamic and important field of study. A full understanding of bone repair is necessary before we can hope to
introduce successful therapies. We theorise that by stimulating bone forming cells and inhibiting bone
resorbing cells we may be able to provide optimal results. Bone resorbing cells, or osteoclasts, have long been
considered essential to the initial stages of bone repair (endochondral ossification) during which the early soft
cartilaginous callus is replaced by hard mineralised callus. Our preliminary studies lead us to believe that
endochondral ossification can indeed proceed without osteoclast activity. If we can safely eliminate osteoclast
function early in the early stages of fracture repair, a number of therapeutic options open up for the
augmentation of bone healing. The return of osteoclast function is necessary in the long term, so our strategy
will also need to take this into account. This study will establish which systems are pivotal in endochondral
ossification and therefore which interventions we should explore.
Research achievements (from final report):
This study examined the role of the bone resorbing cell known as the osteoclast during the process of fractrue
repair. When a fracture heals it forms a soft cartilage callus which is then mineralised and replaced by a hard
bony callus. It is this process of replacing cartilage with bone that was the focus of this study. The osteoclast
has a pivotal role in bone tissue removal however has been considered necessary for cartilage tissue removal
also. The current work has shown in great detail that osteoclastic resorption is in fact not necessary to cartilage
tissue removal during bone repair. Instead we have shown that a group of enzymesknown as matrix
metalloproteinases (MMP's) are essential to proper cartilage tissue removal and hence bone repair. A number
of cell types secrete these enzymes including vascular endothelial cells, cells that line invading blood vessels. ,
The outcomes from this study carry high significance to the clinical management of osteoporosis. A number of
therapeutic agents used to treat this highly common disease target osteoclast acitivity. Hence concerns have
existed about the potential of these agents to interfere with bone repair. Our work suggests these agents will not
impair bone healing due to the elimination of osteoclastic cells from the process.
Expected future outcomes:
This group os studies will aide clinicians in decisions regarding the treatment of osteoporotic patients who
sutain or present with fractures. We will continue to work on a new line of investigation into discreet cellular
processes to provide supporting confirmation of the work we have completed in bone reapir models.
Name of contact:
David Little
Email/Phone no. of contact:
davidl3@chw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 402781
CIA Name: A/Pr Marlene Fransen
Admin Inst: University of Sydney
Main RFCD: Rheumatology and Arthritis
Total funding: $448,792
Start Year: 2006
End Year: 2008
Grant Type: NHMRC Strategic Awards
Title of research award:
Cost Effectiveness of Glucosamine Sulphate for Knee Arthritis (COGS)Cost Effectiveness of Glucosamine
Sulphate for Knee Arthritis (COGS)
Lay Description (from application):
A clinical trial, conducted in general practice, randomising 340 patients with symptomatic knee osteoarthritis to
glucosamine sulphate or matching placebo tablets for 9 months. The main study outcomes will be knee pain,
physical function and analgesia use. Analysis will be undertaken to identify characteristics associated with
treatment responsiveness, such as high body mass index and structural disease severity. An economic analysis
will be conducted alongside this trial.
Research achievements (from final report):
N/A
Expected future outcomes:
N/A
Name of contact:
N/A
Email/Phone no. of contact:
N/A
NHMRC Research Achievements - SUMMARY
Grant ID: 402839
CIA Name: A/Pr Marlene Fransen
Admin Inst: University of Sydney
Main RFCD: Preventive Medicine
Total funding: $462,290
Start Year: 2006
End Year: 2010
Grant Type: Career Development Fellowships
Title of research award:
The effective non-pharmacological management of osteoarthritis.The effective non-pharmacological
management of osteoarthritis.
Lay Description (from application):
Not Available
Research achievements (from final report):
The career development award allowed me to lead two large collaborative groups and successfully fund, three
of the four large projects planned for this Award. , The Long-term evaluation of glucosamine sulfate study,
funded by the NHMRC, will complete the, recruitment and two year follow-up of 605 patients with
symptomatic knee osteoarthritis. Participants, were randomised to receive either glucosamine, chondroitin,
glucosamine and chondroitin or placebo, capsules for two years. All study participants had annual knee Xrays,
with 300 study participants also, having annual knee MRIs. The results of this study will be ready for
publication by mid 2012. , The Maximum recovery after knee replacement (funded by the HCF Health and
Medical Research, Foundation and MBF Foundation) is currently recruiting patients undergoing primary total
knee, replacement surgery at nine sites in NSW, Queensland and Victoria. Patients are randomly allocated to,
standard care or the novel intensive class-based exercise program. As at October 30, 2010, 260 patients, have
been randomised to this study. , Other collaborative work conducted included:, The conduct of a large
population-based survey of older people in Wuchuan County (Inner Mongolia) to, evaluate the prevalence and
burden of painful knee osteoarthritis in rural communities in developing, countries., The publication of metaanalyses of research evaluating the effectiveness of exercise programs for, people with knee or hip
osteoarthritis. Such work provides evidence for clinical practice guidelines., The evaluation of the effect of
obesity on the musculoskeletal system, and specifically the effects of, weight loss on the joint cartilage.
Expected future outcomes:
The results of the LEGS study will determine if these dietary supplements (glucosamine, chondroitin)do reduce
knee pain and slow the rate of cartilage loss in people with knee osteoarthritis., The results of the MARKER
study will determine if increasing the follow-up and intensity of rehabilitation will improve long-term pain and
physical disability outcomes after total knee replacement surgery
Name of contact:
Marlene Fransen
Email/Phone no. of contact:
marlene.fransen@sydney.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 511959
CIA Name: Dr Meilang Xue
Admin Inst: University of Sydney
Main RFCD: Rheumatology and Arthritis
Total funding: $380,559
Start Year: 2008
End Year: 2011
Grant Type: Career Development Fellowships
Title of research award:
Activated protein C suppresses the abnormal immune response in rheumatoid arthritisActivated protein C
suppresses the abnormal immune response in rheumatoid arthritis
Lay Description (from application):
This project will determine whether activated protein C (APC) reduces the severity of rheumatoid arthritis
(RA) by altering the abnormal response of a type of white blood cells known as the T cells. Experiments will
utilise T cells isolated from patients with RA, normal controls and an animal model of RA, to examine a newly
discovered immune pathway now thought to play a major role in causing RA. The results will help clarify
whether and how APC prevents joint destruction in RA
Research achievements (from final report):
Rheumatoid arthritis (RA) is a chronic, progressive and disabling autoimmune disease affecting approximately
1% of the population (range: 0.3-2.1%). It primarily affects the joints, and ultimately, leads to joint destruction,
restricted mobility, and reduced life expectancy. There is no cure for arthritis and as the population ages, the
burden of arthritis is increasing. Our research has demonstrated that activated protein C (APC) reduces the
severity of RA by preventing the abnormal immune and inflammatory response. This approach is different to
that used with the current range of "biological" therapy which targets the main inflammatory mediators, such as
tumour necrosis factor (TNF)-a. By blocking the abnormal Th1 and Th17 immune events upstream of the
inflammatory cascade, APC's actions would be more comprehensive than the current biologicals, as it would
not only suppress upstream inflammatory signal pathways, but also inhibit the overexpression of a range of
inflammatory mediators, such as TNF-a, interleukin (IL)-1 and -17. More importantly, APC restores and
enhances the impaired functions of anti-inflammatory T-regulatory cells in RA, with the potential to restore the
abnormal immune response to normal. In addition, APC is known to have few side-effects. Thus, APC will
provide a wide-ranging and safe therapy for RA with a novel mechanism of action. The knowledge gained
from this project is likely to provide direction for new strategies to prevent joint destruction in arthritis.
Expected future outcomes:
Our research has provided the direct evidence that APC reduces the severity of RA by preventing the
abnormalimmune and inflammatory response. The knowledge gained from this project is likely to provide
direction for new strategies to prevent joint destruction in arthritis.
Name of contact:
Meilang Xue
Email/Phone no. of contact:
meilang.xue@sydney.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 512157
CIA Name: Prof Philip Sambrook
Admin Inst: University of Sydney
Main RFCD: Rheumatology and Arthritis
Total funding: $443,091
Start Year: 2008
End Year: 2010
Grant Type: NHMRC Project Grants
Title of research award:
Common pathways influencing osteoporosis and atherosclerosis clinical riskCommon pathways influencing
osteoporosis and atherosclerosis clinical risk
Lay Description (from application):
It is recognised there are strong inherited effects on bone density and bone turnover as well as cardiovascular
markers like serum cholesterol and arterial function. The study will examine the relationship between
osteoporosis and atherosclerosis risk using the powerful twin model and two established large twin cohorts in
Sydney and Melbourne. The work may lead to better prediction of common risk factors for these two
important conditions.
Research achievements (from final report):
Analysis of data for this study continues and we are currently examining links between bone density, body
composition (fat and lean mass), and risk factors for cardiovascular disease such as hardening of the arteries.
We have completed some analysis looking at the relationship between bone density and biochemical markers
found in the blood. Uric acid is an antioxidant produced by the body which is associated with cardiovascular
disease. We have discovered that high uric acid levels are also associated with better bone density in women
who have commenced and women who have finished menopause. Hence it appears that uric acid may provide
some protection against bone loss.
Expected future outcomes:
With further data analysis we will continue to explore the link between osteoporosis and cardiovascular
disease. This is likely to lead to a better understanding of these diseases and better idenification of those at high
or low risk of these important diseases.
Name of contact:
Monique Macara
Email/Phone no. of contact:
monique.macara@sydney.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 512167
CIA Name: Dr James Melrose
Admin Inst: University of Sydney
Main RFCD: Orthopaedics
Total funding: $605,037
Start Year: 2008
End Year: 2010
Grant Type: NHMRC Project Grants
Title of research award:
The role of perlecan in tensional connective tissuesThe role of perlecan in tensional connective tissues
Lay Description (from application):
Musculoskeletal diseases affect tension and weight bearing connective tissues which have notoriously poor
repair capabilities. These conditions are difficult to treat clinically and surgical repair in many cases does not
provide a return to optimal joint function impinging on the quality of life of afflicted individuals and their
carers. Our project aims to better understand the structure and function of these tissues in health and disease
with a view to improving repair strategies.
Research achievements (from final report):
We have published reviews on the multifunctional properties of perlecan which stabilise connective tissues and
the diverse cell signalling events which perlecan regulates. We also demonstrated the prominent distribution of
perlecan in the development of human foetal spinal tissues and how it differed from other prominent
intervertebral disc matrix components such as the chondroitin sulphate rich proteoglycans versican and
aggrecan. Perlecan isolated from human foetal knee rudiment cartilage was shown to form complexes with
FGF-2 and FGF-18 and these induced cell proliferation in an engineered Baf 32 cell line expressing FGFR2IIIc
and FGFR3IIIc. This cell line does not produce endogenous heparan sulphate proteoglycans thus for the cells
to remain viable and proliferate an exogenous source of heparan sulphate proteoglycan (perlecan) or heparin
must be supplied and the specific effect of a given growth factor on cell proliferation can thus be examined invitro. FGF-2 and 18 both induced cell proliferation when presented to Baf 32 cells when complexed with
perlecan. The interaction between FGF-2 and perlcan was totally dependant on interaction with perlecans HS
side chains, removal of these with heparanase ablated this cell proliferative effect. In contrast FGF-18 still
ellicited a significant cell proliferative response even in the absence of the perlecan HS chains, with ~ 70% of
the response evident with perlecan containing HS chains evident. These publications clearly show the
importance of perlecan in the assembly, maintenance and stabilisation of tensional and weight bearing
connective tissues. Its growth factor binding and regulatory properties may also be of application in
regenerative medicine.
Expected future outcomes:
In on-going studies we have shown that perlecan displays interactive properties with tropoelastin, type VI
collagen and fibrillin-1. Thus perlecan is not just a proteoglycan of vascularised and basement membrane
tissues but also has novel roles to play in the elastic properties of tensional and weight bearing connective
tissues.
Name of contact:
James Melrose
Email/Phone no. of contact:
james.melrose@sydney.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 512545
CIA Name: Dr Charles Allan
Admin Inst: University of Sydney
Main RFCD: Endocrinology
Total funding: $327,793
Start Year: 2008
End Year: 2011
Grant Type: NHMRC Project Grants
Title of research award:
FSH and female ageingFSH and female ageing
Lay Description (from application):
This project will test the proposal that rising follicle-stimulating hormone (FSH) levels in ageing females
directly accelerate reproductive failure and bone loss , major public health issues due to delayed childbearing
and our rising ageing population. We have developed a unique mouse model with elevated FSH levels that
cause premature female infertility. We will now use this model to determine the direct effects of high FSH
upon ovarian and uterine function, as well as bone loss with age.
Research achievements (from final report):
We investigated the impact of elevated levels of follicle-stimulating hormone (FSH) on ovary development and
female ageing. Blood FSH levels rise in ageing women when fertility is rapidly declining, and high FSH is
predicted to accelerate the loss of ovarian eggs (decreasing number and quality). We showed that elevated FSH
induced premature subfertility in female mice. However, rather than decrease egg numbers, our research found
that high FSH increased the ovarian egg reserve and did not decrease egg quality. Our research also showed
that there is a narrow FSH threshold for normal follicle development, with higher FSH levels inducing
abnormal polycystic ovaries. These finding haves implications for FSH administration during assisted
reproductive technology (ART). High FSH may not directly decrease egg quality, but our results highlight the
importance of avoiding excessive FSH actions, and the benefit of sequential dose adjustments for FSH regimes
in ART. , We studied the changes in bone mass in female mice expressing high FSH levels, to test a recent
proposal that high FSH directly causes bone loss in ageing women. We examined mice with high FSH and
reduced estradiol, resembling hormonal changes in perimenopausal women. Unexpectedly, high FSH
increased, rather than decreased, bone mass. We found no evidence for direct FSH actions in bone. Combined,
our findings provide important contributions to our understanding of relevant factors controlling bone loss in
women, which is a rapidly increasing public health issue with our increasing ageing population, considering
that modern women now live half their adult life after menopause and exposed to post-menopausal disease (eg.
osteoporosis).
Expected future outcomes:
Our research into increased FSH levels and ageing is ongoing and highly relevant to understanding the factors
that control the lifespan of ovarian egg production and function, which has major significant to female fertility
and disease associated with age-related loss of ovarian function, such as osteoporosis and ovarian cancer.
Name of contact:
Charles Allan
Email/Phone no. of contact:
charles@anzac.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 512644
Start Year: 2008
CIA Name: Prof Jennifer Gamble
End Year: 2012
Admin Inst: University of Sydney
Grant Type: NHMRC Development Grants
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $335,113
Title of research award:
Development of Inhibitors of PKCzeta for Targeting Vascular LeakDevelopment of Inhibitors of PKCzeta for
Targeting Vascular Leak
Lay Description (from application):
Vascular leak (permeability) is a chief pathophysiological mechanism of many inflammatory diseases and
cancer. Effective methods of reducing vascular permeability are likely to reduce or prevent morbidity. At
present there are no potent broad spectrum inhibitors of vascular permeability. This application focuses on the
development of such inhibitors.
Research achievements (from final report):
Oedema is a major problem in many diseases such as stroke, myocardial infarcts(heart attacks) and cancer.
However there are no drugs available that can be used to specifically control this aspect of pathologies. We
have identified one molecule that is important in controlling oedema induction and which maybe a good target
for drug development. We have identified some potential lead compounds that may be further developed for
such use.
Expected future outcomes:
A drug that inhibits vascular oedema would have huge clinical potential. Our results would suggest that this
maybe possible but further work is required to bring this to fuition.
Name of contact:
Prof Jennifer Gamble
Email/Phone no. of contact:
j.gamble@centenary.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 570921
CIA Name: Prof Christopher Little
Admin Inst: University of Sydney
Main RFCD: Orthopaedics
Total funding: $448,835
Start Year: 2009
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
Novel pathways involving APC and PAR-2 in cartilage degradation in osteoarthritisNovel pathways involving
APC and PAR-2 in cartilage degradation in osteoarthritis
Lay Description (from application):
Loss of the cartilage that normally lines the ends of bones is central to joint failure in arthritis and the need for
replacement surgery. There are presently no treatments that stop cartilage breakdown in joint disease. This
project investigates the role of a new pathway not previously thought to be active in cartilage, in the
progressive damage seen in arthritis. Successful completion of these studies may provide a novel new strategy
to treat joint disease.
Research achievements (from final report):
In the cartilage of all species studied (mouse, sheep and human) we found that: proteins of the activated protein
C (APC) pathway are expressed by the cells in cartilage (chondrocytes), regulated by inflammatory factors (IL1 and TNF) and increased in chondrocytes in osteoarthritis (OA). APC can induce activation of enzymes that
breakdown key cartilage constituents, however APC does not do this directly but requires a co-factor(s), and
the effects of APC in cartilage are not associated with regulation of chondrocyte gene expression. We studied
the effect of administration of APC on cartilage degradation in OA, and far from promoting breakdown, APC
administration from 1 week after injury significantly protected against cartilage loss and underlying bone
thickening. We compared administration at different times and found that only with early and continuous APC
was OA abrogated. To investigate the mechanism whereby APC is active we used genetically-modified mice
where two cell-surface molecules potentially activated by APC are not present (PAR-1 and PAR-2 KO mice).
PAR-2 but not PAR-1 KO decreased early post-injury cartilage erosion, but neither KO had any effect on longterm effect. PAR-2 but not PAR-1 KO mice had reduced bone channge long-term. We found that neither
neither PAR-1 or -2 KO had any effect on cartilage directly and importantly neither PAR KO altered the effect
of APC. These studies not only showed that the action of APC in cartilage was not mediated by PARs, but that
the effects of PAR KO were not directly on cartilage. We have now shown that PAR-2 KO mice have
signficantly reduced synovitis and macrophage infiltration into the joint after injury, and this may explain the
early OA disease modification. These studies have shown the imortance of joint inflammation in OA, and
suggest that inhibiting this may provide a new treatment.
Expected future outcomes:
Future studies will deternine the exact inflammatory cells that are critical to OA development ater injury. These
results can then be translated into clinical trials to treat injured joints and prevent the long-term onset of OA
Name of contact:
Christopher Little
Email/Phone no. of contact:
christopher.litle@sydney.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 570942
CIA Name: A/Pr Hala Zreiqat
Admin Inst: University of Sydney
Main RFCD: Orthopaedics
Total funding: $448,017
Start Year: 2009
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
Novel coatings for orthopaedic implantsNovel coatings for orthopaedic implants
Lay Description (from application):
At present the failure rate of joint replacement is unacceptably high and will continue to rise due to the ageing
and active life styles of the baby-boomer generation, placing an increasing burden on the health budget. We
have developed a new bioactive material with improved mechanical/biological properties for bone
regeneration. We will modify the surface of the currently used orthopaedic implants with this bioactive
material to promote permanent fixation of the prosthesis to the bone.
Research achievements (from final report):
This project has provided new important information on the role surface chemistry modification of commonly
used orthopaedic implants on bone remodelling. The major finding of this study is that we describe for the first
time the development of plasma sprayed novel calcium silicate materials coated onto commonly used
orthopaedic implants (titanium alloy-Ti-6Al-4V). We found that the developed coatings possess significantly
improved bonding strength, chemical stability and cellular bioactivity compared to the currently clinically used
hydroxyapatite (HAp) coating. The chemical stability of the ceramic is an important factor influencing the
long-term stability of the coating. In this study, we found that our novel ceramics when plasma-sprayed coated
has a decreased dissolution rate compared to HAp coating, indicating that our developed novel material
possesses an improved chemical stability, compared to clinically available coatings (HAp). A major finding of
our research was that our developed material is highly bioactive inducing bone cells proliferation and
differentiation, compared to plasma-sprayed HAp coating and uncoated Ti-6Al-4V. Moreover, in vivo we
demonstrated that the novel coating induce bone formation at the skeletal tissue device interface indicating its
potential application as a coating for orthopaedic implants. , This project has the potential of developing new
implant materials with improved osseous integration. With the current rate of prosthetic failures in orthopaedic
patients unacceptably high, and with implant use growing at ~10% per annum, our new biocompatible coating
for implants will make a timely contribution to reducing patient morbidity, benefiting quality of life, and
making significant health care savings.
Expected future outcomes:
With the current rate of prosthetic failures in orthopaedic patients unacceptably high, and with implant use
growing at ~10% per annum, our new biocompatible coating for implants will make a timely contribution to
reducing patient morbidity, benefiting quality of life, and making significant health care savings.
Name of contact:
A/Prof Hala Zreiqat
Email/Phone no. of contact:
hala.zreiqat@sydney.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 570946
CIA Name: A/Pr Hong Zhou
Admin Inst: University of Sydney
Main RFCD: Endocrinology
Total funding: $443,132
Start Year: 2009
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
Osteoblast Control of Mesenchymal Progenitor Cell Differentiation: The Role of Glucocorticoids and Wnt
Signalling.Osteoblast Control of Mesenchymal Progenitor Cell Differentiation: The Role of Glucocorticoids
and Wnt Signalling.
Lay Description (from application):
Osteoporosis is an important and growing health issue. Reduced ability to make new bone is an important
cause of osteoporosis. In this project we will study how the immature cells which eventually make bone are
recruited and controlled. In particular, we will study how genes coding for important growth factors are
regulated so that the proper signals are sent to young cells to induce them to become bone-making rather than
fat-making cells.
Research achievements (from final report):
Osteoporosis is a major health issue characterized by low bone mass, decreased bone formation, increased bone
resorption and increased bone marrow adiposity. Importantly, under this age-related bone loss, there is an
inverse relationship between the number of osteoblasts and bone marrow adipocytes has been noted indicating
a switching in lineage commitments of mesenchymal progenitor (MP) cells between osteoblast and adipocytes.
Using a transgenic mouse model in which intracellular glucocorticoids are inactivated in mature osteoblasts
only - thus disrupting osteoblastic glucocorticoid signalling on a preceptor level - we have established several
novel mechanisms of key relevance to MP cell and osteoblast differentiation: 1. Mature osteoblasts are able to
directly control MP cell lineage commitment; 2. This is achieved through secretion of soluble signalling
molecules, such as Wnt proteins, by the osteoblast; 3. These signals are actively regulated by glucocorticoids
acting on the mature osteoblast; 4. Only mature osteoblasts but not immature precursor cells are capable of
responding to glucocorticoids stimulate expression of Wnt7b and Wnt10b mRNA; and 5. glucocorticoids
regulate Wnt7b and Wnt10b gene expression in a dose-dependent manner whereby low concentrations enhance
and high doses of glucocorticoids inhibit Wnt mRNA expression. These biphasic effects of GCs in regulating
Wnt expression may explain the disparate, i.e. anabolic versus catabolic actions of glucocorticoids on bone
cells. Further, knock-down of either Wnt7b or Wnt10b in osteoblasts severely impairs osteoblast
differentiation. Wnt7b appears to play an essential role in osteoblast differentiation as it is able to partially
compensate for a reduced expression of Wnt10b. In contrast, Wnt10b is also required for osteoblast
differentiation but is unable to compensate for a reduced expression of Wnt7b.
Expected future outcomes:
Our future research will determine the association between endogenous glucocorticoid signalling in osteoblasts
and age-related changes in body composition and energy metabolism. We will establish the mechanisms by
which glucocorticoids regulates ageing process and propensity to age-related diseases such as obesity and
osteoporosis development.
Name of contact:
Hong Zhou
Email/Phone no. of contact:
hzhou@anzac.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 632766
CIA Name: Prof Gustavo Duque
Admin Inst: University of Sydney
Main RFCD: Molecular Targets
Total funding: $475,515
Start Year: 2010
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
Role of Lamin A-C in Osteoblastogenesis and Age-related Bone LossRole of Lamin A-C in Osteoblastogenesis
and Age-related Bone Loss
Lay Description (from application):
Osteoporosis prevalence in Australia has increased, especially in the older population. Patients with accelerated
aging (Hutchinson Gilford) suffer from severe osteoporosis. A mutation in lamin A-C was identified as the
cause of this disease. Therefore it could be the link between aging and bone loss. We will identify the role of
lamin in bone biology. We will generate a new understanding of the connection between aging and bone loss
and a new potential therapeutic target for senile osteoporosis
Research achievements (from final report):
In this study, we looked at the role of a protein known as lamin A/C in maintaining bone and muscle health in
older persons. We discovered that lamin A/C deficiency is associated with osteoporosis and muscle loss. In
addition, we found that high levels of lamin A/C are essential to maintain good muscle and bone quality.
Expected future outcomes:
Stimulating lamin A/C production will be a potential treatment for osteoporosis, falls and fractures in older
persons in the future.
Name of contact:
Professor Gustavo Duque
Email/Phone no. of contact:
gustavo.duque@sydney.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 632767
CIA Name: Prof Gustavo Duque
Admin Inst: University of Sydney
Main RFCD: Endocrinology
Total funding: $416,008
Start Year: 2010
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
Identification of the Mechanisms of Lipotoxicity within the Bone Marrow MilieuIdentification of the
Mechanisms of Lipotoxicity within the Bone Marrow Milieu
Lay Description (from application):
Obesity and osteoporosis two major epidemics of our time. Bone and fat communicate with each other in two
different ways. A hormonal communication links bone and fat in a positive manner. In contrast, at the local
level, increasing levels of marrow fat with aging affect bone quality through the local release of toxic factors.
We will identify these factors and will assess the potential reversibility of lipotoxicity in bone, as a new
therapeutic approach to osteoporosis in the elderly.
Research achievements (from final report):
In this study, we looked at the relationship between fat and bone. Based on our results, fat and bone have a bad
interaction within the bone and therefore could be a cause for osteoporosis and fractures
Expected future outcomes:
Regulating the amount of fat within the bone will facilitate boen formation and will prevent osteoporosis and
fractures in older persons.
Name of contact:
Professor Gustavo Duque
Email/Phone no. of contact:
gustavo.duque@sydney.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 632818
CIA Name: A/Pr Hong Zhou
Admin Inst: University of Sydney
Main RFCD: Orthopaedics
Total funding: $693,185
Start Year: 2010
End Year: 2014
Grant Type: NHMRC Project Grants
Title of research award:
The Role of Endogenous Glucocorticoids in Autoimmune ArthritisThe Role of Endogenous Glucocorticoids in
Autoimmune Arthritis
Lay Description (from application):
Inflammatory joint diseases affect millions of people worldwide and in most patients these often chronic
conditions can not be cured. In an experimental model of arthritis we have found that bone cells can modify the
severity of inflammation when certain hormonal signals are blocked. This study will identify the mechanisms
underlying these hormonal effects with the aim to find new targets for efficient treatments for arthritis.
Research achievements (from final report):
At pharmacological doses, glucocorticoids (GCs) are of great benefit in the treatment of rheumatoid arthritis
and other autoimmune disorders. However, the role of endogenous GCs in autoimmune arthritis remains
unknown. In the current project, we aimed to clarify this question through investigating the effect of cellspecific disruption of endogenous glucocorticoid signalling on joint inflammation and cartilage/ bone damage.
To this aim, we established several mouse models in which glucocorticoid signalling was disrupted specifically
in either osteoblasts ("11ßHSD2 transgenic mice") or chondrocytes ("chondrocyte-specific glucocorticoid
receptor knock out mice"). , Using an experimental model of autoimmune arthritis (the so called "K/BxN
arthritis") we have found that compared to wild type animals, joint inflammation and cartilage degradation
were less pronounced in transgenic mice with disrupted osteoblastic GC signalling. Similar results were
obtained in different arthritis model, the so called "collagen antibody induced arthritis" (CAIA). In both
models, abrohgation of endogenous GC signalling in osteoblasts resulted in significnat attenuation of joint
inflammation. We therfeore conclude that osteoblasts, under the control of endogenous glucocorticoids,
modulate immune-mediated inflammatory responses. , In contrast, and quite unexpected, autoimmune arthritis
was more pronounced when glucocorticoid signalling was disrupted in chondrocytes (with intact osteoblastic
GC signalling). This data suggests that chondrocytes modulate local and systemic inflammation via a local
glucocorticoid-dependent pathway. This work has won the "Most Outstanding Abstract Award" at the 2013
Annual Scientific Meeting of the Australian New Zealand Bone & MIneral Society.
Expected future outcomes:
Our future research will determine whether osteoblasts and chondrocytes are the critical target of
pharmacological GCs in autoimmune arthritis and define the precise mechanisms that mediate their antiinflammatory effect.
Name of contact:
Hong Zhou
Email/Phone no. of contact:
h.zhou@sydney.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 632819
CIA Name: Prof Markus Seibel
Admin Inst: University of Sydney
Main RFCD: Endocrinology
Total funding: $825,254
Start Year: 2010
End Year: 2014
Grant Type: NHMRC Project Grants
Title of research award:
The Role of the Osteoblast in Mediating Glucocorticoid-Induced Metabolic DysfunctionThe Role of the
Osteoblast in Mediating Glucocorticoid-Induced Metabolic Dysfunction
Lay Description (from application):
Glucocorticoids (GC) exceed most other drugs in terms of numbers of patients treated and indications.
Preventing or attenuating the deleterious effects of GC on fuel metabolism is therefore of great clinical
significance. Our studies will create new knowledge regarding the mechanisms of GC-induced diabetes and
osteoporosis, and will contribute to the development of new approaches that are essential to tackle the pressing
medical problem of GC-induced disease.
Research achievements (from final report):
The purpose of this project was to define whether glucocorticoids at pharmacological doses induce bone loss,
obesity and dysmetabolism through targeting the osteoblast. To achieve this aim, we made use of a transgenic
mouse model in which glucocorticoid signalling is disrupted in osteoblasts only. We found that glucocorticoids
induced bone loss in wild-type animals but not in transgenic mice, indicating that both the catabolic and
anabolic skeletal actions of glucocorticoids are mediated by the osteoblast. , We then discovered that
glucocorticoid-treated transgenic mice were also protected from the well-known adverse outcomes of chronic
glucocorticoid treatment, i.e. obesity, insulin resistance, glucose intolerance, hyperlipidaemia, and fatty liver
(or in short: dysmetabolism). These results indicate that the effects of glucocorticoids on energy metabolism
are mediated through the osteoblast. , As glucocorticoids suppress the synthesis of the osteoblast-specific
product, osteocalcin, we employed gene therapy to replace this peptide through stable expression in the liver of
glucocorticoid-treated animals in vivo. We subsequently demonstrated that glucocorticoid-induced
dysmetabolism could be prevented by replacing osteocalcin in the circulation. In addition, heterotopic
expression of osteocalcin led to a significant reduction in hepatic lipid deposition and improved energy
expenditure through 'browning' of white adipose tissue. , Taken together, our data introduce the novel concept
that the effects of glucocorticoids on insulin target tissues and systemic energy metabolism are mediated, at
least in part, through the skeleton. , Our findings have created new knowledge about the primary target cells
and the mechanisms contributing to glucocorticoid-induced dysmetabolism (obesity, diabetes) and
osteoporosis.
Expected future outcomes:
Our future research will determine the molecular mechanisms by which osteocalcin counteracts the effects of
glucocorticoids on systemic energy metabolism.
Name of contact:
Markus Seibel?????
Email/Phone no. of contact:
markus.seibel@sydney.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1008282
Start Year: 2011
CIA Name: Prof Rebecca Mason
End Year: 2013
Admin Inst: University of Sydney
Grant Type: NHMRC Project Grants
Main RFCD: Medical and Health Sciences not elsewhere classified
Total funding: $467,433
Title of research award:
Novel strategies for the treatment of bone disease by nutrient activators of calcium-sensing receptorsNovel
strategies for the treatment of bone disease by nutrient activators of calcium-sensing receptors
Lay Description (from application):
Osteoporosis is a major health problem in the Australian community and will worsen with an ageing
population. This work aims to develop new strategies for the treatment of osteoporosis and associated fractures
based on the nutritional and/or pharmacological activation of calcium-sensing receptors.
Research achievements (from final report):
The study enabled us to demonstrate novel downstream pathways in bone cells activated by calcium and other
non-ionic modulators of the calcium sensing receptor. These included two new mechanisms whereby activation
of calcium sensing receptors resulted in stimulation of a pathway known to be critical in increasing bone mass.
This work has substantially added to our understanding of why the calcium sensing receptor is so important in
determining bone mass. Furthermore, the novel proteins that we have identified as being involved in this
pathway will serve as new therapeutic targets for development of additional agents to combat osteoporosis and
minimal trauma fractures.
Expected future outcomes:
New agents will be identified or developed, which target the novel bone cell pathways we have identified, to
assist with maintenance of bone mass.
Name of contact:
Rebecca S Mason
Email/Phone no. of contact:
rebecca.mason@sydney.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1011922
CIA Name: Prof Arthur Conigrave
Admin Inst: University of Sydney
Main RFCD: Endocrinology
Total funding: $508,004
Start Year: 2011
End Year: 2013
Grant Type: NHMRC Project Grants
Title of research award:
A solution to the parathyroid gland secretion problemA solution to the parathyroid gland secretion problem
Lay Description (from application):
Parathyroid hormone is the master hormone regulator of whole body calcium metabolism and a powerful new
treatment for osteoporosis but the mechanism by which its natural secretion is controlled has never been
solved. In this project we will apply new insights and advanced technical approaches to resolve this most
fundamental question of calcium homeostasis, namely how parathyroid hormone secretion is controlled.
Research achievements (from final report):
The key achievement is the demonstration that intrinsic secretion of human parathyroid hormone (PTH) is
supported by an autocrine/paracrine mechanism dependent on the synthesis and transporter-specific release of
key prostanoids mediated by parathyroid cell-specific expression of their receptors.
Expected future outcomes:
PTH secretion can be suppressed not only by activation of the parathyroid calcium-sensing receptor but also by
inhibitors of prostanoid receptors providing alternative strategies for treating various forms of
hyperparathyroidism.
Name of contact:
Arthur D Conigrave
Email/Phone no. of contact:
arthur.conigrave@sydney.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 218200
CIA Name: Prof Graeme Jones
Admin Inst: University of Tasmania
Main RFCD: Rheumatology and Arthritis
Total funding: $323,625
Start Year: 2002
End Year: 2006
Grant Type: Established Career Fellowships
Title of research award:
Genetics of OsteoarthritisGenetics of Osteoarthritis
Lay Description (from application):
Not Available
Research achievements (from final report):
This fellowship allowed an expansion of research activities in musculoskeletal disease in Tasmania
concentrating on bone development/fracture risk in children and osteoarthritis. Many key results were achieved
with 66 papers in the 5 year time frame, 3 PhD completions, appointment to full professor, appointment as
medical director of Arthritis Australia and appointment to the editotial boards of three international journals
Expected future outcomes:
Continuation of fellowship for next 5 year will allow this work to continue
Name of contact:
Graeme Jones
Email/Phone no. of contact:
g.jones@utas.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 302202
Start Year: 2004
CIA Name: Dr Adele Holloway
End Year: 2006
Admin Inst: University of Tasmania
Grant Type: NHMRC Project Grants
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $243,500
Title of research award:
Role of NF-kB recruited SWI/SNF chromatin remodeling complexes in inducible gene expression in T
cellsRole of NF-kB recruited SWI/SNF chromatin remodeling complexes in inducible gene expression in T
cells
Lay Description (from application):
The immune system consists of a group of cell types, including T cells, which are capable of recognising
foreign agents and eradicating them from the body. T cells are activated by foreign antigen and respond by
producing an array of soluble factors including cytokines, which act as communicators between cells. The
correct expression of these factors is critical for the maintenance and function of the immune system, and is
therefore tightly regulated. The genes encoding these factors are generally maintained in an 'inactive' state but
are switched on rapidly when required. Within the cell, genes or DNA are found wrapped up in a complex
protein structure called chromatin which plays an important role in regulating gene expression. Chromatin
forms a barrier to active gene expression which must be overcome before the gene can be switched on. There
are protein complexes within the cell that are able to alter or remodel chromatin structure from an 'inactive' to
an 'active' state. We are investigating one of these chromatin remodeling complexes to determine which genes
it is able to switch on and how it targets these particular genes. Aberrant gene expression within T cells
contributes to a range of diseases including certain leukemias and inflammatory conditions such as asthma and
rheumatoid arthritis. Understanding the events and protein complexes involved in switching on specific genes
in T cells will potentially identify molecules which can be targeted in an effort to control inappropriate gene
expression in these disease states.
Research achievements (from final report):
The immune system consists of groups of cells, including T cells, which are capable of recognising foreign
agents and eradicating them from the body. They do this by producing 'messenger' molecules called cytokines
that communicate between the cells. The correct expression of these cytokines is therefore critical for the
immune system to function properly, and understanding how these cytokines are produced at the correct time is
of immense interest to understanding how the immune system functions., This study investigated how the DNA
encoding a particular cytokine, GM-CSF, is packaged into cells and provided insight into how this packaging is
altered so that the cytokines can be produced in response to immune signals. We have shown that two cellular
factors (NF-kB and Brg1) are required for these alterations in DNA packaging, and particularly that Brg1 is
positioned on the DNA surrounding the GM-CSF gene, priming it so that it can be switched on rapidly in
response to immune signals. In addition we have identified other cytokine genes which appear to be controlled
in a similar fashion in immune cells, suggesting that this may be a common mechanism by which cytokine
genes are regulated and produced rapidly as required. This work has therefore identified a novel mechanism by
which cytokine genes (and possibly other genes) are primed for activation.
Expected future outcomes:
Work from this project has laid the foundation for further work characterising the regulatory mechanisms
which control expression of cytokine genes in the immune system. It is therefore likely that these studies will
lead to a better understanding of immune gene regulation in the future.
Name of contact:
Dr Adele Holloway
Email/Phone no. of contact:
A.F.Holloway@utas.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 302203
CIA Name: Prof Graeme Jones
Admin Inst: University of Tasmania
Main RFCD: Paediatrics
Total funding: $144,750
Start Year: 2004
End Year: 2005
Grant Type: NHMRC Project Grants
Title of research award:
A longitudinal study of bone development in childrenA longitudinal study of bone development in children
Lay Description (from application):
Osteoporosis is a major public health problem resulting in 50-75,000 fractures each year in Australia costing
the community about 800 million dollars per annum. Bone strength is a risk factor for fractures in both
childhood and in later life. Relatively little is known about bone development with the exception of calcium
intake and physical activity. This study will follow 500 children from birth in 1988 to 2004 with the aim of
understanding the contribution of lifestyle factors to bone development in this time period.
Research achievements (from final report):
This study followed 415 children from birth to age 16 years observing the development of healthy bones in
children. At age 8, we found that breastfeeding, smoking during pregnancy, diet during pregnancy, birthweight,
physical activity, sun exposure, asthma medication and fruit and vegetables were all associated with bone mass.
By age 16, smoking during pregnancy was no longer associated but both breastfeeding and birthweight were
suggesting an effect on peak bone mass. Diet is still being analysed. Vitamin D deficiency was common (40%)
and was associated with bone mass. Fractures were common in these children (179/415) and were predicted by
bone mass (heel ultrasound and DXA), breastfeeding, asthma medication and physical fitness at age 8. Bone
density also tracks from age 8 to age 16. This study has provided novel data on the role of lifestyle factors in
bone development in children which should lead to the development of programs to prevent fractures in both
younger and later life.
Expected future outcomes:
This work is likely to lead to prgrams which increase peak bone mass and decrease fracture risk in both early
and later life
Name of contact:
Graeme Jones
Email/Phone no. of contact:
g.jones@utas.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 302204
CIA Name: Prof Graeme Jones
Admin Inst: University of Tasmania
Main RFCD: Rheumatology and Arthritis
Total funding: $861,925
Start Year: 2004
End Year: 2008
Grant Type: NHMRC Project Grants
Title of research award:
A longitudinal study of knee osteoarthritis using X-ray and magnetic resonance imagingA longitudinal study of
knee osteoarthritis using X-ray and magnetic resonance imaging
Lay Description (from application):
Osteoarthritis is the most common form of arthritis and commonly affects the hand hip and knee in older
Australians with an annual cost of around 4 billion dollars. This study will lead to a greater understanding of
the role of factors influencing the development and progression of osteoarthritis of the knee by utilising a
novel magnetic resonance imaging technique. In particular, it will focus on the role of physical activity and
bone underlying the cartilage. If associations are discovered, accurate public health messages regarding
prevention can then be developed.
Research achievements (from final report):
The TASOAC study has led to major novel observations on the aetiology of osteoarthritis, osteoporosis,
sarcopenia and body fat. There have been 15 papers in high ranking international journals with another 15
either submitted or in preparation and many more still to be analysed. The study has led to improvements in our
understanding of the causes of knee pain with novel associations fo cartilage defects and hip X-ray changes.
Vitamin D and NSAIDs have all been linked prospectively to cartilage loss and have been developed into
clinical trial protocols. The first of these has been funded by NHMRC (605501). The role of steps per day
measured by pedometers in terms of bone mass, body fat and muscle has also been determined. Interleukin-6 (a
marker of inflammation) appears to play a key role in bone loss, knee and hip cartilage loss. Further
information on the association between osteoarthritis and osteoporosis has been obtained with both hip and
knee arthritis predicting bone loss. Collaborative work has been undertaken on genetic factors and
arthritis/bone. Bone marrow lesions have shown to have a key role in osteoarthritis being independently
associated with pain, cartilage loss over time and knee replacement. In contrast, subchondral bone density only
appears important for cartilage defects. Vitamin D levels appear to be determined by body fat, cholesterol,
muscle mass and interleukin-6 and are, in turn, important for muscle function, falls risk and bone loss with
deficiency present in about half of this random sample of 50-80 year olds. Muscle function is also determined
by statin use, sunlight exposure, steps per day in women only and many nutrients.
Expected future outcomes:
The strong observational data from TASOAC has and will be used to design interventional studies to prevent
cartilage, muscle and bone loss. Funding has recently been achieved from NHMRC to perform a trial of
vitamin D for cartilage loss. This will enable musculoskeletal prevention to have a strong evidence base.
Name of contact:
Graeme Jones
Email/Phone no. of contact:
g.jones@utas.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 435700
CIA Name: Prof Graeme Jones
Admin Inst: University of Tasmania
Main RFCD: Rheumatology and Arthritis
Total funding: $360,313
Start Year: 2007
End Year: 2011
Grant Type: Established Career Fellowships
Title of research award:
Practitioner FellowshipPractitioner Fellowship
Lay Description (from application):
I am a rheumatologist and epidemiologist who concentrates on epidemiological studies understanding the
causes and treatment of osteoarthritis and osteoporosis.
Research achievements (from final report):
This fellowship allowed the publication of over 100 papers, 10 international talks and new grants worth over 4
million dollars. During the 5 years, much new data was gleaned from epidemiological studies on causes and
time course of structural changes in osteoarthritis. In the latter period, trials of fish oil, zoledronate and 4jointz
for osteoarthritis were completed, all of which had positive outcomes. Also during this time a key trial in
rheumatoid arthritis was completed with the CI appointed principal investigator. This medication (tocilizumab)
was then listed on the PBS and useage in Australia has been substantially influenced by this trial. Work on
fracture protocols and more appropriate sun guidelines also happened during this time frame. Creation of
NHMRC GRPs for musculoskeletal conditions was also initiated successfully by the CI to attempt to address
underfunding of this national health priority.
Expected future outcomes:
This fellowship has been renewed for a further 5 years. There will be a nmber of trials demonstrating the
efficacy or otherwsie of new treatments for osteoarthritis in this time which will ease the suffering from this
very common disease.
Name of contact:
Graeme Jones
Email/Phone no. of contact:
g.jones@utas.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 605512
CIA Name: Prof Graeme Jones
Admin Inst: University of Tasmania
Main RFCD: Rheumatology and Arthritis
Total funding: $238,168
Start Year: 2010
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
A long term follow-up of the offspring cohort: a controlled study of those at higher risk of knee osteoarthritisA
long term follow-up of the offspring cohort: a controlled study of those at higher risk of knee osteoarthritis
Lay Description (from application):
Osteoarthritis is the most common musculoskeletal disorder. Despite this, relatively little is known about how
the disease develops. This study will use a powerful technique known as MRI scanning to determine the
sequence of changes over 10 years in subjects at higher risk of osteoarthritis (based on their family history) but
who do not yet have established disease on radiographs (even though many have symptoms).
Research achievements (from final report):
This study has, 1. described the rate of cartilage loss in the knee over 10 years, 2.Identified lifestyle and genetic
factors in cartilage loss, 3. Defined the role of structural abnormalities such as bone marrow lesions in cartilage
loss, 4. Defined the natural history of structural change in the knee
Expected future outcomes:
new interventions for osteoarthritis prevention in middle aged subjects
Name of contact:
Graeme Jones
Email/Phone no. of contact:
g.jones@utas.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1003437
CIA Name: Prof Tania Winzenberg
Admin Inst: University of Tasmania
Main RFCD: Rheumatology and Arthritis
Total funding: $223,156
Start Year: 2011
End Year: 2013
Grant Type: NHMRC Project Grants
Title of research award:
Investigations of strategies to address the long term maintenance of bone density in younger women: fracture
risk feedback and vitamin D.Investigations of strategies to address the long term maintenance of bone density
in younger women: fracture risk feedback and vitamin D.
Lay Description (from application):
Fractures in the elderly are an important health problem. We previously studied 470 young women, informing
them of their level of fracture risk and providing osteoporosis education. Women at higher risk more often
started calcium supplements, increased physical activity, and had higher bone density after 2 years than those
at low risk. We will test the same women after 11 years to see if these improvements persist and so might
reduce fractures in old age. We will also assess the effects of vitamin D on bone health in these women.
Research achievements (from final report):
Improvements in bone mass of major clinical and public health significance for fracture risk reduction in the
edlerly can come from incremental improvements over a period of years or even decades in younger people,
even if annual improvements are small. Therefore, studies with very long-term follow up are needed to
accurately determine the effectiveness and clinical usefulness of interventions to improve bone mass in
younger adults. Our study is unique in that it is the first to have performed such follow-up for a behavioural
intervention to improve bone mineral density (BMD) in premenopausal women. , We performed a randomised
controlled trial of two osteoporosis education interventions combined with individualised fracture risk feedback
in 470 premenopausal women over 2000-03. Women who were informed they were at high risk of fracture had
improved calcium supplement use, self-reported physical activity and BMD after 2 years compared to women
with normal fracture risk. For our recently completed study, we successfully followed up 347 of 470 women
(74%) 12 years after the original intervention undertaking comprehensive measures of bone density, lifestyle
behaviours and osteoporosis knowledge and self-efficacy as well as additional measures of vitamin D and
physical function. , To date we have shown that providing feedback of increased fracture risk can have longterm benefits for bone density, even without a structured program to reinforce the original intervention, and
that the intervention also has long-term benefits for smoking cessation and increasing calcium supplement use.
This has potential to be translated into practice to generate public health benefits.
Expected future outcomes:
We expect our results to be published in high quality international peer-reviewed journals (? 3 papers) and be
presented at important national and international bone and primary care conferences. Once this occurs, we will
pursue translation of findings into altered clinical practice around use of bone densitometry in younger women.
Name of contact:
Prof Tania Winzenberg
Email/Phone no. of contact:
tania.winzenberg@utas.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 139137
CIA Name: A/Pr Jiake Xu
Admin Inst: University of Western Australia
Main RFCD: Orthopaedics
Total funding: $196,528
Start Year: 2001
End Year: 2003
Grant Type: NHMRC Project Grants
Title of research award:
Caltrin as a calcium transport inhibitor during osteoclastic bone resorptionCaltrin as a calcium transport
inhibitor during osteoclastic bone resorption
Lay Description (from application):
Excessive bone resorption has been observed in many common bone diseases such as osteoporosis, Paget's
disease and arthritis. These are major health problems in Australia and other developed countries. Increased
activation or formation of osteoclasts is responsible for the excessive bone resorption. Understanding the
mechanisms by which the osteoclasts exert its function and activation is an important step toward developing
strategies to combat excessive bone resorption for the treatment and prevention of osteolytic disorders. This
project attempts to address the important and fundamental issue of osteoclast function. We have identified
caltrin, a known calcium transport inhibitor, that is likely to be biologically important in osteoclast calcium
homeostasis. This project intends to investigate the role of caltrin in calcium-induced apoptosis, osteoclast bone
resorption and the cellular and molecular mechanisms underlined. It will enhance our knowledge of calcium
regulation in osteoclasts and provide information to facilitate the development of new anti-resorptive agents.
Research achievements (from final report):
Osteoporosis, or porous bone, is a disease characterized by low bone mass and structural deterioration of bone
tissue, leading to bone fragility and an increased susceptibility to fractures, especially in the hip, spine, and
wrist. It is caused by an imbalance between the cells that are constantly reabsorbing (osteoclasts) and reforming
bone (osteoblasts). We have discovered a protein expressed by osteoclasts, which has the remarkable ability to
induce intracellular calcium elevation and to stimulate the proliferation of osteoblasts. This data is very
encouraging, and has been patented through the University of Western Australia. Future study is to conduct
further proof-of-concept studies, including small scale in vivo animal trials that this protein can enhance bone
formation, such a treatment for osteoporosis.
Expected future outcomes:
N/A
Name of contact:
Jiake Xu
Email/Phone no. of contact:
N/A
NHMRC Research Achievements - SUMMARY
Grant ID: 212027
CIA Name: Prof Ming Hao Zheng
Admin Inst: University of Western Australia
Main RFCD: Orthopaedics
Total funding: $226,320
Start Year: 2002
End Year: 2004
Grant Type: NHMRC Project Grants
Title of research award:
Structural and functional analyses of rat receptor activator of NF-kb ligandStructural and functional analyses of
rat receptor activator of NF-kb ligand
Lay Description (from application):
Rat RANKL (Xu & Zheng, rat RANKL, AustraliaProvisional Patent PQ3147) has a variety of biological
activities including osteoclast differentiation and polarization, and dendritic cell function. Overproduction or
increased activity of RANKL can result in excessive osteoclast formation, activation, and bone resorption.
This process contributes to many common bone lytic disorders such as osteoporosis, Paget's disease, bone
metastatic diseases, arthritis, aseptic bone loosening and non-union of fractures. This proposal addresses the
important and fundamental issue of RANKL regarding the role of molecular structure on its biological
function. We have established that the TNF-like core domain is the functional domain, important for
osteoclastogenesis, osteoclast polarisation and protecting against Fas-triggered apoptosis. This proposal will
further characterise the mutant forms of the TNF-like core domain of RANKL using site directed mutagenesis
and protein truncation analysis, and assess their respective binding activities to OPG and RANK, and their
biological activities both in vitro and in vivo. It will lead us into better understanding of the structure-function
relationship of RANKL. Ideally, we would like to develop a relative agent for the suppression of osteolysis in
orthopaedic related diseases including osteoporosis. Such an optimized molecule could become a potent
therapeutic agent that selectively inhibits osteoclast formation and bone resorption.
Research achievements (from final report):
Osteoporosis, or porous bone, is a disease characterized by low bone mass and structural deterioration of bone
tissue. Overproduction or activation of osteoclasts underlies many bone lytic disorders such as osteoporosis,
Paget’s disease, bone metastatic diseases, arthritis, aseptic bone loosening and non-union of fractures. The
receptor activator of NF-kB ligand (RANKL) is the “master cytokine” for the induction of osteoclastogenesis
and bone resorption. The binding of RANKL to its receptor RANK induces signal transduction pathways such
as NF-kB and NFAT. In this study, we have generated mutant forms of RANKL recombinant proteins and
found that they inhibit RANKL-induced osteocalstogenesis. In addition, modulation of RANKL signaling
pathway also disrupts osteoclastogenesis. Information gathered has a potential for the development of a range
of therapeutics to control bone lytic diseases such as osteoporosis and arthritis.
Expected future outcomes:
The results might be used to develop anti-resorptive agents for the treatment of osteoporosis.
Name of contact:
Ming Hao Zheng
Email/Phone no. of contact:
zheng@cyllene.uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 254565
CIA Name: A/Pr David Lloyd
Admin Inst: University of Western Australia
Main RFCD: Orthopaedics
Total funding: $431,000
Start Year: 2003
End Year: 2005
Grant Type: NHMRC Project Grants
Title of research award:
A prospective study to identify the mechanical causes and methods for early detection of knee osteoarthritisA
prospective study to identify the mechanical causes and methods for early detection of knee osteoarthritis
Lay Description (from application):
Knee osteoarthritis is a great cost to society, financially and in quality of life. Anti-inflammatory drugs are
commonly used to treat the symptoms, but many people receive joint replacements to stop pain and improve
function. We need to prevent osteoarthritis, but the causes for this common disease are largely unknown.
Animal studies have shown two particular mechanical factors that cause osteoarthritis, which are seen in the
walking and running, or gait, patterns of some people. We call these "pathological gait patterns" as they
impose larger-than-normal forces on the knee's articular surfaces. We measure these knee forces with our new
computer knee model coupled with data that we measure in a gait analysis laboratory. These forces may cause
knee osteoarthritis in humans, but this is still unknown. Currently there is no simple medical test to detect the
early onset of knee osteoarthritis. The bones in the knee are one of the first structures to show osteoarthritic
changes. Using our new computerised analysis of high definition X-ray of the knee we can identify subtle
differences in the knee due to osteoarthritis. This will be compared with changes to joint assessed using MRI.
Osteoarthritis develops slowly in normal people, so to study progression of knee osteoarthritis we need a
human population that has a higher risk of developing the disease. Partial meniscectomy in the knee is a
common surgery performed to improve knee function in those who have suffered a knee meniscus injury.
However, partial meniscectomy patients have a high risk of developing knee osteoarthritis. Therefore, using
partial meniscectomy patients we are investigating if pathological gait patterns cause knee osteoarthritis,
measuring the development of the disease with our new X-ray methods. With the gait analysis methods we can
also identify the movements that characterise these pathological gait patterns so we can formulate rehabilitation
programmes to help prevent knee osteoarthritis.
Research achievements (from final report):
Major objectives achieved 1. Retested 60 arthroscopic meniscectomy patients (APM) and 35 matched controls.
Baseline data at 3 months post surgery was collected from these people (100 APM patients and 50 controls) in
previous NHMRC grant (991134): Retesting included 3 dimensional gait analysis, x-rays and MRI of subject
knees, suite of questionnaires, knee muscle strength., 2. Assessed MRI status of the knee cartilage (cartilage
defects) at 4 years post surgery (1 paper submitted - Mills PM, Wang Y, Cicuttini FM & Lloyd DG.
Osteoarthritis and Cartilage 2007) , 3. Assessed differences in knee motion and loading in APM patients (6
conference proceedings, 1 paper in press, 1 papers submitted i) Sturnieks et al, Medicine and Science in Sports
and Exercise, 2007,, 4. Developed EMG driven model to estimate articular loading and other knee tissue
loading and apply to APM patients (4 conference proceedings, 3 papers published, 1 paper submitted - Winby
CR, Lloyd DG, and Kirk TB Journal of Biomechanics, 2007 ), 5. Developed standard atlas using fractal
analysis of bone of knee radiographs to assess knee OA status (1 conference proceedings, 1 paper in press, 1
paper submitted - Podsiadlo P, Wolski M, and Stachowiak GW Medical Physics, 2007) , 6. The framework of
the study has allowed us to continuing this work with a further NHMRC grant (334151) to assess changed in
cartilage status in APM patients, 7. The modelling and data analysis methods are applied to this current
NHMRC grant (254565) and new NHMRC grant (334151)
Expected future outcomes:
1. Fractal analysis of x-rays to assess knee OA status in APM patients., 2. Examine if knee loading in gait
causes development of pain, dysfunction, cartilage defects and radiographic knee OA in APM patients.
Name of contact:
David Lloyd
NHMRC Research Achievements - SUMMARY
Email/Phone no. of contact:
dlloyd@cyllene.uwa.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 254627
CIA Name: A/Pr Richard Prince
Admin Inst: University of Western Australia
Main RFCD: Preventive Medicine
Total funding: $272,025
Start Year: 2003
End Year: 2004
Grant Type: NHMRC Project Grants
Title of research award:
Extension of the Calcium Intake Fracture Outcome StudyExtension of the Calcium Intake Fracture Outcome
Study
Lay Description (from application):
Osteoporosis is a largely preventable disease yet 1 in 10 Australians have osteoporosis. Every year >64,000
osteoporotic fractures occur, which is one every 8.1 minutes and women are three times as likely to have the
disease than men. The Bone and Calcium Research Group at the University of Western Australia, is studying
how to prevent osteoporosis in elderly women. This study is called the Calcium Intake Fracture Outcome Study
or CAIFOS. During 1998, 1,500 women were recruited to study whether a daily calcium supplement for 5
years helps to prevent fractures compared to a diet without a supplement. To do this only half of the women
were given calcium supplements and the other half were given matched placebo tablets. Each year the study
participants are reviewed and asked whether or not they have broken any bones and have other measurements
to monitor their bone health and overall health. The subjects are entering their last year of treatment and will
finish the study during 2003. At this appointment all subjects will undergo the same series of measurements
that they had at the beginning of the study to determine whether or not they have fractured any bones,
improved their bone mass and overall health during the treatment stage. The main outcome of the study is to
determine whether calcium is useful as a supplement to prevent osteoporotic fracture in elderly women. If this
study finds that fewer women fractured in the calcium treated group compared to the non treated group, given
that both groups were similar to begin with, we can say that supplementation with calcium prevents fractures.
Thus, public health messages about preventing osteoporosis will be able to direct the community to take
supplements to prevent a disease that creates pain and disability in later life. The advantage of this study is that
it is studying other aspects of these women health, so we can determine whether the calcium is safe to use and
improves people's quality of life.
Research achievements (from final report):
The Calcium Intake Fracture Outcome Study (CAIFOS) was a 2 arm, randomized, double-blind, 5 year study
of calcium supplementation (1200mg/d) versus placebo in 1,500 women aged over 70 years. This has been the
largest population based randomized study of calcium supplementation in the world to determine whether
calcium supplementation in elderly women prevents fracture. Recruitment of 1500 women for the study was
accomplished between February and December 1998 from the WA electoral roll. The mean age of the
population at baseline was 75.1±2.7 years. The NHMRC supported this study in 2003 (final year of data
collection) and in 2004 (data analysis phase). We now able to report the fracture and bone density outcomes of
the study powered to determine whether consumption of a calcium supplement for 5 years would reduce
clinical fracture rates. The intention to treat analysis did not indicate that calcium was effective at stopping
fracture, however, in those who took calcium tablets for five years (63%) had a 33% reduction in clinical
fractures compared to those who took the placebo tablet. We also found that there was less bone lost at the
femoral neck site of the hip in those who took calcium. This was confirmed using measurements of the whole
body. We were able to determine using specialised computed tomography of the arm that those reciveing
calcium supplemntation had thicker bone which had a good effect on bone strength. This study shows that
calcium tablets are an effective and safe way of stopping bone loss and fracture for women of this age group.
This is the first study in the world to show such an important effect of calcium supplements and we aim to
publish these results in the medical literature to allow others to see the importance of calcium supplementation
as part of a public health approach to clinical fracture prevention.
Expected future outcomes:
This study shows that calcium tablets are a safe way of stopping bone loss and fracture for all women over the
age of 70 years. This important information will be used to improve the bone health of West Australian women
NHMRC Research Achievements - SUMMARY
and will form the basis of evidence based public health messages regarding prevention of fracture using a
lifestyle approach.
Name of contact:
A/Prof Richard Prince
Email/Phone no. of contact:
rlprince@cyllene.uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 254662
CIA Name: A/Pr Jiake Xu
Admin Inst: University of Western Australia
Main RFCD: Orthopaedics
Total funding: $235,500
Start Year: 2003
End Year: 2005
Grant Type: NHMRC Project Grants
Title of research award:
The role of V-ATPase accessory subunit Ac45 in osteoclastsThe role of V-ATPase accessory subunit Ac45 in
osteoclasts
Lay Description (from application):
Osteoclasts are directly related to many lytic bone disorders including osteoporosis, osteoarthritis and Paget's
diseases. Development of strategies to control the formation or activities of osteoclasts has been a major focus
of bone research. The vacuolar proton pump (V-ATPase) located on the plasma membrane of the osteoclast is
responsible for creating a low pH environment critical for bone resorption, and therefore a potential molecular
target for the discovery of novel bone antiresorptive agents useful for the treatment of lytic bone disorders.
The proposed research will give considerable insight into the role of the both V-ATPase accessory subunit
Ac45 and V-ATPase complex in osteoclasts. Understanding the molecular and cellular mechanisms by which
V-ATPases regulate osteoclast bone resorption will facilitate the development of novel and selective inhibitors
for the treatment of lytic bone disorders.
Research achievements (from final report):
Osteoclasts are the principal cells responsible for bone degradation. Overproduction and excessive activity of
osteoclasts underlines many lytic bone disorders such as osteoporosis, Paget's disease and tumor-induced bone
loss. The critical condition for the removal crystals is the use of a specific low pH in a biological
microenvironment. The vacuolar proton pump H+-adenosine triphosphatases (V-ATPases) located on the boneapposed plasma membrane of the osteoclast, are imperative for osteoclastic bone resorption, and thus serve as a
potential molecular target for the development of novel anti-resorptive agents. Discovery of specific osteoclast
V-ATPases subunits is an important and challenging area of bone research, might facilitate development of
drugs for the treatment of osteoporosis, Paget's disease, and various manifestations of skeletal cancer. The
proposed project addresses the fundamental role of the V-ATPase in osteoclast differentiation, acidification and
bone resorption. Understanding the molecular and cellular mechanisms by which V-ATPases subunits regulate
osteoclast function and bone resorption will facilitate the development of novel and selective inhibitors for the
treatment of lytic bone disorders.
Expected future outcomes:
Understanding the molecular and cellular mechanisms by which specific subunits of V-ATPase regulate
osteoclast function might facilitate the development of novel and selective inhibitors for the treatment of lytic
bone disorders, such as osteoporosis, Paget's disease, bone aseptic loosening and tumor-induced bone
destruction.
Name of contact:
Jiake Xu
Email/Phone no. of contact:
jiake.xu@uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 254743
CIA Name: Prof David Wood
Admin Inst: University of Western Australia
Main RFCD: Orthopaedics
Total funding: $307,400
Start Year: 2003
End Year: 2005
Grant Type: NHMRC Development Grants
Title of research award:
Biological, functional and radiographic evaluation of autologous chondrocyte implantationBiological,
functional and radiographic evaluation of autologous chondrocyte implantation
Lay Description (from application):
We will test the hypothesis that autologous chondrocyte implantation (ACI) and extensor realignment produces
superior clinical, biological and radiographic results when compared with conventional treatment of
realignment and debridement. We will specifically address the following aims: 1. Quantify the clinical outcome
of ACI compared to the traditionally used treatment of debridement through the use of functional evaluation in
a blinded randomised controlled clinical trial; 2. Evaluate the radiographic changes in the patellofemoral joint
that occur as a result of ACI, using high resolution magnetic resonance imaging (MRI) to quantify the
regeneration of hyaline articular cartilage; 3. Using the new technique of confocal arthroscopy, we will
compare the histologic appearances of the ACI graft and its interface with adjacent articular cartilage; 4.
Evaluate patient, surgical and explant chondrocyte characteristics in relation to functional, radiographic and
biological outcomes. With respect to the matrix-induced autologous chondrocyte implantation (MACI)
technique, we wish to clarify the clinical practice as a definitive treatment for articular cartilage defects. This
will be the first randomised, controlled clinical trial of the MACI technique compared to that used by other
groups. A positive clinical outcome from this trial will help promote the three cornerstones of this procedure –
successful cell culture, efficient surgical procedures, and complimentary postoperative rehabilitation.
Furthermore, this research will: a) Enhance the expansion of the MACI technique; b) Encourage development
of endoscopic techniques of implantation using a combination of – • Preoperative defect registration with MRI
• pre-cut custom patches, implanted with • Computer-assisted navigation techniques: c) Increase the potential
to cater for a larger number of patients requiring articular cartilage repair; d) Confirm the long-term durability
of regenerated cartilage in the 4th year and beyond; e) Add further commercial value by demonstrating MACI
may prevent the onset of osteoarthritis.
Research achievements (from final report):
1. The development of matrix induced autologous chondrocyte implantation as a recognised clinical technique
in the treatment of articular cartilage defects., 2.The reduction in invasivness surgery from a wide inscision to
arthroscopic surgery., 3. A greater understanding of the histological appearances and outcomes following
autologous chondrocyte implantation., 4. Development of best practice rehabilitation protocols, in support of
the cellular and surgical advances, to ensure the best possible patient outcomes following this procedure., 5. A
greater understanding of knee joint loading (and therefore, defect graft), during the post-surgery time course
with incremental increases in patient functioning.
Expected future outcomes:
Autologous chondrocyte implantation is now an established surgical procedure for articular cartilage defects, of
the knee. Biologically about 80% of tissue develops into hyaline chondrocytes and the rest into fibrous tissue.
Further outcomes should be aimed at improving the hyaline chondrocyte diifferentiation.
Name of contact:
David Wood
Email/Phone no. of contact:
david.wood@uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 275546
CIA Name: Prof Prue Hart
Admin Inst: University of Western Australia
Main RFCD: Cellular Immunology
Total funding: $432,750
Start Year: 2004
End Year: 2006
Grant Type: NHMRC Project Grants
Title of research award:
How IL-4 suppresses TNF and IL-1 production by activated human monocytes and macrophagesHow IL-4
suppresses TNF and IL-1 production by activated human monocytes and macrophages
Lay Description (from application):
Chronic inflammatory diseases are an enormous and growing health problem. There is a continuing search for
improved and more targeted treatments. We have been studying a cytokine called interleukin-4 which can
suppress the production by blood cells of many of the inflammatory mediators that initiate and maintain
inflammation. With the recognition that interleukin-4 has this anti-inflammatory activity on blood cells, there
was considerable optimism that this molecule may not only be a natural regulator of inflammation but also
used in immunotherapy. However we do not know how this molecule downregulates inflammatory blood
cells. It will be necessary to know this if it is to be used in human gene therapy for treatment of inflammatory
diseases. Cells must be activated before a molecule which is anti-inflammatory can be effective. Different cell
types from different inflammatory sites will be studied to better characterise different activation pathways.
How interleukin-4 regulates these pathways will be studied. Once identified, treatments based on the
properties of interleukin-4 may be designed/optimised.
Research achievements (from final report):
This grant sought to better understand how interleukin 4, a small protein produced by immune cells of the
body, could regulate inflammation. We hypothesised that interleukin 4 was part of the body's natural defence
mechanisms to prevent too strong an inflammatory response. If we better understood how interleukin 4
worked, we reasoned that it may be possible to administer interleukin 4 as part of immunotherapy without any
fear of side effects. The cells that need control in inflammation are macrophages. However to examine their
response to interleukin 4, it was necessary to infect the macrophages with a virus that allowed delivery of
potential molecules for investigation into the cells. The project therefore involved isolation of cells from human
blood or fluids drained from inflammed arthritic joints and infecting them with viruses expressing
'investigative' molecules. Although we did not determine exactly how interleukin 4 suppresses inflammation,
we learnt more about how human blood cells are activated during inflammation, and how they can be
controlled under some conditions.
Expected future outcomes:
This work will benefit patients with inflammatory diseases. Our research is particularly targetted for patients
with inflammatory arthritis as the joint is one target tissue suitable for injection of potential anti-inflammatory
agents.
Name of contact:
Professor Prue Hart
Email/Phone no. of contact:
prueh@ichr.uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 303169
CIA Name: A/Pr Richard Prince
Admin Inst: University of Western Australia
Main RFCD: Preventive Medicine
Total funding: $840,575
Start Year: 2004
End Year: 2008
Grant Type: NHMRC Project Grants
Title of research award:
Environmental and metabolic influences on musculoskeletal and other diseases in a cohort of elderly
womenEnvironmental and metabolic influences on musculoskeletal and other diseases in a cohort of elderly
women
Lay Description (from application):
Osteoporosis is a largely preventable disease yet 1 in 10 Australians have osteoporosis. Every year >64,000
osteoporotic fractures occur, which is one every 8.1 minutes and women are three times as likely to have the
disease than men. The Bone and Calcium Research Group at the University of Western Australia, has been
monitoring a cohort of elderly women for since 1998. This study is called the Calcium Intake Fracture
Outcome Study or CAIFOS. 1,500 women were recruited to study whether a daily calcium supplement for 5
years helps to prevent fractures compared to a diet without a supplement. Each year the study participants are
reviewed and asked whether or not they have broken any bones and have other measurements to monitor their
bone and cardiovascular health and cognitive function. The subjects will end the treatment phase in 2003 and
they will find out the results of the study. More than 93% are interested in being followed for a further 5 years,
where they will be contacted every 6 months and asked questions about their general health including
information on fracture, hospital visits and changes in medication use. The subjects will have a clinic visits at 2
and 5 years post treatment. With the ongoing collection of adverse event data and metabolic and environmental
data from the first phase of the study, we will be able to examine the metabolic and environmental factors that
influence musculoskeletal, cardiovascular and mental health. This is important to determine how we can
prevent disease to maintain the quality of life and independence in the elderly, a growing segment of the
population.
Research achievements (from final report):
, , The aim of this project was to determine the importance of lifestyle, genetic and physiological factors as
determinants of the disease of ageing in a cohort of 1500 older Western Australian women, whose health has
been monitored since 1998. This aim has been realised through the publication of 27 peer-reviewed journal
articles since 2004 with majority of them in high impact journals. , In particular our studies have played a
critical role in:, 1. Proving the hypothesis that genetic factors predict disease outcomes in old age in the area of
musculoskeletal and cardiovascular health. We have examined the role OPG, Klotho, TTTA repeat, BMP4,
LRP5 and calcium sensing receptor gene polymorphisms on bone and cardiovascular diseases in our study. , 2.
Proving the hypothesis that physiological, nutritional and physical activity factors predict disease outcomes in
old age in the area of musculoskeletal and cardiovascular disease. We had 12 publications in this area and
showd the improtance of calcium, vitamin D, physical activity, protein, potassium, tea dreaking and free
estradiol index in maintaining bone health in older women and also that tea drinking is associated with lower
plasma total homocysteine in older women. , 3. Proving the hypothesis that musculoskeletal symptoms predict
deleterious outcomes in old age in the area of musculoskeletal and cardiovascular disease. We have
demonstrated that daily back pain is related to a higher risk of mortality and coronary heart events. We also
evaluated the clinical utility of measured kyphosis as a predictor of vertebral deformities. , These outcomes will
play a significant role in developing guidelines and policies for healthy ageing.
Expected future outcomes:
We obtained a 5-year NHMRC grant to follow the cohort for a further 5 years and we have obtained the data
for hospital morbidity, mortality, cancer registry and emergency department since 1980 for this cohort through
the WA data linkage system. This will enable us to further examine the role of lifestyle, genetic and
physiological factors as determinants of the disease of ageing in this cohort.
Name of contact:
NHMRC Research Achievements - SUMMARY
Prof Richard Prince
Email/Phone no. of contact:
richard.prince@uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 303206
Start Year: 2004
CIA Name: Dr Daniela Ulgiati
End Year: 2006
Admin Inst: University of Western Australia
Grant Type: NHMRC Project Grants
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $466,500
Title of research award:
Transcriptional regulation of the Complement Receptor 2 gene (CR2/CD21) during B cell lineage
committmentTranscriptional regulation of the Complement Receptor 2 gene (CR2/CD21) during B cell lineage
committment
Lay Description (from application):
The complement system is a very important pathway within the human immune system. One of the receptors
within this system is complement receptor 2 or CR2. CR2 has not only been shown to be important within the
inflammatory response and defence against microbes but is also important in normal generation of a B cell
immune response . B cells not only produce antibodies against foreign organisms but in some cases
dysfunction of the B cell can bring about autoimmunity by production of antibodies against self tissues and
cells . How the CR2 gene turns on expression on different cells within the immune system is complex. The
amount of receptor on the surface of antibody producing B cells has important implications to B cell biology.
As CR2 expression is turned on at an important point within the antibody producing B cell and the levels of
this receptor can influence B cell function, understanding how this gene is regulated is important.
Research achievements (from final report):
Complement Receptor 2 (CR2) plays an important role in the generation of normal B cell immune responses.
Our work on the transcriptional control of human CR2 show that this gene is complexly regulated by the
presence of both promoter and intronic silencer elements. During the three years of this grant we have made
significant progress in further understanding the mechanisms that govern CR2 transcription. Within the
functionally important regulatory regions we have identified and characterised several novel transcription
factors. We have also analysed the transcriptional regulation of CR2 during B cell lineage development, when
CR2 expression is tightly controlled, and have successfully demonstrated that the mechanism involves both
cell-specific transcription factors but also chromatin remodelling and histone modifications. In addition, there
is now very clear evidence for CR2 playing a role in the development of Systemic Lupus Erythematosus (SLE).
To explore the role of CR2 in human SLE further, we analysed 1416 individuals from 258 Caucasian and 142
Chinese lupus simplex families and demonstrated that polymorphisms within the CR2 gene were associated
with lupus susceptibility. SNP1, located within the 5'UTR of the CR2 gene, altered transcriptional activity
suggesting a potential mechanism by which CR2 could contribute to the development of lupus. Our findings
reveal that CR2 is a likely susceptibility gene for human lupus at 1q32.2 confirming that CR2 participates in
the pathogenesis of SLE.
Expected future outcomes:
Dysregulation of CR2 expression plays a role in driving a breakdown of tolerance and promoting
autoimmunity. As the appearance of CR2 on the surface of B cells is intricately regulated at the level of
transcription, identification of factors and mechanisms that regulate this gene may result in strategies to alter
CR2 expression and modify B cell autoantibody responses.
Name of contact:
Daniela Ulgiati
Email/Phone no. of contact:
ulgiati@cyllene.uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 353626
CIA Name: Prof David Wood
Admin Inst: University of Western Australia
Main RFCD: Orthopaedics
Total funding: $141,000
Start Year: 2005
End Year: 2006
Grant Type: NHMRC Project Grants
Title of research award:
In vivo patellofemoral joint measurement using kinematic Radiostereometric Analysis (RSA)In vivo
patellofemoral joint measurement using kinematic Radiostereometric Analysis (RSA)
Lay Description (from application):
Complications following total knee joint replacement continue to be a major cause for revision surgery and
leads to a significant financial burden in terms of health care expenditure. Recent studies suggest that many of
these complications are associated with post-surgical pain from the patella knee cap joint, commonly termed
anterior knee pain (AKP). Post-surgery AKP may be influenced by the motion of the patella. Recent
prospective, randomised trials have compared clinical outcomes between people with TKA in which the
patellar surface is replaced (patellar resurfacing) or retained, but have been unable to accurately account for
differences in patellar movement in those people with post-surgery complications. To date, studies of patellar
motion after total knee replacement have been limited to two-dimensional analyses. This study addresses the
technological limitations of previous trials by utilising accurate techniques for directly measuring skeletal
motion using kinematic radiostereometric analysis (RSA). These data will measure patellar kinematics in threedimensions for the first time. This information will allow optimisation of the design of TKA and the surgical
techniques required for their implantation. Furthermore, the results will assist in the identification of surgical
indications for patellar resurfacing, and the kinematic factors associated with anterior knee pain following total
knee replacement surgery.
Research achievements (from final report):
We have established a new technique in terms of evaluating the kinematics of total knee replacements and
patellas. This technique has the potential to be adapted to other prosthetic and non prosthetic joints where
kinematic problems arise through injury or degenerative disease., , Essentially Kinematic RSA involves
insertion of tantalum beads (at least 3 in each fixed body) which can de identified using a calibrated cage with
great accuracy. Each segment identified can be tracked with an accuracy never before achieved. The
combination of these images can also be used to measure wear in total knee arthroplasty.
Expected future outcomes:
This technique may be applied to other joints and orthopaedic procedures to evaluate outcomes. For example,
cruciate ligament reconstruction maybe evaluated by this technique using the same computer program as for
total knee arthroplasty. Other algorithms will be required to evaluate other joints.
Name of contact:
Prof Bo Nivbrant
Email/Phone no. of contact:
bo.nivbrant@uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 353638
CIA Name: A/Pr Richard Prince
Admin Inst: University of Western Australia
Main RFCD: Motor Control
Total funding: $230,900
Start Year: 2005
End Year: 2006
Grant Type: NHMRC Project Grants
Title of research award:
Effects of vitamin D and calcium on bone strength, balance and falls in elderly womenEffects of vitamin D and
calcium on bone strength, balance and falls in elderly women
Lay Description (from application):
Many osteoporotic fractures occur as a result of bone fragility and falls. Both falls and fractures are huge public
health problems in Australia. Falls are the leading cause of injury-related hospitalization and death in person
older than 65 years of age. During 1996 almost 36,000 people attended a hospital after a fall and 5% of these
resulted in fracturing a bone. The incidence of fall-related hospital admission increases exponentially with age,
reaching 4% per annum for men and 7% per annum for women aged 85 years and older. In the community
approximately one third of older people fall each year. Compared to men, women are three times more likely to
be hospitalized or one and half times more likely to die from a fall-related injury. Importantly women have an
increased risk of fracture and over 40% of women over the age of 50 will break a bone. Previous European and
American studies suggest that calcium replacement may improve bone strength while vitamin D may reduce
falls. However, the separation of these two effects has never been studied. We have previously studied elderly
falling women who attended the Emergency Department of large teaching hospitals in Perth and have shown
that many are calcium and vitamin D deficient. We are undertaking a short term randomized controlled trial of
calcium alone or calcium with vitamin D, to study the effects on bone strength as measured non-invasively,
balance and falls in this high risk group of subjects. We have already recruited 100 subjects and six subjects
have completed their 6 months assessment. We plan to recruit the remaining 200 subjects during the following
12 months and give all subjects one year of treatment. At the end of this study we should be able to offer clear
treatment guidelines for this high risk group of patients.
Research achievements (from final report):
Both falls and fractures are huge public health problems in Australia. Falls are the leading cause of injuryrelated hospitalization and death in person older than 65 years of age. In this one year study, we evaluated the
effect of vitamin D and calcium supplementation compared to calcium alone on falls risk in older women at
high risk of falling. The study participants were 302 community-dwelling ambulant women aged 70-90 living
in Perth with high risk of falling due to low vitamin D status and a history of falling in the previous year. Half
of the participants received vitamin D2 1000 IU per day for one year and the other half received identical
placebo and all of them received calcium 1000 mg per day. After one year, vitamin D supplementation is
associated with 19% reduction in the risk of falling. Vitamin D supplementation has no treatment benefit on
falls reduction in summer/autumn when better vitamin D status are achieved with increased incident solar
radiation, but is associated with 23% reduction of the risk of falling in winter/spring to the same level as in
summer/autumn. Thus it is proposed that in older women living in the community at high risk of falling it
would be reasonable to aim to achieve 25-hydroxy vitamin D levels of 60 nmol/L or above to prevent the risk
of falling due to vitamin D deficiency. This has resulted in a publication in a high impact journal - Achives of
Internal Medicine ((Impact factor: 7.92; in press).
Expected future outcomes:
The findings of this study are important for the development of falls prevention guidelines and strategies in
community-dewelling older women, and thus contribute to the reduction of the incidence of falls and fractures
in this population and the associated cost.
Name of contact:
A Prof Richard Prince
Email/Phone no. of contact:
NHMRC Research Achievements - SUMMARY
rlprince@cyllene.uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 353673
CIA Name: Prof Ming Hao Zheng
Admin Inst: University of Western Australia
Main RFCD: Orthopaedics
Total funding: $276,000
Start Year: 2005
End Year: 2007
Grant Type: NHMRC Project Grants
Title of research award:
The Role of P62/A170 in Pathological Bone DestructionThe Role of P62/A170 in Pathological Bone
Destruction
Lay Description (from application):
Approximately up to 30% of patients are admitted to public hospitals in Australia for reasons related to
skeletal disorders, including trauma, osteoarthritis, osteoporosis, primary and secondary bone tumours, genetic
and metabolic disorders. Abnormal bone resorption contributes to most of these diseases and conditions.
Based on the clinical evidence of P62 mutation in patients with Paget's Disease of bone and our observation of
the involvement of P62 in RANKL-induced NF-Kb signaling, we propose that intracellular molecule P62/A172
may play an important part in the switch off/on signals necessary for bone resorbing cells to resorb bone. To
this end, we will study the molecular mechanism of P62 in action, and the interaction with its possible partners
for the facilitation of abnormal bone resorption. The clinical significance of this project is to: 1) enhance
understanding of abnormal bone resorption in Orthopaedic related diseases and conditions. 2) provide a
strategy of drug development for the treatment of these disease and conditions.
Research achievements (from final report):
The aim of this project is to study the role of p62 and p62 UBA mutants in osteocalstogenesis, pathological
bone destruction and signaling pathways related to Paget's disease of bone. , Overproduction and activation of
osteoclasts underlines many lytic bone disorders such as osteoporosis, osteoarthritis and Paget's disease.
Development of strategies to control the formation or activities of osteoclasts has been a major focus of bone
research. The RANKL-induced NF-kB pathway is critical for osteoclastogenesis and osteoclastic bone
resorption and, therefore might represent a potential molecular target for the discovery of novel bone
antiresorptive agents for the treatment of lytic bone disorders. The proposed research addresses the
fundamental role of the adapter molecule p62/A170 in RANKL-induced NF-kB activation and
osteoclastogenesis. Unraveling the molecular and cellular mechanisms by which p62 regulates osteoclast
formation and activation will significantly contribute to the field of knowledge and facilitate the development
of novel and selective inhibitors for the treatment of lytic bone disorders.
Expected future outcomes:
The outcomes of the work proposed will help us to , 1.
Elucidate the role of adapter
molecules p62/A170 in RANKL-induced activation of NF-kB and osteoclastogenesis , 2.
Understand the
role of PKC isoforms in RANKL-induced activation of NF-kB and osteoclastogenesis, either via p62
dependent or independent pathway.
Name of contact:
Jiake Xu
Email/Phone no. of contact:
Jiake.xu@uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 404065
CIA Name: A/Pr Jiake Xu
Admin Inst: University of Western Australia
Main RFCD: Orthopaedics
Total funding: $531,265
Start Year: 2006
End Year: 2008
Grant Type: NHMRC Project Grants
Title of research award:
V-ATPases subunit d2 is critical for acdification and bone resorption.V-ATPases subunit d2 is critical for
acdification and bone resorption.
Lay Description (from application):
Overproduction and excessive activity of osteoclasts underlines many lytic bone disorders such as osteoporosis,
Paget's disease and tumor-induced bone loss. The vacuolar proton pump (V-ATPase) located on the plasma
membrane of the osteoclast is critical for osteoclastic bone resorption and, therefore represents a potential
molecular target for the discovery of novel bone anti-resorptive agents. The proposed project addresses the
fundamental role of the V-ATPase in osteoclast differentiation, acidification and bone resorption.
Understanding the molecular and cellular mechanisms by which V-ATPases regulate osteoclast function and
bone resorption will facilitate the development of novel and selective inhibitors for the treatment of lytic bone
disorders
Research achievements (from final report):
N/A
Expected future outcomes:
N/A
Name of contact:
Jiake Xu
Email/Phone no. of contact:
Jiake.xu@uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 404179
CIA Name: Dr Jianping Wu
Admin Inst: University of Western Australia
Main RFCD: Instruments and Techniques
Total funding: $412,559
Start Year: 2006
End Year: 2010
Grant Type: Early Career Fellowships (Australia)
Title of research award:
Developing confocal arthroscopy for in vivo visualizing the internal microstructure of articular cartilage for
AssessingDeveloping confocal arthroscopy for in vivo visualizing the internal microstructure of articular
cartilage for Assessing
Lay Description (from application):
Not Available
Research achievements (from final report):
Osteoarthritis causes chronic pain and enormous economic expenditure. The pathogeneses is multifactorial
though osteoarthritis is defined as the degeneration of articular cartilage. Today, the effective treatment to this
syndrome is hindered by a technique that can assess the microstructure change in musculoskeletal tissues. MRI,
CT, ultrasounds and video arthroscopy used in orthopaedic diagnosis do not have sufficient imaging resolution
to detect early pathology of tissues at a microstructural level. Although traditional histology is routinely used in
the assessments of microstructural pathology of a tissue, it requires biopsy which can cause irreversible
damages to tissues with a poor self healing capability, such as articular cartilage, ligaments and tendons. The
study carried out by this NHMRC industry fellowship has developed confocal arthroscopy, which permits
studying the microstructure of articular cartilage, ligament and tendon at real time. The confocal arthroscopy
has successfully acquired the microstructure of articular cartilage, ligaments and tendons using a clinical grade
fluorescein contrast agent. Studies carried out by use of this technique have shown it can effectively detect
early osteoarthritis such as chondrocyte hypotrophy and clustery, and tendinopathy such as rounding of
tenocytes and collagen fragment and misalignment.
Expected future outcomes:
The techniques developed in this project will eventurally play a role of optical histology in orthopaedics for
early OA and tendinopathy diagnosis, assessing the efficacy of cellular therapies and drug treatments in
restoration of the microstructure of musculoskeletal tissues, mornitorting in vivo microstrain of a cell
experienced as means of understand cell biomechanics.
Name of contact:
Jianping Wu
Email/Phone no. of contact:
wping@mech.uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 458608
CIA Name: Dr Gina Ambrosini
Admin Inst: University of Western Australia
Main RFCD: Epidemiology
Total funding: $167,707
Start Year: 2007
End Year: 2008
Grant Type: NHMRC Project Grants
Title of research award:
Long Term Supplementation with Retinyl Palmitate (Vitamin A) and the Risk of Bone Fractures: A population
based study.Long Term Supplementation with Retinyl Palmitate (Vitamin A) and the Risk of Bone Fractures:
A population based study.
Lay Description (from application):
Osteoporosis is a major health problem in Australia and other western industrialised countries where
populations are increasingly ageing. In Australia, the number of hip fractures is expected to increase by 36%
between 1996 and 2006, owing to the rise in elderly aged 85 years and over. This is in contrast to projections
in Europe and North America, where the number of hip fractures are expected to double by 2026 and then
stabilise. Clarification of the role of vitamin A in bone health is pertinent, given that the popularity of
supplement use has increased markedly in western industrialised countries over the past two decades. Around
37% of the adult population in Australia is thought to take a supplement regularly and figures range from 28%
to 54% of adults in the US, with women and adults aged over 49 years being more likely to use supplements.
Furthermore, the fortification of food with minerals and vitamins is increasing. For all of these reasons, is it
imperative that the role of vitamin A in inducing fractures be clarified. Results from this study will contribute
to knowledge about the safety of retinol and beta carotene supplements in relation to bone health, which is
especially relevant to people at risk of osteoporosis, and people who take vitamin A supplements. We will also
be able to clarify the upper levels of dietary retinol, beta carotene and vitamin A intake beyond which fracture
risk increases. Because of the age range of subjects in our study, our results should be applicable to the whole
population, not only the elderly or post menopausal. The results of our study will be useful to agencies such as
Food Standards Australia and New Zealand which regulates our food supply.
Research achievements (from final report):
Earlier studies have suggested that the risk of bone fractures is greater among people taking Vitamin A
supplementation. This project examined the risk of bone fractures among participants of a cancer prevention
program taking long term supplementation with Vitamin A. A strength of this study was that Vitamin A and
fracture risk was examined in two ways (1) the level of vitamin A in blood plasma and (2) the amount of
Vitamin A taken as a supplement. In summary, risk of any fracture or any osteoporotic fracture was not
associated with either the level of vitamin A in blood plasma or the amount of supplement taken.
Expected future outcomes:
N/A
Name of contact:
Dr Gina Ambrosini
Email/Phone no. of contact:
Gina.Ambrosini@mrc-hnr.cam.ac.uk
NHMRC Research Achievements - SUMMARY
Grant ID: 458625
CIA Name: A/Pr Richard Prince
Admin Inst: University of Western Australia
Main RFCD: Endocrinology
Total funding: $478,947
Start Year: 2007
End Year: 2009
Grant Type: NHMRC Project Grants
Title of research award:
Dietary protein effects in elderly women: musculoskeletal, renal, cardiovascular and body composition
endpointsDietary protein effects in elderly women: musculoskeletal, renal, cardiovascular and body
composition endpoints
Lay Description (from application):
Fractures and falls of the elderly are major health problems in our community in terms of disability and cost. It
is critical to the future health of our aging population to develop non-pharmaceutical interventions to maintain
health into old age. Epidemiologic studies have shown that relatively high protein intake is associated with
increased bone mineral mass and reduced incidence of osteoporotic fracture in elderly people. Low protein
intakes can lead to loss of muscle mass. To date there have been no randomised trials of sufficient duration to
examine the effects of increased dietary protein intake on bone and muscle health of the elderly. The aim of
this study is to examine the effectiveness of protein supplementation for the prevention of osteoporosis and
muscle wasting in elderly women, and the safety of such an intervention through monitoring renal function and
risk factors for cardiovascular disease. Two hundred and twenty women will be recruited to this study and be
assigned to protein group or placebo group. Women in the protein group will received 250 ml high protein
drink (containing 30 g protein) per day and women in the placebo group will receive placebo drink containing
the same amount of energy, calcium but no additional protein. Bone structure, muscle mass, body composition,
renal function and risk factors for cardiovascular disease will be monitored during the 2 year study period. The
results of this randomised, controlled study will clarify the role of protein on bone mass and structure, muscle
mass and body composition in the elderly. At the same time, the safety of such intervention on renal and
cardiovascular endpoints will also be evaluated. It is envisaged that the results of this study if positive will
translate into both immediately applicable intervention strategies that are relevant at a program and an
individual level.
Research achievements (from final report):
The protein intake metabolic effects study (PIMES) is a 2-year double-blind placebo controlled trial deigned to
determine the effects of protein supplementation on bone structure and muscle mass and to examine the safety
of such intervention. This aim has been realised through the successful recruitment of 219 community-dwelling
women aged 70-80 years into the study, the development and delivery of study drinks, and the successful
completion of the 2-year study with 180 subjects attended the final visit. In particular out study is the first longterm clinical trial with sufficient sample size to examine the effects of increased protein intake on bone and
mascle health in older women. Our study plays a critical role in demonstrating that in healthy ambulant women
with baseline protein intake above current Estimated Average Requirement of 0.75g/kg body weight/day
recommended by NHMRC (1.14±0.33 g/kg body weight/day), extra protein was not a critical beneficial or
deleterious regulator of their bone mass, muscle mass and renal function. ,
Expected future outcomes:
Several papers based on the findings of this study on the effects of protein supplementation on bone, muscle
and metabolic endpoints are in preparation and will be submitted for publication. This will contribute to the
current knowledge on the effects of extra dietary protein on health of older people.
Name of contact:
Prof Richard Prince
Email/Phone no. of contact:
richard.prince@uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 458765
CIA Name: Prof Ming Hao Zheng
Admin Inst: University of Western Australia
Main RFCD: Orthopaedics
Total funding: $391,510
Start Year: 2007
End Year: 2009
Grant Type: NHMRC Project Grants
Title of research award:
Interaction of Rab3D and Tctex-1 is required for bone resorption through the regulation of post-TGN vesicle
traffickingInteraction of Rab3D and Tctex-1 is required for bone resorption through the regulation of post-TGN
vesicle trafficking
Lay Description (from application):
Osteoclasts are multinucleated cells responsible for the breakdown/resorption of bone tissue. Elevated
osteoclast numbers and/or activities is a major hallmark of a number of debilitating Orthopaedic-related
diseases including osteoporosis, arthritis, bone cancer and aseptic loosening. Among these, osteoporosis is
endemic in Western society with an estimated 1 in 2 women and 1 in 3 men sustaining a fracture in their
lifetime. It is well accepted that the transport of carrier vesicles containing bone destructive enzymes is
critical for bone resorption by osteoclasts. Although vesicle transport has been shown to be associated with
microtubules (the cells skeleton), the molecular mechanisms responsible for vesicle and microtubule
interaction are largely unknown. We have identified a novel interaction between Rab3D, a vesicle transport
molecule, with Tctex-1, a microtubule-binding protein. We propose that the binding of Rab3D to Tctex-1 in
osteoclasts is essential for the interaction of vesicles with microtubules and, hence, osteoclast function. The
focus of this project is to further confirm our hypothesis by analysing the importance of this interaction in
osteoclast-mediated bone resorption. The anticpated outcomes of the proposed project are: 1) Rab3Dmediated vesicle transport is directed via the microtubule network; 2) Interaction between Rab3D and Tctex-1
is cruical for the coupling of Rab3D-mediated vesicle transport to the microtubules; and 3)Disruption of the
Rab3D-Tctex-1 interaction may impair bone resorption. Understanding the molecular mechanisms which
regulate osteoclastic vesicle trafficking might therefore enable us to develop new strategies to specifically
target and inhibit breakdown of bone tissue.
Research achievements (from final report):
Osteoclasts are large multinucleated cells responsible for the physiological resorption of bone. Excessive bone
resorption is a pathological hallmark of several debilitating bone diseases among which osteoporosis is
endemic in western society. The bone resorption process requires tight coordination between carrier vesicles
and microtubules, however, the molecular mechanisms involved remain unclear. The aims of this project were
therefore to characterise a novel interaction between Rab3D (a regulator of vesicle transport) and Tctex-1 (a
microtubule motor protein) and its contribution toward the function of bone resorption by osteoclasts. Our
findings indicate that interaction between Rab3D and Tctex-1 bridges the interface between carrier vesicles and
the microtubule network. Furthermore, disruption of Tctex-1 function impairs the ability of osteoclasts to
resorb bone, attesting to the notion that components of the Rab3D transport machinery are required for bone
resorption. Understanding the molecular mechanisms of intracellular transport in osteoclasts offers the exciting
potential of identifying new and specific therapeutic targets for the treatment and alleviation of bone loss.
Expected future outcomes:
It is anticipated that this work will provide the foundation to build future NHMRC projects exploring the
precise functional role of Tctex-1 in bone-resorbing osteoclasts through the generation of specific mouse
knockout models
Name of contact:
W/Prof. Ming-Hao Zheng
Email/Phone no. of contact:
minghao.zheng@uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 513724
CIA Name: Dr Ian Dick
Admin Inst: University of Western Australia
Main RFCD: Endocrinology
Total funding: $237,708
Start Year: 2008
End Year: 2011
Grant Type: NHMRC Project Grants
Title of research award:
Functional effects of polymorphic variation of the aromatase (CYP19) gene on enzyme activity:relationship to
diseaseFunctional effects of polymorphic variation of the aromatase (CYP19) gene on enzyme
activity:relationship to disease
Lay Description (from application):
After menopause, oestrogen synthesis changes from an ovarian to an adipose source by concersion of
androgens to estrogens, a process catalyzed by aromatase, the product of the CYP19 gene. We will generate
mutants of the CYP19 gene that we have previously found in humans by site-directed mutagenesis and observe
the effects of these mutants on aromatase function. This research will help with diagnosis and treatment of
breast and other cancers and osteoporosis in humans .
Research achievements (from final report):
, The work conducted under this grant has involved deciphering the key components of variation responsible
for enzyme activity within the aromatase gene and applying it back to a well characterised population to
examine the phenotype/genotype relationship. , , Initially studies showed that wild-type aromatase
demonstrated substrate inhibition by androstenedione which, although well recognised for other P450-mediated
reactions has not previously been reported for CYP19A1.
Expected future outcomes:
N/A
Name of contact:
Joshua Lewis
Email/Phone no. of contact:
joshua.lewis@uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 513832
CIA Name: Prof Jiake Xu
Admin Inst: University of Western Australia
Main RFCD: Orthopaedics
Total funding: $424,189
Start Year: 2008
End Year: 2010
Grant Type: NHMRC Project Grants
Title of research award:
Regulation of osteoclast differentiation and function by the PKC pathway.Regulation of osteoclast
differentiation and function by the PKC pathway.
Lay Description (from application):
Developing strategies to control the formation of osteoclasts which underlines many disorders such as
osteoporosis and osteoarthritis has been a major focus of bone research.The proposed research examines the
fundamental role of Protein Kinase C (PKC) in bone resorption.This work will help elucidate the role of PKC
in osteoclast formation;define the physiological role of PKC in bone structure and bone resorption in vivo and
develop the treatment of bone disorders.
Research achievements (from final report):
1) The project increases our understanding in the regulation and function of osteoclasts by PKC delta and its
signalling molecules, thus advancing our scientific knowledge., 2) The information generated will assist future
development of anti-resorbing agents to treat osteolytic bone diseases., 3) The project helps to train up
postdoctoral research fellows and graduate students., 4) The project has resulted in publications that help to
disseminate the updated knowledge in osteoclasts and bone biology.
Expected future outcomes:
The scientific knowledge regarding the role of PKC delta in osteoclasts and bone biology will be advanced.
The information gathered will help to develop novel PKC delta inhibitors for the potential treatment of
osteolysis, including cancer-induced bone loss.
Name of contact:
Jiake Xu
Email/Phone no. of contact:
jiake.xu@uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 513869
CIA Name: Prof Thomas Ratajczak
Admin Inst: University of Western Australia
Main RFCD: Endocrinology
Total funding: $480,212
Start Year: 2008
End Year: 2010
Grant Type: NHMRC Project Grants
Title of research award:
IMMUNOPHILINS IN STEROID RECEPTOR- AND TISSUE-SPECIFIC ACTIONS: IMPLICATIONS FOR
TREATMENT OF STEROID-BASED DISEASEIMMUNOPHILINS IN STEROID RECEPTOR- AND
TISSUE-SPECIFIC ACTIONS: IMPLICATIONS FOR TREATMENT OF STEROID-BASED DISEASE
Lay Description (from application):
To convert steroid hormone signals in the cell steroid receptors rely on Hsp90 molecular chaperone machinery
that is essential for receptor function and in particular 'helper' cohaperones that form part of receptor- Hsp90
complexes and fine-tune receptor responses to hormone. The present study addresses the fundamental role of
the receptor "helper' chaperone cyclophilin 40. Our study may have important implications for the treatment of
steroid-based disease.
Research achievements (from final report):
To convert steroid hormone signals in cells steroid receptors rely on their association with heat shock protein
90 (Hsp90) molecular chaperone machinery, that is essential for receptor function, and in particular, so-called
"helper" cochaperones that form part of receptor-Hsp90 complexes and fine-tune receptor responses to
hormone. To begin to address the fundamental role of the Hsp90 "helper" cochaperone, cyclophilin 40 (CyP40)
our research has generated knockout mice that don't express CyP40. An evaluation of the phenotype of these
mice and examination of receptor activity in specific tissues and cells derived from the animals will provide
important insights into the selective role CyP40 may play in the function of specific receptors. Since CyP40
was first isolated with estrogen receptor-Hsp90 complexes, we anticipate the CyP40-deficient phenotype will
reveal a loss of some estrogen-regulated processes. It may also define a role for CyP40 in the tissue-specific
activities of the androgen receptor. Indeed, our study has observed a decrease in estrogen receptor activity with
CyP40 depletion in MCF-7 breast cancer cells. Identification of specific contacts that occur between steroid
receptors and "helper" cochaperones may identify unique ways of controlling receptor function. Such
interactions may be dependent on the conformation of the receptor ligand-binding domain, which can be
modified by different ligands. Using bioluminescence resonance energy transfer (BRET) analysis for
monitoring protein-protein interactions we have observed a constitutive BRET signal for androgen receptor
interaction with the "helper" cochaperone FKBP52, which is known to be important for androgen receptor
function.
Expected future outcomes:
Our research has provided a mutant mouse model for the Hsp90 "helper" cochaperone, CyP40. These animals
and cells generated from them will be used for assessing the physiological role of CyP40 in general and
specifically its role in modulating steroid hormone action through steroid receptors.
Name of contact:
Professor Thomas Ratajczak
Email/Phone no. of contact:
tom.ratajczak@uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 572604
CIA Name: A/Pr Kun Zhu
Admin Inst: University of Western Australia
Main RFCD: Endocrinology
Total funding: $869,724
Start Year: 2009
End Year: 2013
Grant Type: NHMRC Project Grants
Title of research award:
Determinants of musculoskeletal and other diseases, health service utilisation and mortality in a cohort of older
womenDeterminants of musculoskeletal and other diseases, health service utilisation and mortality in a cohort
of older women
Lay Description (from application):
This longitudinal study aims to identify determinants of musculoskeletal and cardiovascular diseases, cognitive
decline, mortality and health service utilisation with ageing in a cohort of well-characterised older women,
whose health has been monitored since 1998. This study is unique in that it will have followed patients from
mean age 75 to 90 years with longitudinal clinical data collected and complete ascertainment of health service
utilisation through the WA Data Linkage System.
Research achievements (from final report):
The aim of this project was to determine the importance of lifestyle, physiological measures, performance
measures, and genetic factors as determinants of the health outcomes in a cohort of 1,500 older Western
Australian women, whose health has been monitored since 1998. This aim has been realised through the
publication of 26 peer-reviewed journal articles since 2009 with majority of them in high impact journals. , In
particular our studies have played a critical role in:, 1. Proving the hypothesis that nutrition, physical
performance and physiological factors predict disease outcomes in old age in the area of musculoskeletal
disease. We had 7 publications in this area and showed the importance of adequate intake of dairy, protein and
potassium intake in maintaining bone health in older women, and the negative influence of homocystine on
bone. We are the first to show that physical performance as measured by the Timed Up and Go test is a
predictor of fracture in older women, and to study the predictors of knee replacement. , 2. Providing important
evidence that oral calcium supplementation do not increase the risk of atherosclerotic vascular disease in older
women. We had 3 publications in this area. , 3. Proving the hypothesis that physiological and nutritional factors
predict disease outcomes in old age in the area of cardiovascular disease. We had 4 publications in this area and
showed that the decline in estimated glomerular filtration rate and elevated osteoprotegerin concentrations are
associated with increased cardiovascular disease risk, whereas chocolate intake and yogurt intake are
associated reduced risk. , 4. Proving the hypothesis that genetic factors predict bone quality and fracture, and
participated in the genome-wide association study on determinants of osteoporotic fracture, bone density and
heel bone properties. We had 5 publications in this area.
Expected future outcomes:
We have recently obtained 15 years hospital morbidity and mortality data in this cohort via the Western
Australia Data Linkage System. Therefore, further publications in the areas for determinants of fracture,
cardiovascular disease, cancer and mortality are expected from this cohort study.
Name of contact:
Kun Zhu
Email/Phone no. of contact:
kun.zhu@uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 572638
CIA Name: Prof David Joyce
Admin Inst: University of Western Australia
Main RFCD: Respiratory Diseases
Total funding: $270,013
Start Year: 2009
End Year: 2011
Grant Type: NHMRC Project Grants
Title of research award:
Macrophage uncoupling protein-2 regulation and expression in inflammatory joint disease and hyperoxic lung
damageMacrophage uncoupling protein-2 regulation and expression in inflammatory joint disease and
hyperoxic lung damage
Lay Description (from application):
Oxygen radicals (OR) are made by white blood cells (WBC) when they protect against microbes and cancer
cells. However, excessive production also damages normal tissue, for example in lungs that receive too much
oxygen (hyperoxic lung damage) or in inflamed joints. One type of WBC, the macrophage has a protein named
UCP2, that limit the amount of OR formation. This project aims to find out how macrophages activate UCP2
and whether they do so in inflammatory arthritis and hyperoxic lung damage.
Research achievements (from final report):
The body sends macrophages to some sites of infection, inflammation or tissue damage, to defend and repair.
There, they need oxygen and nutrients for energy. These may be limited in infected or damaged tissue, but
macrophages are equipped to gain energy from a range of nutrients. In the process of oxidising nutrients for
energy, macrophages produce oxygen radicals (reactive oxygen species: ROS) from cell mitochondria. ROS
assist in clearing some infectants, but can also damage cell components. Macrophages can mount a protective
response to ROS. In the work funded by this grant, we have examined situations where macrophages are under
particular ROS stress, in the clinical conditions of hyperoxia-associated lung injury (HALI) and endotoxaemia
caused by gram-negative bacteria. We found that macrophages responded in each condition by expressing
uncoupling protein-2 (UCP2) in mitochondria, which served to contain mitochondrial ROS generation. In
HALI, we found evidence that ROS themselves initiated UCP2 expression. In endotoxaemia models, it
depended on one hallmark product of the M1 differentiated macrophage, nitric oxide (NO), and was part of a
wider adaptation in energy metabolism. M1 macrophages are especially good at immune function. In each case,
control was post-transcriptional and UCP2 appeared and disappeared within hours. UCP2 was not found in
joint macrophages of mice with chronic inflammatory collagen arthritis, implying that UCP2 expression is a
sudden, brief response in macrophages and is not required later in the chronic joint inflammatory condition.
Understanding early protective, phenotype-restricted events in macrophages may reveals means to modulate
their activity in disease.
Expected future outcomes:
We will explore whether UCP2 expression makes macrophages better at immune functions, more resistant to
ROS damage or more likely to retain M1 phenotype or adopt an alternative M2 phenotype. We are also
exploring UCP2 regulation, observing links to central controllers of energy metabolism, including mTOR and
AMP-kinase in macrophages.
Name of contact:
David A Joyce
Email/Phone no. of contact:
david.joyce@uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 572670
CIA Name: Prof Minghao Zheng
Admin Inst: University of Western Australia
Main RFCD: Orthopaedics
Total funding: $671,613
Start Year: 2009
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
The interaction of Ac45 with V-ATPase and its function in osteoclastic bone resorptionThe interaction of Ac45
with V-ATPase and its function in osteoclastic bone resorption
Lay Description (from application):
Osteoporosis is a disease characterized by low bone mass and structural deterioration of bone tissue, leading to
bone fragility and increased susceptibility to fractures. Of concern is osteoporotic fractures in the elderly are
linked with increased mortality rates. Also, diseases associated with excess bone resorption place significant
financial burden on the health care systems. We will examine the role of proton pump in bone resorption as a
potential target for the treatment of osteoporosis.
Research achievements (from final report):
Osteoporosis and related osteolytic diseases are largely attributed to the overactivation of bone-resorbing
osteoclasts (OCs). The exclusive ability of OCs to resorb bone requires the ongoing secretion of acid to
dissolve mineralized bone matrix. The V-ATPase proton pump, located on the bone-apposed ruffled border
membrane of OCs is an established prerequisite for proton secretion and bone homeostasis. We have
previously demonstrated that V-ATPase accessory subunits Ac45 is differentially expressed in OCs and its
cytoplasmic tail is required for efficient bone resorption. The aims of this project was to further characterize the
role of Ac45 in the OC differentiation, acidification and bone resorption, and physiological relevance of Ac45
in bone homeostasis. Our findings indicate that Ac45 is required for V-ATPase-mediated acidification and
endocytosis, both are prerequisites for OC-mediated bone resorption. Ac45 was also found to be required for
OC formation, with knockdown of Ac45 attenuating RANKL-induced osteoclastogenesis owing to a reduced
fusion capacity of OC precursor cells. Our initial attempt to generate OC-specific Ac45 conditional knockout
(cKO) mice resulted in early embryonic lethality of Ac45-floxed mice as a consequence of marked
disturbances in CNS development. This unexpected outcome was due to the neomycin cassette interfering with
the expression of Ac45 during embryonic development. A revised strategy was developed which led to the
successful generation of OC-specific Ac45 cKO mice. Understanding the molecular and cellular interplay with
which V-ATPase subunits regulate OC formation and function offers exciting potential for the development of
novel and selective inhibitors for the treatment of osteolytic diseases.
Expected future outcomes:
This work will provide further structural and functional insights into the molecular mechanism governing VATPase-mediated OC functions, and provide the foundation to build future NHMRC projects that explore other
yet-to-be characterized V-ATPase subunits in bone homeostasis.
Name of contact:
Prof. Ming Hao Zheng
Email/Phone no. of contact:
minghao.zheng@uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 572671
CIA Name: Prof Jiake Xu
Admin Inst: University of Western Australia
Main RFCD: Orthopaedics
Total funding: $605,123
Start Year: 2009
End Year: 2011
Grant Type: NHMRC Project Grants
Title of research award:
The role of the secreted SVS7 protein in bone HomeostasisThe role of the secreted SVS7 protein in bone
Homeostasis
Lay Description (from application):
Osteoporosis is a disease characterized by low bone mass and structural deterioration of bone tissue leading to
bone fragility and an increased susceptibility to fractures caused by imbalance between cells that are constantly
reabsorbing and reforming bone. The cost to society with our aging population and individuals who become
disabled by hip fractures could triple by the year 2040.The proposed project studies a novel factor that controls
bone mass. Its potential is for therapeutic treatment.
Research achievements (from final report):
1) The project increases our understanding in the regulation and function of SVS7 in bone biology, thus
advancing our scientific knowledge., 2) The information generated will assist future development of
therapeutic agents to treat osteolytic bone diseases; including osteoporosis. , 3) The project helps to train up
postdoctoral research fellows and graduate students., 4) The project has resulted in publications that help to
disseminate the updated knowledge in bone biology.
Expected future outcomes:
The scientific knowledge regarding the role of SVS7 in bone biology will be advanced. The information
gathered will help to develop the potetnial use of SVS7 for treatment of osteolysis, including cancer-induced
bone loss.
Name of contact:
Jiake Xu
Email/Phone no. of contact:
jiake.xu@uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 634511
CIA Name: Prof Jiake Xu
Admin Inst: University of Western Australia
Main RFCD: Orthopaedics
Total funding: $565,695
Start Year: 2010
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
The role of CHKB in osteoclastic bone resorption and bone homeostasisThe role of CHKB in osteoclastic bone
resorption and bone homeostasis
Lay Description (from application):
Osteoporosis is a devastating disorder. Osteoporotic fractures in the elderly have been correlated with increased
mortality rates. Osteoporosis alone costs $13.8 billion p.a. in USA and tens of millions of dollars in Australia.
Cost to society of our ageing population for people become disabled by hip fractures alone could triple by the
year 2040. Our research examines the role of CHKB in bone loss which may underscore its potential as a new
molecular target for anti-resorptive drug development.
Research achievements (from final report):
The maintenance of bone homeostasis requires tight coupling between the bone-forming osteoblasts and boneresorbing osteoclasts. However, the precise molecular mechanism(s) underlying the activities of these
specialized cells are still largely unknown. In search of novel molecules involved in bone homeostasis, we
systematically screened a number of ENU-induced mutant mouse lines. Here we identify choline kinase beta
(CHKB), a kinase involved in the biosynthesis of phosphatidylcholine, as a novel regulator of bone
homeostasis. Choline kinase beta mutant mice (flp/flp) exhibit a systemic low bone mass phenotype
comparable to osteoporosis. Consistently, osteoclast numbers and activity are elevated in flp/flp mice.
Interestingly, osteoclasts derived from flp/flp mice exhibit reduced sensitivity to excessive levels of
extracellular calcium, a feature that allows them to persist at sites of bone resorption. Conversely,
supplementation of CDP-choline (Cytidine 5'-diphosphocholine) in vivo and in vitro, a regimen which
bypasses CHKB deficiency, restores osteoclast numbers to physiological levels. Finally, we demonstrate that,
in addition to modulating osteoclast formation and function, a loss of CHKB also corresponds with a reduction
in bone formation by osteoblasts. Taken together, these data posit CHKB as a new modulator of bone
homeostasis.
Expected future outcomes:
We have indentified that choline kinase beta (CHKB), a kinase involved in the biosynthesis of
phosphatidylcholine, is a novel regulator of bone homeostasis. This information is useful for the design of drug
treatment for osteolytic diseases; including osteoporosis, paget's disease of bone, and tumor-induced bone loss.
Name of contact:
Jiake Xu
Email/Phone no. of contact:
jiake.xu@uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1010256
Start Year: 2011
CIA Name: Prof Jiake Xu
End Year: 2013
Admin Inst: University of Western Australia
Grant Type: NHMRC Project Grants
Main RFCD: Medical and Health Sciences not elsewhere classified
Total funding: $479,507
Title of research award:
Roquin plays a critical role in bone homeostasisRoquin plays a critical role in bone homeostasis
Lay Description (from application):
Osteoporosis, or porous bone, is a disease characterized by low bone mass and structural deterioration of bone
tissue, leading to an increased susceptibility to fractures. Understanding the nature of bone loss may lead to the
discovery of a new drug target for the treatment of osteoporosis..
Research achievements (from final report):
Pathological bone loss induced by excessive osteoclast formation is the major mechanism underlying many
debilitating bone diseases, including osteoporosis, Paget's disease, lupus, and aseptic loosening of orthopaedic
implants. A better understanding of the underlying cause of bone destruction? as well as molecules involved is
vital for an improved therapeutic strategy against osteolytic bone diseases. To gain insights into the molecular
genetics and mechanisms of bone loss, we have screened for bone phenotypes in chemical (ENU)-induced
mutant mice to identify key molecules that regulate bone homeostasis. We have uncovered one mouse line
(namely sanroque) which carries a M199R mutation in the roquin gene, and exhibits severe bone loss. We
show that the Roquin mutant mice display 1) substantial bone loss with reduced trabecular and cortical bone
volume; 2) an increase of TRACP positive cells ex vivo and osteoclastogenesis in vitro; 3) an increase of
RANKL gene expression in T cells. These intriguing and novel observations indicate that Roquin plays a
critical role in bone homeostasis by intrinsic and extrinsic mechanisms. , ?????
Expected future outcomes:
1) Understand the intrinsic mechanism of bone loss in Roquin mutant mice. , 2) Understand the physiological
role of Roquin in osteoclast differentiation, bone resorption, and osteoblasts, and the molecular regulation of
Roquin in RANKL signaling pathways?, 3) Understand the extrinsic mechanism of bone loss in Roquin mutant
mice via activated T cells in osteoimmunology?????
Name of contact:
Jiake Xu
Email/Phone no. of contact:
jiake.xu@uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1010420
CIA Name: Prof Jiake Xu
Admin Inst: University of Western Australia
Main RFCD: Orthopaedics
Total funding: $562,816
Start Year: 2011
End Year: 2013
Grant Type: NHMRC Project Grants
Title of research award:
Molecular Mechanisms and Therapeutic Effects of Novel Parthenolide Analogs on OsteolysisMolecular
Mechanisms and Therapeutic Effects of Novel Parthenolide Analogs on Osteolysis
Lay Description (from application):
Rheumatoid arthritis and osteoporosis are common bone diseases with features of bone loss. Drugs that inhibit
bone loss are needed for the prevention and treatment of bone diseases. The proposed research explores the
potential use of novel herbal inhibitors for the suppression of bone resorbing cells, and their potential as
treatments for bone loss.
Research achievements (from final report):
Pathological bone destruction by the osteoclast is a characteristic of many bone diseases such as rheumatoid
arthritis, osteomyelitis, septic arthritis and periodontitis-related bone loss. These disorders are major bone and
joint diseases in Australians. Drugs that inhibit osteolysis are critically needed for the prevention and treatment
of bone loss by osteoclasts. ,
Development of strategies to control
the formation or activities of osteoclasts has been a major focus on the suppression of osteolysis. The proposed
research explores the potential use of novel NF-kB inhibitors for the suppression of osteoclastogenesis, and
their potential as treatments for infection related bone diseases in Australians. , Acheivements include:, 1)
Detailed examination of NF-kB
signaling pathways in osteoclasts exposed to parthenolide analogs, to identify the immediate molecular
target(s);, 2)
Detailed characterization of the
actions of parthenolide analogs on osteoclastogenesis and osteoclastic bone resorption in vitro;,
3)Understanding of the therapeutic potential of parthenolide analogs in the inhibition of osteoclastic activity
using an animal model of ostoelysis., ???
Expected future outcomes:
1)
Understand the mechanisms of action
of parthenolide analogs, as the prototype of NF-kB inhibitors., 2)
Provide background understanding
needed to develop bioinformatic and large-scale laboratory screening procedures to identifying parthenolide
analogs., 3)
Provide initial pre-clinical
information on the parthenolide analog approach to control of arthritis, in anticipation of later clinical
development of compounds that successfully pass through screening.?????
Name of contact:
Jiake Xu
Email/Phone no. of contact:
jiake.xu@uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1010494
Start Year: 2011
CIA Name: A/Pr Scott Wilson
End Year: 2013
Admin Inst: University of Western Australia
Grant Type: NHMRC Project Grants
Main RFCD: Quantitative Genetics (incl. Disease and Trait Mapping Genetics)
Total funding: $438,600
Title of research award:
The role of genomic copy number variation in regulation of bone disease phenotypesThe role of genomic copy
number variation in regulation of bone disease phenotypes
Lay Description (from application):
We have been working to identify quantitative trait loci for key clinical traits relevant to osteoporosis, for the
past 15 years, with substantial success. We recently completed a Genome Wide Association Study and
identified 20 loci with strong evidence for a role in the regulation of key bone disease phenotypes. In this
project we will extend that highly acclaimed research to study genomic copy number variation and define the
role of those genetic variants in osteoporosis.
Research achievements (from final report):
N/A
Expected future outcomes:
N/A
Name of contact:
A/Prof Scott Wilson
Email/Phone no. of contact:
scott.wilson@uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 455255
CIA Name: Dr David Mahns
Admin Inst: University of Western Sydney
Main RFCD: Systems Physiology
Total funding: $288,210
Start Year: 2007
End Year: 2009
Grant Type: NHMRC Project Grants
Title of research award:
Neural Mechanisms of Bone PainNeural Mechanisms of Bone Pain
Lay Description (from application):
Pain associated with bone cancer, fractures, osteoporosis, osteoarthritis, osteomyelitis (and other bone
infections) often presents the clinician with a difficult problem of treatment as the pain can be debilitating and
intractable. Most current treatments for bone pain are based on the assumption that the neural mechanisms
underlying pain from different sources, whether it be visceral, cutaneous, muscular or bony, are the same, and
can therefore be targeted with similar therapies. However, little is known of the response properties, structure
and organization of receptors and neurones responding to, and relaying information about painful stimuli, from
bone to the brain. The objectives of this project are to reveal the fundamental neural mechanisms that account
for the perception of bone pain. The project will test a series of specific hypotheses in order to explain why
bone pain is often poorly controlled by standard pharmacological or surgical approaches. It is expected that
this study will reveal the neural mechanisms responsible for relaying sensory information, in particular, that
regarding painful stimuli, from bone to the brain. It will lead to a better understanding of the mechanisms of
bone pain and form the template for future studies of its treatment.
Research achievements (from final report):
, The broad aim of this project is to determine the neural mechanisms that account for the perception of bone
pain: We have shown that the anatomical arrangement, fibre composition (Zhou et al 2007) and responsiveness
of periosteal primary afferents (Mahns et al 2007) is constant across two at least two species. Recordings from
the spinal cord revealed that bone inputs are clustered in the ~C7-T1, with individual cells responding to
convergent inputs from but being unresponsive to focal periosteal stimulation. In contrast, focal stimulation of
the skin readily activated dorsal horn neurones. Multiple cortical processing sites for inputs arising from bone
afferents have been identified in both the cat and rabbit. Dual cortical projections of bone inputs and a limited
capacity of the cortex to respond to repeated stimulation of inputs arising from bone (Ivanusic et al 2009). By
using a 63 array multiple channel recording apparatus we (Chelvanayagam & Mahns, 2010) have been able to
simultaneously record and document the differential cortical localisation for bone, muscle and cutaneous
inputs. Discrete lesions of the spinothalamic, spinocervical tract and dorsal columns on the timing, amplitude
and distribution cortical responses evoked by activation of bone, muscle and cutanteous inputs have been
presented in abstract form (Chelvanayagam et al Mahns, 2011) experiment have been completed and draft
manuscript is in preparation.
Expected future outcomes:
We have shown that low threshold C-mechanoreceptors have access to central pain pathways. Furthermore,
psychophysical experiments (in press) have shown C-mechanoreceptors play a significant role in the allodynia
observed during skin and muscle pain. The role C-mechanoreceptors in distinguishing between pleasure and
pain will form the focus of future work.
Name of contact:
David Mahn
Email/Phone no. of contact:
d.mahns@uws.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 354127
CIA Name: Prof Julie Steele
Admin Inst: University of Wollongong
Main RFCD: Medical Biotechnology
Total funding: $169,500
Start Year: 2005
End Year: 2005
Grant Type: NHMRC Development Grants
Title of research award:
Reducing the Burden of Joint Replacement: An Innovative Biofeedback Device for Post-Surgical
Rehabilitation.Reducing the Burden of Joint Replacement: An Innovative Biofeedback Device for PostSurgical Rehabilitation.
Lay Description (from application):
This project aims to develop a robust wearable device capable of providing immediate audible feedback with
respect to knee motion for enhanced post-knee replacement surgery rehabilitation, suitable for use by older
people both independently and supervised at home or in the clinic. As there is a current unmet need for such
wearable biofeedback devices, this project will lead to intellectual property generation, strengthened
partnerships between the involved parties and identification of an industry partner to commercialise the
technology.
Research achievements (from final report):
This project aimed to improve the robustness of a wearable biofeedback joint sleeve for knee replacement
patients. The textile substrate had been identified previously. This textile substrate was initially coated with
polymers, metals and polymer-metal combinations to resolve the stability issues. Without extensive
optimisation, the metallated textiles were too conductive for the biofeedback device and polymer-coated
textiles were considered more appropriate. Therefore, we further optimised our conducting-polymer coating
processes such that the textile sensors were more stable within a variety of environmental conditions, including
water, sweat and humidity (30-80%). These processes were applied to a modified U-shaped sensor to enable
robust attachment to electronics and therefore a robust device. The sensors and electronics were then applied to
the device and human trials were conducted to assess the validity and reliability of the device when used in
rehabilitation programs for knee replacement patients. Seventeen subjects were assessed performing typical
movements involved in rehabilitation programs. Data from the biofeedback device were compared to data
collected using an optoelectronic motion analysis system. Human trial results revealed the joint sleeve was
valid, in that the programmed angle was equal (+ 10 degrees) to the angle at which the audible signal was
emitted to the wearer, and reliable, in that intraclass correlation coefficients calculated from the knee flexion
angle at onset of the audible signal ranged from R1 = 0.954 to 0.981. However, a disposable textile sensor is
still required due to structural creep changes within the textile itself leading to altered sensor performance with
extended use (> 60 minutes) or consistently large strains (> 50%). Therefore, the biofeedback joint sleeve was
deemed appropriate for use in rehabilitation programs for knee replacement patients.
Expected future outcomes:
The wearable biofeedback joint sleeve is being further developed for use in rehabilitation programs for knee
replacement patients. There is high end-user support for the device and, although interest has been received
from an international company who develop rehabilitaton devices, commercialisation of the device will be our
focus for the future.
Name of contact:
Professor Julie Steele
Email/Phone no. of contact:
julie_steele@uow.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 181625
Start Year: 2002
CIA Name: Prof Phillip Hogarth
End Year: 2004
Admin Inst: Victoria University
Grant Type: NHMRC Project Grants
Main RFCD: Humoral Immunology and Immunochemistry
Total funding: $905,280
Title of research award:
Structure and Function of Receptors for IgG (FcgammaR)Structure and Function of Receptors for IgG
(FcgammaR)
Lay Description (from application):
This reasearch project is attempting to understand one of the most important mechanisms of resistance to
infectious disease and one of the most important mechanisms of induction of destructive inflammation in
autoimmune disease. These studies will define how blood proteins called antibodies, antibodies bind to the
surface of white blood cells via proteins called Fc receptors that activate these white blood cells. Under normal
circumstances this system provides resistance to infection but is involved in some of the most debilitating
diseases, including allergies, bleeding disorders called thrombocytopoenias, inflammation of blood vessels,
vasculitis, as well as aspects of rheumatoid arthritis. The successful conclusion of this project will result in
knowledge that will enable the development of more effective and highly specific therapeutic approaches to the
treatment of disease and a better understanding of the functioning of the immune system.
Research achievements (from final report):
The analysis of the interaction between antibodies and Fc receptors in this grant has led to the first
understanding of the precise mechanism that led to the activation of white blood cells by antibodies which are
the primary mechanims of resistance of infection and play a major role in destructive autoimmune diseases
such as rheumatoid arthritis. Specifically, we have: 1) identified unique organisational states in members of the
Fc receptor family, 2) solved the structures of allelic forms of FcgammaRIIa for the first time, 3) established
crucial systems for measuring receptor organisation, 4) defined functional important areas in the Fc receptor
family, 5) shown that the receptor organisation influenced antibody binding specificity.
Expected future outcomes:
This work will lead to the design of new anti-infllammatory protein and drugs that antagonise Fc receptor
function. In addition, understanding of Ig FcR interaction will lead to improved therapeutic antibodies for the
treatment of diseases such as cancer.
Name of contact:
Ms Susan Collins
Email/Phone no. of contact:
s.collins@ari.unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 171610
CIA Name: Dr Paul Egan
Admin Inst: Walter and Eliza Hall Institute
Main RFCD: Rheumatology and Arthritis
Total funding: $332,250
Start Year: 2001
End Year: 2004
Grant Type: Early Career Fellowships (Australia)
Title of research award:
Evaluation of cytokine inhibitors in animal models of rheumatoid arthritisEvaluation of cytokine inhibitors in
animal models of rheumatoid arthritis
Lay Description (from application):
Not Available
Research achievements (from final report):
Suppressor of cytokine signalling (SOCS) proteins were evaluated as potential regulatory molecules that could
limit the extent and severity of rheumatoid arthritis. Mice lacking either SOCS-1 or SOCS-3 were found to
develop more severe arthritis in animal models, validating the strategy of over-expressing SOCS proteins
within arthritic joints as a potential therapeutic targets. Experiments designed to over-express SOCS proteins
initially used adenovirus vectors to deliver SOCS genes into the joint, although viral expression in the joint was
not sufficient to provide protection against arthritis. Alternative strategies to increase the expression of SOCS
proteins are currently being investigated., , Blockade of the pro-inflammatory cytokine, GM-CSF, was also
investigated as an alternative strategy for the treatment of rheumatoid arthritis. A fully human monoclonal
-CSF receptor and was found to block the
activity of GM-CSF in vivo. Clinical trials to test the safety and efficacy of this antibody are now under
development.
Expected future outcomes:
Inhibitors of the GM-CSF receptor will move forward into human clinical trials for the treatment of rheumatoid
arthritis. Systems designed to over-express SOCS proteins in synovial cells will be investigated to validate the
use of SOCS proteins as therapeutic agents for rheumatoid arthritis.
Name of contact:
Dr Paul Egan
Email/Phone no. of contact:
pegan@wehi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 215408
CIA Name: Prof Ian Wicks
Admin Inst: Walter and Eliza Hall Institute
Main RFCD: Rheumatology and Arthritis
Total funding: $269,750
Start Year: 2002
End Year: 2006
Grant Type: Established Career Fellowships
Title of research award:
Molecular mediators in murine models of inflamatory joint diseaseMolecular mediators in murine models of
inflamatory joint disease
Lay Description (from application):
Not Available
Research achievements (from final report):
This practitioner fellowship allowed me to study the immunopathogenesis of inflammatory joint diseases and
identify new therapeutic targets for diseases such as rheumatoid arthritis. Two targets have been examined in
detail - G-CSF and GM-CSF. These molecules were discovered at WEHI and characterised as growth factors
for the blood cell system. My research shows these molecules also have important roles in inflammation. These
findings have led to collaborations with Australian biotechnology partners to develop and evaluate novel
antagonists of G- and GM-CSF for human cllinical trials. In parallel, I initiated and then collaborated with
colleagues on a clinical research program covering accelerated atherosclerosis in rheumatoid arthritis and joint
replacement surgery services for patients with arthritis. These initiatives led to new approaches to diagnosis
and prevention of atherosclerosis accompanying RA and a more rational prioritisation system for joint
replacement surgery.
Expected future outcomes:
New therapeutic agents for inflammatory diseases; diagnosing and preventing atherosclerosis in rheumatoid
arthritis; better management of joint replacement surgery services.
Name of contact:
Brad Allan
Email/Phone no. of contact:
allan@wehi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 305523
CIA Name: Dr Paul Egan
Admin Inst: Walter and Eliza Hall Institute
Main RFCD: Rheumatology and Arthritis
Total funding: $444,910
Start Year: 2004
End Year: 2006
Grant Type: NHMRC Project Grants
Title of research award:
The role of SOCS-1 and SOCS-3 in regulating acute inflammatory arthritis.The role of SOCS-1 and SOCS-3 in
regulating acute inflammatory arthritis.
Lay Description (from application):
Rheumatoid arthritis (RA) is a chronic inflammatory disease which mainly targets joints. The disease causes
chronic joint pain, stiffness and loss of joint mobility, leading to increasing difficulty in carrying out day to day
activities. Treatment for RA has gradually improved, but remains inadequate for many patients. Although the
cause is unknown, progress has been made in understanding the molecular pathways which drive RA. The
disease is characterised by the production of high levels of inflammatory mediators called cytokines. This
finding has led to the development and introduction of specific cytokine inhibitors into clinical practice,
although a significant number of patients fail to respond to treatment. An alternative approach to develop new
treatments for RA would be to use the body's natural inhibitors to limit the actions of inflammatory cytokines.
One such inhibitor is Suppressor of Cytokine Signalling-1 (SOCS-1). Using animal models, we have shown
that mice lacking SOCS-1 develop more severe arthritis and have identified the different cell types it acts on.
Further studies are still needed before SOCS-1 can be developed as a treatment for RA. We aim to identify the
major cell type responsible for the increased severity of disease seen when SOCS-1 is absent. This will allow
for treatment to be targetted to the most appropriate cells in the joint. We also aim to study the related molecule
SOCS-3, to see whether it has similar effects on inhibiting the severity of disease. These studies will provide
more information on the activity of SOCS proteins during inflammatory diseases in general and RA in
particular and and may lead to new approaches for the treatment of RA.
Research achievements (from final report):
Rheumatoid arthritis (RA) is caused by uncontrolled inflammation in the joints. Understanding the mechanisms
by which inflammation is controlled may lead to new therapies for the treatment of RA. The suppressor of
cytokine signalling (SOCS) proteins are a family of proteins that regulate the activity of cytokines, soluble
proteins that can drive inflammation. We have used genetically modified mice that lack genes for SOCS-1 and
SOCS-3 to define how SOCS proteins control inflammation in mouse models of RA. Following induction of
inflammatory arthritis, mice lacking SOCS-1 developed more severe joint inflammation than wild type mice
due to an accumulation of activated macrophages in the synovium. Mice lacking SOCS-3 in bone marrowderived cells also developed more severe arthritis, although the predominant inflammatory cell in these mice
were neutrophils. This demonstrates that both SOCS-1 and SOCS-3 are required to regulate the severity of
inflammatory arthritis, although they regulate the activity of different cell types. Mice lacking SOCS-3 only in
T lymphocytes also developed more severe inflammatory arthritis, although the severity was reduced compared
to mice lacking SOCs-3 in all bone marrow-derived cells. These results show that SOCS-1 and SOCS-3 are
important in the regulation of inflammatory arthritis and identify the key cell types in which these proteins act
to control inflammation.
Expected future outcomes:
We have shown that SOCS-1 and SOCS-3 are important in regulating the severity of inflammatory arthritis and
the cell types in which SOCS proteins are most effective in controlling inflammation. Future outcomes would
be to identify ways of boosting the expression of SOCS proteins in these cell types and determining whether
this strategy could be used to develop new therapeutics.
Name of contact:
Dr Paul Egan
Email/Phone no. of contact:
NHMRC Research Achievements - SUMMARY
pegan@wehi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 305558
CIA Name: Prof Ian Wicks
Admin Inst: Walter and Eliza Hall Institute
Main RFCD: Rheumatology and Arthritis
Total funding: $88,329
Start Year: 2005
End Year: 2005
Grant Type: NHMRC Development Grants
Title of research award:
Development and pre-clinical evaluation of G-DSF inhibitors for inflammatory joint diseaseDevelopment and
pre-clinical evaluation of G-DSF inhibitors for inflammatory joint disease
Lay Description (from application):
G-CSF was originally identified as a cytokine regulating the production of neutrophils and haemopoietic stem
cells from the bone marrow and it is currently used clinically for these properties in bone marrow transplant
patients around the world. Anti-cytokine therapy with TNF blockade has recently been introduced for the
treatment of rheumatoid arthritis. However, not all patients respond to TNF inhibition. We have gathered
extensive data which shows that G-CSF also promotes inflammation in experimental models of inflammatory
joint disease. We propose to develop inhibitors of G-CSF as a novel form of anti-cytokine therapy for
inflammatory joint disorders, such as rheumatoid arthritis.
Research achievements (from final report):
This project was only part funded, but this was sufficient to generate, express and purify soluble versions of the
mouse and human G-CSF receptors as immunoglobulin fusion proteins. An assay for testing biological potency
of the inhibitors has been developed and the inhibitors were shown to successfully antagonise G-CSF effects.
The project provided the basis for optimisation of the inhibitors and a large scale production system.
Expected future outcomes:
The project has attracted keen biotechnology interest and led to a commercial collaboration to between Zenyth
Therapeutics, Murigen Therapeutrics and WEHI to fund development towards clincial trials.
Name of contact:
Ian Wicks
Email/Phone no. of contact:
wicks@wehi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 381413
Start Year: 2006
CIA Name: Prof Antony Burgess
End Year: 2012
Admin Inst: Walter and Eliza Hall Institute
Grant Type: NHMRC Enabling Grants
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $2,509,000
Title of research award:
The Australian Proteomics Computational Facility (APCF)The Australian Proteomics Computational Facility
(APCF)
Lay Description (from application):
In recent years, Australia has invested in the equipment capable of identifying proteins important in health and
medicine. This sophisticated equipment requires high capacity computing support. The Australian Proteomics
Computational Facility will establish a single advanced computing cluster accessible to scientists at proteomics
centres all over the country. This integrated approach to proteomics computing and the sharing of databases
will put Australia at the forefront of the world’s efforts to identify the proteins associated with the early
detection of our major diseases
Research achievements (from final report):
The Australian Proteomics Computational Facility (APCF) has established, maintained and upgraded an
advanced computing cluster accessible to researchers all over Australia. There are over 600 current users from
more than 100 laboratories who have access to the APCF. Almost 200,000 protein identification searches have
been performed via the APCF cluster. The original UNITE software platform (LICR) has been superceded by
an independent software tool MSILE 1.0 (Bio21 Institute). Based on publically available software the APCF
(through the Bio21 Institute) is developing MSILE 2.0 which will allow APCF users to access many more
analysis packages. The APCF computing cluster has been upgraded and will be available to users via the
WEHI for the next four years. The integrated protein database continues to support APCF users. This database
is being upgraded with appropriate biological annotation (Latrobe University) and will be available to APCF
users for the next four years.
Expected future outcomes:
The APCF hardware is state-of-the-art and is expected to be sufficient to support the users for the next 4 years.
Mascot licences and the proteomics database will be maintained and available for protein identification.
Name of contact:
Penny Fannin
Email/Phone no. of contact:
fannin@wehi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 406645
CIA Name: Prof Ian Wicks
Admin Inst: Walter and Eliza Hall Institute
Main RFCD: Orthopaedics
Total funding: $348,393
Start Year: 2006
End Year: 2008
Grant Type: NHMRC Project Grants
Title of research award:
The role of suppressor of cytokine signalling-3 (SOCS-3) in chondrocytes during development and diseaseThe
role of suppressor of cytokine signalling-3 (SOCS-3) in chondrocytes during development and disease
Lay Description (from application):
Cytokines are messenger proteins produced and secreted from one cell which then bind to specific receptors on
the surface of other cells. After binding, a series of intracellular events occurs, termed "signalling", that results
in the target cell changing its behaviour. Cytokine signalling, if allowed to proceed unchecked, can result in
various disease states. The suppressor of cytokine signalling (SOCS) proteins are key negative regulators of
cytokine signalling within the cell. They are induced by a wide range of stimuli, especially from a group called
the "IL-6 family". We have preliminary data showing that cartilage cells (chondrocytes) normally produce a
particular SOCS protein, called SOCS-3. We have also shown that when SOCS-3 production is dysregulated,
the chondrocytes undergo excessive proliferation. Normal chondrocyte function is important during skeletal
development and diseases such as osteoarthritis are thought to result from abnormal chondrocyte behaviour. It
is likely that SOCS-3 has a key role in regulating chondrocyte function. The aim of this proposal is therefore to
examine the role of SOCS-3 in chondrocytes, during development and in disease. Much of our understanding
of the role of the SOCS proteins comes from the construction of mutant mice that lack a particular SOCS
protein. When mutant mice are made that lack SOCS-3 in the whole animal the mice die before birth and so
virtually nothing is known about the role of SOCS-3 in chondrocytes and the implications for cartilage in
disease states, such as arthritis. To answer this we will create mice that lack SOCS-3 specifically in their
chondrocytes. Evaluating the role of SOCS-3 in cartilage development and chondrocyte function during
degenerative and inflammatory disease states is potentially of major clinical importance in improving our
understanding of arthritis and of cartilage repair.
Research achievements (from final report):
We have developed a mouse that lacks a key regulatory protein, suppressor of cytokine signalling-3 (SOCS-3),
specifically in cartilage cells (chondrocytes) in order to understand its role in arthritis. SOCS-3 normally serves
to regulate the cellular response to inflammatory stimuli, such as cytokines We found that such mice were
viable and developed normally. However, when the mice were evaluated in experimental models of
inflammatory arthritis they developed markedly more severe disease than wild-type control mice. SOCS-3deficient chondrocytes were hyper-responsive to in vitro stimulation with the proinflammatory cytokine IL-1,
showing enhanced nitric oxide production. These findings suggest that SOCS-3 is critical in regulating the
chondrocyte response to inflammatory stimuli during arthritis. The data also show that chondrocytes
themselves can significantly influence the inflammatory response in the joint. These studies challenge the
common perception that chondrocytes are targets of, rather than contributors to, the inflammatory reponse in
arthritis. Our studies also suggest that finding ways to enhance SOCS-3 expression in chondrocytes could be
therapeutically useful in the treatment of arthritis.
Expected future outcomes:
Our findings highlight the significant impact that cartilage cells can make to the disease response in arthritis. A
possible outcome is that it may be therapeutically beneficial to develop drugs that specifically control SOCS
proteins in chondrocytes.
Name of contact:
Michelle Trevorrow
Email/Phone no. of contact:
communityrelations@wehi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 461203
CIA Name: Prof Ian Wicks
Admin Inst: Walter and Eliza Hall Institute
Main RFCD: Rheumatology and Arthritis
Total funding: $360,313
Start Year: 2007
End Year: 2011
Grant Type: Established Career Fellowships
Title of research award:
Practitioner FellowshipPractitioner Fellowship
Lay Description (from application):
I am a clinician-scientist investigating the immunopathogenesis of rhematoid arthritis in order to discover and
develop new forms of therapy and prevent disease complications. I am interested in improving patient care
through research on patient educatio
Research achievements (from final report):
My research focus is on autoimmune-mediated inflammatory diseases, in particular Rheumatoid Arthritis (RA).
Clinical research achievements include 1. identifying and preventing atherosclerosis in RA 2. evaluation and
improvement of patient education about medications, especially Methotrexate for RA 3. establishment of a
synovial tissue bank for research on biomarkers in RA 4. joint replacement surgery wait list reforms, now
implemented throughout Victoria and in other states. My laboratory-based research has led to several patents
and a major collaboration with CSL to develop an antagonist of the cytokine, G-CSF. A partnership that I
initiated between WEHI and CSL has led to Phase 1 and 2 clinical trials of a GM-CSF antagonist for RA. My
role as a clinician-scientist now combines leadership of the Rheumatology Unit at Melbourne Health, with
leadership of a new Division of Inflammation at WEHI.
Expected future outcomes:
Continuing work is evaluating G- and GM-CSF antagonism in other inflammatory diseases, including uveitis
and vasculitis, as well as RA and a new collaboration with CSL addresses IL-3 antagonism in systemic lupus
erythematosus. I have also initiated new research on diagnosis and treatment of acute rheumatic fever, which
remains a major health problem for indigenous Australians.
Name of contact:
Penny Fannin
Email/Phone no. of contact:
fannin@wehi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 461243
CIA Name: Prof Ian Wicks
Admin Inst: Walter and Eliza Hall Institute
Main RFCD: Rheumatology and Arthritis
Total funding: $531,485
Start Year: 2007
End Year: 2009
Grant Type: NHMRC Project Grants
Title of research award:
Understanding how endogenous G-CSF mediates inflammatory arthritisUnderstanding how endogenous GCSF mediates inflammatory arthritis
Lay Description (from application):
Rheumatoid Arthritis (RA) is a common chronic inflammatory disease which targets joints. Currently, there is
no cure for RA and the available anti-rheumatic drugs have limited efficacy and frequent side effects. Progress
has been made in understanding the molecular pathways which drive RA and the disease is characterised by
high levels of inflammatory mediators (called cytokines). This finding has led to the development and
introduction of specific cytokine inhibitors into clinical practice. These inhibitors work well for some, but not
all, patients. The reason why certain RA patients fail to respond to this treatment is not clear. There is great
interest in identifying new cytokines in RA and in developing more effective cytokine inhibitors. Our recent
research shows that a cytokine best known for its effect on blood cell development (granulocyte-colony
stimulating factor or G-CSF) also plays a major role in experimental models of RA. This discovery has led to
two Australian biotechnology companies - Zenyth Therapeutics Ltd., and Murigen Therapeutics Ltd, entering
into a partnership to develop G-CSF antagonists for clinical trials. However, before we can take such
antagonists to the clinic, we need to conduct careful pre-clinical studies to understand the basis for our findings
on G-CSF in much greater detail. This will ensure this new therapy is used in the safest and most effective
way.
Research achievements (from final report):
Our previous and current work on this project has created a strong pre-clinical rationale for targeting
endogenous G-CSF in inflammatory diseases and led to a patent and a commercialisation agreement between
WEHI and CSL. The project also led to Dr Ian Campbell from CIA's laboratory receiving an NHMRC Industry
Fellowship to work in collaboration with CSL.
Expected future outcomes:
CSL has developed a fully humanised monoclonal antibody that potently antagonises human G-CSF receptor
signalling and planning is underway for clinical trials of this antibody in inflammatory disease.
Name of contact:
Professor Ian Wicks
Email/Phone no. of contact:
wicks@wehi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 461253
CIA Name: Dr Jose Villadangos
Admin Inst: Walter and Eliza Hall Institute
Main RFCD: Enzymes
Total funding: $423,565
Start Year: 2007
End Year: 2009
Grant Type: NHMRC Project Grants
Title of research award:
Regulation of synthesis, dimerisation and secretion of the amyloidogenic protease inhibitor cystatin
CRegulation of synthesis, dimerisation and secretion of the amyloidogenic protease inhibitor cystatin C
Lay Description (from application):
The cells that compose our tissues are embedded in a complex mesh of extracellular proteins (for example
collagen) that provide support, strenght and elasticity to the tissues. This "extracellular matrix" is not static; it
is constantly remodelled when, for example, the cells of the immune system move through interstitial spaces to
monitor the healthiness of the tissues. When infections or injuries occur, the inflammatory reactions that
develop, and the processes involved in tissue repair, also involve profound changes in the composition of the
extracellular matrix. Such processes are also important for tumour growth; the cancer cells need to clear their
way through interstitial space to escape to circulation and metastasize. During all these processes, the cells
release to the extracellular space proteases that degrade collagen and the other components of the extracellular
matrix. Obviously, these proteases must be tightly regulated to prevent them running out of control, so the cells
also produce inhibitors of the proteases. The amount of proteases and inhibitors contained in the extracellular
space must be maintained properly. If this equilibrium is disrupted, this can lead to pathology For instance,
atherosclerosis is caused in part by excessive proteolysis of the blood vessel wall. In this project we want to
study the mechanisms of one of the most abundant and important inhibitors of extracellular proteolysis:
Cystatin C. We have discovered that certain cells of the immune system called dendritic cells posses interesting
mechanisms to regulate how much Cystatin C they secrete. Furthermore, one of this mechanisms, which
consists of pairing the protein to produce inactive dimers, may be the cause of some diseases characterised by
accumulation of Cystatin C in the extracellular space. Our study may allow us to design therapies for the
treatment of pathologies associated with defective or excessive production of Cystatin C.
Research achievements (from final report):
We have characterised the fundamental biology of cystatin C, a secreted protease inhibitor. Cystatin C is
implicated in many diseases, including cardiovascular disease.
Expected future outcomes:
We expect this research to generate future outcomes that are relevant to the treatment of disease, in particular
cardiovascular disease.
Name of contact:
Jose Villadangos
Email/Phone no. of contact:
villadangos@wehi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 481374
Start Year: 2008
CIA Name: Dr Kim Jacobson
End Year: 2013
Admin Inst: Walter and Eliza Hall Institute
Grant Type: Early Career Fellowships (Overseas)
Main RFCD: Humoral Immunology and Immunochemistry
Total funding: $437,253
Title of research award:
The role of B7 family members in the generation of immunological memoryThe role of B7 family members in
the generation of immunological memory
Lay Description (from application):
Memory immune cells remember antigens that have previously induced an immune response. Therefore, they
can react quickly and rigorously to stop subsequent infections. This project will study the role of the B7 family
of proteins in communication between memory cells and other cells of the immune system to produce lifetime
protection against foreign antigens. Understanding these processes will assist in creating more effective
vaccines and treatments for immunodeficient or autoimmune patients.
Research achievements (from final report):
Antibody-mediated vaccines are vital for the health of both first and third worlds. The continuing development
of new vaccines, as well as improving the efficacy of current vaccines is essential to global health. Memory
immune cells remember antigens that have previously induced an immune response. Therefore, they can react
quickly and rigorously to stop subsequent infections. This work investigated the mechanisms regulating
immune memory formation. Our findings have revealed the role of the B7 family of proteins in communication
between immune cells to produce lifetime protection against foreign antigens. Our work has also identified
previously unknown genes and epigenetic regulators that are essential for the production and maintenance of
immune memory.
Expected future outcomes:
Understanding how immune memory is formed and maintained will assist in creating more effective vaccines.
It is also relevant for research into imbalances of the immune system during production of antibody, and thus
can lead to new treatments for immunodeficient or autoimmune patients.
Name of contact:
Penny Fannin
Email/Phone no. of contact:
fannin@wehi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 516705
Start Year: 2008
CIA Name: Dr Sandra Nicholson
End Year: 2013
Admin Inst: Walter and Eliza Hall Institute
Grant Type: NHMRC Research Fellowships
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $690,502
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
I am a protein biochemist investigating how SOCS box proteins regulate intracellular signal transduction.
Research achievements (from final report):
Viral infections such as influenza cause profound morbidity and mortality and remain a significant global
health issue. The innate immune system presents the first line of defense against infectious viral and bacterial
pathogens. We have been interested in understanding how the host response is regulated and the consequences
of excessive inflammatory signalling the so-called "cytokine storm". The suppressors of cytokine signalling
SOCS box proteins are classic examples of negative regulators that control cytokine signalling and the
inflammatory response. In particular we have investigated the physiological role of two lesser known SOCS
proteins SOCS4 and SOCS5. Our interests have extended to another protein family the SPSB proteins and the
central role of a protein-protein interaction domain called a SPRY or B30.2 domain. This project has
significantly enhanced our understanding of how these intracellular proteins regulate the host response to
infectious and inflammatory disease. The findings have been published in high impact scientific journals and
presented at a variety of national and international meetings. The project has also contributed to the training of
several PhD and Honours students.
Expected future outcomes:
Understanding the structural details of the intracellular protein complexes involved in the host response to
infection and the physiological consequences of enhancing this response will provide an opportunity for the
development of new anti-viral therapies.
Name of contact:
Penny Fannin
Email/Phone no. of contact:
fannin@wehi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 516730
Start Year: 2008
CIA Name: Dr Thomas Garrett
End Year: 2010
Admin Inst: Walter and Eliza Hall Institute
Grant Type: NHMRC Project Grants
Main RFCD: Protein Targeting and Signal Transduction
Total funding: $453,943
Title of research award:
Structural studies on cell signalling via the LIF receptor and gp130Structural studies on cell signalling via the
LIF receptor and gp130
Lay Description (from application):
The cytokines play important roles in the immune system during blood cell development and inflammation,
and in nerve growth, bone remodeling, reproduction and heart development. Cell responses are initiated by a
cytokine bringing together on the cell surface a "receptor" complex made up of multiple molecules. This
project will investigate the atomic structure of the cell surface macromolecular complex, and hence the
underlying mechanism by which cytokine signals are initiated.
Research achievements (from final report):
This grant aims to use structural biology and site-directed mutagenesis to characterise in detail the molecular
interactions of the IL-6/gp130 family of receptors and cytokines that play important roles in the immune
system during hematopoiesis and inflammation, and in neurogenesis, bone remodelling, reproduction and heart
development. We have determined the first crystal structure of the entire extracellular portion of human gp130
at atomic resolution. A structural model of the complete extracellular gp130 signalling complex has also been
constructed. These structures have greatly improved our understanding of how signal through the gp130 family
of receptors is initiated on the cell surface and also provided us with useful information for future design of
drugs that targets abnormal gp130 signalling for the treatment of many human diseases.
Expected future outcomes:
We obtained important structural information that provides a starting point for the future design of drugs that
target abnormal gp130 signalling
Name of contact:
Thomas Garrett
Email/Phone no. of contact:
tgarrett@wehi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 602516
CIA Name: A/Pr John Silke
Admin Inst: Walter and Eliza Hall Institute
Main RFCD: Signal Transduction
Total funding: $568,861
Start Year: 2010
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
Analysis of the functions of a novel class of ubiquitin E3 Ligases in TNF signalling in vivoAnalysis of the
functions of a novel class of ubiquitin E3 Ligases in TNF signalling in vivo
Lay Description (from application):
The aim of this project to discover the role of a novel ubiquitin ligase complex that regulates TNF superfamily
signalling. It will increase understanding of the TNF pathway and improve our ability to manipulate it
pharmacologically, or otherwise, in the large number of debilitating human diseases including Rheumatoid
Arthritis and Crohn's disease that result from aberrant TNF signalling. Because of the role of TNF in
tumorigenesis it may also contribute to novel anti-cancer treatments.
Research achievements (from final report):
We made major contributions to understanding how inflammation is regulated, and how failure to regulate
results in diseases like psoriasis. This work resulted in high profile publications in Nature and Immunity and
one patent.
Expected future outcomes:
Investigating causes of psoriasis continues to be a rich vein leading to novel insights.
Name of contact:
Penny Fannin
Email/Phone no. of contact:
fannin@wehi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 637367
CIA Name: Dr Ben Croker
Admin Inst: Walter and Eliza Hall Institute
Main RFCD: Rheumatology and Arthritis
Total funding: $340,725
Start Year: 2010
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
Pathogen sensing in autoinflammatory and autoimmune diseasePathogen sensing in autoinflammatory and
autoimmune disease
Lay Description (from application):
Mammals have evolved an array of mechanisms to sense microbes. These immune sentinels must distinguish
self from non-self to activate an immune response. The initiation, amplification and quenching of an immune
response is a carefully orchestrated process that eliminates invading pathogens while minimising collateral
damage to host tissues. This research focuses on proteins that restrict immune responses to prevent
inflammatory diseases such as rheumatoid arthritis and psoriasis.
Research achievements (from final report):
Changes in the lifespan of white blood cells called neutrophils have been associated with acute lung injury,
sepsis, pneumonia, acute respiratory distress syndrome (ARDS) and pathogenic infections, including influenza,
Streptococcus pneumoniae, RSV, Herpes Simplex Virus and human cytomegalovirus. We have identified
proteins that control the lifespan of neutrophils and that also control the production of inflammatory molecules
during the process of cell death. We demonstrate that the molecules involved in regulating one type of cell
death also regulate a form of cell death triggered by cells of the immune system called T cells and natural killer
cells. We have also demonstrated that the recognition of infection by neutrophils can switch off cell death
programs in neutrophils, otherwise fated to die. This enables neutrophils to ignore instructions from T cells and
NK cells, and instead deal with potentially life-threatening infections before undergoing cell death.
Expected future outcomes:
This research will help define the mechanisms that govern both the activation of neutrophils at a site of
infection and the subsequent cell death and disposal of neutrophils to understand how distinct processes
including pathogen recognition and cell death pathways integrate to drive inflammatory disease.
Name of contact:
Penny Fannin
Email/Phone no. of contact:
fannin@wehi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1002426
CIA Name: Prof Benjamin Kile
Admin Inst: Walter and Eliza Hall Institute
Main RFCD: Innate Immunity
Total funding: $634,460
Start Year: 2011
End Year: 2013
Grant Type: NHMRC Project Grants
Title of research award:
Defining the role of Nlrp1 and the inflammasome in host defence and inflammatory diseaseDefining the role of
Nlrp1 and the inflammasome in host defence and inflammatory disease
Lay Description (from application):
The immune system protects the body from invading pathogens, but it can also attack the body causing
inflammatory and autoimmune diseases like arthritis and multiple sclerosis. This project will focus on the
molecular regulation of the ‘inflammasome’, a protein complex that senses invading pathogens and triggers the
immune response. Understanding the inflammasome may hold the key to a better understanding of how the
good and bad functions of the immune system can be balanced to prevent disease.
Research achievements (from final report):
Cytopenias are key prognostic indicators of life-threatening infection, contributing to immunosuppression and
mortality. Here we define a role for Caspase-1-dependent death, known as pyroptosis, in infection-induced
cytopenias by studying inflammasome activation in hematopoietic progenitor cells. The NLRP1a
inflammasome is expressed in hematopoietic progenitor cells and its activation triggers their pyroptotic death.
Active NLRP1a induced a lethal systemic inflammatory disease that was driven by Caspase-1 and IL-1? but
was independent of apoptosis-associated speck-like protein containing a CARD (ASC) and ameliorated by IL18. Surprisingly, in the absence of IL-1?-driven inflammation, active NLRP1a triggered pyroptosis of
hematopoietic progenitor cells resulting in leukopenia at steady state. During periods of hematopoietic stress
induced by chemotherapy or lymphocytic choriomeningitis virus (LCMV) infection, active NLRP1a caused
prolonged cytopenia, bone marrow hypoplasia, and immunosuppression. Conversely, NLRP1-deficient mice
showed enhanced recovery from chemotherapy and LCMV infection, demonstrating that NLRP1 acts as a
cellular sentinel to alert Caspase-1 to hematopoietic and infectious stress.
Expected future outcomes:
Our work adds weight to the idea that Caspase-1 inhibitors may prove useful in preventing cell death triggered
by infection. Recent work from another group working on HIV provides additional impetus (Doitsh et al.
Nature 2014505:509).
Name of contact:
Penny Fannin
Email/Phone no. of contact:
fannin@wehi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 258700
Start Year: 2003
CIA Name: A/Pr Cory Xian
End Year: 2007
Admin Inst: Women's and Children's Hospital, Adelaide
Grant Type: Career Development
Fellowships
Main RFCD: Orthopaedics
Total funding: $435,500
Title of research award:
Mechanisms for bone growth arrest following injury of the growth plate cartilage and developments of growth
factor and..Mechanisms for bone growth arrest following injury of the growth plate cartilage and developments
of growth factor and..
Lay Description (from application):
Not Available
Research achievements (from final report):
During my 5 year's RD Wright CDA, I have focused on bone growth, growth plate injury and repair, an area
relatively unexplored and yet clinically critically impacting on children's bone growth, bone mass
accumulation, and adult bone health. We have been mainly focused on two areas: (1) Growth plate trauma
injury-induced growth defects: Growth plate trauma injury is a common and significant problem as the inured
growth plate is often repaired by bony tissue leading to growth defects. I have revealed injury responses &
cellular mechanisms for the "undesirable" repair. I have observed the presence of marrow-derived
mesenchymal stem cells and chondrogenic differentiation at the growth plate injury site. (2) Chemotherapyinduced growth defects: Cancer chemotherapy negatively affects bone growth and cause osteoporosis; yet the
underlying mechanisms remain largely unknown and there are no preventative treatments. Using rat models, I
have revealed that bone growth defects directly result from growth plate dysfunction, reduced marrow
osteoprogenitor cell pool and bone formation, and aggravated bone resorption. I have recently identified one
clinically used substance that can effectively protect bone growth in our rat chemotherapy model. (3) Research
independence and contributions to the discipline: I have rapidly formed my large research team (12 members in
2007), excellent collaboration network with expert scientists and clinicians, won several competitive grants
(including NHMRC project), was awarded NHMRC Senior Research Fellowship (starting 2008), made a
substantive contribution to this area of bone biology, presenting as major speakers in international bone
conferences in both research areas, producing seminal publications including top journals J Bone Miner Res
(IF=6.5) and Endocr Rev (IF=23.9).
Expected future outcomes:
My work in the area of children's bone growth and injury repair research will contribute significantly towards
understanding the mechanisms for trauma-induced bone growth defects, chemotherapy-induced bone growth
defects and bone marrow damage after chemotherapy, and towards developing biological preventative
treatments.
Name of contact:
A/Prof Cory Xian
Email/Phone no. of contact:
cory.xian@unisa.edu.au