NHMRC Research Achievements - SUMMARY
END OF GRANT REPORTS
OUTCOMES OF NHMRC FUNDED RESEARCH INTO DIABETES
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Austin Hospital Medical Research Foundation
Austin Research Institute
Australian National University
Baker IDI Heart and Diabetes Institute
Bond University
Cancer Council Victoria
Centre for Eye Research Australia Ltd
CSIRO Division of Human Nutrition
Curtin University of Technology
Deakin University
Edith Cowan University
Flinders University
Garvan Institute of Medical Research
Griffith University
Howard Florey Institute
Institute for Breathing and Sleep
International Diabetes Institute Inc
James Cook University
La Trobe University
Macfarlane Burnet Institute for Medical Research and Public Health
Macquarie University
Menzies Research Institute
Menzies School of Health Research
Monash University
Murdoch Childrens Research Institute
Prince Henry's Institute of Medical Research
Queensland Institute of Medical Research
Queensland University of Technology
RMIT University
Royal Melbourne Institute of Technology
Royal Prince Alfred Hospital
St Vincent's Institute of Medical Research
Swinburne University of Technology
Sydney West Area Health Service
The Children's Hospital at Westmead
The Dr Edward Koch Foundation Limited
University of Adelaide
University of Melbourne
NHMRC Research Achievements - SUMMARY
University of New South Wales
University of Newcastle
University of Queensland
University of South Australia
University of Sydney
University of Tasmania
University of Technology Sydney
University of Western Australia
University of Wollongong
Victor Chang Cardiac Research Institute
Victoria University
Walter and Eliza Hall Institute
NHMRC Research Achievements - SUMMARY
Grant ID: 266505
Start Year: 2004
CIA Name: Prof George Jerums
End Year: 2006
Admin Inst: Austin Hospital Medical Research Foundation Grant Type: NHMRC Project Grants
Main RFCD: Nephrology and Urology
Total funding: $288,900
Title of research award:
Normoalbuminuric and albuminuric pathways to renal insufficiency in type 2 diabetesNormoalbuminuric and
albuminuric pathways to renal insufficiency in type 2 diabetes
Lay Description (from application):
Up to one third of patients with type 2 diabetes develop kidney disease (diabetic nephropathy). An increase in
protein excretion in the urine (albuminuria) is usually the first sign of kidney disease. Albuminuria usually
progresses from normal levels to an intermediate phase (microalbuminuria) lasting 5-10 years and is then
followed by overt nephropathy (macroalbuminuria). It has been traditionally believed that onset of a decline in
kidney function, measured as glomerular filtration rate, accompanies the development of diabetic kidney
disease. However, recent studies by our group have shown that about one quarter of patients with type 2
diabetes have impaired kidney function without an increase in albuminuria. This raises the possibility that an
alternate non-albuminuric pathway leads to kidney disease in a subgroup of patients with type 2 diabetes.
This study will compare kidney structure and function in patients with type 2 diabetes and impaired kidney
function with or without increases in albuminuria. The comparison will be accompanied by measurements of
the rate of decline in kidney function over 5 years or more, in subjects with or without increases in albuminuria
in order to confirm that kidney function may decline independently of albuminuria. The demonstration of
alternate mechanisms of renal injury has the potential to identify new targets for the treatment of kidney
disease in patients with type 2 diabetes.
Research achievements (from final report):
The research that we have performed has highlighted the potential benefits of accurately detecting kidney
dysfunction in people with type 2 diabetes by performing a blood test and measuring cystatin C levels. This
finding is an advancement in the way that kidney function is monitored. Current methods for estimating
glomerular filtration rate based on the measurement of creatinine are not accurate across the full spectrum of
filtering capacity displayed by the kidneys of people wih diabetes. These creatinine-based melthods also
require a calculation that is based on age and gender. We have shown for the first time that people wih diabetes
and impaired kidney filering capacity have a greater burden of disease affecting the arateries within the kidney
compared to those with normal filtering capacity. In particular, the intrarenal arteries of subjects with diabetes
and impaired kidney function are "stiffer" than the arteries in people with normal kidney function. Our
preliminary biopsy results suggest that the structural changes seen within the kidneys of people wilth diabetes
and non-albuminuric chronic kidney disesae (CKD) are different to those seen in subjects with CKD associated
with micro- or macro-albuminuria. Although there is a fair degree of overlap between the structural changes
seen in non-albuminuric and albuminuric subjects with CKD, we have not seen the classical structural changes
of diabetic nephropathy in non-albuminuric subjects. In contrast, subjects with non-albuminjuric CKD have
kidney biopsy samples that display changes ranging from mild to advanced arteriosclerosis. These findings
potentially suggest that therapies targeting arterial disease and arterial stiffness may improve kidney function in
people with diabetes and either albuminuric or non-albuminuric renal insufficiency.
Expected future outcomes:
We expecat that methods for estimating glomerular filtration rate (GFR) based on cystatin D along with the
measurement of urinary albumin excretion (AER) will emerge as the expected standard of care for monitoring
kidney function in subjects with diabetes. Our findings should also provoke clinical trials of therapies that
target arterial disease and arterial stiffness.
Name of contact:
George Jerums
NHMRC Research Achievements - SUMMARY
Email/Phone no. of contact:
ah-endo@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 385004
Start Year: 2006
CIA Name: A/Pr Zeinab Khalil
End Year: 2008
Admin Inst: Austin Hospital Medical Research Foundation Grant Type: NHMRC Project Grants
Main RFCD: Therapies and Therapeutic Technology
Total funding: $407,924
Title of research award:
A novel sensory nerve stimulator to improve neuropathy in patients with diabetesA novel sensory nerve
stimulator to improve neuropathy in patients with diabetes
Lay Description (from application):
We have developed a painless, self-applied, cheap, battery powered electrical stimulation treatment that
improves sensory nerve function in some people with diabetic peripheral neuropathy. We have tested this
technique in laboratory animals and in people with diabetes and have shown it is effective in some. We now
propose to test this technique in a large sample of people similar to the participants in the successful group of
our pilot study - 55-65 year old people with diabetes of shorter duration. In addition, older people up to 75
years of age, with up to 10 years duration of diabetes will be included separately. If successful, the electrical
stimulation could improve sensation leading to fewer ulcerations and amputations. Much suffering and
expense would be avoided. - The magnitude of reduction in suffering and expense can be judged from the fact
that people with diabetes have 15 times the risk of amputation as do people without diabetes. In Australia half
of non-traumatic amputations are done to people with diabetes. Foot ulcers precede amputations in most cases,
and in themselves cause much suffering and expense. Australia needs to act on this now because, if current
trends continue, the number of people with diabetes will increase as the population ages. -The number of
people aged over 65 will increase from around 2.3 million at present to over 6 million in the next half century.
The increase in those over 85 will be even more marked with numbers increasing four fold to over one million
people. Diabetes affects approximately 23% of people aged 75 or older.
Research achievements (from final report):
By 2051, it is estimated there will be 6 million Australians over the age of 65. Among people aged 65-74 some
20% are diagnosed with Diabetes Mellitus (DM). Many of those older patients suffer from the complications of
DM, which increase with increasing duration of DM, with lower extremity amputation (LEA) being a
significant complication of the disease. , The primary aim of this research is to test the a novel treatment, Low
Frequency Sensory Nerve Stimulation (LF-SNS), to reduce neuropathic symptoms in people with diabetic
peripheral neuropathy (DPN), and to improve sensory nerve function thus reduce DPN and consequently leg
ulcers. , We recently finalised data collection (end of May 2009) and broke the study code. The statistical
analyses to date show that the use of the relatively inexpensive, non-invasive, LF-SNS technique for 12 weeks
resulted in improvement in:, o
sensory nerve function that is
demonstrated by improvements in skin microvascular blood flow, time to initial flare and area of flare to
capsaicin as well as C fibres perception threshold., o
diabetic peripheral neuropathy
shown by both objective (Neuropathy impairment score) and subjective (Neuropathy symptoms profile)
measures., The significance of the project for Australians and the health care system: We were able to show
that the inexpensive, non-invasive, self-applied, sensory nerve stimulation technique (LF-SNS) improves
sensory nerve function and its continuous use could alleviate much burden of illness. It could potentially
prevent the formation of diabetic foot ulcers, or speed their healing, through preventing or improving DPN.
This would avert much suffering, including LEA, and health care expenditure. This study therefore provides
evidence needed to induce alterations to clinical practice; to have LF-SNS incorporated into the standard
management of such conditions as DPN, thus improving health outcomes for many Australians and providing
enormous health cost benefits.
Expected future outcomes:
Further research should look more fully into the effects LF-SNS has on aged skin. Since the current study
showed that C-fibre function improves with this therapy and as these nerves are necessary to maintain skin
integrity, then the regular use of LF-SNS may well help maintain (if not improve) skin integrity in the older
population. This in turn may help prevent the formation of ulcers.
NHMRC Research Achievements - SUMMARY
Name of contact:
Zeinab Khalil
Email/Phone no. of contact:
zeinab@unimelb.edu.au
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: 219167
CIA Name: Prof Christopher Goodnow
Admin Inst: Australian National University
Main RFCD: Not Allocated
Total funding: $3,348,000
Start Year: 2001
End Year: 2006
Grant Type: International Collaborations
Title of research award:
Molecular analysis of pathways in diabetes (MAPDB) studyMolecular analysis of pathways in diabetes
(MAPDB) study
Lay Description (from application):
The sequence of human genome provides a complete "part-list" of the genes and proteins that make our bodies.
A most unknown subset of these parts work together in molecular pathways that underpin susceptibility and
resistance to Type 1 diabetes and its complications. The MAPDB study will link patients, families, doctors,
genome experts, immunologists, physiologists, statisticians and data base programmers together to illuminate
these molecular pathways. In particular, the study will reveal genes and pathways that medicate protection
from diabetes and its complications - either by inhibiting T cell responses to pancreatic beta cells, protecting or
regenerating beta cells in the face of metabolic or immunologic stress, or protecting eyes and kidneys from the
damaging effects of high blood glucose. By identifying genes and proteins with these functions, the study will
enable new treatments to be developed aimed at augmenting these protective pathways, to prevent diabetes
starting in children at risk, and to preserve beta cell mass, protect transplanted stem cells or beta cells, and
prevent eye and kidney damage in people already affected by Type 1 diabetes. Genes and proteins that are
needed for T cell attack on beta cells will also be revealed. This information will enable new treatments to be
developed that block these processes, to prevent diabetes from starting, to preserve beta cell mass and to
prevent destruction of transplanted stem cells or beta cells. The MAPDB study will also identify different
versions-alleles- of many of the genes in the pathways described above. Particular combinations of these gene
alleles will be defines that can identify people at high risk of developing Type 1 diabetes, risk of cell or islet
transplantation rejection, or at most risk for eye/kidney complications. Different gene combinations may be
found that allow different kinds of Type 1 diabetes to distinguished. By creating ways to identify and
distinguish people's individual risk, the study will yield diagnostic tests to enable new treatments and clinical
trials to be targeted.
Research achievements (from final report):
1. Successfully established a unique approach for discovering genes and pathways regulating diabetes, by
combining a sensitised transgenic mouse strain with controlled variation of the mouse genome sequence., 2.
Discovered that the Aire gene is required for thymic deletion of islet-specific T cells. , 3. Discovered a novel
ubiquitin ligase gene and peripheral tolerance mechanism, repressing follicular helper T cells and the
costimulatory receptor ICOS, which when crippled leads to severe diabetes and islet autoantibodies in the
sensitised transgenic strain. That work - published as an Article in Nature - further validates our approach and
provides a unique entry point into new pathways for regulating T cells in lymph nodes and within islets. , 4.
Discovered a gene defect causing Type 2 diabetes, obesity, hypercholesterolemia, and liver pathology. This
gene is an orthologue of a gene recently identified as causing Type 2 diabetes and obesity in humans, and the
mouse strain provides a unique animal model for understanding the coordination between islet cells and
metabolism. , 5. Developed a new theory to explain the pathogenesis of Type 1 diabetes and other autoimmune
diseases.
Expected future outcomes:
The program is continuing with JDRF support, and has spun off a parallel collaborative project between
Australian and Singapore immunologists. These projects will continue to reveal new pathways and mechanisms
for controlling T cell destruction of islets to prevent and cure diabetes.
Name of contact:
Chris Goodnow
NHMRC Research Achievements - SUMMARY
Email/Phone no. of contact:
chris.goodnow@anu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 224206
CIA Name: Dr Charmaine Simeonovic
Admin Inst: Australian National University
Main RFCD: Transplantation Immunology
Total funding: $504,750
Start Year: 2003
End Year: 2005
Grant Type: NHMRC Project Grants
Title of research award:
Major xenoantigens for neovascularised porcine xenografts: the role of PERV and MHC in rejection and
toleranceMajor xenoantigens for neovascularised porcine xenografts: the role of PERV and MHC in rejection
and tolerance
Lay Description (from application):
Cross-species transplants (xenografts) of pig organs which use donor pig blood vessels are rejected by antibody
which recognises a special target (xenoantigen) on the pig blood vessels; other pig tissue transplants ("cellular"
transplants) which use recipient (not donor pig) blood vessels, are rejected by white blood cells called CD4 T
cells. The pig targets recognised by the xenoreactive CD4 T cells are unknown. We plan to identify the major
target(s) involved in "cellular" xenograft rejection. This information can then be used to specifically remove or
disable only those CD4 T cells capable of recognising the pig tissue and hence facilitate xenograft survival or
tolerance without immunosuppression. In this way, the remainder of the CD4 T cell population and immune
system is preserved intact. Recent studies have demonstrated that a pig virus (PERV) can be transmitted from
pig tissue xenografts to recipient tissues. Our studies have also suggested that the process of xenograft rejection
and the immunological recognition of transplant recipient cells infected with the pig virus, are closely related.
We plan to investigate this relationship and ascertain whether the immunological destruction of the pig tissue
xenograft is largely due to an immune response generated against the pig virus(es) it carries. As an extension of
this concept, we will investigate whether long-term xenograft survival (tolerance) is associated with lack of
immune reactivity to the pig virus and hence a continual capacity for pig virus to be transmitted to host tissues.
This outcome could result in the development of unwanted disease(s) in transplant patients. To prevent these
problems, our studies will determine whether it will be essential for such pig virus to be eliminated from the
donor pig tissue before transplantation, e.g. by the development of potent anti-viral agents and/or via the
development of pig herds that have been genetically engineered to be pig virus (PERV)-deficient.
Research achievements (from final report):
This project demonstrated that preimmunisation of mice with PERV virions (Porcine Endogenous Retrovirus)
purified from porcine cells generates a CD4 T cell response which induces accelerated rejection of porcine
thyroid xenografts. The xenografts were more rapidly rejected following immunisation with porcine PK15 cells
than with pig PBL and this did not correlate with higher Class I MHC levels but with production of more
PERV RNA and high production of PERV virions by the PK15 cells. Using PERV purified from an infected
human 293 cell line for preimmunisation, where the anti-PERV immune response generated was not
complicated by an accompanying immune response to swine MHC, accelerated rejection of pig thyroid
xenografts was observed. Likewise preimmunisation with purified PERV from porcine cells induced
accelerated rejection of xenografts of PERV-infected human 293 cells, where graft recognition was restricted
to PERV antigens alone (in the absence of non-PERV porcine antigens e.g. MHC). Using peptide
immunisation for ultimate clarification of the role for PERV xenoantigens, preimmunisation with PERV
peptide was more effective in inducing accelerated rejection than donor-specific swine MHC peptide.
Nevertheless, anti-pig spleen cells responded equally to each peptide in secondary MLRs. Xenograft tolerance
was not induced after treatment of neonatal mice with PERV (±irradiation), PERV-producing pig cells
(±irradiation) or PERV-ve pig PBL. PERV transmission to host cells following xenotransplantation was
transient, suggesting that PERV-infected host cells were cleared by the immune system early in the posttransplant period. We conclude that PERV xenoantigens can function as important transplantation antigens,
that MHC antigens may not be dominant over other cell surface antigens in a xenogeneic system and that
tolerance to xenografts may require non-immunogenic delivery of a range of porcine cell-surface xenoantigens.
Expected future outcomes:
NHMRC Research Achievements - SUMMARY
This study suggests that following clinical xenotransplantation of porcine tissue, PERV-infected humans cells
would be immunologically cleared in under-immunosuppressed patients but not in xenograft-tolerant
recipients. Since PERV produces xenoantigens recognised on pig tissue xenografts and may also infect
transplant recipients, the development of PERV-deficient pig herds should be beneficial.
Name of contact:
Charmaine Simeonovic
Email/Phone no. of contact:
Charmaine.Simeonovic@anu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 366772
Start Year: 2007
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: $575,948
Title of research award:
Genetic and molecular mechanisms dysregulating CD4 T cell tolerance in organ-specific autoimmunityGenetic
and molecular mechanisms dysregulating CD4 T cell tolerance in organ-specific autoimmunity
Lay Description (from application):
This project will analyse mechanisms that regulate CD4 T cells and normally prevent the immune system from
attacking parts of our own body. Unknown errors in the control of T cells result in autoimmune diseases such
as Type 1 diabetes, multiple sclerosis, Addison s disease and thyroid disease, where T cells damage or destroy
vital organs. In order to develop rational, specific methods for treating and preventing these diseases, it is
necessary to identify and understand the genetic and biochemical mechanisms that normally control T cell
responses to self components, and how inherited defects lead these mechanisms to break down. The project
focuses on defining how CD4 T cell regulation breaks down in a well established but poorly understood
example of polygenic inherited susceptibility to autoimmune disease. Polygenic diseases are those where
susceptibility is inherited in a complex way involving many different genes either acting together or in
opposition, and the molecular basis for this kind of inheritance is particularly poorly understood. The project
will analyse the basis for this kind of inheritance pattern by analysing the direct action of diabetes susceptibility
genes at the level of the specific T cells responsible for autoimmune attack and in terms of the biochemical
pathways within the T cells that are dysregulated. By identifying the mechanisms and biochemical pathways
that are dysregulated in autoimmune disorders, the results of this project will concepts and targets for
understanding and diagnosing autoimmune diseases and for developing new drugs or vaccines to prevent T
cells damaging vital organs and cure these diseases.
Research achievements (from final report):
The study identified a large program of genes whose expression is induced during the elimination of forbidden
clones of T cells within the thymus. This information advances understanding about how the body normally
avoids autoimmune diseases such as Type 1 Diabetes, thyroid disease, multiple sclerosis, rheumatoid arthritis,
systemic lupus, and many other diseases that collectively affect five percent of Australians. The study also
identified how inherited susceptibility to diabetes and other autoimmune diseases, in the NOD mouse model of
these disorders, results from faults in the induction of the clone elimination gene program. This result provides
a molecular map for understanding the complex pattern of inherited susceptibility to autoimmune diseases.
This will enable future research to predict individuals at most risk of autoimmunity, and to tailor prevention or
treatment at the underlying cause of these illnesses.
Expected future outcomes:
We are continuing to refine the components of the gene program that eliminates forbidden clones of T cells in
the thymus, testing the function of key elements of the program and how they are altered by subtle inherited
differences, and expect to submit further high impact publications on this during 2009.
Name of contact:
Chris Goodnow
Email/Phone no. of contact:
Chris.Goodnow@anu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 418077
CIA Name: A/Pr Christopher Nolan
Admin Inst: Australian National University
Main RFCD: Endocrinology
Total funding: $480,828
Start Year: 2007
End Year: 2009
Grant Type: NHMRC Project Grants
Title of research award:
Biochemical basis of islet beta-cell compensation and failure in normal pregnancy and gestational diabetes
mellitusBiochemical basis of islet beta-cell compensation and failure in normal pregnancy and gestational
diabetes mellitus
Lay Description (from application):
The factors causing the current world-wide crisis of rapidly rising diabetes prevalence remain poorly
understood. Of potential major importance, however, is the hypothesis that abnormalities in the maternal
metabolic environment, as occur in gestational diabetes (GDM) (diabetes that develops in pregnancy), result in
abnormal development of metabolic systems in the baby resulting in higher risk of adult onset diabetes in the
babies. Therefore, it is of importance to understand the mechanisms causing GDM, such that effective
measures can be developed to counter this passing on of diabetes risk from mother to baby. It is known that a
key factor causing GDM is failure of maternal pancreatic islet beta-cells to compensate for increased demands
for insulin production in pregnancy. Poorly understood, however, are the cellular mechanisms of islet beta-cell
compensation in normal pregnancy and failure of this compensation in GDM pregnancy. We have recently
shown that there is a pathway of fat metabolism (triglyceride/ free fatty acid cycle) within the islet beta-cell
that has an important role in amplyfing insulin secretion necessary to maintain normal blood glucose and
protecting the islets from failure in obese rats. The major focus of this project is to test the hypothesis that this
pathway has a key role in the adaptation of pancreatic islets to normal pregnancy and its dysfunction
contributes to the causation of GDM. Of great interest from preliminary findings is that a "master" regulator of
glucose and fat metabolism, PGC1alpha, is markedly reduced in islets during normal pregnancy. Studies will
also be directed to PGC1alpha's role in islet adaptation to pregnancy and failure in GDM. We expect that
successful completion of this project will lead to the development of highly targeted counter measures to
prevent GDM and to slow and reverse the current epidemic of diabetes.
Research achievements (from final report):
For SPECIFIC AIM 1, we showed that enhanced islet function in late pregnant rats can partly be explained by
increased augmentation of glucose-stimulated secretion by fatty acids. Furthermore, increased glucosestimulated fatty acid esterification and lipolysis processes, consistent with increased glycerolipid/fatty acid
cycling, is associated with the increased fatty acid effect on secretion. These results are consistent with
alterations in islet lipid signaling processes being involved in beta-cell compensation for insulin resistance in
pregnancy., For SPECIFIC AIM 2, we confirmed our preliminary data that PGC1α is significantly reduced in
islets in pregnancy. , For SPECIFIC AIM 3, we established a previously described surgical model of
intrauterine growth restriction (IGR) in Sprague-Dawley rats. Our IGR pups are resistant to developing obesity,
gestational diabetes or diabetes compared to controls. Most interesting, is the recent finding that the IGR rat
has severely dysmorphic pancreatic islets with evidence of extensive iron accumulation. Pancreatic beta-cell
mass is preserved in this model though, suggesting the islets of our model are very robust with excellent
proliferative capacity. The results are indicative of an effect of IGR on islet iron metabolism. Iron is known to
be highly toxic to the beta-cell, such this the effects of IGR on increasing the risk of type 2 diabetes later in life
could be due to iron toxicity. This very novel and exciting result is the basis for application for ongoing
NHMRC funding.
Expected future outcomes:
Two further publications are being written. One related to the role of glycerolipid/fatty acid cycling in islet
beta-cell compensation for insulin resistance in pregnancy. The second relates to the severely abnormal islet
morphology and islet iron accumulation in our model of intrauterine growth restriction.
Name of contact:
NHMRC Research Achievements - SUMMARY
Christopher J Nolan
Email/Phone no. of contact:
christopher.nolan@anu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 418101
CIA Name: Prof Geoffrey Farrell
Admin Inst: Australian National University
Main RFCD: Hepatology
Total funding: $449,592
Start Year: 2007
End Year: 2009
Grant Type: NHMRC Project Grants
Title of research award:
MECHANISMS OF DISORDERED HEPATIC LIPID PARTITIONING IN NON-ALCOHOLIC
STEATOHEPATITISMECHANISMS OF DISORDERED HEPATIC LIPID PARTITIONING IN NONALCOHOLIC STEATOHEPATITIS
Lay Description (from application):
Fatty liver is the commonest form of liver disease. It is strongly associated with obesity and maturity onset
diabetes. The majority of cases of fatty liver disease cause no complications, but when inflammation and liver
damage also occur, in the condition of non-alcoholic steatohepatitis or NASH, liver scarring and eventually
cirrhosis or liver cancer can result. The reason why some people with fatty liver disease develop NASH and
others do not ("benign" or "simple steatosis") is unknown and is the subject of this research. The studies will
be performed in a novel mouse model of obesity and diabetes, the "fat aussie" mouse, in which all animals
develop fatty liver disease after a few months. When fat aussie mice are fed a "Macdonald's diet" [high in
saturated fat] they develop full-blown NASH with liver scarring. Before NASH develops in fat aussie mice,
blood levels of adiponectin (a protein produced from fat storage cells) fall. Together with high blood insulin
and high blood sugar levels, it is proposed that these changes are what leads to an extraordinarily high build up
of fat (lipid) molecules in the liver, to the extent that the fat ultimately damages the liver in a process called
lipotoxicity. The planned research will first test whether this hypothesis is correct, and then set about ways to
prevent or reverse such a dangerous build up of fats in the liver. Strategies include a high olive oil diet (which
is protective in another model of steatohepatitis), correction of blood adiponectin levels, lowering of insulin
and blood sugar levels. The anticipated results are a much better understanding of how complications come
about in fatty liver disease, and therefore insights into how this disorder can be prevented or reversed in those
who are predisposed.
Research achievements (from final report):
1.
Confirmation that the most likely
candidate hepatic lipid pool in NASH is free cholesterol, including documentation of plasma membrane
localisation as the most important subcellular site., 2.
Demonstration that the hepatic lipid
(fatty acid and cholesterol) uptake pathway cluster differentiation protein (CD)36 is pivotal to NASH
pathogenesis., 3.
Discovery that genetic background
has major modulatory effects on development of insulin resistance, dyslipidemia and fall in serum adiponectin
in mice with hyperphagic obesity fed a high fat diet., 4."outstanding young investigator" recognition to Derrick
van Rooyen at Australian Gastroenterology Week 2010.
Expected future outcomes:
Understanding the causation of severe forms of fatty liver disease
Name of contact:
Professor Geoff Farrell
Email/Phone no. of contact:
geoff.farrell@anu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 418138
CIA Name: Prof Christopher Parish
Admin Inst: Australian National University
Main RFCD: Autoimmunity
Total funding: $3,242,772
Start Year: 2008
End Year: 2013
Grant Type: International Collaborations
Title of research award:
Role of heparan sulfate, heparanase inhibitors in the development and prevention of type 1 diabetesRole of
heparan sulfate, heparanase inhibitors in the development and prevention of type 1 diabetes
Lay Description (from application):
Our recent studies have shown that a special protein (an enzyme called heparanase) and the special
carbohydrate (heparan sulfate or HS) that it degrades, play a previously unrecognised role in the development
of Type I diabetes (T1D) in mice. We will explore whether destructive immune cells use heparanase to damage
insulin-producing islets and deplete them of HS, resulting in islet cell death and T1D. We will develop new
agents to inhibit this damage, prevent T1D and protect islet transplants.
Research achievements (from final report):
Type 1 diabetes (T1D) is a serious, growing health concern world-wide. There is currently no treatment
available that can prevent or modify the progression of T1D. While insulin treatment keeps T1D individuals
reasonably healthy, serious vascular complications can develop in the long-term. There exists a critical need for
better treatments for T1D. In this project we have demonstrated that insulin-producing islet beta cells
unconditionally require the complex sugar "heparan sulfate" (HS) for their survival . We have found that the
normal HS content of beta cells is severely compromised and ultimately ablated during T1D disease onset and
progression, as well as during the isolation of insulin-producing islets. We have demonstrated that the HSdegrading enzyme, heparanase, plays a previously unrecognised role in the development of T1D in diabetesprone NOD mice and that T1D can be prevented by treatment with dual activity drugs that act as both
heparanase inhibitors and HS mimetics. Significantly, we have shown that beta cells deficient in HS following
islet isolation can be rescued in vitro from dying in culture and from free radical-induced damage by HS
replacement, using these same dual activity drugs. Our findings suggest that heparanase inhibition and HS
replacement early in T1D disease, using our chemically modified heparin derivatives which have a high safety
profile, could play vital roles in preserving beta cell survival and function, thereby preventing T1D progression
and associated T1D complications in humans.
Expected future outcomes:
We propose that our heparanase inhibitor/HS replacer drugs will prevent degradation of islet beta cell and
extracellular HS required for T1D progression. Our future aim is to advance our novel HS-preserving therapy
to the clinic for preventing T1D progression in newly diagnosed humans, initially as a proof-of-concept clinical
trial.
Name of contact:
Christopher Parish
Email/Phone no. of contact:
Christopher.Parish@anu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 525473
CIA Name: Dr Claire Larter
Admin Inst: Australian National University
Main RFCD: Gastroenterology and Hepatology
Total funding: $199,486
Start Year: 2009
End Year: 2013
Grant Type: Early Career Fellowships (Australia)
Title of research award:
Obesity, insulin resistance and hepatocarcinogenesis: metabolic mediators and molecular mechanismsObesity,
insulin resistance and hepatocarcinogenesis: metabolic mediators and molecular mechanisms
Lay Description (from application):
Liver cancer (or hepatocellular carcinoma, HCC) is the 3rd most common cause of cancer death, with the
incidence in Australia increasing. Recently, it has been shown that obesity, diabetes and fatty liver disease can
lead to HCC; this project will explore how metabolic diseases promote HCC. The role of insulin and fatty acids
in promoting DNA damage and cell growth will be examined. Understanding how metabolic disease increases
HCC risk will improve prevention strategies and possible treatments.
Research achievements (from final report):
This project provided some validated that liver cancer development is accelerated in genetically obese animals,
and that dietary composition may alter liver cancer development.
Expected future outcomes:
N/A
Name of contact:
Claire Larter
Email/Phone no. of contact:
claire.larter@gmail.com
NHMRC Research Achievements - SUMMARY
Grant ID: 585411
CIA Name: Prof Geoffrey Farrell
Admin Inst: Australian National University
Main RFCD: Gastroenterology and Hepatology
Total funding: $533,541
Start Year: 2010
End Year: 2013
Grant Type: NHMRC Project Grants
Title of research award:
MECHANISTIC ROLE OF CHOLESTEROL IN NON-ALCOHOLIC STEATOHEPATITISMECHANISTIC
ROLE OF CHOLESTEROL IN NON-ALCOHOLIC STEATOHEPATITIS
Lay Description (from application):
Fatty liver is present in 15-30% of Australians, related to obesity, diabetes and heart attack. Two-thirds of cases
reverse easily. The remainder evolve to non-alcoholic steatohepatitis (NASH), liver damage that can lead to
cirrhosis and liver failure. This research seeks to find out why some cases of fatty liver lead to NASH, and
whether cholesterol that accumulates in the livers of mice with NASH is what causes that damage. If so, we
will find new ways to treat NASH by diet or drugs.
Research achievements (from final report):
Using models of steatosis and steatohepatitis NASH we tested the hypothesis that cholesterol mediates liver
cell injury and inflammatory recruitment in non-alcoholic fatty liver disease NAFLD. We characterised the
molecular pathways whereby cholesterol accumulates in NASH showing that hepatic uptake via CD36 and
LDLR are increased as is esterolysis of cholesterol esters to free cholesterol FC. Conversely cholesterol
synthesis biotransformation to bile acids and canalicular secretion of FC and bile acids is suppressed. In
primary hepatocytes high insulin levels up-regulated LDLR via SREBP2 and down-regulated bile salt export
pump. Derrick van Rooyen PhD student won the Gastroenterological Society of Australia's YIA in October
2010 for this work now published in GASTROENTEROLOGY and reviewed in Hepatology. We designed
dietary and drug interventions to modulate hepatic FC levels to test the hypothesis about cholesterol and NASH
pathogenesis. Removing cholesterol from high fat diet prevented FC accumulation and NASH; increasing
dietary cholesterol exacerbated hepatic FC accumulation ALT apoptosis macrophage recruitment NASH
severity and liver fibrosis. Ezetimibe alone or with artorvastatin reduced hepatic FC to reverse JNK activation
apoptosis macrophage recruitment NASH and fibrosis; this work has been published in the Journal of
Hepatology 2013. Using primary hepatocyte cultures we have devised a novel method to load cells with FC.
Such FC loading activates the JNK1 pathway to cause mitochondrial injury and cell death by both apoptosis
and necrosis. JNK1 inhibitors cyclosporine A a mitochondrial protectant and caspase 3 inhibitors protected
hepatocytes from cholesterol-induced injury and are potential new therapies for NASH.
Expected future outcomes:
we have now established a method for studying the effects of cholesterol crystals on Kupffer cell activation via
the NLRP3 inflammasome
Name of contact:
Geoff Farrell
Email/Phone no. of contact:
geoff.farrell@anu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 244622
Start Year: 2003
CIA Name: Dr Karen Andrews
End Year: 2007
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: Early Career Fellowships
(Australia)
Main RFCD: Endocrinology
Total funding: $267,150
Title of research award:
Endothelial control of vascular tone in microvessels of diabetic ratsEndothelial control of vascular tone in
microvessels of diabetic rats
Lay Description (from application):
Not Available
Research achievements (from final report):
Nitric oxide (NO) is an important and potent compound produced by the endothelium. NO acts on the smooth
muscle layer allowing blood vessels to dilate. NO is produced by a catalyst (enzyme) called endothelial nitric
oxide synthase (eNOS) in the endothelial cells from an amino acid, L-arginine. L-arginine is also broken down
by another enzyme called arginase.Where the two enzymes (arginase and eNOS) are found together, arginase
may potentially interfere with the conversion of L-arginine to NO. Several conditions and diseases such as high
cholesterol, high blood pressure, diabetes, stroke and heart failure have reduced NO production. This reduction
in NO contributes to abnormal endothelial (vascular) function. Treatment of alleviating impaired endothelial
function is by administration of a drug called GTN (glyceryl trinitrite). GTN is an organic nitrate, which
increases NO availability in the blood vessel and therefore enhances the relaxation of blood vessels. However,
a limitation with this drug is the development of tolerance (the effects of the drug are diminished) that occurs
after long-term use. We have found that inhibiting arginase II prevents the development of tolerance.
Furthermore we have also investigated another potential drug which we have found does not develop tolerance,
Angeli's salt, which acts by donating nitroxyl (HNO), a compound that differs from NO by only one electron.
Expected future outcomes:
Further investigation into nitric oxide signalling may result in better therapeutic agents for cardiovascular
disease
Name of contact:
Karen Andrews
Email/Phone no. of contact:
karen.andrews@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 268900
Start Year: 2004
CIA Name: Prof Bronwyn Kingwell
End Year: 2006
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Endocrinology
Total funding: $283,500
Title of research award:
A novel mechanism for manipulation of peripheral glucose utilization in patients with type 2 diabetes
mellitus.A novel mechanism for manipulation of peripheral glucose utilization in patients with type 2 diabetes
mellitus.
Lay Description (from application):
Significance: Over 600,000 Australians have type 2 diabetes (approximately half are undiagnosed) and it is
estimated that this number will increase substantially to 10% of the adult population over the next 10 years. At
the conclusion of this grant we expect to understand whether specific signalling molecules might plausibly
represent the basis of a novel therapeutic approach to control blood glucose. If successful, this work could
contribute to improved metabolic control and prevention of diabetic complications through new blood glucose
lowering agents. Hypotheses: Muscle is the major site of glucose disposal in the body and the two most
relevant stimuli for glucose uptake into muscle are insulin and muscle contraction (exercise). The insulin
pathway is impaired in patients with type 2 diabetes leading to high blood glucose and complications. Glucose
uptake in response to exercise however appears to be normal in patients with type 2 diabetes. Indeed we have
evidence to suggest that this pathway may compensate for impaired insulin action in type 2 diabetes. We
hypothesise that molecules activated by contraction (exercise) may be useful as therapies to improve resting
glucose control in type 2 diabetic patients. Aims: We plan a series of three studies to examine whether glucose
uptake may be improved both acutely and chronically at rest by an agent implicated in exercise mediated
glucose uptake.
Research achievements (from final report):
Excess glucose in the blood stream, as occurs in diabetes causes blood vessel damage which ultimately leads to
serious complications in the kidneys, eyes, peripheral blood vessels and most importantly, the heart. Insulin
removes glucose from the blood into metabolically active tissues including muscle where it can be used as a
fuel source. Recent research has shown that exercise also causes movement of glucose from the blood into
muscle, but via a mechanism which does not involve insulin and may involve the molecule nitric oxide (NO).
The aim of this project was to determine whether NO donor drugs could represent a new therapeutic approach
to the treatment of diabetes through simulation of the effects of exercise. We have shown that acute
administration of the NO donor drug, sodium nitroprusside increases glucose uptake into the leg muscle under
resting conditions. We expanded this study to examine the effects of chronic NO administration on glucose
metabolism. This involved an initial pilot investigation to determine which of two nitrate drugs was the best
NO donor. The data from this study suggested that chronic nitrate therapy did not influence glucose
metabolism. Concurrent research within the lab however suggested that good (HDL) cholesterol may play an
important role in glucose and fat metabolism. We pursued this observation and now have convincing data that
HDL increases glucose uptake and stimulates fat metabolism in cells derived from human muscle. Our findings
offer a common molecular mechanism explaining the role of low HDL levels in diabetes and provide a
rationale for designing therapies to raise levels of circulating HDL to address the metabolic syndrome, type 2
diabetes mellitus and obesity., ,
Expected future outcomes:
Our finding that HDL stimualtes glucose and fat metabolism is being pursued in a proof of concept clinical
trial. If successful, these studies will support a unified concept describing the aetiology of the metabolic
syndrome, and provide a rationale for therapeutic approaches to raise levels of circulating HDL to manage the
metabolic syndrome, type 2 diabetes mellitus (DM) and obesit
Name of contact:
A/Prof Bronwyn Kingwell
NHMRC Research Achievements - SUMMARY
Email/Phone no. of contact:
bronwyn.kingwell@baker.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 268904
Start Year: 2004
CIA Name: A/Pr Terri Allen
End Year: 2007
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: Career Development Fellowships
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $352,000
Title of research award:
The role of the AT2 receptor in diabetes associated atherosclerosis: novel interventions and human studiesThe
role of the AT2 receptor in diabetes associated atherosclerosis: novel interventions and human studies
Lay Description (from application):
Not Available
Research achievements (from final report):
We were able to determine that some of the commonly used drugs for treating high blood pressure may also
give good results for other end organ disease such kidney and large blood vessel disease. I was also able ot
show that a treatmetn fo rcancer ws laso useful in preventing diabetic blood vessel disease. Since getting the
CDA I have now been successful in obtaining a NHMRC Senior research fellowship
Expected future outcomes:
More combinatin therpay may be used for treating patients with cardiovascular disease and diabetes
Name of contact:
Terri Allen
Email/Phone no. of contact:
terri.allen@baker.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 268909
Start Year: 2004
CIA Name: Prof Mark Cooper
End Year: 2008
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: Established Career Fellowships
Main RFCD: Endocrinology
Total funding: $796,750
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
In this period I made significant advances in the area of diabetic complications extending my original research
into renal disease into the major area of diabetic macrovascular disese. Furthermore, I was able to commence
very exciting studies on the phenomenon of metabolic memory which identified a key role for epigenetic
events in conferring sustained changes on genes as a result of past periods of elevated glucose levels. These
studies have led to new treatments which have intitally been performed in animal models and clinical studies
have just commenced for some of these treatments. It is hoped that such treatments will ultimately result in a
major decrease in the burden of diabetes, primarily as a result of the kidney and large blood vessel
complications which lead to heart disease and kidney failure.
Expected future outcomes:
We plan to further characterise at a molecular level the changes that occur in response to glucose in cells. We
are prediciting that new targets will be identified to generate new betetr treatments. It is hoped that such
treatments will ultimately result in a major decrease in the burden of diabetes, specifically its kidney and blood
vessel complications.
Name of contact:
Laurel Ring
Email/Phone no. of contact:
laurel.ring@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 268916
Start Year: 2004
CIA Name: A/Pr Josephine Forbes
End Year: 2006
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Endocrinology
Total funding: $431,700
Title of research award:
Interactions between advanced glycation and oxidative stress in diabetic renal and cardiac
complicationsInteractions between advanced glycation and oxidative stress in diabetic renal and cardiac
complications
Lay Description (from application):
Kidney and heart disease are serious complications of diabetes. These complications are the major cause of
disability and premature death in the western world. Studies from our group and others have shown that
diabetic complications appear to be a consequence of a number of different processes. These pathways include
a sugar dependent pathway of irreversible interactions between proteins such as collagen and sugar known as
advanced glycation. The process of advanced glycation alters the body's ability to renew these protein, hence
causing accelration of the ageing process. In fact, it is estimated that this process occurs almost fifty times
faster in diabetes. These sticky complexes accumulate in tissues causing disruption ot the normal tissue
structure. Our group has a drug which can act as scissors and cut the sticky sugar off the proteins allowing it to
be turned over. Unfortunately this does not fix all of the damage. These AGE molecules are involved in a
number of other harmful processes including the production of toxic oxygen derived molecules which are
harmful byproducts of diabetes. While these oxygen 'radicals' have been implicated in heart attack and stroke
their source has remained a mystery in diabetes. Previously, the only way to remove these molecules was to
mop them up with antioxidants such as Vitamin E. Antioxidants work slowly and so some damage is already
done before they 'detoxify' these oxygen radicals. We propose to use combinations of medicines to see if we
can achieve more effective protection against these processes in experimental diabetes. This may provide new
therapies for threatment of kidney and heart disease in diabetes.
Research achievements (from final report):
More than 1 million Australians have diabetes. Although diabetes per se is an enormous burden on our health
system it is in fact the complications of diabetes which are the most costly to both the patient themselves in
terms of quality of life and to our national health care budgets. In particular kidney disease as a consequence of
diabetes affects up to 40% of persons with diabetes. Diabetic kidney disease eventually leads to a lifetime of
kidney replacement therapy with dialysis (artificial blood filtration/cleaning) or transplants. In addition kidney
disease is the major predictor of heart attacks and strokes which are the prominent causes of death in diabetic
patients. Current first line therapy for patients with diabetic kidney disease is with drugs that bklock the actions
of the hormone angiotensin. Although these drgus have improved kidney outcomes in these patients, their
kidney disease is only slowed down but not cured. Therefore it is clear that other complimentary strategies are
required to combat this epidemic of kidney disease as a consequence of diabetes., Our research has focussed on
medicines which have the capacity to decrease specific abormalities seen in the kidney as the result of high
sugar. These include the formation of toxic oxygen free radicals and "toffee like" additions on proteins called
advanced glycation end products (AGEs). Over the course of this project we discovered a number of
detrimental events which affect kidney cell function caused specifically by AGEs and oxygen free radicals
which are not normalised by the currently used clinical therapy for diabetic kidney disease. In particular these
are abnormalities in the energy producing systems within the cells in "powerstation" compartments known as
mitochondria. We have identified two significant targets for new medicines which will likely lead to a
reduction in diabetic kidney disease.
Expected future outcomes:
We anticipate that follow up studies of these medicines both preclinically and then subsequently in humans will
produce promising new therapies for patients with diabetic kidney disease.
Name of contact:
NHMRC Research Achievements - SUMMARY
Josephine Forbes
Email/Phone no. of contact:
josephine.forbes@baker.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 268918
Start Year: 2004
CIA Name: Prof Mark Cooper
End Year: 2006
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Endocrinology
Total funding: $414,000
Title of research award:
Role of advanced glycated end products in mediating diabetes associated atherosclerosisRole of advanced
glycated end products in mediating diabetes associated atherosclerosis
Lay Description (from application):
Diabetes is on the increase in the Western world and with this increase comes the burden of increased
complications. One of these is atherosclerosis which leads to heart attacks, strokes and gangrene. In this grant
we consider the role of a biochemical reaction where sugar attaches to proteins called advanced glycation and
how it may promote atherosclerosis. We will use novel drugs to block vessel damage in a model of diabetic
mice prone to atherosclerosis. We will also inject these sugar-attached proteins (AGEs) into mice to see how
they directly influence the vessel wall. We will characterise molecular and cellular changes in response to
these AGEs. These studies will ultimately lead to better treatments to prevent, slow down or reverse blood
vessel damage in diabetes.
Research achievements (from final report):
Our studies have provided further evidence that the AGE/RAGE axis plays a pivotal role in diabetes associated
macrovascular disease. We could demonstrate that inhibition of AGE formation with aminoguanidine and the
cross link breaker ALT 711 (alagebrium) were able to significantly reduce plaque area in a model of diabetes
accelerated atherosclerosis, the diabetic apoE knockout mouse. More recntly, we have also shown that AGE
inhibition in established atherosclerosis was able to attenuate progression of preexisting atherosclerosis. The
anti-atherosclerotic effect of AGE inhibitors was associated with attenuation of inflammatory and pro-fibrotic
pathways. Specifically, we were able to demonstrate potential molecular mediators of vascular injury including
CTGF, VCAM-1 and MCP-1 which appeared to be directly regulated via the AGE/RAGE axis.
Expected future outcomes:
These studies have provided further evidence that the AGE receptor RAGE plays a critical role in
macrovascular disease in the presence and absence of diabetes. Therefore, RAGE has become a potential target
in the prevention and treatment of diabetes associated atherosclerosis. Further studies will now investigate
RAGE knockout and transgenic mice, overeexpressing RAGE in endothelial cells.
Name of contact:
Professor Mark Emmanuel Cooper
Email/Phone no. of contact:
mark.cooper@baker.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 268928
Start Year: 2004
CIA Name: A/Pr Peter Little
End Year: 2006
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $500,750
Title of research award:
Inhibition of c-Abl as a target for shortening glycosaminoglycan length on proteoglycans and preventing
atherosclerosisInhibition of c-Abl as a target for shortening glycosaminoglycan length on proteoglycans and
preventing atherosclerosis
Lay Description (from application):
The major health issue developing in Australia is vascular and cardiovascular disease resulting from obesity
and diabetes. Whilst prevention strategies based on lifestyle changes are preferable, treating cardiovascular risk
factors with the latest drugs has been shown to produce significant benefits but there is a large remaining
component of disease. New therapies are required and these will most likely target blood vessels directly. We
are working on the basic cause of atherosclerosis with the aim of finding a mechanism and developing a drug
to prevent the process - we have recently identified such a target and it is the subject of this research grant
proposal. A group of very large molecules which have recently received increasing attention are the
proteoglycans, combined protein-sugar molecules which are heavily coated with negatively charged groups. It
has recently been published in the prestigious journal, Nature, that the binding of lipids in the blood to the wall
of the blood vessel is the main cause of atherosclerosis. Proteoglycans are the molecules which cause the lipids
to be stuck in blood vessels. Specifically, the length of the sugar (GAG) chains on the proteoglycan determines
the binding of the lipids. We have now discovered a pathway and have one drug candidate which prevents the
elongation of the GAG chains on proteoglycans. The exciting possibility is use of this agent with existing
agents, for example, to use a "statin" drug to lower blood cholesterol and a new GAG elongation inhibitor to
prevent the cholesterol sticking in the wall. The outcome will be the proof of the potential of a target for the
direct therapy of atherosclerosis and a clear pathway for the development of a drug to be used in people
susceptibility to atherosclerosis which is particularly people with diabetes.
Research achievements (from final report):
Cardiovascular disease is the largest cause of premature death in the developed world. Most of the treatments
for cardiovascular disease are targeted at changes in blood borne factors and blood pressure. This strategy has
limited effectiveness with only 30 per cent of disease being prevented. We are working on targets within the
wall of the blood vessel that directly affect of course of the disease. Our specific target is the sugar chains
(glycosaminoglycans) on molecules known as proteoglycans where the sugar chains have increased stickiness
for lipids (Low Density Lipoprotein cholesterol). A definitive study of human vessel has recently shown that
the binding of lipids to the sugar chains of proteoglycans is an initiating step in atherosclerosis. In this study we
have fully characterised several new drugs which can reduce the stickiness of glycosaminoglycan chains for
lipids. The studies have progressed as far as to demonstrate that a molecule highly characterised in the
laboratory in cell based studies can reduce lipid deposition in the wall of the blood vessel of high fat fed
animal. The hypotheses of targeting proteoglycans is new and our initial studies provide evidence that this
might be a valid target for the prevention of atherosclerosis.
Expected future outcomes:
The studies provide a pathway to the ultimate development of a product which includes a statin drug to lower
blood cholesterol and a proteoglycan inhibitor to block the binding of the cholesterol in the vessel wall. Further
studies will further characterise the target of the new drugs, describe the changes in proteoglycan occurring in
the vessel wall of animals and provide a pathway for the testin
Name of contact:
Peter Little
Email/Phone no. of contact:
NHMRC Research Achievements - SUMMARY
peter.little@baker.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 292902
Start Year: 2004
CIA Name: Prof Mark Febbraio
End Year: 2007
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: Established Career Fellowships
Main RFCD: Cell Physiology
Total funding: $373,000
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
In 2000, together with my collaborator Professor Bente Klarlund Pedersen, I made the vital discovery that
muscles produce and secrete cytokines that have biological reactivity. This formed the basis of my successful
SRFB application. During the period of my fellowship, we made the very important discovery that IL-6 and
other IL-6 family cytokines can be used as anti-obesogenic compounds and this has culminated in the
publications in journals such as Nature Medicine, Journal of Clinical Investigation, Cell Metabolism, Diabetes,
Journal of Biological Chemistry and FASEB Journal., as well as the filing of a patent for gp130 receptor
ligands as anti-obesity therapies.
Expected future outcomes:
I have recently filed of a patent for the use of gp130 receptor ligands as anti-obesity therapies. Our expected
future outcome is that we will take drugs that activate the gp130 receptor into clinical trials to treat obesity and
insulin resistance.
Name of contact:
Ebru Yaman
Email/Phone no. of contact:
ebru.yaman@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 317810
Start Year: 2005
CIA Name: A/Pr Dmitri Sviridov
End Year: 2009
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: Established Career Fellowships
Main RFCD: Medical Biochemistry: Lipids
Total funding: $595,500
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
Major achievements of our research are in the area or understanding the mechanisms and treating heart
diseases. Specifically, a substantial progress has been made in testing various forms of therapy aimed in raising
levels of good cholesterol. These studies were conducted on the laboratory level as well as in clinic. Two
approaches were tested, direct infusion of high density lipoprotein (good cholesterol) that was made in a tube,
and creating small molecules that can mimic the properties of good cholesterol. Both approaches are
progressing to clinical trials and may become a widely used therapy in few years. Another direction of our
research was investigating a connection between infectious diseases and heart diseases. Specifically we
established mechanisms of how HIV infection causes heart diseases and went further establishing new class of
compounds that may treat both HIV and heart disease. Further, we investigated the basic mechanisms of how
cells handle cholesterol and established new principles that can then be targeted for prevention and treating of
heart disease. Finally we conducted research establishing the mechanisms causing high risk of heart disease at
diabetes and obesity. Our finding would lead to new paradigms in treating and preventing heart disease.
Expected future outcomes:
In the future we will continue to develop new treatments for heart disease, new prevention measures and new
predictive testing methods for heart disease and conditions that are associated with high risk of heart disease.
The priority will be given to infectious diseases, diabetes and obesity.
Name of contact:
Dmitri Sviridov
Email/Phone no. of contact:
Dmitri.Sviridov@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 317832
Start Year: 2005
CIA Name: Prof Mark Cooper
End Year: 2007
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Endocrinology
Total funding: $453,750
Title of research award:
Understanding vasoactive hormone pathways in diabetic complicationsUnderstanding vasoactive hormone
pathways in diabetic complications
Lay Description (from application):
High blood pressure damages tissues. In clinical practice blood pressure is measured in large arteries, such as
the brachial artery in the arm. However, it is the pressure within the organ such as the kidney that actually
causes the damage. In particular, the sieving apparatus of the kidney (called the glomerulus), is especially
sensitive to the effects of pressure. In diabetes, the pressure within the glomerulus is high because its outflow
valve (called the efferent arteriole) is tightly constricted. Therefore even if blood pressure is thought to be
normal when measured in the arm, it may still be excessively high within the kidney. Studies have already
shown that lowering within-kidney pressure may have a major impact on the progression of kidney disease in
diabetes. However, to date this reduction of within-kidney pressure has been sub-maximal. The planned
studies will involve the use of new compounds which have more powerful effects in reducing the formation or
action of hormones which promote constriction of vessels in the kidney leading to elevated pressure within the
kidney. Furthermore, some of these very new agents can open up or dilate these kidney vessels thereby
achieving excellent reductions in the pressure inside the kidney. The proposed studies aim to examine new
strategies for preferentially lowering pressure within the kidney down to these ideal levels. These hormones
also have other effects which could be relevant to non-kidney sites of injury in diabetes including blood vessels
and the retina.
Research achievements (from final report):
Activation of the renin angiotensin system (RAS) is considered to be among the most important mediators of
renal damage in diabetes. Traditionally, the RAS has been viewed as simply a vasoconstrictor pathway, arising
from the formation of angiotensin II (Ang II) and the subsequent activation of the AT1 receptor. While
blocking the actions of Ang II attenuates renal damage, it does not prevent renal hypertrophy or hyperfiltration
in experimental models of type 1 diabetes. Similarly, in individuals with diabetes, the protection afforded by
angiotensin converting enzyme (ACE) inhibitors is only partial and, despite their treatment, many patients with
diabetes ultimately develop diabetic renal disease, albeit at a slower rate. Recently, the traditional view of the
RAS has been challenged by the discovery of novel components that regulate vasodilator and trophic pathways
in the kidney, in a balancing and complementary manner to traditional vasoconstrictor actions. Specifically,
these novel components include the angiotensinase ACE2, the vasodilatory angiotensin peptide, Ang 1-7 and
the AT2 receptor subtype, which act to counterbalance the actions of ACE, Ang II and the AT1 receptor
respectively in the kidney., , The major finding from our study was that the expression of ACE2 is significantly
modified by diabetes, which impacts on the pathogenesis of kidney disease. Of clinical importance is the fact
that for ACE inhibitors (therapy used in diabetic kidney disease) to work maximally a normal functioning level
of ACE2 is required. Indeed, this may explain why not all people with diabetes respond well to ACE inhibitor
therapy.
Expected future outcomes:
It is now possible for patients with diabetic kidney disease to have their levels of ACE2 measured. This will
allow us to predict patients who will respond well to ACE inhibitor therapy. The non-responders can then be
treated with other treatment regimes.
Name of contact:
Professor Mark E Cooper
Email/Phone no. of contact:
NHMRC Research Achievements - SUMMARY
mark.cooper@baker.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 325645
Start Year: 2005
CIA Name: Dr Clinton Bruce
End Year: 2009
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: Early Career Fellowships
(Australia)
Main RFCD: Endocrinology
Total funding: $308,250
Title of research award:
Fatty acid oxidation and muscle insulin sensitivityFatty acid oxidation and muscle insulin sensitivity
Lay Description (from application):
Not Available
Research achievements (from final report):
Understanding the mechanisms that cause obesity and insulin resistance is a key to understanding the
aetiology of, and developing preventative strategies for, Type 2 diabetes. A prominent feautre of obesity and
insulin resistance is defective fat metabolism in muscle which manifests as an inability to burn fat. As a result
fat builds up in muscle which causes insulin resistance and Type 2 diabetes. This project examined wheter
targeting pathways to accelerate the fat burning capacity of muscle can improve insulin sensitivity. The results
obtained from these studies show that being able to burn more fat prevents the build up of fat within muscle.
This leads to an improvement in insulin sensitvity. Therefore, implementing strategies to increase fat use is
likely to be beneficial in the treatment of type 2 diabetes.
Expected future outcomes:
It is expected that future outcomes will determine exactly which type of fat is causing the insulin resistance in
muscle and whether increasing the ability to burn fat will prevent these fats from accumulating.
Name of contact:
Clinton Bruce
Email/Phone no. of contact:
clinton.bruce@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 342115
Start Year: 2005
CIA Name: Prof Mark Febbraio
End Year: 2007
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $360,750
Title of research award:
Novel therapeutic interventions to increase blood flow to skeletal muscleNovel therapeutic interventions to
increase blood flow to skeletal muscle
Lay Description (from application):
Over the past decade it has become clear that the cytokine interleukin (IL)-6 is produced in and released from
tissues such as fat and muscle to mediate metabolic processes. In this respect, it acts in a "hormone like"
manner. During this period it has also become apparent that the hormone insulin increases blood flow to
skeletal muscle. There is emerging evidence that IL-6 plays a role, not only in metabolic and signalling
processes within skeletal muscle, but also in blood flow. This project will determine whether the cytokine IL-6
is a viable therapeutic target in the treatment of blood flow disorders in patients with type 2 diabetes. This has
major ramifications since type 2 diabetes has reached pandemic levels in Australia and is estimated to cost the
community approximately 800 million dollars per year.
Research achievements (from final report):
We hypothesised that IL-6 may promote endothelial cell signaling and capillary recruitment leading to
enhanced insulin stimulated glucose uptake. Contrary to our hypothesis, we observed that IL-6 blunted insulin
stimulated endothelial cell signalling and capillary recruitment via the activation of TNFalpha. However, IL-6
alone did not negatively affect either endothelial cell signalling or capillary recruitment. This is significant
because the data demonstrate that insulin can act in a pro-inflammatory manner
Expected future outcomes:
The future outcomes may be that, from a clinical perspective, one should be cautious when prescribing insulin
as a glucoselowering therapy in obesity since circulating IL-6 is elevated in obesity and these two proteins act
in a synergistic manner to promote inflammation in endothelial cells
Name of contact:
Mark A Febbraio
Email/Phone no. of contact:
mark.febbraio@baker.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 367602
Start Year: 2006
CIA Name: A/Pr Josephine Forbes
End Year: 2008
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Nephrology and Urology
Total funding: $333,813
Title of research award:
Mediation pathways for the receptor for advanced glycation end products in diabetic nephropathyMediation
pathways for the receptor for advanced glycation end products in diabetic nephropathy
Lay Description (from application):
Excess sugar in the blood from diabetes is detrimental and can accelerate a process where sugar attaches itself
to proteins, fats and DNA. Although facilitated by high sugar, the reaction occurs happily in the presence of
low sugar with high levels of free oxygen radicals. These complexes are called advanced glycation end
products or AGEs. In addition, we ingest vast volumes of AGES from our diet which are taken into the blood.
These AGEs are known to be involved in the development of kidney disease in diabetic subjects. AGEs exert
most of their effects on the body by binding to specific proteins, the most common and nasty of which is the
receptor for advanced glycation end products, RAGE. RAGE is a known participant in other serious diseases
such as Alzheimer's disease and evidence is mounting for its central role in the development of kidney disease
in diabetic subjects. There is not much known about the processes which mediate RAGE which is why this is
the aim of this proposal. This will enable us to stop the relentless progression of kidney disease in diabetes.
Research achievements (from final report):
Diabetes and specifically its resultant kidney complications affects more than 400,000 Australian. There is no
cure for this disease and the only available treatments are costly and undesirable for patients, including kidnye
transplants and dialysis. This proposal involved a systematic series of studies to explore the modulation of a
protein, RAGE which is known to be involved in the the development of kidney disease in diabetes. This was
explored by changing the interactions of other proteins with RAGE ligand (by reducing AGEs or the AGE
clearance receptor, AGE-R1), by altering the ratio of good (soluble) to bad (full length) RAGE present in the
diabetic kidney and by modulating cell signalling pathways for RAGE via NF-κB. Each of these regulatory
pathways is a potential therapeutic target to dampen the expression of full length pathogenic RAGE to halt the
progression of diabetic nephropathy. It is essential that new therapies, which have additive or synergistic
actions to current therpies used for diabetic kidney disease such as RAS blockers, are developed as diabetic
nephropathy continues to provide a significant socio-economic burden on the community.
Expected future outcomes:
We anticipate that within the next stage of these studies, we will establish whether activation of other AGE
receptors such as AGE-R1, can produce more "good" soluble RAGE facilitating improvements in kidey disease
as the result of diabetes.
Name of contact:
Josephine Forbes
Email/Phone no. of contact:
josephine.forbes@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 367620
Start Year: 2006
CIA Name: Prof Mark Cooper
End Year: 2008
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Nephrology and Urology
Total funding: $454,023
Title of research award:
Role of growth and transcription factors in tubulointerstitial injury in diabetesRole of growth and transcription
factors in tubulointerstitial injury in diabetes
Lay Description (from application):
Progressive kidney disease occurs as a result of a range of molecular and cellular pathways. One of the
commonest causes of kidney disease is diabetes and this appears to be partly related to increased expression
and action of certain growth factors such as CTGF. These factors promote the deposition of scar tissue in the
kidney and one of the ways these promote this scarring is to change a cell s behaviour so that it now lays down
collagen. This proposal will not only focus on how CTGF promotes scarring but will explore 2 novel factors
called Snail and Slug which can act directly on particular genes such as CTGF to inhibit these deleterious
effects. By further characterising these pathways involving Snail, Slug and CTGF in the kidney it will be
possible to generate new targets and therapies for various forms of progressive kidney disease including
diabetic kidney disease.
Research achievements (from final report):
A common cause of kidney disease is diabetes and is partly related to increased expression and action of
growth factors such as TGFβ and CTGF. These factors promote the deposition of scar tissue in the kidney by
acting on a novel class of intracellular regulator molecules called microRNAs, to change the cell's
characteristics such that cells begin laying down excess collagen leading to fibrosis in the kidney. In this study
we identified that most of the profibrotic actions of TGFβ occur via CTGF and that blocking CTGF may in fact
be a method by which renal fibrosis may be controlled. We further observed that the expression of a number of
kidney specific microRNA molecules was altered by these factors in renal cells and was associated with
increased expression of extracellular proteins as happens in renal fibrosis. Similar observations were also made
in a model of experimental diabetes. Interestingly, restoring the expression of these molecules reversed some of
the effects of TGFβ.
Expected future outcomes:
Confirmation that microRNAs are altered in the kidney as a consequence of diabetic kidney disease presents us
with a unique opportunity to study these novels molecules in the context of renal fibrosis. This work may
potentially lead to the development of novel strategies for the treatment of diabetic kidney disease.
Name of contact:
Phillip Kantharidis
Email/Phone no. of contact:
Phillip.Kantharidis@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 367621
Start Year: 2006
CIA Name: Prof Mark Cooper
End Year: 2008
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Endocrinology
Total funding: $438,521
Title of research award:
Role of epigenetic mechanisms in diabetic vascular complicationsRole of epigenetic mechanisms in diabetic
vascular complications
Lay Description (from application):
Diabetic complications including heart attacks, strokes, kidney disease and blindness appear to be related to the
high glucose (sugar) level but how glucose itself induces end-organ injury remains to be fully determined. In
this proposal it is suggested that the long-term damaging effects of glucose relate to its ability to damage the
regulation of genes by directly affecting DNA and its covering known as histones. Specifically glucose,
possibly by altering certain biochemical pathways called oxidation pathways, interferes with enzymes which
affect the structure of DNA and related molecules resulting in altered expression of many proteins. One of
these proteins known as NF kappa B is activated in diabetes, probably by mechanisms involving regulation of
these enzymes which play a central role in modifying gene structure. By clarifying the exact mechanisms at a
molecular level that mediate the effect of glucose on genes and proteins it will be possible to target these
molecules and develop new treatments to prevent, retard or reverse the blood vessel complications that are so
common in diabetes.
Research achievements (from final report):
Diabetic complications including heart attacks, strokes, kidney disease and blindness appear to be related to the
high glucose (sugar) level but how glucose itself induces end-organ injury remains to be fully determined. In
this study we defined how long-term damaging effects of glucose are related to the regulation of genes by
directly affecting DNA and its covering known as histones. Specifically glucose, by altering certain
biochemical pathways called oxidation pathways, interferes with enzymes which affect the structure of DNA
and related molecules resulting in altered expression of many proteins. One of these proteins known as NF
kappa B is activated in diabetes, probably by mechanisms involving regulation of a particular enzyme which
play a central role in modifying gene structure. By clarifying the exact mechanisms at a molecular level that
mediate the effect of glucose on genes and proteins it will now be possible to target these molecules and
develop new treatments to prevent, retard or reverse the blood vessel complications that are so common in
diabetes.
Expected future outcomes:
By clarifying the exact mechanisms at a molecular level that mediate the effect of glucose on genes and
proteins it will now be possible to target these molecules and develop new treatments to prevent, retard or
reverse the blood vessel complications that are so common in diabetes.
Name of contact:
Assam El-Osta
Email/Phone no. of contact:
assam.el-osta@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 367625
Start Year: 2006
CIA Name: A/Pr Merlin Thomas
End Year: 2008
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Nephrology and Urology
Total funding: $297,523
Title of research award:
Circulating low -molecular weight AGEs in the development and progression of diabetic
complicationsCirculating low -molecular weight AGEs in the development and progression of diabetic
complications
Lay Description (from application):
High levels of sugars seen in patients with diabetes leads to damage of many organs including the heart, the
eyes and the kidneys. These high sugars cause damage through a number of mechanisms, one being the
formation of advanced glycation end products or AGEs, formed by the irreversible reaction between proteins
and glucose. This reaction leads to a change in the shape and function of AGE-modified molecules that
progressively contributes to organ damage. AGEs also bind and activate specific receptors that promote the
damage and scarring of tissue. Where the glucose concentration is high, AGEs accumulate much more quickly.
This is one reason why patients with good sugar control do better than those who are unable to control their
blood sugars. The importance of this AGE pathway is illustrated by the fact that blocking the formation of
AGEs is able to prevent kidney damage in animals with diabetes. In addition, exposure to AGEs can cause
diabetes-like changes in the absence of high sugars. Our laboratory is a world leader in the study of the
advanced glycation and methods blocking this process. The research proposed will investigate circulating
levels of AGEs in experimental animals and patients with diabetes, and correlate them with the development
and progression of complications of diabetes
Research achievements (from final report):
AGEs are formed when sugars bind to protein, making it sticky, sweet and brown. In food like chocolate and
caramel, this reaction is appetizing. But when sugar accumulates in diabetes, this same process contributes to
blindness, kidney failure and heart disease. This grant has examined the damage caused by AGEs and ways of
measuring their accumulation. In diabetes, tissue such as lens, skin and cartilage as well as circulating proteins
become fluorescent. I have shown that this correlates with the development and severity of diabetic
complications. This increase in fluorescence has been attributed to the accumulation of AGEs. In this work, we
describe the chemical identity of the major 'AGE- fluorophores' in the circulation. I have used this data to
develop quantitative assays that will increase understanding of this chemistry. I have also been able to measure
each these fluorophores in over 300 blood samples and determined which peaks are best associated with
cardiovascular and kidney (dys)function. The potential utility of this methodology can be illustrated by my
studies in children with type 1 diabetes, that showed that a gluten-free diet also reduced the accumulation of
fluorophores. I have also completed in experimental studies some of their potential regulators. For example,
mice deficient in the receptor for advanced glycation (RAGE) do not increase circulating levels of
fluorophores, paralleling their protection from diabetes associated vascular complications. Similarly animals
that do not increase their kidney function in response to diabetes, actually have an increase in circulating
fluorophores and a worse outcome.
Expected future outcomes:
It is anticipated that a better understanding of the mediators of circulating fluorescence will lead to improved
risk assessment not only in diabetes but also cardiovascular disease and ageing. It will also facilitate new trials
of interventions whose focus is to reduce advanced glycation.
Name of contact:
A/Prof Merlin Thomas
Email/Phone no. of contact:
mthomas@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 367628
Start Year: 2006
CIA Name: Prof Peter Little
End Year: 2011
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: Established Career Fellowships
Main RFCD: Medical and Health Sciences not elsewhere classified
Total funding: $639,194
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
The focus of the work was cardiovascular disease and the underlying process of atherosclerosis.
Atherosclerosis in humans commences with a pre-inflammatory stage involving the trapping of lipids in the
vessel wall by modified proteoglycans followed by an inflammatory stage involving multiple immune cells
resulting in the formation of atherosclerotic plaques. Treatments for atherosclerosis are directed at the above
risk factors but even in clinical trials these strategies only prevent one third of the cardiovascular events. What
is required is a greater understanding of the mechanisms of plaque formation and determinants of stability and
liability in the vessel wall and the generation of novel therapeutic agents which address these drivers of the
atherosclerotic process. My laboratory worked on modified proteoglycans and we discovered a process and a
drug that could inhibit the modifications to proteoglycans in the vessel wall that makes it stickier for
cholesterol - this drug reduced lipid deposition in a mouse model of atherosclerosis. We following work will be
aimed at identifying the exact target of the action of the drug and developing new agents suitable for use in
humans. Such as agent would be used with a lipid lowering statin drug with the aim of greatly reducing
cardiovascular events.
Expected future outcomes:
These studies have contribuited to the understanding of the disease process of atherosclerosis and provided a
patwhay to the development of new targetted drugs to prevent this disease and reduce heart attacks.
Name of contact:
Prof Peter Little Am
Email/Phone no. of contact:
peter.little@rmit.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 367629
Start Year: 2006
CIA Name: Prof Bronwyn Kingwell
End Year: 2008
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: Established Career Fellowships
Main RFCD: Clinical Sciences not elsewhere classified
Total funding: $357,250
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
Since award of the fellowship in 2006 my laboratory has made significant progress in three main, clinically
relevant areas., 1. HDL and metabolism, Demonstration that HDL cholesterol lowers blood glucose in patients
with type 2 diabetes through a variety of novel mechanisms including both increased glucose uptake into
skeletal muscle and increased secretion of insulin from pancreatic beta cells. This work has implications for the
use of HDL-raising agents for treatment of type 2 diabetes., 2. Peripheral Arterial Disease, Demonstration that
the ACE inhibitor, ramipril has efficacy in controlling claudication more effectively than current therapies. Our
work demonstrates that ramipril has benefits beyond reduction in vascular events in this high-risk population,
and provides substantial improvement in clinical symptoms and quality of life. , 3. Marfan Syndrome, In
patients with Marfan syndrome, therapy with the ACE inhibitor, perindopril for 24 weeks reduced aortic
stiffness by up to 60% and aortic diameter by between 3 and 7 mm. These are substantial changes over a
relatively short intervention period and are highly clinically significant. It is likely that ACE inhibitor therapy
would delay the need for surgery and reduce the incidence of aortic rupture. , ACE inhibitors are now
recommended in the latest guidelines for patients with peripheral arterial disease and Marfan Syndrome as a
result of my work.
Expected future outcomes:
All three areas listed above will move into further clinical trials in 2010 and will make important contributions
to the evidence base for treatment of type 2 diabetes, peripheral arterial disease and abdominal aortic aneurysm.
Name of contact:
Prof. Bronwyn Kingwell
Email/Phone no. of contact:
bronwyn.kingwell@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 367649
Start Year: 2006
CIA Name: A/Pr Barbora de Courten
End Year: 2013
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: Career Development Fellowships
Main RFCD: Endocrinology
Total funding: $490,219
Title of research award:
Anti-inflammatory therapy:a novel approach to improve insulin sensitivity in obesityAnti-inflammatory
therapy:a novel approach to improve insulin sensitivity in obesity
Lay Description (from application):
Media Summary not available
Research achievements (from final report):
My research plan for my CDA fellowship was to investigate links between chronic inflammation and its causal
relationship to type 2 diabetes. , We have shown for the first time that certain pathways (NF?B /I?B kinase and
JNK pathways) which has been shown to play important role in animals are driving also the relationship in
humans. We have also shown that neither pathway is associated with insulin signalling in humans so other
mechanisms are likely to be involved. We have also shown from NIH study designed and partially conducted
by me that salicylates, which are known to lower glucose levels, do not improve insulin resistance or insulin
secretion directly but rather act on insulin clearance., The next step was to develop interventions, which
reduced chronic inflammation and improve risk for diabetes. Advanced glycation end-products (AGEs), which
increase chronic low-grade inflammation, present risk for development of diabetes via reduction in insulin
sensitivity and secretion in rodents. I designed and completed a NHMRC funded clinical trial (ID 586655)
where we have shown that a reduction in AGEs can improve risk for diabetes. I have designed also another
NHMRC funded trial (ID1047897) that explores use of vitamin D, which also ameliores chronic inflammation,
for prevention of insulin resistance. In addition, we have found for the first time in the cross-sectional study
that carnosine, over-the-counter available food additive, which reduces both chronic inflammation and AGEs,
is associated with insulin resistance. We are currently conducting a clinical trial to explore this area with
scarcity of human data.
Expected future outcomes:
Future studies are warranted to both explore new interventions (and mechanisms involved) which reduce
chronic low grade inflammation and by that improve diabetes outcomes.
Name of contact:
Barbora De Courten
Email/Phone no. of contact:
barbora.decourten@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 367651
Start Year: 2006
CIA Name: A/Pr Karin Jandeleit-Dahm
End Year: 2008
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: Career Development Fellowships
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $272,000
Title of research award:
Elucidating the metabolic & inflammatory pathways in diabetic macrovascular disease: experimental and
clinical studies.Elucidating the metabolic & inflammatory pathways in diabetic macrovascular disease:
experimental and clinical studies.
Lay Description (from application):
Not Available
Research achievements (from final report):
During the time of the NHF/NHMRC CDA I have made significant discoveries in terms of the role of
inflammation and oxidative stress in diabetes related vascular complications. For example, I could show that
the AGE/RAGE axis plays an important role in diabetes assictaed atherocslerosis. RAGE deletion in diabetic
apoE KO mice was associated with reduced plaque area via effects on inflammation and ROS generation.
Furthermore, I could demonstrate that oxidative stress related pathways play a major role in diabetic vascular
comlications. Specific NOX KO mice demonstrate less plaque area and microvascular disease in diabetes. I
have also been able to confirm findings obatined in our expetimental animal models in human atherosclerotic
plaques from patients with and without diabetes.
Expected future outcomes:
The results of my ongoing research will further delineate the role of inflammation and oxidative stress in
diabetes associated vascular complications. Furthermore, based on our experimental findings, we have
identified novel treatment targets. These findings need to be translated to the clinical context.
Name of contact:
Karin Jandeleit-Dahm
Email/Phone no. of contact:
karin.jandeleit-dahm@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 367652
Start Year: 2006
CIA Name: Prof Merlin Thomas
End Year: 2010
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: Career Development Fellowships
Main RFCD: Medical Biochemistry: Carbohydrates
Total funding: $390,260
Title of research award:
Circulating AGEs; markers and mediators of renal injury in diabetes.Circulating AGEs; markers and mediators
of renal injury in diabetes.
Lay Description (from application):
Not Available
Research achievements (from final report):
Diabetes is the single most common cause of kidney disease in the Australia. Although a number of factors
operate in diabetes, one pivotal pathway appears to be the formation and accumulation of advanced glycation
end products (AGEs). My research has characterized the role of AGEs in kidney disease associated with
diabetes and hypertension, as well as their impact in cardiovascular complications associated with these
diseases. This research has demonstrated the pivotal role of AGEs in these complications and the potential
utility of targeting them in the prevention of diabetic complications. This grant has examined novel ways of
measuring their accumulation. In this work, I have described the chemical identity of the major 'AGEfluorophores' in the circulation. I have used this data to develop quantitative assays that will increase
understanding of this chemistry. The potential utility of this methodology can be illustrated by my studies in
children with type 1 diabetes, that showed that a gluten-free diet also reduced the accumulation of
fluorophores. I have also completed in experimental studies some of their potential regulators. In particular, I
have shown that their ability to activate specific receptors is able to activate a range of pathogenic pathways,
and in the absence of these receptors, complication may not only be prevented, but potentially detrimental
stimuli (like fat and high glucose) can be transformed into protective mediators. For example, mice deficient in
the receptor for advanced glycation (RAGE) do not increase circulating levels of fluorophores, paralleling their
protection from diabetes associated vascular complications. .
Expected future outcomes:
It is anticipated that a better understanding of AGEs will lead to improved risk assessment not only in diabetes
but also cardiovascular disease and ageing. It will also facilitate new trials of interventions whose focus is to
reduce advanced glycation products and their detrimental effects on human health.
Name of contact:
Prof Merlin Thomas
Email/Phone no. of contact:
mthomas@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 367660
Start Year: 2006
CIA Name: Dr Anna Calkin
End Year: 2012
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: Early Career Fellowships
(Australia)
Main RFCD: Endocrinology
Total funding: $241,125
Title of research award:
Diabetes-Associated Atherothrombosis: Characterisation of Platelet Activation andDiabetes-Associated
Atherothrombosis: Characterisation of Platelet Activation and
Lay Description (from application):
Not Available
Research achievements (from final report):
Stroke and heart attack are the major causes of death amongst individuals with diabetes, which is of great
concern given that over 1 million Australians are estimated to have diabetes. Small blood cells known as
"platelets" stick to diseased areas of the blood vessel, accumulating at the site of injury to form a blood clot.
However, excessive accumulation of platelets can lead to a clot that may block blood flow resulting in a stroke
or heart attack. It has been suggested that individuals with diabetes have platelets which are "hyper-reactive" or
"stickier" and thus are more likely to form larger blood clots, leading to a greater risk of stroke and heart attack.
It is known that high levels of HDL "good" cholesterol are associated with a reduced risk of heart disease but
little is known about its effects on platelet reactivity. My studies focused on the effect of a particular type of
HDL called reconstituted HDL (rHDL) which is cholesterol "poor". We demonstrated that individuals with
type 2 diabetes remarkably had a greater than 50% reduction in the reactivity of their platelets after a 4-hour
infusion of rHDL. Further studies demonstrated that the cholesterol poor rHDL was able to accept cholesterol
from the platelets themselves which made them less reactive and behave more like platelets seen in nondiabetic individuals. This suggests that raising levels of rHDL may be a promising therapy to reduce the risk of
stroke and heart attack in individuals with diabetes., , CAVEAT: If this summary and future outcomes is to be
made available to the public please contact bronwyn.kingwell@bakeridi.edu.au to comply with MTA
agreements with CSL.
Expected future outcomes:
Future studies are required to investigate therapies that can raise levels of "cholesterol poor" HDL in both the
short- and long-term as well as examine whether raising cholesterol poor HDL has benefit above and beyond
current anti-clotting therapies.
Name of contact:
Anna Calkin
Email/Phone no. of contact:
acalkin@mednet.ucla.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 392206
Start Year: 2006
CIA Name: Prof Mark Febbraio
End Year: 2008
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Cell Metabolism
Total funding: $602,673
Title of research award:
Ciliary Neurotrophic Factor: a novel theraputic agent for the prevention of muscle insulin resistanceCiliary
Neurotrophic Factor: a novel theraputic agent for the prevention of muscle insulin resistance
Lay Description (from application):
In 1995 leptin was discovered and scientists world-wide hoped that this was the "great panacea" in the
treatment of obesity related disorders. Alas, from 1995-1997 the identification of a novel cytokine inducible
compound termed suppressor of cytokine signaling (SOCS) that negatively regulated leptin signalling and lead
to "leptin resistance", quashing hopes for a viable "anti-obesogenic" drug. Recently, however, work from our
group has demonstrated that the neuropoietic cytokine, ciliary neurotrophic factor (CNTF), can act in an antiobesogenic fashion in a manner similar to leptin. However, unlike leptin, when we place rodents on a high fat
diet, the effects of CNTF persist and override induction SOCS proteins. This project will examine the
biochemical pathways that allow the actions of CNTF to persist in the presence of diet-induced obesity. This is
of major significance because in completing this work, the potential for the development of peripheral tissue
drug targets for the treatment of obesity related diseases are both tangible and realistic.
Research achievements (from final report):
The aim of this project was to elucidate the mechanisms by which CNTF can act as an anti-obesogenic drug
and, in contrast with leptin, overcome the negative effects of elevated SOCS protein expression. We showed
that CNTF can overcome leptin resistance both centrally and in peripheral tissue . We showed that while
STAT3 signalling was not an absolute requirement for gp130 receptor signalling, truncating the cytoplasmic
domain of the gp130 receptor distal to the SHP2 domain (Tyr759) resulted in a failure for CNTF to adequately
signal through the gp130 receptor.
Expected future outcomes:
The second phase of the grant was to design a cytokine that may have better efficiency than CNTF as a
therapeutic strategy. We synthesized a novel protein by transferring the putative "LIF receptor (LIFR) binding
module" from CNTF to IL-6. We hope that this compound will result in a new drug.
Name of contact:
Mark Febbraio
Email/Phone no. of contact:
mark.febbraio@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 418916
Start Year: 2007
CIA Name: Prof Mark Cooper
End Year: 2009
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $389,522
Title of research award:
Role of advanced glycation end products and their receptors in diabetes accelerated atherosclerosisRole of
advanced glycation end products and their receptors in diabetes accelerated atherosclerosis
Lay Description (from application):
Diabetes is on the increase in the Western world and with this increase comes the burden of increased
complications. One of these is atherosclerosis which leads to heart attacks, strokes and gangrene. In this grant
we consider the role of a biochemical reaction where sugar attaches to proteins called advanced glycation and
how these advaced glycated proteins (AGEs) interact with specific receptors to promote atherosclerosis. We
will use novel animal models overexpressing the receptor RAGE or with deletion of the gene for this receptor.
We will investigate if these animals are protected against blood vessel disease when made diabetic and will
unravel the mechanisms involved. Furthermore we will investigate novel drugs to block vessel damage in a
model of diabetic mice prone to atherosclerosis. One of these interventions will involve giving a free form of
the receptor RAGE which will trap the circulating AGEs and prevent them from binding to RAGE in the blood
vessel wall. This therpeutic principle has been shown in animals to prevent blood vessel disease in diabetes.
We will also feed the sugar-attached proteins (AGEs) to these mice prone to atherosclerosis and to the
genetically modified mice to see how these proteins directly influence the vessel wall even if diabetes is not
present. These studies will ultimately lead to better treatments to prevent, slow down or reverse blood vessel
damage in diabetes.
Research achievements (from final report):
The findings of this grant showed that RAGe deletion protected form diabetes associated atherosclerosis via
effects on inflammation and fibrosis. Furthermore, there was attenuation of vascular macrophage and
lymphocyte infiltration suggetsing that RAGE expression on immune cells mat play an important part in
diabetes related atherosclerosis.
Expected future outcomes:
These findings further support the ongoing drug discovery program to develo RAGE antagonists for clinical
use in diabetci vacsular complications.
Name of contact:
Prof Mark Cooper
Email/Phone no. of contact:
mark.cooper@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 418920
Start Year: 2007
CIA Name: Prof Bronwyn Kingwell
End Year: 2009
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Endocrinology
Total funding: $349,683
Title of research award:
Novel Metabolic Actions of HDL with Potential Therapeutic Implications for Type 2 Diabetes and the
Metabolic Syndrome.Novel Metabolic Actions of HDL with Potential Therapeutic Implications for Type 2
Diabetes and the Metabolic Syndrome.
Lay Description (from application):
There are currently in excess of 170 million patients diagnosed with type 2 (late onset) diabetes in the world
and this figure is expected to double by 2030. Almost one in four Australians 25 years and over has either
diabetes or a condition of impaired glucose metabolism. These conditions pose significant problems in terms
of both individual suffering and economic burden. Poor diet, sedentary lifestyles with resultant weight gain
and increased obesity rates underlie the escalating prevalence of type 2 diabetes. Our proposal investigates a
novel approach to treat these conditions. We have identified an important link between HDL (good)
cholesterol and glucose and fat metabolism in human muscle cells. We have shown that HDL increases
glucose uptake into muscle cells. This process would be expected to remove glucose from blood vessels
where it causes damage which ultimately contributes to heart attack and stroke. Furthermore, we have shown
that HDL increases the amount of fat the body uses. HDL may therefore not only remove damaging fat from
blood vessels, but also help to reduce body weight. Our study seeks to determine the relevance of these
mechanisms in both healthy individuals and patients with type 2 diabetes. At the conclusion of this grant we
expect to understand whether HDL raising strategies may be a an effective new therapy for type 2 diabetes.
Specifically, we will understand: 1. how HDL exerts its beneficial effects and 2. whether acute and chronic
HDL elevation using drugs improves glucose and fat metabolism in humans.
Research achievements (from final report):
, This research concerned HDL (good cholesterol) which is well known for its protective actions in the context
of cardiovascular disease. The most significant outcome was the discovery that HDL elevation over a 4 hour
period lowers blood glucose in patients with type 2 diabetes. Studies in cells have uncovered novel
mechanisms in both muscle and the pancreas to explain our observation. This work represents a paradigm shift
from low HDL being a bystander to active player in the glucose intolerance of the metabolic syndrome, and is
highly relevant to the rising epidemic of diabetes and its dramatic impact on cardiovascular disease. These
findings suggest that HDL elevation could represent a novel therapeutic approach to preventing and treating
type 2 diabetes., , , , , , , .
Expected future outcomes:
This work is being further developed through a subsequent NHMRC project grant to determine whether
elevation of HDL over a period of weeks results in sustained blood glucose reduction. Chronic HDL raising
therapies are already in advanced clinical development for vascular disease so this work is primed for rapid
translation should the outcome of our subsequent investigations be positive.
Name of contact:
Prof. Bronwyn Kingwell
Email/Phone no. of contact:
bronwyn.kingwell@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 418937
Start Year: 2007
CIA Name: A/Pr Karin Jandeleit-Dahm
End Year: 2009
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Endocrinology
Total funding: $460,397
Title of research award:
The role of specific Nox isoforms in diabetic renal disease and atherosclerosisThe role of specific Nox
isoforms in diabetic renal disease and atherosclerosis
Lay Description (from application):
Diabetes is increasing worldwide and in Australia. The majority of patients with diabetes eventually will
develop kidney disease and will die of blood vessel complications such as heart attacks and stroke. Oxidative
stress (the generation of free oxygen radicals that react quickly with other proteins in the body causing tissue
damage) has been suggested to play an important role in kidney and blood vessel disease observed in diabetic
patients. This proposal will try to identify and measure specific proteins in the kidney and vessels that are
involved in the production of oxidative stress. We aim to define which one of these proteins is the most
important. We will assess in detail how these proteins work and which other factors are activated leading to
tissue damage. The ultimate goal of these studies is to find new treatment options to decrease the production of
harmful molecules in the kidney and blood vessel wall thereby reducing kidney failure, heart attacks, stroke
and gangrene in diabetes. In our studies, we will use medications already used in patients to treat high blood
pressure in diabetes. In preliminary studies we have shown that these drugs also reduce oxidative stress.
Furthermore, we will use novel, more specific treatments that the harmful ptoteins. Through a collaboration
with Professor Harald Schmidt and his group from Germany who have recently moved to Monash University
in Melbourne we will have access to mice in which specific genes for harmful proteins have been knocked out.
These mice when made diabetic will most likely develop less or no kidney and blood vessel damage. Our
studies will help to identify the most important oxidative stress producing protein associated with kidney and
vessel disease. This knowledge will lead to more effective and more potent treatments for patients with
diabetes to prevent, stop or even improve kidney and blood vessel disease thereby reducing disability and death
in this high risk group of patients.
Research achievements (from final report):
We have investigated the role of oxidatie stress in diabetic kidney disease and atherosclerosis. We showed that
there is significant upregulation of oxidative stress parameters in the kidney and vasculature and that treatments
which redcue oxidative stress such as apocynin or the ARB candesartan were associated reduced end-organ
injury in diabetes. Furthermore we have successfully generated mice with specific deletions of the various
NOX isoforms (NOX1, 2 and 4) on the C57 and apoE -/- background and have induced diabetes in these mice.
Expected future outcomes:
In our ongoing studies we are now investigating the mechanisms how the NOX isoforms mediate renal and
vascular injury. Furthermore, we have now established floxed NOX knockout mice and are in process of
generating cell specific NOX knockout mice which will be investigated in the context of diabetes.
Name of contact:
Karin Jandeleit-Dahm
Email/Phone no. of contact:
karin.jandeleit-dahm@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 431200
Start Year: 2007
CIA Name: Dr Jeremy Jowett
End Year: 2009
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Endocrinology
Total funding: $558,920
Title of research award:
Identification of Novel Genes Influencing Development of Type 2 DiabetesIdentification of Novel Genes
Influencing Development of Type 2 Diabetes
Lay Description (from application):
Type 2 diabetes is usually associated with obesity and is often part of a wider disturbance affecting an
individual's energy metabolism. The number of affected people with type 2 diabetes has trebled since 1981 in
Australia and is still increasing. Apart from individual suffering, this presents a major public health burden for
the country (approx $3 billion annually). Currently available lifestyle based and pharmaceutical therapies are
inadequate to control the increasing numbers of affected individuals. Unfortunately the cause of disease is
poorly understood, although genetic factors are known to be important, in other words it "runs in the family".
This project proposes to identify some of these factors (genes) and how they contribute to the disease. Using
"molecular flags" on the DNA (like DNA fingerprinting) we have previously found that a small region on
chromosome 12 is likely to carry one or more of these disease genes. But there are over 100 genes in the
region. To help choose the most likely candidates first for testing, we have developed an automated computer
database searching program ranked the genes based on what is already known about them. We have also taken
a large number of physiological measures in a large group of people. Some of these measures are controlled by
the same chromosome 12 region - thus to improve our chances of finding the genes quickly we will look at
those that change the most between people with diabetes and people without diabetes. In this project we shall
investigate the 20 genes most likely affect diabetes based on changes in physiological measures and what is
already known about them.A successful finding means we will know more about the mechanism of disease
development and be able to better develop new therapies for treatment and prevention. If none of these genes
are the culprit, we would continue examination of the next set of genes likely to be involved and so on until we
are successful.
Research achievements (from final report):
, Type 2 diabetes is associated with obesity and is part of a wider disturbance affecting an individual's energy
metabolism. The number of affected people with type 2 diabetes has trebled since 1981 in Australia and is still
increasing. Currently available lifestyle based and pharmaceutical therapies are inadequate to control the
increasing numbers of affected individuals., , Unfortunately the cause of disease is poorly understood, although
genetic factors are known to be important, in other words it "runs in the family". In this project we sought to
dramatically improve our understanding of these factors (genes) and how they contribute to the disease. We
examined over 2,000 variations in over 100 genes using our advanced lab technology and tested for whether
they contribute to type diabetes. We were able to see some suggestions that new genes were involved, however
stronger scientific evidence is needed., , The main impediment was the unexpectedly high level of natural
variation in human genes, and this project has taught us that despite using state of the art technology in 2007,
this would not appear to be sufficient for the task. Fortunately the project has allowed us to successfully
complete the first test and proof of principle experiments of an even newer technology that can find and catalog
variation far more efficiently and cost-effectively than previously possible. We have applied for further funding
to carry this important work forward into the next exciting stage that may reveal the genes, and lay the
foundations for new drugs and personalised medicine.
Expected future outcomes:
Our results and those from others on genetic studies to date show that the best possible approach for gene
discovery is in combining new sequencing technology with family cohorts. We propose to do exactly that in
our new application to improve understanding of disease mechanism for new treatments in the future.
Name of contact:
NHMRC Research Achievements - SUMMARY
Dr Jeremy Jowett
Email/Phone no. of contact:
jeremy.jowett@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 431203
Start Year: 2007
CIA Name: A/Pr David Dunstan
End Year: 2009
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Public Health and Health Services not elsewhere classified
Total funding: $334,955
Title of research award:
A behavioural intervention for the adoption & maintenance of physical activity in type 2 diabetesA behavioural
intervention for the adoption & maintenance of physical activity in type 2 diabetes
Lay Description (from application):
For people with type 2 diabetes (T2DM) it is essential that blood glucose levels are managed well to reduce the
risk of developing complications. Physical activity is essential for maintaining glucose levels because it helps
make the muscles use glucose more effectively. In particular, being active through strength training not only
improves blood glucose levels, but can be very effective for maintaining good physical functioning, which is
known to be reduced by having T2DM. This study builds on our earlier research which demonstrated
significantly improved blood glucose levels from a strength training program for older adults with T2DM. The
strength training program is to be administered nationally in a research to practice trial (Lift for Life); however,
the original research found that those who did not complete the program as it was intended (ie, poor adherence)
did not show significant improvements in blood glucose levels. Furthermore, maintenance of strength training
exercises after completion of the program was poor and resulted in return of blood glucose levels back to prestarting levels. In people without diabetes, we have collected pilot data that shows that the use of behavioural
strategies based on behavioural theories whereby each person's motivations and barriers are taken into
consideration is more effective than the traditional one-treatment-fits-all approach. This study will evaluate the
effectiveness of using behavioural strategies for improving adherence and maintenance to the Lift for Life
strength training program (Enhanced L4L) for older adults with T2DM compared with the Standard L4L
program. It will also follow-up participants 6 months later to determine the extent to which the changes in
behaviour can be maintained. The study will provide information that will assist in the design, delivery and
uptake of programs to improve treatment strategies in older adults with T2DM through the maintenance of
healthier behaviours and lifestyles.
Research achievements (from final report):
The project has successfully recruited a large community-based sample of 318 older adults with or at risk of
developing type 2 diabetes to establish the impact of adding regular motivational strategies (including
telephone counselling) to a national strength training program (Lift for Life) on program adoption and
maintenance compared to the existing standard Lift for Life program (ie: without motivational strategies). A
major achievement has been the excellent retention rates during the 6-month intervention and 6-month followup phases, with more than 80% of the participants completing the 12-month study. The project is the largest
study of its kind in the world to have investigated the effects of strength training in the 'real-world' setting in
people with or at risk of developing type 2 diabetes. It will provide new insights into the success of various
proven motivational strategies to encourage people to not only 'start-up' their strength training program within
local community facilities, but also whether the addition of these strategies helps people to maintain their
strength training by themselves once the initial intervention has been completed. Additionally, the effects of the
Lift for Life program, both with and without motivational strategies, on muscle strength and blood glucose
levels will be examined.
Expected future outcomes:
The project provides new evidence that will assist in the design, delivery and uptake of community-based
physical activity programs and the maintenance of healthier behaviours and lifestyles in older adults with or at
risk of developing type 2 diabetes.
Name of contact:
David Dunstan
NHMRC Research Achievements - SUMMARY
Email/Phone no. of contact:
David.Dunstan@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 445300
Start Year: 2007
CIA Name: Prof Mark Febbraio
End Year: 2009
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Cell Metabolism
Total funding: $503,426
Title of research award:
Role of FoxO proteins in the regulation of skeletal muscle anabolism, catabolism and insulin sensitivityRole of
FoxO proteins in the regulation of skeletal muscle anabolism, catabolism and insulin sensitivity
Lay Description (from application):
Loss of muscle tissue or muscle wasting is a hallmark of many common health problems including diabetes,
cancer, Cushing's syndrome, sepsis, HIV-Aids and renal failure. In the past 2-3 years important progress has
been made in understanding the molecular regulation of both catabolism (muscle wasting) and anabolism
(muscle growth) within mammalian skeletal muscles. It has been known for some time that a certain family of
transcription factors, known as FoxO proteins, activate catabolic pathways. However, recently, we have shown
that FoxO proteins also cause muscle wasting by blocking anabolic pathways. Our new data heighten the
importance of targeting FoxO proteins are therapeutics for human diseases where muscle tissue wasting
occurs. This proposal will investigate methods that will allow for blocking the action of FoxO proteins in the
hope that muscle wasting can be prevented.
Research achievements (from final report):
We have identified that FoxO1increases muscle oxidative capacity when overexpressed. Moreover, when
FoxO1 is deleted from skeletal muscle, mice are prone to weight gain
Expected future outcomes:
We expect to determine the precise molecular mechanism as to how FoxO1regulates mitochondrial metabolism
Name of contact:
Mark A Febbraio
Email/Phone no. of contact:
mark.febbraio@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 445302
Start Year: 2007
CIA Name: Prof Mark Febbraio
End Year: 2011
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: Established Career Fellowships
Main RFCD: Cell Metabolism
Total funding: $807,633
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
I am a cell biologist/whole body physiologist determining the cellular and molecular mechanisms that lead to
insulin resistance in insulin sensitive tissues such as skeletal muscle, liver and adipose tissue. My work
primarily focuses on the role of inflam
Research achievements (from final report):
During the period of my PRF fellowship, I published several important papers and also made two important
discoveres with respect to gp130 Receptor signalling and the role of HSP72 in metabolis disease.
Expected future outcomes:
I hope to take two drugs I have developed through this research into the clinic.
Name of contact:
N/A
Email/Phone no. of contact:
mark. febbraio@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 472603
Start Year: 2008
CIA Name: A/Pr Terri Allen
End Year: 2013
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Research Fellowships
Main RFCD: Endocrinology
Total funding: $690,502
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
I am a physiologist and my diabetes research involves a preclinical approach to address the issue of diabetes
and its major renal and cardiovascular complications
Research achievements (from final report):
My work concentrated on different pathways in diabetic atherosclerosis. We published a few papers and
reviews in this area.
Expected future outcomes:
New treatments for diabetic atherosclerosis.
Name of contact:
Terri Allen
Email/Phone no. of contact:
terri.allen@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 472638
Start Year: 2008
CIA Name: Prof Mark Cooper
End Year: 2010
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Nephrology and Urology
Total funding: $483,737
Title of research award:
Pathogenic role of CDA1 via its profibrotic action in diabetic nephropathyPathogenic role of CDA1 via its
profibrotic action in diabetic nephropathy
Lay Description (from application):
We cloned a CDA1 several years ago and found that it played a major role in controlling a series of molecular
events leading to production and accumulation of extracellular matrix causing scarring, as seen in diabetic
nephropathy. This project aims to study the biological functions and molecular mechanisms of CDA1 in the
context of diabetic nephropathy, hence allowing us to consider CDA1 as a molecular target for drug
development to treat this condition and related complications.
Research achievements (from final report):
TGF-beta is the key growth factor known to regulate kidney fibrosis in diabetic nephropathy. We have
established the pathological role for CDA1 in promoting the profibrotic effect of TGF-beta in human proximal
tubule cells and in experimental diabetic as well as non-diabetic nephropathy animal models. We have also
identified an interacting protein for CDA1 (CDA1BP1) and developed several novel short peptides targeting
the CDA1/CDA1BP1 interaction, which is preliminarily shown to inhibit the profibrotic effect of CDA1 and
TGF-beta in cells. , Major findings:, 1. Elevation of CDA1 expression levels in two diabetic nephropathy
animal models (SHR and ApoE-/- mice), and interestingly in another non-diabetic model of renal fibrosis,
ischemia/reperfusion injury in both rat and mouse., 2.
Adenoviral delivered CDA1 overexpression robustly enhanced, and retroviral delivered siRNA knockdown of CDA1 attenuated, TGF-β
mediated SMAD signaling and expression of collagen I and III, as well as other genes including CTGF,
fibronectin and collagen IV., 3.
CDA1BP1, a putative receptor for
CDA1, has been identified and appears to enhance the profibrotic effect of CDA1 in HK-2 cells., 4. N-, but not
C-terminal amino acid residues expanding from the core 6-amino acid binding site in CDA1BP1 are
contributing to protein-protein binding., 5.
Several short peptide designed based
on the above findings were shown to interrupt CDA1/CDA1BP1 interaction in a cell free binding assay. These
peptides were further modified allowing them to enter cells, and inhibited expression of collagen I and III
genes in human proximal tubule cells, HK-2, when added to the cultured cells.
Expected future outcomes:
We have now generated a CDA1 KO mouse being used to validate CDA1 in DN in vivo. The newly developed
short peptide will further provide validation for CDA1, ultimately leading to novel therapies for kidney
diseases associated with fibrosis such as DN.
Name of contact:
Mark E Cooper
Email/Phone no. of contact:
mark.cooper@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 472650
Start Year: 2008
CIA Name: Prof Mark Febbraio
End Year: 2010
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Cell Metabolism
Total funding: $467,720
Title of research award:
Activation of HSP70: a therapeutic target to treat obesity-induced insulin resistanceActivation of HSP70: a
therapeutic target to treat obesity-induced insulin resistance
Lay Description (from application):
Type 2 diabetes is a prevalent and serious disease and the development of new strategies to treat it is
warranted. In recent experiments we have been able to show that by upregulating a particular protein, referred
to as a "heat shock protein", we can reduce the clinical markers of type 2 diabetes by reducing key
inflammatory pathways known to lead to insulin resistance. In this series of studies we will investigate whether
activation of this protein is a target for therapeutic treatment.
Research achievements (from final report):
In studies supported by this NHMRC project grant , we discovered that overexpression or activation of heat
shock protein 72 (HSP72; the inducible form of the 70kDa family of heat shock proteins) in skeletal muscle
reduced obesity-induced insulin resistance. These findings identified an essential role for HSP72 in preventing
insulin resistance in the context of genetic obesity or high fat feeding. The study generated excitement amongst
the scientific community as evidenced by the fact that it featured as a research highlight in Nature Medicine,
and the observation that a number of subsequent studies verified our original finding. Importantly, we
demonstrated that a small molecule activator of HSP72, namely BGP-15, was effective in preventing insulin
resistance. This drug has now proceeded to a large scale human clinical trial.
Expected future outcomes:
We expect to have BGP-15 in the clinic within 5 years
Name of contact:
Mark A Febbraio
Email/Phone no. of contact:
mark.febbraio@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 472672
Start Year: 2008
CIA Name: A/Pr Peter Meikle
End Year: 2012
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Research Fellowships
Main RFCD: Medical Biochemistry: Lipids
Total funding: $581,968
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
My research activity is focused on the application of metabolomics to understand the role of lysosomes in
health and disease. I have a major interest in understanding the molecular mechanisms of pathology resulting
from lysosomal dysfunction. The outcomes
Research achievements (from final report):
Obesity, type 2 diabetes and cardiovascular disease are major health problems in Australia and result in many
tens of thousands of deaths each year. Changes in our metabolism lead to an imbalance in lipids (fats)
circulating in our blood (dyslipidemia) which contributes to the disease process. Over the past five years we
have developed lipid profiling technology that enables us to and are able to quantitatively profile over 400 lipid
species within 20 minutes from 10 uL plasma. We have used this technology to measure the plasma lipid
profiles from different patient groups. We have been able to demonstrate the patients with unstable coronary
artery disease have a different profile from patients with stable coronary artery disease. These profiles can
improve on traditional risk factors for theidentification of those individuals with unstable coronary artery
disease.We have performed plasma lipid profiling on individuals with type 2 diabetes and demonstrated that
again the plasma lipid profile is able to improve on traditional risk factors to correctly identify those with type
2 diabetes or those at high risk of developing type 2 diabetes. From these studies we have identifies new lipid
classes and individual lipid species that are associated with these disease states. This information is providing
insight into disease pathogenesis and new directions for future research.
Expected future outcomes:
We are now in the process of validating the plasma lipid profiles for their predictive ability in type 2 diabetes
and cardiovascular disease. We are working to translate this technology into new clinical test to identify those
at high risk of developing type 2 diabetes or having a cardiovascular event.
Name of contact:
Peter Meikle
Email/Phone no. of contact:
peter.meikle@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 472673
Start Year: 2008
CIA Name: A/Pr Rebecca Ritchie
End Year: 2013
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Research Fellowships
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $690,502
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
I am a cardiac pharmacologist investigating new therapies for the precursors of, and preventing their transition
to, heart failure. My core activities focus on factors that control cardiac hypertrophy and ventricular function,
in both the absence and pres
Research achievements (from final report):
Heart failure is a major cause of death, with >3 million Australians at risk of developing, or already affected
by, heart failure. The achievements of this six year fellowship include significant contributions to knowledge
regarding the causes of heart failure, and identification of new potential means for delaying its onset, and its
progression. With her particular focus on identifying new drug strategies for maintaining myocardial function
in response to myocardial infarction (heart attack), diabetes, and other causes of abnormal cardiac remodelling,
A/Prof Ritchie's work thus has the potential to enrich the quality and length of life for Australians at risk of, or
already affected by, heart failure. Her contributions to knowledge over the fellowship duration included
identification (and mechanisms) of innovative mechanisms for targeting diabetic cardiomyopathies, abnormal
cardiac muscle growth, and myocardial infarction, some of which are derived from novel endogenous factors.
She has achieved a reputation for her contributions, recognised by 64 career publications (33 during the term of
the fellowship), the prestigious 2013 Millennium Award for Type 1 Diabetes (awarded once/yr) and the 2012
ASCEPT Achievement Award and significant, ongoing research support. Ritchie has been invited to 8
prestigious world congresses (6 symposium speaker, 7 chair), with 10 invitations to other international
conferences and 15 to international institutions. Nationally, she has 24 and 14 national symposium speaker &
session chair career invitations, served on 9 organizing committees, and 37 invited seminars. Ritchie has also
made significant contributions to scientific discipline, mentoring, policy and public awareness of science.
Expected future outcomes:
Ritchie's vision is obtaining key scientific breakthroughs in understanding causes of heart failure, particularly
myocardial infarction and diabetes, via her paradigm-shifting discoveries. By continuing to identify new targets
for heart failure precursors and development of innovative pharmacotherapies for delaying their progression,
her research addresses a clear area of clinical need.
Name of contact:
A/Prof Rebecca H Ritchie
Email/Phone no. of contact:
rebecca.ritchie@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 472705
Start Year: 2008
CIA Name: A/Pr Chiew Wong
End Year: 2011
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: Early Career Fellowships
(Australia)
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $210,055
Title of research award:
Effect of laparoscopic gastric banding and angiotensin converting enzyme inhibitor on metabolic myocardial
diseaseEffect of laparoscopic gastric banding and angiotensin converting enzyme inhibitor on metabolic
myocardial disease
Lay Description (from application):
The proposed research studies will add novel information about the effects of drug acting on ReninAngiotensin-Aldosterone system and substantial weight reduction by key hole surgery on heart muscle
stiffening and scar tissue formation due to obesity and diabetes. The knowledge gained will be essential to
gain important insights into the underlying process of heart failure due to over-nutrition, high blood pressure,
diabetes and define strategies aimed at reducing future heart failure.
Research achievements (from final report):
Assessment of cardiac function to include measures linked with the syndrome of 'Heart Failure with Normal
Ejection Fraction' is an important area for clinical research given the contribution that HFNEF makes to
clinical heart failure presentation. We found that defining the HFNEF can be difficult in clinical trials based on
the current best available cardiac imaging techniques. Assessing myocardial torsion dynamics using the latest
advanced echocardiography imaging provided a new dimension in assessing myocardial function dynamic. LV
torsion dynamics acquired immediately after exercise stress test can be a good indicator of exercise capacity,
and an useful tool for assessing myocardial mechanics beyond the non inasive measure for myocardial filling
pressure. We also found that substantial weight reduction by gastric banding improved myocardial function in
early stage of disease process, hence therapeutic implication for both surgical and non surgical interventions to
control weight in morbid obesity.
Expected future outcomes:
encourage ongoing studies in the growing epidemic of HFNEF, new preventive measures to curb HFNEF to be
developed in parellel with new sensitive method of assessing myocardial torsional dynamics.
Name of contact:
Chiew Wong
Email/Phone no. of contact:
chiew.wong@wh.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 472710
Start Year: 2009
CIA Name: Dr Luciano Pirola
End Year: 2009
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: International Exchange Early
Career Fellowships
Main RFCD: Endocrinology
Total funding: $75,250
Title of research award:
Epigenetic Control in Type 2 DiabetesEpigenetic Control in Type 2 Diabetes
Lay Description (from application):
Not Available
Research achievements (from final report):
During this 1-year fellowship, I have learn the foundamental methodologies to explore the epigenetic control of
the chromatin structure. Chromatin immunoprecipitation (ChIP) techniquers have been applied to study insulidependent transcriptional regulation of candidate genes. Also, ChIP has been used to study the global histone
acetylation profile in endothelial cells treated by prolonged hyperglycaemia to gain insight into the basic
mechanisms underlying the development of vascular diabetic complications.
Expected future outcomes:
Furher ChIP experiments in endothelial cells will be directed to the definition of chromatin methylation
modifications.
Name of contact:
Luciano Pirola
Email/Phone no. of contact:
luciano.pirola@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 526605
Start Year: 2009
CIA Name: Prof Karin Jandeleit-Dahm
End Year: 2013
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Research Fellowships
Main RFCD: Endocrinology
Total funding: $580,752
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
I am a clinician scientist and fully trained nephrologist. My research involves preclinical and clinical
translational approaches to identify new targets and to develop new treatments to prevent, reverse and retard
diabetes related micro-and macrovascular
Research achievements (from final report):
During the course of the fellowship I have made significant contributions in the major research areas as
outlined in the felloship application. I have published on endothelin-receptor antagonism showing simultaneous
reno-and atheroprotection (published in Diabetologia). Furthermore my work has shown atheroprotection with
urotensin antagonists and with AT2 receptor antagonists (both published in Diabetologia). I have produced
seminal papers on the role of RAGE in diabetes associated atherosclerosis and renal disease (both published in
Diabetes). More recently my work has identified Nox1 as the most important Nox isoform in diabetes
associated atherosclerosis (published in Circulation 2013) and the role of Nox4 in diabetic nephropathy
(published in JASN, 2014). The work is ongoing with several other publications in progress. Furthermore, this
work has been widely communicated as invited presentations at the major international and national diabetes,
heart and kidney conferences. We have submitted an ongoing project grant to continue this work. We have
established and expanded collaborations with the top groups in the world in this field and have an ongoing
collaboration with industry to investigate novel more specific Nox inhibitors initially preclinically and
ultimately in the clinical context.
Expected future outcomes:
My future research includes identification of new targets to inhibit early dicarbonyls such as methylglyoxal and
its interaction with RAGE. We also work on innovative approaches to increase glyoxalase activity.
Furthermore, we continue to assess and validate novel Nox inhibitors targeting specific Nox isoforms.
Name of contact:
Karin Jandeleit-Dahm
Email/Phone no. of contact:
karin.jandeleit-dahm@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 526606
Start Year: 2009
CIA Name: Prof Mark Febbraio
End Year: 2011
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Cell Metabolism
Total funding: $708,267
Title of research award:
Novel gp130 receptor ligands to treat metabolic diseaseNovel gp130 receptor ligands to treat metabolic disease
Lay Description (from application):
Over the past decade work from our group has identified that a group of cytokines termed the gp130 receptor
cytokines can lead to weight loss in animals and humans. Unfortunately, due to side effects, clinical trials using
peptides analogues of these cytokines have failed. We believe that we know why this has occurred and we
think we have developed new peptides that will alleviate these side effects. This application will test the
efficacy of these novel peptides in mammals in vivo.
Research achievements (from final report):
This grant allowed us to make a pivotal discovery. We synthesized a novel protein by transferring the putative
"LIF receptor (LIFR) binding module" from CNTF to IL-6. Excitingly,we showed that this new cytokine,
termed IC7, has similar positive metabolic effects as CNTF, but may overcome the negative effects
experienced bythe drug Axokine®. CIA Febbraio, together with CIC Rose-John, has filed world wide patents
(60/920822-USA, 2008234408-Australia, 2681935-Canada, 08733275.5-EU) with claims directed to the use of
IC7 to treat type 2 diabetes (T2D) and obesity.
Expected future outcomes:
IC7 could be usedtherapeutically in the treatment of obesity-induced insulin resistance
Name of contact:
Mark Febbraio
Email/Phone no. of contact:
mark.febbraio@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 526608
Start Year: 2009
CIA Name: Dr Clinton Bruce
End Year: 2011
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Cell Metabolism
Total funding: $450,391
Title of research award:
Sphingosine kinase as a target therapeutic for obesity induced insulin resistanceSphingosine kinase as a target
therapeutic for obesity induced insulin resistance
Lay Description (from application):
Obesity is linked to the development of insulin resistance and diabetes, which represent a significant health
issue in Australia. A number of factors contribute to the development of insulin resistance, including defective
fatty acid metabolism. This study proposes to investigate whether manipulating sphingosine kinase, a key
enzyme in lipid metabolism, affects the development of insulin resistance. These studies may identify novel
targets for the treatment of insulin resistance and diabetes.
Research achievements (from final report):
Obesity is an escalating global health problem. It is associated with a number of disorders including type 2
diabetes. The prevalence of these diseases has increased dramatically over the last two decades reaching
epidemic proportions. In fact, obesity and type 2 diabetes are among the most significant health issues in
Australia today. Although the exact causes of type 2 diabetes are not known, it is clear that defects in the way
muscle metabolises fat is involved. In these studies we have identified a pathway, that once activated, can
improve muscle fat metabolism and as a result prevent insulin resistance, the precursor to type 2 diabetes. More
importantly, we show that a drug which can act on aspects of this pathway is effective in treating insulin
resistance. These results are particularly exciting as this drug has recently received approval for the treatment
of an unrelated disease. The results from these studies may therefore, provide new strategies for the treatment
of obesity and type 2 diabetes.
Expected future outcomes:
Although further studies are required, our intial findings indicated that we may have identified a novel therapy
for the treatment of type 2 diabetes. As this drug is already in clinical use, rapid translation of these findings is
possible.
Name of contact:
Clinton Bruce
Email/Phone no. of contact:
clinton.bruce@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 526614
Start Year: 2009
CIA Name: Prof Dmitri Sviridov
End Year: 2011
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Medical Biochemistry: Proteins and Peptides
Total funding: $372,472
Title of research award:
Impact of advanced glycation on anti-atherogenic properties of high density lipoproteinImpact of advanced
glycation on anti-atherogenic properties of high density lipoprotein
Lay Description (from application):
Type 2 diabetes is a rapidly growing medical problem in Australia and around the world. Diabetes affects
human health through its complications and the cardiovascular complications are a cause for major concern.
One of the complications is the effect on plasma lipids: it makes cholesterol carrying particles to accumulate in
the blood vessels, causing atherosclerosis. We intend to investigate how diabetes modify these particles making
them atherogenic.
Research achievements (from final report):
Diabetes is associated with elevation of plasma levels of glucose and that leads to modification of many
proteins and impairment of their function. This study has established that severe modification of a protein
apolipoprotein A-I, the main protein of HDL ("Good Cholesterol") impairs its functions and as a result Good
Cholesterol is no longer good. It loses its capacity to remove cholesterol from cells and it also loses its capacity
to reduce inflammation. In cases of severe atherosclerosis this may be a significant factor contributing to the
development of atherosclerosis and elevation of the risk of heart attack in patients with diabetes and may
requires a specific treatment. On the other hand we established in animal models and in patients, that if diabetes
is controlled, the levels of modification of apoA-I are less severe and changes in functional capacity of good
cholesterol in this situation are fully compensated. We conclude that if diabetes is controlled, that may be
sufficient to eliminate the effects of this specific modification on risk of cardiovascular disease; however in
uncontrolled diabetes a specific treatment is needed. We also established that other diabetes-related
modifications of HDL may also contribute to the impairment of HDL functional properties.
Expected future outcomes:
In this study we investigated only one diabetes-related factor that reduces protection against atherosclerosis.
We now are focusing on other factors to establish those that contribute the most and on treatments capable of
modifying these factors.
Name of contact:
Prof. Dmitri Sviridov
Email/Phone no. of contact:
Dmitri.Sviridov@Bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 526619
Start Year: 2009
CIA Name: Prof Mark Febbraio
End Year: 2011
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Cell Metabolism
Total funding: $511,295
Title of research award:
Can blocking fatty acid transport in myeloid cells prevent insulin resistance?Can blocking fatty acid transport
in myeloid cells prevent insulin resistance?
Lay Description (from application):
Over the past 5 years it has become apparent that blood cells can become inflamed as people become obese.
These inflamed blood cells can contribute to insulin resistance or "pre-diabetes". Our hypothesis is that these
blood cells become inflamed because they take up fat via fatty acid transporters. Our approach is to knock out
one of these fatty acid transporters specifically in blood cells and reduce inflammation and insulin resistance
due to overnutrition.
Research achievements (from final report):
The general aim of this project was to examine the role of FAT/CD36 in macrophages on the aetiology of
obesity-induced insulin resistance.While CD36 does not appear important in saturated fatty acid induced
macrophage lipid accumulation, our study uncovers a novel role for CD36 in the migration of proinflammatory phagocytes to adipose tissue in obesity, with a concomitant improvement in insulin action. This
paper was published in Diabetes in 2011 .
Expected future outcomes:
CD36 could be an important molecule to target therapeutically in the treatment of obesity-induced insulin
resistance
Name of contact:
Mark Febbraio
Email/Phone no. of contact:
mark.febbraio@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 526638
Start Year: 2009
CIA Name: A/Pr Rebecca Ritchie
End Year: 2011
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Basic Pharmacology
Total funding: $487,670
Title of research award:
TARGETING ROS-INDUCED DAMAGE RESCUES THE DIABETIC HEARTTARGETING ROSINDUCED DAMAGE RESCUES THE DIABETIC HEART
Lay Description (from application):
Over 1 million Australians have diabetes. Many of these patients die from cardiovascular disease. We have
identified free radicals as a major cause of decreased pumping function and impaired recovery from each
heartbeat in the diabetic heart. Stronger antioxidant approaches and-or activation of protective protein
pathways is a more effective treatment for reversing impaired function in the diabetic heart, preventing or
delaying heart failure in patients with diabetes.
Research achievements (from final report):
Patients with diabetes are 2.4-fold more likely to develop heart failure, even when adjusted for age and
coronary artery disease. The onset of heart failure occurs earlier in diabetes, with heart failure prevalence
increased 5- 8-fold in adults <65yrs old. In particular, how the heart recovers from each heart beat (cardiac
muscle relaxation, known as diastolic function) in diabetic patients takes longer, and is less efficient, than in
people without diabetes. This impaired recovery is directly related to patient prognosis over the longer term.
The alarming global epidemic of diabetes thus gives rise to an ever-increasing heart failure burden. We have
now identified two different signalling pathways that regulate cardiac function in the diabetic heart. One of
these pathways is detrimental for cardiac function, the generation of toxic chemicals (known as free radicals)
by the heart muscle, which is triggered by high blood glucose levels. The other pathway isprotective. We now
demonstrate that a novel protective protein called PI3K? (previously identified by Dr McMullen in other
cardiac pathologies) preserves cardiac function in diabetes. This work has attracted 2 major conference
speaking invitations (Cardiac Society of Australia and New Zealand 2012; International Society of Heart
Research World Congress 2010), as well as 7 national and 4 international university seminar programs. Ten
publications have resulted , plus another currently in review and two additional manuscripts are in preparation.
Our research may ultimately facilitate the development of exciting new ways to treat diabetic cardiac disease,
and hence increase survival, in humans suffering diabetes.
Expected future outcomes:
Diabetes is Australia's fastest-growing chronic disease, affecting ~1000000 Australians; many more await
diagnosis. Cardiovascular complications represent their major cause of death. We have identified detrimental
and protective signals that regulate diabetic heart function. Targeting the interaction between these signals may
reduce progression to heart failure and death in diabetic patients.
Name of contact:
A/Prof Rebecca H Ritchie
Email/Phone no. of contact:
rebecca.ritchie@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 526639
Start Year: 2009
CIA Name: Prof Josephine Forbes
End Year: 2011
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Nephrology and Urology
Total funding: $505,786
Title of research award:
Cytosolic oxidative disturbances as a source of mitochondrial dysfunction in diabetic nephropathyCytosolic
oxidative disturbances as a source of mitochondrial dysfunction in diabetic nephropathy
Lay Description (from application):
There is a critical need to identify new therapies for the growing number of patients with diabetic kidney
disease. Current medicines only retard progressive disease. Our studies investigate defects in the power
houses of the cell, the mitochondria. These defects cause generation of toxic free oxygen radicals which
eventually starve the cell of energy production. Therefore, reversal of mitochondrial defects in diabetic kidney
disease may be a novel therapeutic target.
Research achievements (from final report):
Not Available
Expected future outcomes:
N/A
Name of contact:
Josephine Forbes
Email/Phone no. of contact:
jforbes@mmri.mater.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 526642
Start Year: 2009
CIA Name: Prof Merlin Thomas
End Year: 2011
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Nephrology and Urology
Total funding: $453,145
Title of research award:
The role of angiotensin converting enzyme 2 in diabetic complicationsThe role of angiotensin converting
enzyme 2 in diabetic complications
Lay Description (from application):
Most heart attacks and strokes arise from narrowing of the arteries. This process is regulated by a number of
hormonal pathways. One of the most important is the renin angiotensin system. Our group has demonstrated
important changes in this pathway which play a pivotal role in regulating the development of atherosclerosis
and its response to treatment. It is predicted that these studies will provide critical information to develop
innovative treatment strategies for cardiovascular disease.
Research achievements (from final report):
The RAS is a common target for drug interventions for the prevention of cardiovascular and kidney disease.
However, it complexities are still poorly understood. Our research has focused on the ACE2/A1-7 axis,
particularly in the context of diabetes. We have demonstrated that suppression of ACE2 is required for diabetes
associated complications and that ACE2 deficiency is able to cause a range of problems in the heart, kidneys
and blood vessels. We believe that these findings will directly lead to improved therapeutic approaches that
target ACE2 to achieve superior renal and vascular protection than occurs currently with conventional blockade
of the RAS, as well as identifying new strategies to retard or reverse micro- and macrovascular damage
associated with diabetes.
Expected future outcomes:
It is expected that better understanding of the renin angiotensin system and its players will lead to the
identification of more effctive ways to modulate its activities than are currently available.
Name of contact:
Merlin Thomas
Email/Phone no. of contact:
mthomas@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 526656
Start Year: 2009
CIA Name: Dr Judy de Haan
End Year: 2011
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $358,319
Title of research award:
Antioxidant glutathione peroxidase (GPx) mimetics and atherosclerosis: a role for targeted antioxidant
therapy.Antioxidant glutathione peroxidase (GPx) mimetics and atherosclerosis: a role for targeted antioxidant
therapy.
Lay Description (from application):
This proposal investigates the use of antioxidant therapy, targeted at increasing the function of the body's
important antioxidant enzyme GPx1, to reduce atherosclerosis both in a non-diabetic and diabetic setting.
Strong clinical evidence and our recently published data support an important role for GPx1 in limiting
atherosclerosis. We will now investigate the molecular mechanisms involved in mediating these effects and
whether compounds that mimic GPx1 function reduce atherosclerosis.
Research achievements (from final report):
Diabetic complications such as atherosclerosis remain a significant health issue despite intensive glucose and
blood pressure lowering therapeutics. The quest for additional treatment regimens remains a highly desirable
aim. Therapies to lessen oxidative stress is a major focus of many health programs; however no clear
cardiovascular benefits have emerged in clinical trials using standard antioxidants. We believe a targeted
antioxidant approach is more likely to yield clinical benefits. Research undertaken as part of NHMRC project
#526656 focussed on the use of mimetics of the antioxidant enzyme, GPx1, to reduce the burden of diabetesasociated atherosclerosis (DAA). This study was built on our very significant earlier findings that showed an
important anti-atherogenic role for GPx1 in diabetic mouse models. GPx1 is responsible for the removal of
damaging reactive oxygen species such as peroxynitrite and hydrogen and lipid peroxides. The data generated
in NHMRC grant #526656 showed that GPx1 mimetics that removed these particular ROS, were able to lessen
atherosclerosis, as well as pro-inflammatory and pro-atherogenic pathways in diabetic mouse models. Our data
also revealed that this class of antioxidant (we investigated both the parent compound ebselen as well as
modifications of ebselen that rendered the compound more efficacious) was able to reduce inflammation via
the inhibition of key modifications to pro-inflammatory mediators such as p-JNK and p-IKK. Our results
therefore highlight the important anti-atherogenic potential of synthetic GPx1 mimetic compounds, making this
class of compound an attractive therapeutic option in the treatment of DAA.
Expected future outcomes:
It is anticipated that our results, published in prestigious journals such as ATVB and Diabetes, will lead to
clinical investigations of synthetic GPx1 mimetics to lessen diabetes-associated atherosclerosis. Our results
therefore have the potential to significantly impact treatment options to lessen atherosclerosis in diabetics as
well as the general population.
Name of contact:
Judy De Haan
Email/Phone no. of contact:
judy.dehaan@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 526663
Start Year: 2009
CIA Name: Prof Mark Cooper
End Year: 2011
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Nephrology and Urology
Total funding: $490,202
Title of research award:
Growth factors and their effect on microRNAs and transcription factors in tubulointerstitial fibrosis in
diabetesGrowth factors and their effect on microRNAs and transcription factors in tubulointerstitial fibrosis in
diabetes
Lay Description (from application):
A common cause of kidney disease is diabetes and is partly related to increased expression and action of
growth factors such as CTGF. These factors promote the deposition of scar tissue in the kidney by acting on a
novel class of intracellular regulator molecules called microRNAs, to change the cell's characteristics such that
cells begin laying down excess collagen. This proposal will focus on how growth factors act on microRNAs
and the role of microRNAs in diabetic kidney disease.
Research achievements (from final report):
, Diabetes is characterised by high blood sugar levels and elevated levels of certain factors that result in kidney
damage. The most important of these factors is TGF-β1. The combination of these factors cause the production
and accumulation of excess collagen in the kidney resulting in scaring of the kidney and loss of kidney
function. In our studies we have made several important discoveries that have changed the way we think of the
development of kidney damage that occurs in diabetes., We have found that
TGF-β1 causes a
significant decrease in the level of certain members of a family of small RNA molecules called microRNAs.
These molecules are known to important in normal physiology and disease condition like kidney scarring. We
demonstrated in different experimental diabetes models that microRNAs-192/214, the microRNA-200 and the
microRNA-29 families are all decreased in the kidney and in kidney cell lines. The result of the decreased
levels of these microRNAs results in elevated synthesis and accumulation of collagens and other proteins that
contribute to scarring and loss of kidney function. Our experiments have demonstrated that restoring
expression of these microRNAs reverses the damage by preventing the synthesis of collagen by kidney cells
and reducing the accumulation of collagen in the kidney. This work has now been published in 5 papers and
another 2 manuscripts are aboout to be submitted for publication.,
Expected future outcomes:
Our work has identified the use of microRNAs as a possible alternative treatment option for dealing with
diabetic kidney fibrosis in diabetic patients. Whilst some hurdles remain as to how to deliver this treatment
clinically, a major global effort is underway to overcome these obstacles.
Name of contact:
Mark E Cooper
Email/Phone no. of contact:
mark.cooper@bakerdid.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 526685
Start Year: 2009
CIA Name: Prof Mark Cooper
End Year: 2011
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Nephrology and Urology
Total funding: $474,619
Title of research award:
Role of chromatin remodelling in diabetic renal and vascular complications: in vivo studiesRole of chromatin
remodelling in diabetic renal and vascular complications: in vivo studies
Lay Description (from application):
Even after diabetics return to improved blood glucose levels after a period of poor blood glucose control, the
kidney and blood vessel complications progress. The cause of this metabolic memory remains unexplained.
This proposal focuses on sustained changes as a result of prior glucose levels in proteins called histones that are
part of the wrapping of DNA. Using a new technique called carrier ChIP we will study histone modifications in
the blood vessels and kidneys in diabetes.
Research achievements (from final report):
, Diabetes is characterised by high blood sugar levels and elevated levels of certain factors that result in blood
vessel damage. This grant explores a phenomenon known as metabolic memory where the effects of previous
episodes of poor glycaemic control have sustained deleterious effects on organs including blood vesselds in
diabetes. We have identified that a particular enzyme known as Set7 involved in modification of proteins that
wrap DNA in the nucleus called histones plays a central role in conferring this memory. We explored the
regulation of this enzyme in response to glucose and showed how sugar promotes the shuttling of this enzyme
from the cytoplasm to the nucleus to methylate certain histones thus modulating expression of genes encoding
proteins implicated in the inflammation of blood vessels as seen in diabetes. This work has now led to a
combined genetic deletion and pharmacological approach to explore if inhibiting this enzyme Set7 will lead to
a reduction in diabetic complications. This work has now been published in a number of high impact journals
and the prominence of this work is further reflected by multiple international invitations to present this work as
well as requests to write reviews on this subject.,
Expected future outcomes:
Our work has identified the critical role of the histone methyl transferase Set7 in diabetic complications as well
as conferring metabolic memory. This work has been the impetus for considering this enzyme as a potential
target for end-organ protective therapies in diabetes.
Name of contact:
Mark E Cooper
Email/Phone no. of contact:
mark.cooper@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 540107
Start Year: 2009
CIA Name: Prof David Dunstan
End Year: 2012
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Public Health and Health Services not elsewhere classified
Total funding: $416,597
Title of research award:
Understanding the acute and cumulative metabolic effects of prolonged sitting in adultsUnderstanding the
acute and cumulative metabolic effects of prolonged sitting in adults
Lay Description (from application):
Sedentary behaviour (sitting time) has been linked to an increased risk of chronic illnesses, including type 2
diabetes and obesity, but recent evidence suggests that light-intensity activity (non-exercise activities of daily
living) is associated with reduced risk. These studies will examine whether breaking up sitting time with
frequent short periods of activity can overcome the negative effects of prolonged sitting on blood glucose and
blood fats in overweight older adults.
Research achievements (from final report):
, It is well known that being physically active is important for maintaining good health. However, evidence has
emerged showing that sedentary time (sitting for prolonged periods) is adversely associated with indicators of
poor health (eg. elevated blood glucose and blood triglycerides), even in the presence of meeting physical
activity guidelines. Observational evidence suggests that the manner in which sedentary time is accumulated
may also be important, since people who break up their sitting time throughout the day have lower levels of
risk markers of diabetes and cardiovascular disease (eg. blood glucose, insulin and triglycerides) than people
who sit for prolonged periods without activity breaks. This research involved the first ever clinical study to
examine the extent to which interruptions to prolonged sitting influences metabolic outcomes. In a supervised
laboratory setting, this study found that interrupting a 5 hour period of prolonged sitting with frequent short (2
mins) bouts of light- or moderate-intensity walking activity every 20 mins reduced elevations in blood glucose
and insulin levels (two risk factors for diabetes) when compared with prolonged sitting. Furthermore, the effect
of the light-intensity activity breaks was comparable to the moderate-intensity physical activity breaks, the
activity intensity level that is the current focus of public health messages. This suggests that interrupting sitting
time, even with gentle walking, may be useful to prevent the negative consequences of prolonged sitting.
Expected future outcomes:
We are currently in the process of analysing the data collected from the second study undertaken as part of this
project grant that examined whether prolonged sitting after repeated days worsened metabolic outcomes and
whether this is attenuated by incorporating intemittent short bouts of light-intensity walking activity.
Name of contact:
David Dunstan
Email/Phone no. of contact:
david.dunstan@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 586626
Start Year: 2010
CIA Name: Prof Bronwyn Kingwell
End Year: 2012
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Endocrinology
Total funding: $559,472
Title of research award:
Novel Metabolic Actions of HDL with Therapeutic Potential for Type 2 DiabetesNovel Metabolic Actions of
HDL with Therapeutic Potential for Type 2 Diabetes
Lay Description (from application):
Our proposal investigates a novel approach to treat type 2 (late onset) diabetes. We have identified an
important link between HDL (good) cholesterol and glucose metabolism. The current proposal is to conduct
studies in humans to determine whether therapies which increase HDL result in sustained reduction of blood
glucose. Given the escalating global prevalence of obesity and type 2 diabetes, this work is potentially of great
significance.
Research achievements (from final report):
Recent clinical studies by our laboratory and others indicate that high-density lipoprotein (HDL) cholesterol
('good' cholesterol) exerts beneficial actions beyond protection from heart and blood vessel disease, which may
extend to type 2 diabetes. Many drugs are now in development to raise HDL and are being tested for their
ability to prevent heart and blood vessel disease. One of these HDL-raising drug classes in advanced clinical
trials is cholesteryl ester transfer protein (CETP) inhibitors. Based on our previous work showing that HDL has
multiple effects on glucose metabolism through both effects on muscle (which is where most glucose in the
body is used) and in the pancreas (which makes and releases insulin) we examined the effects of CETP
inhibition on pancreatic function. Our work shows that a novel CETP inhibitor has potentially favourable
effects on plasma insulin levels after a meal. Furthermore we showed that plasma from patients in this clinical
trial directly stimulated insulin release from pancreatic cells grown in culture. This effect occurred in the
presence of glucose which mimics meal consumption, but not under basal (low glucose or fasting) conditions.
This suggests that HDL elevation may potentially protect against large exursions in post meal blood glucose
levels which are known to harm blood vessels.These studies will support therapeutic approaches to raise levels
of circulating HDL for indications beyond vascular disease to manage type 2 diabetes. Given the escalating
global prevalence of metabolic syndrome and type 2 diabetes, therapies targeting both glycaemic control as
well as cardiovascular complications have the potential for significant impact.This grant resulted in 12
publications in leading cardiovascular and diabetes journals inlcuding (Circulation Research, European Heart
Journal, Diabetes and Nature Reviews (Endocrinology)).
Expected future outcomes:
N/A
Name of contact:
Bronwyn Kingwell
Email/Phone no. of contact:
bronwyn.kingwell@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 586636
Start Year: 2010
CIA Name: Prof Mark Febbraio
End Year: 2012
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Cell Metabolism
Total funding: $560,045
Title of research award:
A novel lipid sensitive kinase and its role in obesity-induced inflammation and insulin resistance.A novel lipid
sensitive kinase and its role in obesity-induced inflammation and insulin resistance.
Lay Description (from application):
It is now apparent that obesity leads to chronic low grade inflammation which results in insulin resistance or
pre-diabetes. The mechanisms that link obesity-induced inflammation to insulin resistance are not well
understood, but involve lipid oversupply. We have preliminary data identifying that a protein, not known to
previously play a role in metabolic diseases, is a critical mediator of lipid-induced inflammation. We will
investigate the clinical potential of blocking this protein.
Research achievements (from final report):
The aim of the current study was to determine the role of double-stranded RNA-dependent protein kinase
(PKR) in the aetiology of diet induced obesity and insulin resistance. Specifically, the aims of project were to
examine (1) the role of PKR in obesity and insulin resistance by studying a mouse harbouring a global deletion
of the PKR gene and (2) the contribution of PKR specifically within the haematopoietic system to the
development of obesity-associated inflammation and insulin resistance. Accordingly, we have completed the
studies.
Expected future outcomes:
This work has reviewed favourably by the Journal Cell Metabolism:Lancaster GI, et al. Deletion of PKR
prevents saturated fatty acid-induced inflammation in vitro, but promotes obesity and insulin resistance in
vivo.The reviewers have requested hyperinsulinemic, euglycemic clamp experiments and pair feeding
experiments. We are in the process of completing these experiments.
Name of contact:
Mark Febbraio
Email/Phone no. of contact:
mark.febbraio@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 586645
Start Year: 2010
CIA Name: A/Pr Melinda Coughlan
End Year: 2012
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Nutritional Physiology
Total funding: $483,352
Title of research award:
Restricting dietary advanced glycation end product intake as a potential therapeutic tool in diabetic
nephropathy.Restricting dietary advanced glycation end product intake as a potential therapeutic tool in
diabetic nephropathy.
Lay Description (from application):
Kidney disease is a serious complication of diabetes and may occur as a result of a biochemical process known
as advanced glycation. These advanced glycation end products (AGEs) accumulate in the kidney causing
disruption of function. Due to modern food processing techniques, the Australian diet has a high AGE content.
Over-eating foods which are high in AGEs may worsen diabetic kidney disease. This proposal will test the
effects of dietary AGE restriction and overfeeding on kidney function.
Research achievements (from final report):
Due to convenience, Australians eat diets high in processed foods. Environmental factors, including overnutrition and excess dietary intake of processed foods may contribute to the progression of diabetic kidney
disease. Due to modern food processing techniques, the Australian diet has a high advanced glycation end
product (AGE) content. It is thought that when these AGEs accumulate within the body, that they may
contribute to the development of kidney disease and other chronic diseases. Since, one in three Australians are
at risk of developing kidney disease, over-consumption of processed food high in AGE content may accelerate
the development of kidney disease. This project investigated the effects of restricting dietary intake of AGEs
on the development of kidney disease in rodent models. We discovered that excess consumption of highly
processed foods led to the development of chronic kidney disease in susceptible rodents, however, if diabetes
was already established in these rodents, restricting dietary AGEs did not lead to an improvement in kidney
function. This study significantly advanced science in the area of Nutrition Science as it uncovered new
biological mechanisms by which processed foods have effects in the body. It has facilitated further studies, in
particular, on the effects of AGEs on activation of the immune system, which has the potential to make a large
impact in the area of Nutrition Science.
Expected future outcomes:
It is expected that this project will lead to further studies which will fully characterise the effects of dietary
AGEs on chronic disease progression in humans. The ultimate future outcome would be changes in dietary
guidelines for Australians.
Name of contact:
Melinda Coughlan
Email/Phone no. of contact:
Melinda.Coughlan@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 586655
Start Year: 2010
CIA Name: A/Pr Barbora de Courten
End Year: 2012
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Metabolic Medicine
Total funding: $240,931
Title of research award:
Will a reduction in dietary AGEs improve insulin sensitivity and secretion in overweight individuals?Will a
reduction in dietary AGEs improve insulin sensitivity and secretion in overweight individuals?
Lay Description (from application):
Advanced Gycation end-products (AGE) are formed when foods brown during heating, processing or long
term storage. This study will examine the AGE content of a typical Australian diet. Also, an intervention
study will be undertaken to determine whether an 75% reduction in AGE intake can reduce blood markers of
chronic inflammation, improve insulin secretion and action and thus reduce diabetes and heart disease risk.
Research achievements (from final report):
The high AGE diet reduced insulin sensitivity by -1.06 mg/kg/min (95% CI,-2.01 to -0.11;p=0.03) while the
low AGE diet improved insulin sensitivity by +0.98 mg/kg/min (+0.11 to +1.84; p=0.03). The overall change
in insulin sensitivity was 2.04 mg/kg/min (0.99 to 3.08, p=0.001) compared to baseline. Insulin secretion
showed a trend to increase during the high AGE diet (9 mU/l) whereas the low AGE diet somewhat reduced
insulin secretion (-15 mU/l) (both p=ns) with a net difference between the two diets of 23 mU/l. An association
between a change insulin secretion and change in plasma AGE (CML) concentrations was also seen (r=-0.51,
p=0.02). , The diets had no significant effects on any of the AGE parameters tested (ie urinary or serum AGEs,
soluble RAGE, esRAGE plasma concentrations , the expression of RAGE on PBMC and AGE receptor 1 on
PBMC . However, there was a significant change in AGE-R1 expression on CD14+ monocytes and
macrophages following the high and low AGE diet (p=0.04) in a subset of the study population (n=7) where
this measurement was available. , The diets had no significant effects on any of the plasma inflammation
parameters (ie TNFα, hs-CRP, NF-κB, MCP-1). , Our data support the hypothesis that consuming a diet high in
AGE content may contribute to the development of type 2 diabetes in susceptible populations such as
overweight and obese individuals. In addition, a diet low in AGEs is protective. Specifically, a 2-week
consumption of a high and low AGE diet was able to modulate insulin sensitivity. The trends for a change in
insulin secretion likely represent, at least in part, a compensation for the changes in insulin sensitivity.
Expected future outcomes:
, Future studies are warranted to both explore the mechanisms by which AGEs influence insulin sensitivity and
secretion and to examine the effects dietary AGE interventions of longer duration in large-scale trials.
Name of contact:
Barbora De Courten
Email/Phone no. of contact:
Barbora.deCourten@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 586667
Start Year: 2010
CIA Name: Prof Markus Schlaich
End Year: 2012
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $455,365
Title of research award:
Sympathetic nervous system inhibition for the treatment of diabetic nephropathySympathetic nervous system
inhibition for the treatment of diabetic nephropathy
Lay Description (from application):
One of the commonest consequences of diabetes is the development of renal impairment, in the worst case
scenario resulting in renal failure reuqiring renal replacement therapy. We aim to test a novel therapeutic
strategy based on inhibition of the sympathetic nervous system to halt progression of renal failure and to
improve outcomes in patients with this condition.
Research achievements (from final report):
Diabetic nephropathy is one of leading causes of end stage renal disease in Australia. Despite the successful
and effective introduction of lower blood pressure targets for patients with diabetes and the use of inhibitors of
the renin-angiotensin system, an immportant cardiovascular control system relevant in this context, current
treatment strategies only provide partial protection and a substantial proportion of these patients remain at
considerable residual risk for complications affecting both the kidnyes and the heart. There is an urgent need
for the development of novel strategies to curb this global burden of complications. Targeting the sympathetic
nervous system is an obvious but clearly neglected therapeutic strategy and its usefulness and effectiveness in
reducing albuminuria in diabetic nephropathy and related factors needs was the aim of this investigation. The
study is a randomized controlled trial in a cross over design and has not yet reached its final recruitment target,
hence final results are not yet available.
Expected future outcomes:
If our hypothesis is correct and inhibition of the sympatheic nervous system by means explored in this study
can reduce albuminuria, this could become a standard tretament for this conditon.
Name of contact:
Professor Markus Schlaich
Email/Phone no. of contact:
markus.schlaich@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 586676
Start Year: 2010
CIA Name: Prof Karin Jandeleit-Dahm
End Year: 2012
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Endocrinology
Total funding: $542,860
Title of research award:
Targeting the AGE-RAGE axis in diabetes associated atherosclerosisTargeting the AGE-RAGE axis in
diabetes associated atherosclerosis
Lay Description (from application):
Based on extensive preliminary data we porpose that the AGE intercation with RAGE plays an important role
in diabetes associated atherosclerosis. We will perform studies using a soluble form of the receptor RAGE
which will trap AGEs in the blood and tissues and thus prevent diabetes related blood vessel damage.
Furthermore, we will investigate if RAGE receptor on inflammatory cells such as macrophages plays a pivotal
role in blood vessel injury in diabetes.
Research achievements (from final report):
Based on the results generated by this grant we have made significant discoveries that inhibiton of the
AGE/RAGE pathway should include interventions at both sides, including inhibition of AGE formation as well
as inhibition of the interaction with RAGE. These findings have significant clinical implications. Furthermore,
we have identified that inhibition of early AGE intermediates such as methylglyoxal is the most promising
apporach to prevent diabetic complications.
Expected future outcomes:
This work will stimulate the development of novel agents to interfere with AGE and methyglyoxal formation
as well as blocking the interaction with receptors such as RAGE. Furthermore, it has stimulated the search for
potential activators of the glyoxylase system which detoxifies MGO.
Name of contact:
Karin Jandeleit-Dahm
Email/Phone no. of contact:
karin.jandeleit-dahm@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 586678
Start Year: 2010
CIA Name: A/Pr Terri Allen
End Year: 2012
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Endocrinology
Total funding: $405,594
Title of research award:
The Role of Urotensin II in Diabetes-Associated AtherosclerosisThe Role of Urotensin II in DiabetesAssociated Atherosclerosis
Lay Description (from application):
People with diabetes most commonly die from stroke or heart attack and we need to determine what makes
them more prone to these problems. The recently discovered UII system is increased in people with diabetes
and has been found in diseased parts of blood vessels. Thus, the aim of this project is to characterise the UII
system in the setting of diabetes using 2 unique genetically altered mice and a blocker a to study the effects of
high cholesterol, diabetes and a deletion of UII.
Research achievements (from final report):
N/A
Expected future outcomes:
N/A
Name of contact:
Assoc Prof Terri Allen
Email/Phone no. of contact:
N/A
NHMRC Research Achievements - SUMMARY
Grant ID: 586691
Start Year: 2010
CIA Name: Prof Josephine Forbes
End Year: 2010
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: Career Development Fellowships
Main RFCD: Nephrology and Urology
Total funding: $156,230
Title of research award:
Synergistic partways contributing to renal dysfunction in diabetesSynergistic partways contributing to renal
dysfunction in diabetes
Lay Description (from application):
Diabetes is the main cause of kidney disease in Australia, which has large social and economic burdens. Indeed
this disorder affects some 400,000 Australians. My research includes an integrative program to find new targets
to combat diabetic kidney disease in the hope of designing new drugs and producing new biomarkers for early
intervention in this disease.
Research achievements (from final report):
This award was only received for one year after which it was updated to an SRF fellsohip following the
awarding at that level. During this 12 months I completed a numbr of studies addressing the role of advanced
glycation and interconnecting pathways in the pathogenesis of diabetic kidney disease. Specifically, these
included AGE or AGE-receptor mediated effects on mitochondrial function and interactions with the renin
angiotensin system.
Expected future outcomes:
This research has led to the instigation of a clinical trial in patients with diabetic kidney disease as well as
many follow up studies in humans and in more advanced mouse models.
Name of contact:
Porf Josephine Forbes
Email/Phone no. of contact:
jforbes@mmri.mater.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1002663
Start Year: 2011
CIA Name: A/Pr Dianna Magliano
End Year: 2013
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Preventive Medicine
Total funding: $412,291
Title of research award:
The Australian and New Zealand Diabetes and Cancer CollaborationThe Australian and New Zealand Diabetes
and Cancer Collaboration
Lay Description (from application):
Diabetes, obesity, metabolic syndrome, hypertension and cancer are chronic diseases faced by many
Australians. There is some evidence to suggest that those with diabetes or are obese are at an increased risk of
cancer. Sufficiently large studies to examine these relationships do not exist in Australia. This project aims to
pool Australian and New Zealand longitudinal studies which have information on diabetes and obesity to
examine the relationship between diabetes, obesity and cancer.
Research achievements (from final report):
We have successfully linked one of the world's largest diabetes registries to obtain death and cancer outcomes
in almost 1.5 million people. This was a great achievement. Using this dataset, we have shown that mortality
from cancer is becoming an increasing burden among people with diabetes as treatment for cardiovascular
diasese improves. We also show a relatively large excess risk for many types of cancer in people with diabetes
compared to the general population. For type 1 diabetes, this has previously not been shown as most studies are
limited by small sample sizes. This work is particularly important in light of the current diabetes epidemic,
coincinding with an aging population allowing people to live long enough to get cancer. This means we are
likely to see a double burden of diabetes and cancer in the future if current trends continue.Screening for cancer
among people with diabetes is one measure that may prevent premature mortality from cancer in the future.
Expected future outcomes:
This project will allow a better and fuller assessment of the likely burden and consequences of diabetes,obesity,
and cancer as well as informing clinical practice about the appropriate care of diabetic and/or obese patients.
This may include routine screening of cancer among diabetes patients or patients attending obesity clinics.
Name of contact:
Dianna Magliano
Email/Phone no. of contact:
dianna.magliano@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1004212
Start Year: 2011
CIA Name: Dr Robert Lee-Young
End Year: 2013
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Systems Physiology
Total funding: $575,527
Title of research award:
Understanding the metabolic consequences of impaired AMPKa2 and nNOSµ in skeletal muscle: implications
for the Metabolic SyndromeUnderstanding the metabolic consequences of impaired AMPKa2 and nNOSµ in
skeletal muscle: implications for the Metabolic Syndrome
Lay Description (from application):
The inability of muscle to utilise sugar from the blood is a major problem that contributes to obesity and Type
2 diabetes. Since the number of people with these diseases will at least double by 2030, we need to find out
what causes this problem. We will examine whether two muscle proteins that are impaired in obesity and Type
2 diabetes are also responsible for impaired sugar utilisation. We think that increasing these muscle proteins
will fix the “sugar problem”, and remedy these diseases.
Research achievements (from final report):
The inability of muscle to utilise sugar from the blood is a major problem that contributes to obesity and Type
2 diabetes. This project grant examined whether two muscle proteins (termed AMPK-?2 and nNOS-µ) that are
impaired in obesity and Type 2 diabetes are also responsible for impaired sugar utilisation seen in these disease
states. Specifically, this grant examined whether (1) nNOS-mu played a role in determining how muscle
utilised sugar, and (2) whether AMPK-?2 played a role in the regulation of nNOS-µ in muscle., , Our first
finding was that obesity, arising from excess consumption of a high-fat diet, impaired the function of nNOS-µ
in muscle, and this was associated with a defect in muscle sugar utilisation. We then found that increasing
muscle nNOS-µ expression, using novel gene therapy techniques, improved the muscle's ability to utilise sugar,
demonstrating that (1) nNOS-µ does indeed play a role in muscle sugar utilisation. This improvement in sugar
utilisation was associated with increased expression of other genes known to improve sugar utilisation,
suggesting that nNOS-µ played a role in regulating these other genes. Finally, we found that (2) increasing
AMPK-?2 in muscle led to an increase in nNOS-µ, which suggested that an interaction occurs between AMPK?2 and nNOS-µ in muscle., , Collectively, our findings demonstrated that nNOS-µ plays a role in regulating
how muscle utilises sugar, laying the groundwork for subsequent studies to determine exactly how nNOS-µ
can be regulated in muscle.
Expected future outcomes:
Given that we have found a role for nNOS-µ in the regulation of muscle sugar utilisation, future research will
examine how nNOS-µ is regulated in muscle, and what causes nNOS-µ to become defective in obesity and
diabetes.
Name of contact:
Dr. Robert Lee-Young
Email/Phone no. of contact:
robert.lee-young@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1004441
Start Year: 2011
CIA Name: Prof Mark Febbraio
End Year: 2013
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Systems Physiology
Total funding: $656,033
Title of research award:
Activation of HSP72 in skeletal muscle as a therapeutic target for obesityActivation of HSP72 in skeletal
muscle as a therapeutic target for obesity
Lay Description (from application):
We recently discovered that activation of a protein, namely Heat Shock Protein 72, can prevent obesity and
insulin resistance in mice. We have developed a small molecule activator of this protein which has undergone
preliminary human clinical trials. This project will extend upon this initial finding to determine the precise
mechanism by which activation of this protein prevents obesity and insulin resistance.
Research achievements (from final report):
Approximately 5 years ago our research group made the pivotal discovery that over-expression or activation of
heat shock protein 72 (HSP72; the inducible form of the 70kDa family of heat shock proteins) in skeletal
muscle reduces obesity-induced insulin resistance. These findings led to the development of the small molecule
activator of HSP72, namely BGP-15, which was recently shown to be display efficacy for the treatment of type
2 diabetes (T2D) in a Phase 2b, multi-centre clinical trial co-ordinated, in part, by CIA Febbraio. T
Interestingly, while we originally ascribed the mechanism of action of HSP72 in skeletal muscle to blocking
inflammation2, we have recently published back to back papers in the journal Diabetes that demonstrate that
HSP72 is both necessary and sufficient to maintain mitochondrial structure and function in the context of
obesity and insulin resistance. Moreover, during the course of this grant we discovered that the effect of HSP72
on the mitochondria is the principal mechanism of action of its insulin sensitising effect. These recent results
are most significant as they suggest that HSP72 may be a therapeutic target for not only T2D, but for
conditions in which mitochondrial function is impaired. Importantly, mitochondrial function declines with age
and is thought to contribute to many diseases associated with aging.
Expected future outcomes:
Accordingly, weexpect that activation of HSP72, using a drug that is proven to be effective in treating T2D,
with an excellent safety profile and good tolerability in humans, will lead to improvements in mitochondrial
function and capacity, particularly in diseases associated with impaired mitochondrial function, metabolic
syndromes and premature aging.
Name of contact:
Mark Febbraio
Email/Phone no. of contact:
mark.febbraio@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1005851
Start Year: 2011
CIA Name: Prof Karin Jandeleit-Dahm
End Year: 2013
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $441,512
Title of research award:
NOX isoforms in diabetes associated vascular injury: implications for therapeutic strategiesNOX isoforms in
diabetes associated vascular injury: implications for therapeutic strategies
Lay Description (from application):
These studies will investigate the role of oxidative stress and enzymes involved in oxidative stress production
in diabetes associated blood vessel injury and kidney damage, leading to heart attacks, stroke and kidney
failure. We will use unique knockout animal models and novel drug treatments. Ultimately, we aim to develop
novel treatments to better treat and prevent diabetes related complications.
Research achievements (from final report):
This grant has been very succesful. In our work we have identified Nox1 as the most important Nox isoform in
diabetes associated atherosclerosis (published in Circulation 2013) and Nox4 in diabetic nephropathy
(published in JASN in 2014). The work is ongoing with several other publications in progress. Furthermore,
this work has been widely presented as invited presentations at the major international and national diabetes,
heart and kidney conferences. We have submitted an ongoing project grant to continue this work. We have
established and expanded collaborations with the top groups in the world in this field and have an ongoing
collaboration with industry to investigate novel more specific Nox inhibitors initially preclinically and
ultimately in the clinical context.
Expected future outcomes:
Our work has shown that Nox4 in the vasculature may be beneficial. Ongoing and future research will
delineate the role of Nox4 and the human isoform Nox5 in the vasculature and in the kidney in diabetes. We
will identify novel targets and validate them in animal models as well as in investigator driven early phase
clinical trials.
Name of contact:
Karin Jandeleit-Dahm
Email/Phone no. of contact:
karin.jandeleit-dahm@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1007465
Start Year: 2011
CIA Name: Prof Mark Febbraio
End Year: 2013
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Medical Physiology not elsewhere classified
Total funding: $593,888
Title of research award:
An essential role for skeletal muscle FoxO1 in protecting against obesity-induced insulin resistanceAn essential
role for skeletal muscle FoxO1 in protecting against obesity-induced insulin resistance
Lay Description (from application):
Skeletal muscle is the largest organ in the human body and accounts for approximately 80% of glucose
disposal after a meal. We have identified a transcription factor, namely FoxO1, that appears protect against
obesity-induced insulin resistance by promoting energy consumption. This project will examine whether
skeletal muscle specific activation of FoxO1 is a possible therapeutic target for the treatment of obesityinduced insulin resistance.
Research achievements (from final report):
The general aim of this project was to examine the role of FoxO1 in skeletal muscle on the aetiology of
obesity-induced insulin resistance and nutrient homeostasis.Contrary to what was expected, we have found that
overexpression of FoxO1 in skeletal muscle, protects mice from the deleterious effects of high fat feeding in
the absence of differences in fat mass or fat free mass compared with littermate control mice . In addition, we
saw the opposite in FoxO1 deficiency. These data provide a previously undescribed role for FoxO1 in the
eatiology of metabolism.
Expected future outcomes:
We are now attempting to elucidate a mechanism for these results before we publish the data
Name of contact:
Mark Febbraio
Email/Phone no. of contact:
mark.febbraio@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1010098
Start Year: 2011
CIA Name: Prof Mark Cooper
End Year: 2013
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Nephrology and Urology
Total funding: $578,352
Title of research award:
Novel strategy to reduce renal fibrosisNovel strategy to reduce renal fibrosis
Lay Description (from application):
Kidney fibrosis is a serious complication seen in diabetic subjects. This process is mainly controlled by
transforming growth factor beta (TGF-beta). However, direct targeting of TGF-beta as a therapeutic approach
is inappropriate due to its other important functions. Our preliminary data show that Cell Division Autoantigen
1 (CDA1) is critical for the disease causing activity of TGF-beta. We propose to use our recently generated
unique CDA1 gene knockout mouse to demonstrate this important role of CDA1.
Research achievements (from final report):
We have demonstrated in vivo that CDA1 deletion retarded renal fibrosis in experimental diabetic nephropathy
(DN) using our global CDA1KO and CDA1/ApoE double KO (dKO) mice rendered diabetic by streptozotocin
injections. Diabetes associated increases in renal protein and gene expression of molecules involved in TGFbeta pathway and extracellular matrix protein accumulation were shown to be attenuated in CDA1 KO and in
CDA1/ApoE dKO mice due to CDA1 deficiency. This effect of CDA1 deficiency was shown to be associated
with attenuated Smad3 phosphorylation in these mice, which is a signaling molecule mediating the profibrotic
effect of TGF-beta in renal fibrosis. Furthermore, we have shown that a pharmacological approach using our
novel peptide CHA-061 with a cell penetrating leader fragment was effective to retard DN in diabetic ApoE
KO mice, which were treated with this peptide at 5 weeks after diabetes for a further 5 weeks. Diabetes
associated increased renal gene expression of TGF-beta2, CTGF, collagens I, III, fibronectin and MMP2 were
significantly attenuated by the peptide treatment. These genetic and pharmacological approaches successfully
validate CDA1 as an effective molecular target for retarding renal fibrosis in mouse DN. We have also shown
that CDA1 is strongly stained in biopsy kidney samples from subjects with sclerotic renal diseases including
those with DN, which implicates the pathological role of CDA1 in DN and further strengthens the rationale and
clinical relevance to targete CDA1.
Expected future outcomes:
These studies strengthen further explore mechanisms underlying the pathological role of CDA1 in order to
identify a druggable target to inhibit CDA1. Our novel anti-CDA1 peptide with its efficacy demonstrated in
this study has great potential to be further translated into clinical application in the future.
Name of contact:
Mark Cooper
Email/Phone no. of contact:
mark.cooper@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1029844
Start Year: 2012
CIA Name: Dr Andrew Carey
End Year: 2013
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Cell Physiology
Total funding: $323,301
Title of research award:
Adrenergic activation of brown adipose tissue in humans.Adrenergic activation of brown adipose tissue in
humans.
Lay Description (from application):
Obesity is a major health and financial threat to society in the near future, thus new anti-obesity therapies are
essential. Activation of brown adipose tissue (BAT) can increase resting energy expenditure by 20%, and its
recent conclusive identification in adults renewed interest in its potential as an anti-obesity target. We will
determine whether BAT can be activated pharmacologically in humans, whether obesity reduces its activity
and if long-term drug treatment can increase BAT function.
Research achievements (from final report):
As a result of this grant we identified that brown adipose tissue (BAT) in humans can be stimulated to increase
energy burning via a single dose of a drug. This class of drug replicates the brain signal that is sent to BAT in
response to cold exposure. This outcome directly informs future drug development strategies that target BAT
for the treatment of obesity. Since we now know it is possible to activate BAT with a pharmacological agent,
we know that evolutinarily developed signalling pathways remain in adult human BAT that we may be able to
manipulte with more specific drugs.
Expected future outcomes:
Current work extending directly from the outcomes of this grant involves the study of whether pharmacological
interventions can enhance brown fat function in humans.
Name of contact:
Andrew Carey
Email/Phone no. of contact:
andrew.carey@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1040122
Start Year: 2011
CIA Name: Dr Celine Latouche
End Year: 2012
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: International Exchange Early
Career Fellowships
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $74,973
Title of research award:
Novel actions of HDL cholesterol: a potential new strategy for treatment of diabetesNovel actions of HDL
cholesterol: a potential new strategy for treatment of diabetes
Lay Description (from application):
There are currently in excess of 170 million patients diagnosed with type 2 diabetes worldwide. Recent studies
have identified novel actions of HDL cholesterol in relation to glucose and fat metabolism which provide a
rationale for therapeutic approaches to raise levels of circulating HDL to manage the metabolic syndrome and
type 2 diabetes. This research will investigate HDL signaling pathways and contribute significantly to our
understanding of the metabolic actions of HDL in Humans.
Research achievements (from final report):
80% of individuals with type 2 diabetes mellitus will die of cardiovascular complications, such as heart attack
or stroke. There are currently approximately 500,000 Australians who have been diagnosed with type 2
diabetes and it is estimated the same number of Australians remain undiagnosed. To further understand the
mechanisms of metabolic dysfunction in impaired glucose tolerance/impaired fasting glucose and type 2
diabetes, people free of disease, pre-diabetics, or type 2 diabetics have been recruited and subjected to a muscle
biopsy. , Genes are made of a chemical called Deoxyribonucleic Acid, commonly known as DNA. DNA is
sometimes compared to a set of blueprints because it contains the instructions for all the other components of
cells. In this study, we investigated which and how genes are switched on and off by factors unrelated to the
DNA sequence itself, especially short ribonucleic acid molecules called microRNA (this kind of study is called
epigenetics). , Our study highlights some of the regulated mechanisms during the progression of diabetes. We
have identified candidate genes, as well as potential microRNAs, which are likely to contribute to the
development of type 2 diabetes and represent potential new targets for treatment.
Expected future outcomes:
Once identified the mechanisms involved in the progression of diabetes, we will investigate the effectiveness of
a number of drugs (or potential new drugs) which target these mechanisms. We will also investigate the
epigenetic changes that may occur after treatment with the compounds in development.
Name of contact:
Celine Latouche
Email/Phone no. of contact:
celine.latouche@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 511217
Start Year: 2008
CIA Name: Prof Jenny Doust
End Year: 2012
Admin Inst: Bond University
Grant Type: NHMRC Strategic Awards
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $499,199
Title of research award:
Implementation and cost-effectiveness of absolute risk for prevention of cardiovascular disease in
AustraliaImplementation and cost-effectiveness of absolute risk for prevention of cardiovascular disease in
Australia
Lay Description (from application):
Cardiovascular disease (CVD) causes more deaths and accounts for more hospital costs than any other disease
in Australia. Providing the best possible mix of treatments to prevent CVD in those at risk has the greatest
potential to reduce deaths, disability and costs associated with this disease. There is evidence that improving
the current mix of treatments that patients at risk of CVD receive would lead to significant improvements in
health in Australia. The project will determine the best mix of treatments that can be provided for patients at
risk of CVD whilst keeping spending on treatments to prevent the disease at current levels. We will also
examine how to increase the number of healthy years of life (and not just the number of people affected by
disease) by looking at how the mix of treatments can affect the timing of CVD. The project will develop a
decision support system for GPs to be able to a) establish the risk of CVD for an individual patient and b) a
treatment algorithm for patients at risk of CVD that can be used in general practice and that can take into
account other diseases that patients may also have. The treatment algorithm will then be tested in a randomised
controlled trial. The project differs from the Harris (510173) and Nelson (490042) projects in that it will assess
a mix of drug treatments and lifestyle interventions to determine the optimal balance. This project also
includes a formal cost-effectiveness component and has the support of the chair of the PBAC, Prof Lloyd
Samson.
Research achievements (from final report):
Better targeting of medications used for cardiovascular disease (CVD) prevention, such as blood pressure and
lipid lowering drugs, would improve the effectiveness and cost-effectiveness of these widely used drugs. We
conducted:, 1) a systematic review of CVD risk equations (Liew et al, 2011). We showed that recent analyses
are confounded by treatment effects, leading to potentially spurious associations (Liew et al, 2012). Treatment
effects explain the observed over-prediction of risk by the Framingham risk equation in recent populations, and
re-calibration of the equation is not necessary. , 2) an analysis of the AusDiab cohort, showing that the absolute
risk approach significantly changes who is treated with blood pressure and lipid lowering medications (Doust
et al, 2012). A further explanation of the clinical application of this analysis is outlined in a paper recently
accepted by the MJA (Nelson and Doust, 2013)., 3) a qualitative study of GPs and consumers and a vignette
study. These studies showed that a number of factors impact on GP prescribing other than the CVD risk level,
such as patient motivation for lifestyle interventions and attitudes to medication. There is also some ongoing
misundertanding of the clinical application of the absolute risk approach (2 publications ready for submission).
These factors need to be considered in improving the uptake of the absolute risk approach, and better targeting
of medication for CVD prevention.
Expected future outcomes:
We are currently analysing an economic evaluation of the absolute risk approach in Australia, based on the
distribution of risk factors from the AusDiab cohort. We are conducting the process evaluation of a NHMRC
funded trial of a decision aid for CVD risk prediction and the use of the heart age tool to better communicate
CVD risk to patients.
Name of contact:
Jenny Doust
Email/Phone no. of contact:
NHMRC Research Achievements - SUMMARY
jdoust@bond.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 520316
CIA Name: Dr Allison Hodge
Admin Inst: Cancer Council Victoria
Main RFCD: Epidemiology
Total funding: $304,002
Start Year: 2008
End Year: 2011
Grant Type: Early Career Fellowships (Australia)
Title of research award:
Dietary antioxidants and fatty acids and heart disease risk in Southern European migrants and Indigenous
AustraliansDietary antioxidants and fatty acids and heart disease risk in Southern European migrants and
Indigenous Australians
Lay Description (from application):
The aim in this research program is to learn more about how nutrition, particularly different types of dietary fat
and antioxidants from fruit and vegetables, can affect the risk of cardiovascular disease and diabetes. Data
from Indigenous Australians known to be at high risk for these conditions, as well as Greek and Italian
migrants to Australia, with low risk for cardiovascular disease, will be analyzed.
Research achievements (from final report):
Identification of important associations between healthy diet and a range of conditions including anxiety and
depression, impaired vision, osteoarthritis, cardiovascular risk factors, cancer and diabetes. Dietary patterns
including fruit and vegetables, limited amounts of red and processed meat and omega-3 fats or olive oil, lower
salt and moderate carbohydrate intake were associated with lower risks of these conditions, although we found
some evidence that consumption of red meat below the level recommended in the Australian dietary guidelines
was associated with mood and anxiety disorders., We developed a definition of healthy ageing based on the
absence of chronic disease, depression or anxiety and disability and found this was less common in people who
had diabetes 12 years earlier, was associated with consuming more calcium, important for bone health, and less
energy, and having an eating pattern reflecting that of southern European migrants to Australia, as well as
healthy weight, not smoking and being physically active in middle-age. Social interaction did not appear to be
associated with healthy ageing by our objective criteria, but may modify how people perceive the ageing
process (these papers are not yet published). Having a healthy weight in middle age was also associated
specifically with less disability after 70 years of age., On the basis of observations regarding diet and mental
health we are planning a study to see what happens when we provide food and advice on healthy diet to people
with clinical depression compared with others who get no dietary advice or food.
Expected future outcomes:
Results of above intervention study in depression if as hypothesised will add to options for treatment of
depression. Modelling dietary change over time to evaluate the benefits of a mediterranean style diet for
cardiovascular and total mortality will be important methodologically as it avoids the need to conduct
intervention studies.
Name of contact:
Allison Hodge
Email/Phone no. of contact:
allison.hodge@cancervic.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 475605
Start Year: 2008
CIA Name: Prof Tien Wong
End Year: 2010
Admin Inst: Centre for Eye Research Australia Ltd Grant Type: NHMRC Project Grants
Main RFCD: Endocrinology
Total funding: $396,818
Title of research award:
Prediction of Microvascular Complications in Type 1 Diabetes Using Novel Retinal Vascular Imaging
TechniquesPrediction of Microvascular Complications in Type 1 Diabetes Using Novel Retinal Vascular
Imaging Techniques
Lay Description (from application):
Children with type 1 diabetes face the risk of developing severe complications later in life involving their eyes
(retinopathy), kidneys (nephropathy) and nerves (neuropathy). This study aims to determine if subtle, early
changes seen in the retinal blood vessels, as measured from new computer imaging techniques, predict the
subsequent development of these diabetes complications in children/adolescents with type 1 diabetes.
Research achievements (from final report):
The study commenced in 2008. To date, over 1200 baseline retinal images have been assessed and graded for
novel measures of retinal vascular architecture including retinal vascular caliber, tortuosity, branching angles
and fractal dimensions. We have demonstrated that retinal vascular geometry (branching angle, tortuosity,
optimality deviation) are altered following the advancement of adverse diabetes risk profiles (duration of
diabetes, HbA1c level, blood pressure, and cholesterol), and are associated with prevalent retinopathy and early
nephropathy. Furthermore we demonstrated that baseline arteriolar length to diameter ratio (LDR) and simple
tortuosity (ST) predicted incident retinopathy (manuscript under review - Diabetes Care). We are currently
studying the relationship between venular changes and early renal dysfunction. Longitudinal plantar fascia
study (adult follow up) had 152 patients with 278 visits graded for vessel calibre and fractal dimension, a total
of 555 eyes. Patients have been reassessed for follow-up examinations and undergone small artery elasticity,
blood pressure and plantar fascia thickness assessments as well as retinal photography. Grading of these images
was completed in December 2009. Abstracts were submitted for both Aims 1 and 2 and data presented at
several international meetings. The manuscript is currently being revised and will be submitted for publication
in March 2011. We completed recruitment of 310 patients and 125 controls for the cross-sectional plantar
fascia study in October 2010. Grading of vessel calibre and fractal dimension has been completed for 310
patients and the data is currently being analysed.
Expected future outcomes:
We expect to identify novel biomarkers for diabetic complications that are sensitive and specific, as well as
practical for clinical use.
Name of contact:
Prof. Tien Wong
Email/Phone no. of contact:
twong@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 529902
Start Year: 2009
CIA Name: A/Pr Ecosse Lamoureux
End Year: 2012
Admin Inst: Centre for Eye Research Australia Ltd Grant Type: Career Development Fellowships
Main RFCD: Public Health and Health Services not elsewhere classified
Total funding: $387,490
Title of research award:
The effectiveness of a new Diabetic Retinopathy screening strategy for people with diabetes.The effectiveness
of a new Diabetic Retinopathy screening strategy for people with diabetes.
Lay Description (from application):
A simple way to prevent and treat people suffering from diabetic retinopathy, a terrible eye disease resulting
from diabetes, is to identify the disease early. This research will screen people with diabetes who do not think
they have diabetic retinopathy or who have not had an eye examination in the last 2 years when attending a
pathology centre for their diabetes-related tests. The study will follow participants over 4 years to look at
subsequent treatment and compliance with eye examination.
Research achievements (from final report):
Up to 50% of Australians with diabetes do not undertake screening or follow-up for diabetic retinopathy and
are at risk of diabetic retinopathy. The Australian public healthcare system does not have an effective screening
strategy to tackle this issue. My research investigated an innovative screening modality for diabetic retinopathy
using pathology collection centres as screening sites. It demonstrated that 35% of people with diabetes
attending one urban pathology centre had not undertaken screening for diabetic retinopathy in the previous two
years but of these a significant number (94%) accepted a screening check by pathology personnel. Almost 20%
of participants were identified to have diabetic retinopathy. I also determined that pathology personnel can be
effectively trained to take digital retina images using a non-mydriatic fundus camera. These results indicate the
substantial potential for this screening model to boost screening rates and early detection of diabetic
retinopathy in those non-compliant to screening guidelines. This research attracted productive collaborations
with Diabetes Australia-Victoria, four pathology organisations, the Australian College of Optometry, and an
international collaboration with NORC at the University of Chicago (USA). Funding was successfully obtained
from two Centres for Clinical Research Excellence (CCRE on Diabetes [NHMRC#454461] and Eye Diseases
[NHMRC#529902]), the Windermere Foundation and the Melbourne Strategic Research Initiatives Fund. Also,
my research was granted 5-year funding by the NHMRC (APP1012454) to build upon these findings and
investigate the effectiveness and economic benefits of this screening model in people with diabetes attending
10 urban and rural pathology collection centres.
Expected future outcomes:
Based on the funding opportunities obtained and strong collaborative links I have developed, I am building
upon this research to investigate the effectiveness and economic benefits of the proposed screening model in
ten urban and rural pathology locations and in English and non-English speaking individuals.
Name of contact:
Associate Professor Ecosse Lamoureux
Email/Phone no. of contact:
ecosse@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 529923
Start Year: 2009
CIA Name: Prof Tien Wong
End Year: 2014
Admin Inst: Centre for Eye Research Australia Ltd Grant Type: Centre of Clinical Research
Excellence
Main RFCD: Opthalmology and Vision Science
Total funding: $2,552,356
Title of research award:
Translational Clinical Research in Major Eye Diseases (TCR-Eye)Translational Clinical Research in Major
Eye Diseases (TCR-Eye)
Lay Description (from application):
The four eye diseases that cause the majority of vision loss in Australia, age-related macular degeneration,
diabetic retinopathy, cataract and glaucoma, impose a significant socio-economic burden, costing our nation $lo billion a year. This CCRE will fund a world leading, broad-based, clinical and translational research
program in Melbourne and Sydney to tackle these eye diseases. The new knowledge and innovative clinical
strategies developed in this CCRE will impact on clinical ophthalmology and the practice of other medical
disciplines.
Research achievements (from final report):
o
The team published a number of high
impact papers (e.g. Nature Genetics) on genes associated with age-related macular degeneration (AMD),
diabetic retinopathy (DR), glaucoma and corneal diseases (e.g. keratoconus). CIs Wong, Mitchell Wang,
Guymer and Baird published valuable data on gene-environment interactions based on data from the Blue
Mountains Eye Study and the Melbourne Collaborative Cohort Study. Higher red meat and alcohol
consumption was associated with early-onset AMD; high GI consumption in children was associated with
retinal arteriolar widening (a marker for future cardiovascular disease risk)., o
In the area of
DR, CI Wong has developed a semi-automated evaluation tool for retinal artery and venular calibre grading; CI
Guymer has worked closely with CenterVue on the development and use of Macular Integrity Assessment
Microperimetry, which has been incorporated into many AMD trials to assess retinal sensitivity., o CI
Lamoureux were awarded an NHMRC Project grant to trial Ret-Path, a screening study which uses pathology
centres as designated screening sites for DR. The Access Economics report published by CIs Crowston and
Keeffe was the first comprehensive health economic report in glaucoma, was presented to representatives from
State and Federal Health Departments and initiated a subsequent NHMRC funded trial on first line glaucoma
treatment., o
CI Guymer is leading a world-first
RCT of a nanosecond laser intervention in high-risk early AMD. The investigators are working closely with
pharmaceutical and biotechnology companies on novel treatments for these sight-threatening disorders.
Expected future outcomes:
The team has made excellent progress against the aims and will leverage the support from the NHMRC to
continue collaborating across the 6 themes with the ultimate aim of making changes to health policy and
practice based on their research. Further publications arising from this study are expected.
Name of contact:
Prof Tien Wong
Email/Phone no. of contact:
twong@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 590212
Start Year: 2010
CIA Name: Prof Tien Wong
End Year: 2012
Admin Inst: Centre for Eye Research Australia Ltd Grant Type: NHMRC Project Grants
Main RFCD: Epidemiology
Total funding: $754,255
Title of research award:
Novel Retinal Architectural Vascular Signs and Risk of Cardiovascular Disease: The AusDiab StudyNovel
Retinal Architectural Vascular Signs and Risk of Cardiovascular Disease: The AusDiab Study
Lay Description (from application):
Cardiovascular disease (CVD) and diabetes are major health problems. Identifying 'people at risk' is critical to
design preventative strategies. We have developed new computer software to measure detailed characteristics
of retinal vessels. By appling this system to predict CVD or diabetes in the AusDiab Study we aim to find 'the
best combination of risk factors' to predict CVD and diabetes. This will open up the possibility of new risk
assessment using a simple 'eye scan.'
Research achievements (from final report):
Cardiovascular disease (CVD), diabetes and its vascular complications are major causes of morbidity and
mortality in Australia. Early identification at asymptomatic stage is the key for successful prevention. We
aimed to examine whether retinal architectural parameters are sensitive measures to predict systemic vascular
diseases.We performed computer-based image analysis using retinal images and clinical data of the AusDiab
study participants at the Baseline (1999-2000) and 5-year follow up (2004-5). We refined the retinal imaging
technique to quantify retinal parameters of the fractal dimensions (FD), vessel tortuosities and calibres. We
also performed a validation study to evaluate how pulse cycle affects the measurements of retinal vessel
parameters; we confirmed that retinal vascular characteristics are stable against pulse cycle.We have collected
CVD outcome using questionnaires and medical records review from AusDiab study participants nationwide in
2010-12. Although we have completed a data collection, adjudication of clinical information is underway; we
could not fully utilize the information in the current analysis. Although we could not utilize CVD outcomes, we
have looked at cross-sectional associations of retinal architectural parameters to other systemic outcomes. We
found that persons with higher retinal FD were more than 50% more likely to have diabetes compared to the
persons with smaller FD. We also found Serum apolipoprotein are associated with microvascular endothelial
dysfunction. Higher retinal vascular tortuosities were also associated with diabetes and diabetic retinopathy.
These are in concordance with our hypothesis that retinal architectural parameters are associated with vascular
diseases.
Expected future outcomes:
Our proposed study will provide new insights into the inter-relationship between early microvascular changes
and subsequent risk of CVD, diabetes and its vascular complications. Furthermore, our research may
potentially allow the use of non-invasive retinal imaging as a tool to identify asymptomatic persons with higher
risk of CVD.
Name of contact:
Professor Tien Wong
Email/Phone no. of contact:
tien_yin_wong@nuhs.edu.sg
NHMRC Research Achievements - SUMMARY
Grant ID: 590218
Start Year: 2010
CIA Name: Dr Mohamed Dirani
End Year: 2011
Admin Inst: Centre for Eye Research Australia Ltd Grant Type: Early Career Fellowships
(Australia)
Main RFCD: Epidemiology
Total funding: $109,415
Title of research award:
Identifying the predictors for poor diabetes care and diabetic retinopathy in adults with type 1 and 2
diabetesIdentifying the predictors for poor diabetes care and diabetic retinopathy in adults with type 1 and 2
diabetes
Lay Description (from application):
Diabetes affects 1 million Australians, with 50% of cases still undiagnosed. Diabetes has associated problems,
such as heart failure and sight-threatening eye disease. Studying patients with diabetes will identify the factors
contributing to poor diabetes care and diabetic eye disease. We also intend to use eye imaging to predict the
development of poor diabetes care and diabetic eye disease. We can then use preventive measures to reduce the
problems associated with diabetes, such as blindness.
Research achievements (from final report):
Not Available
Expected future outcomes:
My work provides
Name of contact:
A/Prof Ecosse Lamoureux
Email/Phone no. of contact:
ecosse@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1016698
Start Year: 2011
CIA Name: Dr Ryo Kawasaki
End Year: 2012
Admin Inst: Centre for Eye Research Australia Ltd Grant Type: Early Career Fellowships
(Australia)
Main RFCD: Ophthalmology
Total funding: $107,169
Title of research award:
Novel morphological retinal vascular features as early biomarkers of vision-threatening eye diseases.Novel
morphological retinal vascular features as early biomarkers of vision-threatening eye diseases.
Lay Description (from application):
Vision loss is not just a personal health burden, but a huge socio-economical burden. Management of major
vision-threatening eye diseases such as diabetic retinopathy, age-related macular degeneration and glaucoma
will be improved if we can successfully identified persons at risk of developing the disease before clinical
presentation to benefit from preventive treatment. My research aims to contribute to the prediction of these
blinding diseases using advanced computer imaging analysis for simple retinal photographs.
Research achievements (from final report):
, My research involved clinical data from large population-based cohort studies to investigate the retinal
vascular risk characteristics associated with vision-threatening eye diseases. I used clinical and epidemiological
data collected from population-based cohorot studies (e.g., the Blue Mountains Eye Study and AusDiab Study),
and clinical study data (e.g., Diabetic Retinopathy Cohort, the Japan Diabetes Complications Study, Singapore
Multi-ethnic cohorts, and Royal Victorian Eye and Ear Hospital patient database) to address 4 major topics
related to my aims. Major results and findings from this work were:, 1. Retinal vascular characteristics
associated with ocular diseases;, 2. Epidemiology of vision-thretening ocular diseases;, 3. Developing new
retinal vascular imaging; and, 4. Retinal vascular imaging associated with systemic diseases., Potential benefit
of this fellowship can be summarized as (1) identification of new risk factors for diabetic retinopathy
(apolipoprotein subfraction, fruits intake etc.), (2) potential of retinal vessel signs as a surrogate marker of
progression of ocular and systemic diseases, and (3) development of new retinal vascular imaging system with
standardized and quantitateive parameters.
Expected future outcomes:
Based on newly identified risk characteristcs, more precise risk prediction models for sight thretening eye
diseases such as diabetic retinopathy and age-related maculopathy will be developed. Automated image
grading system to help improve risk prediction models will be developed in ocular and systemic cardiovascular
risk evaluation.
Name of contact:
Ryo Kawasaki
Email/Phone no. of contact:
rkaw@unimelb.edu.au / rkawasaki@gmail.com
NHMRC Research Achievements - SUMMARY
Grant ID: 403976
Start Year: 2006
CIA Name: Prof Kanagasingam Yogesan
End Year: 2011
Admin Inst: CSIRO Division of Human Nutrition Grant Type: NHMRC Research Fellowships
Main RFCD: Ophthalmology and Vision Science
Total funding: $746,472
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
Media Summary not available
Research achievements (from final report):
This fellowship gave me the opportunity to develop novel diagnostic technologies for early detection of
needless blindess due to diabetic retinopathy and glaucoma. One of the outcomes, EyeScan device, was
licensed to a US company (Ophthalmic Imaging Systems, CA) and sold around the world. This is the first such
multifunctional device for diagnosis of both front and retinal diseases. In addition, various tele-ophthalmology
services has been implemented in WA. A patent portfolio of more than 30 applications came out of this
fellowship.
Expected future outcomes:
The technologies and methods developed during this fellowship lead to ocular biomarkers for early detection of
systemic diseases such as Alzhimer's disease and stroke. The comprehensive evaluation of telemedicine
technologies also lead to sustainable eye care for rural and remote population, espcially for the Indegenious
population.
Name of contact:
Yogesan Kanagasingam
Email/Phone no. of contact:
kan063@csiro.au
NHMRC Research Achievements - SUMMARY
Grant ID: 455241
Start Year: 2011
CIA Name: Prof Bernard Tuch
End Year: 2011
Admin Inst: CSIRO Division of Human Nutrition Grant Type: NHMRC Project Grants
Main RFCD: Endocrinology
Total funding: $763,317
Title of research award:
Xenotransplantation of encapsulated insulin-producing pig cellsXenotransplantation of encapsulated insulinproducing pig cells
Lay Description (from application):
The ideal treatment for insulin-dependent diabetes is the replacement of insulin-producing cells. Currently, this
is carried out using a whole pancreas or experimentally with cells isolated from the pancreas of donor humans.
Despite the success of these procedures, demand for human organs far exceeds supply, thus driving the search
for suitable alternatives. Pigs are physiologically similar to humans, and insulin-producing cells can be easily
isolated from the fetal pig pancreas as islet-like cell clusters; 8% of the cells in the cluster produce insulin and
the remaining cells develop this capability after transplantation. Transplantation requires chronic
immunosuppression with drugs which increase the risk of infection and cancer. To many people with diabetes,
the side effects will be greater than the potential benefit. Placing cells inside microcapsules made of a
biologically inert material may prevent graft rejection without chronic immunosuppression. The Investigators
have demonstrated that encapsulated insulin-producing pig cells survive and function when transplanted into
diabetic immunodeficient mice, but not when xenografted into immunocompetent mice. It is hypothesised that
this is due to an immunological or inflammatory response by the host in response to the shedding of molecules
by the encapsulated pig cells. A pre-clinical model to test the efficacy of encapsulated insulin-producing pig
cells is the humanized mouse. It is hypothesized that transient administration of anti-rejection drugs will be
needed to allow the survival of pig cells xenografted into these mice and normalization of BGL once diabetes
has been induced.The aims of this study are: 1. To assess the nature of the host response when encapsulated
insulin-producing fetal pig cells are transplanted into diabetic BALB/c mice. 2. To normalize blood glucose
levels (BGL) in diabetic humanized mice transplanted with encapsulated insulin-producing fetal pig cells.
Research achievements (from final report):
Xenotransplantation in the context of treating diabetes in humans requires the transplantation of animal insulinproducing cells into humans who would normally administer insulin multiple times each day to stay alive.
Placing the pig cells inside microcapsules made of a product from seaweed was a way of preventing the
immune system of the recipient from recognizing the pig cells as foreign and destroying the graft., A mouse
recipient model was used to simulate what might occur in human recipients of porcine tissue. , Within 7 days
of mice receiving pig cells, an inflammatory response was observed around the outside of the microcapsules,
with resultant death of the cells inside., Several strategies were adopted to try and overcome this fibrotic
reaction, with human tissue being substituted for the pig cells, when pig tissue became difficult to obtain. The
only strategy that reduced the inflammatory response was mixing adult rodent stem cells, which have antiinflammatory properties, with the encapsulated insulin-producing cells. Adult human stem cells with antiinflammatory properties were unhelpful. Inhibiting activation of immune cells, with genetically modified mice,
showed no benefit. Coating the surface of the microcapsules with the anti-inflammatory agent, heparin, also
was unsuccessful, although this strategy did reduce the inflammation observed in rodents transplanted with
rodent insulin-producing cells.
Expected future outcomes:
It is expected that strategies to prevent the fibrotic reaction observed when encapsulated cells are xenografted
will be improved, such that the inflammation observed previously will be prevented, thereby allowing the
insulin-producing cells to function and normalize blood glucose levels.
Name of contact:
Dr Bernie Tuch
NHMRC Research Achievements - SUMMARY
Email/Phone no. of contact:
bernie.tuch@csiro.au
NHMRC Research Achievements - SUMMARY
Grant ID: 229030
Start Year: 2003
CIA Name: Dr Spencer PROCTOR
End Year: 2004
Admin Inst: Curtin University of Technology
Grant Type: Early Career Fellowships (Overseas)
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $174,288
Title of research award:
To characterise & attenuate cholesterol deposition in animal models of abesity, insulin resistance & diabetes
using noveTo characterise & attenuate cholesterol deposition in animal models of abesity, insulin resistance &
diabetes using nove
Lay Description (from application):
Not Available
Research achievements (from final report):
Cardiovascular disease (CVD) is the most common cause of death and morbidity in all prosperous societies,
leading to heart attacks, strokes and kidney disease. A major contributor to CVD is obesity non-insulin
dependent diabetes mellitus (NIDDM), or type-2 diabetes. CVD is caused by the accumulation of cholesterol
and lipid in blood vessels, which can lead to a complete blockage in the artery and stop blood flow. In diabetes,
the accumulation of cholesterol in arterial vessels is accelerated and CVD develops and progresses more
quickly, unfortunately it is still not clear how this happens. Strangely, the 'bad' types of cholesterol (called
LDL) that are thought to cause heart attacks, appear to be normal in people with early diabetes. We have
discovered recently that humans (and animals) with insulin-resistance (early type-2 diabetes) have raised levels
of dietary cholesterol (called chylomicrons), which are different from the traditional 'bad' cholesterol called
LDL.
Expected future outcomes:
We have developed an animal model that will allow us to explore how the intestine is modulated during
chronic disease and contrbutes to CVD risk
Name of contact:
Spencer Proctor
Email/Phone no. of contact:
spencer.proctor@ualberta.ca
NHMRC Research Achievements - SUMMARY
Grant ID: 323519
CIA Name: Dr Sarah McNaughton
Admin Inst: Deakin University
Main RFCD: Nutrition and Dietetics
Total funding: $275,438
Start Year: 2005
End Year: 2009
Grant Type: Early Career Fellowships (Australia)
Title of research award:
Development and application of practical tools for the assessment of dietary patterns in the Australian
population.Development and application of practical tools for the assessment of dietary patterns in the
Australian population.
Lay Description (from application):
Not Available
Research achievements (from final report):
, The primary objective of this postdoctoral fellowship research program was the development and application
of methods for assessing dietary patterns, diet quality and the impact of specific dietary patterns on chronic
disease outcomes. While previous research has tended to focus on individual nutrients, there is increasing
interest in investigating aspects of total or overall diet and dietary patterns. This is an innovative approach in
nutritional epidemiology., A major contribution of my research was the development of a diet quality index.
This is the first comprehensive measure designed for use in Australia and I have shown that it is a valid
indicator of diet quality and has been shown to predict abdominal obesity, hypertension, and type 2 diabetes.
Importantly, this tool provides an integrated measure of eating patterns that can be used in population health
research. It is novel and practical way to characterise total diet and investigate the interactions between diet and
other health behaviours and the predictors of healthy eating. Requests for use of this index have been received
from the WA Department of Health, the Australian Longitudinal Study of Women's Health and researchers at
University of Sydney, Flinders University, Queensland Institute of Medical Research and Monash University.
Expected future outcomes:
This research has led to development of key methodological tools in assessing diet quality and dietary patterns
which underpin future research on diet across the life-course. An understanding of how dietary patterns and
their determinants vary across the life-course is critical to the development of preventative health strategies.
Name of contact:
Sarah Mcnaughton
Email/Phone no. of contact:
sarah.mcnaughton@deakin.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 374241
Start Year: 2007
CIA Name: Prof Kylie Ball
End Year: 2012
Admin Inst: Deakin University
Grant Type: NHMRC Strategic Awards
Main RFCD: Public Health and Health Services not elsewhere classified
Total funding: $2,072,674
Title of research award:
Preventing obesity among socioeconomically disadvantaged women and childrenPreventing obesity among
socioeconomically disadvantaged women and children
Lay Description (from application):
The research will investigate the causes of the increased risk of obesity among socioeconomically
disadvantaged women and children. It will also focus on women and children who appear ‘resilient’ to obesity
and will explore the possibility of applying the lessons learned to other women and children, in order to help
support them in adopting and maintaining obesity-protective behaviours. The research aims to provide
evidence to inform policies and programs that should be put into place to prevent obesity among
socioeconomically disadvantaged groups.
Research achievements (from final report):
The mechanisms by which social and economic disadvantage influence lifestyle choices that promote obesity
are poorly understood, and to date there has been insufficient evidence to inform primary prevention programs
and policies. This research yielded among the first multilevel data internationally on the mechanisms
underlying socioeconomic variations in obesity. It demonstrated that a number of socioeconomically
disadvantatged women and children mange to remain 'resilient' to obesity risk, despite their disadvantage, and
identified key characteristics associated with this resilience (e.g., behavioural skills; social support; positive
environmental perceptions) that serve as potential intervention levers in initiatives to promote healthy eating
and physical activity and reduce obesity. The research program also provided novel evidence from
experimental studies on the impact of modifications to perceptions and environments that resulted in improved
eating and physical activity attitudes and behaviours among socioeconomically disadvantaged individuals (e.g.
cognitive approaches to improving perceptions of healthy food affordability; refurbishments to a park in a
disadvantaged neighbourhood). The research has to date been published in 43 peer-reviewed journal papers and
at more than 50 scientific conferences and meetings. Findings have and continue to be translated in various
forums and to different key stakeholders (e.g. local govt/councils; Victorian Centre for Excellence in
Intervention and Preventive Science (CEIPS); Heart Foundation; Dept of Health) in order to inform best
practice in terms of future obesity prevention approaches.
Expected future outcomes:
Findings will lead to more evidence-based obesity prevention initiatives being rolled out by government and
NGOs, helping to address high rates of poor eating, inactivity and obesity in disadvantaged individuals and
communities.
Name of contact:
Professor Kylie Ball
Email/Phone no. of contact:
kylie.ball@deakin.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 400446
Start Year: 2006
CIA Name: Dr Sean McGee
End Year: 2009
Admin Inst: Deakin University
Grant Type: Early Career Fellowships (Australia)
Main RFCD: Neurology and Neuromuscular Diseases
Total funding: $276,750
Title of research award:
Molecular mechanisms mediating contraction-induced metabolic gene expression andMolecular mechanisms
mediating contraction-induced metabolic gene expression and
Lay Description (from application):
Not Available
Research achievements (from final report):
This work culminated in discovering a novel signaling cascade involving the AMP activated protein kinase and
histone deacetylase 5 (HDAC5). This signalling pathways regulates skeletal muscle metabolism by controlling
the expression of a range of genes involved in substrate handling and oxidation. This pathway is activated by
physiological stimuli such as exercise and is conversely dysregulated in disease states, such as type 2 diabetes.
Importantly, this work also showed that inhibitors of HDAC5 were therefore able to normalise skeletal muscle
metabolism in disease states such as type 2 diabetes. These data highlight that the AMPK-HDAC5 signalling
pathway could be a therapeutic target to combat metabolic disease.
Expected future outcomes:
We expect to find new compounds and small molecules that can be manipulated to target this siganlling
pathway to provide more efficacious treatments for metabolic diseases like type 2 diabetes.
Name of contact:
Sean Mcgee
Email/Phone no. of contact:
sean.mcgee@deakin.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 425865
CIA Name: Dr Nicole Stupka
Admin Inst: Deakin University
Main RFCD: Cell Physiology
Total funding: $299,189
Start Year: 2007
End Year: 2011
Grant Type: Early Career Fellowships (Australia)
Title of research award:
Type 2 diabetes and ageing-associated muscle atrophy: role of oxidative stress and redox sensitive signalling
pathwaysType 2 diabetes and ageing-associated muscle atrophy: role of oxidative stress and redox sensitive
signalling pathways
Lay Description (from application):
Not Available
Research achievements (from final report):
This postdoctoral fellowship enabled me to further my research interests into the cellular mechanisms in
skeletal muscle which promote adaptation to stress and enhance repair in order to improve tissue structure,
function and metabolism. During the course of the fellowship, I established and developed an independent
research program which is focused on the following two themes:, (1)
To investigate the consequences of
nutrient excess on oxidative and endoplasmic reticulum stress responses in muscle cells, and to characterize the
functional role of a novel selenoprotein (SEPS1) and the thioredoxin antioxidant system in regulating these
responses. SEPS1 and the endogenous inhibitor of the thioredoxin antioxidant system (TBP-2) are associated
with insulin resistance in vivo and their expression can be dysregulated by excessive nutrients., (2) To
examine the role of secreted ADAMTS proteinases in connective tissue remodelling during skeletal muscle
repair, and to test the potential of ADAMTS proteinases as therapeutic targets for muscular dystrophy. There
are no effective therapeutic strategies to prevent or treat fibrosis in muscular dystrophy and appropriate
connective tissue remodelling is essential to prevent scaring and fibrosis and help maintain functional muscle
mass., I am continuing to grow this research program in my new role as a Lecturer in Medical Physiology in
the School of Medicine, Deakin University., I have also maintained a productive, cross-disciplinary
collaboration with the Department of Chemistryto develop and validate novel approaches to measure cellular
redox state (e.g. glutathione), and to test the antioxidant potential of biological compounds in various muscle
cell culture systems.
Expected future outcomes:
The fellowship was disrupted by maternity leave and at the conclusion of the fellowship I began a new role as a
Lecturer in Medical Physiology, there is a need to publish the latter half of my postdoctoral research. The aim
for 2012 is to begin work to validate cell culture findings in transgenic animal models.
Name of contact:
Nicole Stupka
Email/Phone no. of contact:
nstupka@deakin.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 533824
CIA Name: Dr Juan Carlos Molero-Navajas
Admin Inst: Deakin University
Main RFCD: Cell Metabolism
Total funding: $341,884
Start Year: 2009
End Year: 2011
Grant Type: NHMRC Project Grants
Title of research award:
Transcription-based identification of Insulin Resistance SubtypesTranscription-based identification of Insulin
Resistance Subtypes
Lay Description (from application):
A key feature of type 2 diabetes is the failure of metabolic tissues such as muscle and fat to respond to normal
levels of insulin. This 'insulin resistance' is caused by a number of mechanisms. We will use cutting-edge
technology to identify small sets of genes that define each variety of insulin resistance. These gene sets will be
used to diagnose sub-types of insulin resistance and will facilitate the development of personalised therapies to
effectively treat individuals with type 2 diabetes.
Research achievements (from final report):
Presently, there are significant challenges to finding effective therapies for the long-term management of type 2
diabetes. We investigated the hypothesis that insulin resistance represents a multifactorial series of disorders, in
order to target treatment of individuals according to their subtype(s) of insulin resistance (a personalised
medicine approach to type 2 diabetes). Using a novel, unbiased genomics-based approach to identify a
'fingerprint' of an individual's biological state, known as a Gene Expression Signature (GES), we generated and
published the first GES based on excess inflammation (Physiological Genomics, 2011), which we subsequently
used as a screening tool to identify a new anti-diabetic compound (Diabetes, 2012) that is currently in clinical
trials (Verva Pharmaceuticals). Advantage of GESs is that they provide a global snapshot of the integrated
response to an insult, irrespective of the complexity and interplay involved. We have generated and identified
an additonal 3 GESs based on 3 different causes of insulin resistance (excess fat, glucocorticoid or ER stress),
which are being validated in a human cohort to determine if the GESs can identify insulin resistant subtypes in
individuals. Futhermore, we investigated the functional significance of selected GES genes and our findings
highlight an additional unforseen utility of the GES approach; the potential identification of novel diabetes
candidates. Additionally, pathway analysis has been completed on all 4 models of insulin resistance to identify
the pathways being altered and our findings, coupled with the identity of the 4 GESs, demonstrate that
therapies for type 2 diabetes need to be individualised.
Expected future outcomes:
Our findings show that GES technology can be used for both the discovery of anti-diabetic compounds and the
characterisation of patients into subtypes of insulin resistance, opening the potential to develop optimised
medical treatments (i.e., personalising medicine) for patients with type 2 diabetes.
Name of contact:
Nicky Konstantopoulos
Email/Phone no. of contact:
nicky.konstantopoulos@deakin.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 219125
CIA Name: Prof Neil Thomson
Admin Inst: Edith Cowan University
Main RFCD: Not Allocated
Total funding: $50,000
Start Year: 2002
End Year: 2003
Grant Type: SRDC - Research
Title of research award:
Development of a collaborative intervention model to improve diabetes outcomes in a rural aboriginal
communityDevelopment of a collaborative intervention model to improve diabetes outcomes in a rural
aboriginal community
Lay Description (from application):
Not Available
Research achievements (from final report):
The Noongar Family Diabetes Project (NFDP) aimed to develop a collaborative family-centred model of
diabetes care for the Noongar community in the Central Great Southern district of WA. The project was based
on the principles of Aboriginal ownership and empowerment of Aboriginal Health Workers (AHWs) to work
as members of the Integrated Diabetes Team (IDT), providing diabetes education and care for their Noongar
clients., As capacity-building for AHWs was an integral part of the NFDP, a skills audit was conducted at its
commencement. This audit revealed that AHWs possessed a range of skills and experience, but identified the
need for update/development of their knowledge of diabetes prevention and management. In addressing this
need, seven AHWs completed the 'Health Worker program in diabetes prevention and management', a
nationally recognised competency-based course., Building on qualitative research undertaken with Noongar
residents of Tambellup, the model of diabetes care developed by the NFDP provides for AHWs to work
alongside clients, to help build self-esteem, and to encourage belief in their own abilities. The model uses
yarning as a consultative technique for working with Noongar clients. Yarning, described by the AHWs as
'getting alongside people', recognises the importance of client expertise and sees people as assets to be
developed., The NFDP model describes a collaborative patient-professional partnership that supports client
autonomy in the day-to-day management of their condition as well as providing traditional clinical care and
diabetes education., Using tools developed to assist AHWs, the development of diabetic action plans with
families addressing identified priorities has commenced., Full implementation of the model will depend on its
use by the district health-care team, AHWs feeling empowered to take their role as professional members of the
IDT, and on the development and maintenance of cultural competence for mainstream health workers.
Expected future outcomes:
The NFDP model of diabetes care should enable development of diabetes action plans by Noongar families.
This will depend on: use of the model by the district health-care team; support for AHWs in their work as
Aboriginal Diabetes Health Officers and in raising the cultural competence of the health workforce; and
acknowledgment of Noongar perspectives in diabetes programs for local Noongar people.
Name of contact:
Professor Neil Thomson
Email/Phone no. of contact:
n.thomson@ecu.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: 275526
Start Year: 2004
CIA Name: Dr Anthea Magarey
End Year: 2006
Admin Inst: Flinders University
Grant Type: NHMRC Project Grants
Main RFCD: Public Health and Health Services not elsewhere classified
Total funding: $407,300
Title of research award:
Management of overweight pre-pubertal children - a randomised controlled trialManagement of overweight
pre-pubertal children - a randomised controlled trial
Lay Description (from application):
Obesity is an increasingly common problem in the Australian community, affecting both adults and children.
Up to 1 in 4 Australian children are overweight or obese, making it one of the most common chronic disorders
in this age-group. Obesity in childhood is associated with such complications as high blood pressure, risk of
diabetes, high cholesterol levels, hip, knee and ankle problems, and psychological distress. Given the impact
of overweight and obesity on the health of children, how can it be best treated? Surprisingly, there is little
information available to guide the management of this common problem. In this study we will test the
hypothesis that the addition of a parent skills training program will significantly increase the effectiveness of a
diet-activity program designed to reduce weight in overweight 6 to 9-year-olds. Children enrolled in the study
will receive one of two interventions (i) parenting + activity-diet or (ii) diet-activity. Parents in the parenting
intervention will participate in a parenting skills training program (Triple P) preceding the diet-activity
program. Triple P comprises four 2-hour weekly group sessions and four, 15 minute follow-up phone calls
which will focus on the skills and strategies required to supervise lifestyle changes. The diet-activity program
comprises 8 group sessions for parents over a 5 month period on specific dietary and activity changes and
simultaneous structured activity sessions for the children. "Success" will be judged in several ways. Over a
2 year period, we will monitor the child's weight, self-esteem, sense of well-being, blood pressure and
cholesterol levels. We will also monitor the family's functioning and the parents' parenting skills and sense of
efficacy. Results from the study should allow us to determine which treatment approach for management of
childhood obesity is the most appropriate to be established in community settings.
Research achievements (from final report):
This is the largest RCT evaluating treatment of overweight pre-pubertal children published to date. The
program (Parenting Eating and activity for child health (PEACH)evaluated the effectiveness of the addition of
parenting skills to a lifestyle education program for families with an overweight 5 to 9-year-old child. There
was a clinically relevant signficant weight loss of 8 to 13% at the end of the 6 month program in both arms of
the study (both BMI SD and waist SD). The addition of parenting skills training resulted in a significantly
lower BMI SD at the end of the 6-month intervention (12% versus 8%) but did not confer any significant
improvement in relative weight reduction at subsequent follow-up compared with the lifestyle only group.
There was no group effect on waist SD. However an additional important finding was that with no further
contact (other than 6-monthly measurement) the loss in waist SD was maintained for a further 18 months ie to
24 months from baseline and there was a further 2.5% reduction in BMI SD (p=0.02). In addition, at the end of
the 6 month program there were signficant improvements in parent reported child quality of life as well as
lifestyle factors (diet and activity) and these changes were maintained longer-term. The program was well
accepted by participants. This program offers an effective intervention for management of overwight and obese
pre-pubertal children.
Expected future outcomes:
Demonstration of the effectiveness of PEACH when delivered in the wider community by health professionals
after undertaking facilitator training. This trial will begin in 2008. Dissemination of the program in the wider
community will provide an effective weight management program to which families with an overweight or
obese child may be referred
Name of contact:
Dr Anthea Magarey
NHMRC Research Achievements - SUMMARY
Email/Phone no. of contact:
anthea.magarey@flinders.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 375103
Start Year: 2006
CIA Name: Prof Keryn Williams
End Year: 2010
Admin Inst: Flinders University
Grant Type: Established Career Fellowships
Main RFCD: Clinical Sciences not elsewhere classified
Total funding: $739,574
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
My research is focussed on common eye diseases prevalent in our community, and spans the interface between
the clinic and the laboratory bench. Highlights over the past 5 years:, 35 publications in the international
literature;, presentation of 2 named lectures and 10 invited talks at national and international meetings;, 5 PhD
student completions;, appointment to the NHMRC Academy, 2008-11;, award of 5 NHMRC project grants and
>AUD $9 million in research funding overall., My group and I have produced clinically-relevant discoveries in
the field of gene therapy to improve corneal graft survival, in the field of new ocular therapeutics and of
biomaterials suitable for use in the eye, and we have started to untangle the basis for heritable influences in
experimental retinopathy of prematurity. Further, a number of highly-cited publications have emanated from
the Australian Corneal Graft Registry, of which I am scientific director. This clinical database contains archival
records of over 22,000 Australians who have received a corneal transplant, submitted by over 700 clinicians in
a wide variety of practice settings. This Register is widely acknowledged to contain the most extensive
repository of information about clinical corneal transplantation in the world.
Expected future outcomes:
Two further PhD student completions and a number of publications.
Name of contact:
Keryn A Williams
Email/Phone no. of contact:
keryn.williams@flinders.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 375110
CIA Name: A/Pr Xin-Fu Zhou
Admin Inst: Flinders University
Main RFCD: Sensory Systems
Total funding: $457,268
Start Year: 2006
End Year: 2008
Grant Type: NHMRC Project Grants
Title of research award:
Analysis of functional role of the BDNF precursor in sensory neuronsAnalysis of functional role of the BDNF
precursor in sensory neurons
Lay Description (from application):
Neurotrophins, which are generated from their precursors, are essential for the survival and function of the
nervous system. One of neurotrophins, brain derived neurotrophic factor (BDNF), is made in sensory neurons
and transported towards nerve terminals. Mutation of a single amino acid in the precursor of BDNF disrupts
this transport. This project will examine whether the precursor of BDNF has any function within sensory
nerves. We will examine whether the precursor of BDNF gets into the nerve via its receptors and whether it
plays any role in the development of pain and maintenance of neuropathic pain after nerve injury. Successful
execution of the project will eludicate mechanisms of pain, especially neuropathic pain, and will provide
important information to assist in the design of drugs for neurological diseases.
Research achievements (from final report):
BDNF is a critical molecule for the brain development and brain functions. However, the functions of the
precursor of BDNF (proBDNF) are not known. This project investigates functions of proBDNF. We have made
following findings:, 1. We found that proBDNF, similar to the mature counterpart, is transported both
anterogradely and retrogradely in the primary sensory neurons. , 2. We found that injection of neutralization of
antibody to proBDNF can partially protect sensory neurons from death. Application of furin-resistant
exogenous proBDNF in the nerve stumps exaggerated the death., 3. We found that injection of exogenous
proBDNF suppresses the migration of neurons from external granule layer (EGL) to the internal granule layer
whereas the neutralizing antibody to proBDNF promotes the migration of these neurons. Exogenous proBDNF
suppresses the proliferation of granule cells in EGL whereas the neutralizing antibody promotes the
proliferation of these cells in EGL.
Expected future outcomes:
This work may lead to use proBDNF as a therapeutic target for the treatment of neurological diseases. For
example use of proBDNF antibodies may be neuroprotective for neurodegenerative diseases and neurotrauma.
Name of contact:
Xin-Fu Zhou
Email/Phone no. of contact:
zhou0010@flinders.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 375134
CIA Name: Dr Penelope Lynn
Admin Inst: Flinders University
Main RFCD: Peripheral Nervous System
Total funding: $372,390
Start Year: 2006
End Year: 2008
Grant Type: NHMRC Project Grants
Title of research award:
Sensory innervation of the anal region in normal and diabetic guinea pigsSensory innervation of the anal region
in normal and diabetic guinea pigs
Lay Description (from application):
Until something goes wrong, we take it for granted that we can empty our bowels on a regular basis, at a time
and place of our choosing. Failure to achieve this is very distressing and substantially diminishes quality of life,
if it occurs regularly. Disordered defecation, fecal incontinence and constipation are surprisingly common and
their prevalence will continue to increase as our population ages and the incidence of diseases such as diabetes
increases. In many people suffering these problems, there is a detectable dysfunction of the sensory nerves in
the anal region. These nerves supply information from the anal region to the spinal cord that can cause us to
sense activity in our lower bowel and initiate defecation reflexes. These sensory pathways are important for
clinical gastroenterology, but remarkably little is known about them. We are now able to investigate what it is
the sensory nerves in the anal region sense, what they look like and where they go to in the spinal cord - in a
single project. To do this we will use simple, but novel techniques that have been developed in this laboratory
in an animal model. Once we know this, we will compare the function of sensory nerves in the anal region in
diabetic animals with normal animals. This will give us insight into the role of sensory nerves in the
development of fecal incontinence an unpleasant symptom for many people suffering advanced diabetes. My
systematic approach will provide understanding of the basic cellular mechanisms and nerve pathways that
underlie sensation in the anal region, helping both clinicians and patients understand the cause of defecatory
disorders and potentially pointing the way to new therapies and strategies for diagnosis.
Research achievements (from final report):
Fecal incontinence is distressing. Fecal incontinence can occur from damage to the nerves innervating the anal
region. Prevention of damage and future potential treatments rely on a good understanding of the nerves that
innervate the anal region. We identified some of the types of nerves that are likely to be responsible for
sensation from the anal region and that give voluntary control over defecation. The anal region was
investigated in the guinea pig for comparison with the well documented innervation of nearby gut regions.
Electrophysiology was used to record the activity of nerves in response to movement or compression of the
anal region. A group of nerves that responded readily to stretch of the internal anal sphincter was identified that
had both similar function and nerve pathways to a documented rectal class of nerves, but had quite different
endings. The difference in the shape, size and distribution of these endings suggests different requirements to
maintain nerve function. The external anal sphincter was innervated by different nerves to the internal anal
sphincter. Two functional classes of nerves were identified. The first displayed similar stretch and compression
sensitivity as observed for other parts of the gut, including the internal anal sphincter. The other displayed
phasic responses to vibration only, a previously undescribed phenomena in the gut. Together with an
examination of the neurochemical markers nerve endings in the anal region, we documented some previously
unknown differences in the classes of nerves innervating the anal region of the guinea pig.
Expected future outcomes:
We hope this work will encourage others in the field to pursue a greater understanding of the physiology and
pathophysiology of the anal region neural innervation.
Name of contact:
Penny Lynn
Email/Phone no. of contact:
NHMRC Research Achievements - SUMMARY
penny.lynn@flinders.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 426711
CIA Name: Prof Thomas Gordon
Admin Inst: Flinders University
Main RFCD: Autoimmunity
Total funding: $254,592
Start Year: 2007
End Year: 2009
Grant Type: NHMRC Project Grants
Title of research award:
An autoantibody in type 1 diabetes that mediates autonomic complicationsAn autoantibody in type 1 diabetes
that mediates autonomic complications
Lay Description (from application):
Type 1 diabetes is a chronic autoimmune disease characterised by destruction of insulin producing cells in the
pancreas. One of the most common and serious complications of type 1 diabetes is disruption of the
autoimmune nervous system, and once symptoms appear the 5-year mortalityrate is approximately 50%.
Symptoms of autonomic dysfunction can be extensive, and involve the stomach, intestine, bladder, heart and
reproductive organs. Currently, the management of autonomic dysfunction remains primative due to our poor
understanding of the mechanisms underlaying the disease. Recent work from our group has identified an
excitatory autoantibody (an antibody against the self) to calcium channels in patients with type 1 diabetes. The
anti-calcium channel autoantibody profoundly disrupts gut and bladder function by interfering with autonomic
regulation of smooth muscle within these organs. The anti-calcium channel autoantibody is the first functional
autoantibody to be detected in type 1 diabetes, and represents a conceptual advance in our understanding of
immune mechanisms in this disease. Using animal models and a panel of novel, functional assays of colon,
stomach and bladder we will investigate how the anti-calcium channel autoantibodies contribute to autonomic
dysfunction in type 1 diabetes. Understanding the mechanisms by which this autoantibody effects autonomic
regulation of organ function will enable the development of new therapeutic strategies for better management
of patients.
Research achievements (from final report):
Type 1 diabetes is an autoimmune disease characterised by the loss of insulin secreting cells in the pancreas. In
addition, patients often develop diabetic autonomic neuropathy (DAN). DAN affects multiple components of
the nervous system, resulting in dysfunctions of the heart, gastrointestinal tract and urinary bladder. However,
the mechanisms by which DAN alters organ function are largely unknown. Our laboratory has used a novel
approach to identify autoantibodies (antibodies against self tissues) that contribute to DAN in patients with
type 1 diabetes. By using whole organ preparations, we have discovered an autoantibody that alters the activity
of calcium channels, structures that are vital for normal performance of the smooth muscle found in many
organs, including the gut and bladder. The autoantibody is only found in the serum of patients with type 1
diabetes, and alters the way in which the nervous system regulates gastrointestinal and bladder function. A
major achievement of this grant was the development of a cell-based assay for detecting the autoantibody,
which will aid studies to determine the role that these pathogenic autoantibodies play in the autonomic
dysfunction associated with type 1 diabetes, and could lead to improved clinical management of patients.
Expected future outcomes:
This research has considerably increased the knowledge of how autoantibodies contribute to the pathogenesis
of type 1 diabetes. In addition, the development of a cell-based assay for the autoantibody will facilitate
screening for the antibody in patients, and may lead to improved clinical management of symptoms associated
with autonomic dysfunction.
Name of contact:
Dr. Michael W. Jackson
Email/Phone no. of contact:
michael.jackson@flinders.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 595918
CIA Name: A/Pr Kathryn Burdon
Admin Inst: Flinders University
Main RFCD: Ophthalmology
Total funding: $982,203
Start Year: 2010
End Year: 2013
Grant Type: NHMRC Project Grants
Title of research award:
A genome-wide association scan to identify genetic risk factors for sight threatening diabetic retinopathyA
genome-wide association scan to identify genetic risk factors for sight threatening diabetic retinopathy
Lay Description (from application):
Diabetic eye disease is an important complication of diabetes that can lead to blindness. Very little is known
about how diabetes causes eye disease, but genetics is known to play a role. We aim to identify genes that
contribute to eye disease in diabetes patients. We will compare genes between patients with diabetes with and
without severe diabetic eye disease using cutting edge genomic technology. We hope to be able to better
predict risk of blindness and to move towards novel treatments.
Research achievements (from final report):
This project has identified new genes that may contribute to the risk of diabetic retinopathy, a complication of
diabetes that can lead to blindness. By comparing the genomes of patients going blind from diabetic eye
disease to those of patients with diabetes but no eye disease we have identified regions of the genome that
appear to contribute to the risk of blindness from diabetes. We have shown an effect of these genetic
differences in both type 1 and type 2 diabetes and in multiple ethnicities, including Australians. Work is
continuting to understand the specific genes involved and to develop this knowledge into both genetic tests for
predicting who is at risk as well as novel treatments that may be able to prevent future blindness.
Expected future outcomes:
Knowledge gained from this project will contribute to understanding the underlying causes of diabetic eye
disease which will lead to improved medical outcomes for patients.
Name of contact:
Kathryn Burdon
Email/Phone no. of contact:
kathryn.burdon@utas.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1008816
CIA Name: A/Pr Damien Keating
Admin Inst: Flinders University
Main RFCD: Endocrinology
Total funding: $446,610
Start Year: 2011
End Year: 2013
Grant Type: NHMRC Project Grants
Title of research award:
RCAN1 IS A MASTER REGULATOR OF BETA CELL FUNCTION AND INSULIN SECRETIONRCAN1
IS A MASTER REGULATOR OF BETA CELL FUNCTION AND INSULIN SECRETION
Lay Description (from application):
Type 2 diabetes affects over 1.5 million Australians and is caused by insufficient insulin release by beta cells in
the pancreas. We have discovered a new regulator of insulin secretion called RCAN1 and we now aim to
understand how this regulation occurs. We also believe RCAN1 may be responsible for the transition from
healthy to dysfunctional beta cell in Type 2 diabetes and this project will identify whether this is the case.
Research achievements (from final report):
We focused on the role of a specific protein, called RCAN1, in causing reduced insulin secretion that drives
Type 2 diabetes. We identified that expression of this protein is increased in ?-cells (the insulin-secreting cells)
of Type 2 diabetics and some of the mechanisms regulating this. When we increase the expression of RCAN1
in mice, they develop diabetes and this is because their ?-cells become dysfunctional and less insulin is
produced. We identified a mitochnondrial and beta cell proliferation defect when we alter RCAN1 levels in ?cells. This involves reduced ATP production negatively affecting insulin secretion, and reduced calcineurin
activity negatively affecting proliferation. These are two of the major changes that occur in Type 2 diabetes ?cells., Further to this we assessed the glucose handling properties and glucose homeostasis of mice with no
RCAN1 expression and the function of beta cells from these mice. Our data indicate that these mice do not
develop diabetes, unlike mice in which RCAN1 is transgenically overexpressed. Furthermore, these mice,
when placed on a high fat diet, have a reduced susceptibility to diabetes. This outcomes tested one of our major
hypotheses in this project that high RCAN1 causes insulin insufficiency in Type 2 diabetes and that reducing
RCAN1 levels may be a beneficial approach in fighting this disease.
Expected future outcomes:
We will further validate preliminary data that RCAN1 expression increases in Type 2 diabetes islets and
idenify the mechanisms by which RCAN1 effects ?-cells function. The outcomes will be to create methods to
alter RCAN1 expression in ?-cells and thus treat Type 2 diabetes.
Name of contact:
Damien Keat Keatingkeatingkeat0024@Flinders.Edu.Au
Email/Phone no. of contact:
keat0024@flinders.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 188829
Start Year: 2002
CIA Name: Dr David Ross Laybutt
End Year: 2006
Admin Inst: Garvan Institute of Medical Research Grant Type: Career Development Fellowships
Main RFCD: Not Allocated
Total funding: $425,000
Title of research award:
Islet B-cell growth, differentiation and function in typpw 2 diabetes:Islet B-cell growth, differentiation and
function in typpw 2 diabetes:
Lay Description (from application):
Not Available
Research achievements (from final report):
In Australia over 7% of the population have type 2 diabetes. This epidemic represents a major health problem.
The majority of overweight individuals do not develop diabetes because their insulin-secreting pancreatic betacells adequately compensate with over-secretion. It is the failure of this so called, beta-cell compensation, that
is fundamental to the development of diabetes. We proposed that in susceptible individuals, a gradual rise in
blood glucose levels resulting from obesity and insulin resistance leads to beta-cell failure and overt diabetes.
This project investigated the mechanisms responsible for beta-cell failure in a mouse model with a similar
time-dependent progression to obesity and type 2 diabetes as that seen in humans. db/db mice progress from a
pre-diabetic phase of insulin over-secretion, obesity and insulin resistance to a diabetic state characterised by
the appearance of high blood glucose and lipid levels and the loss of insulin secretory capacity., Our findings
suggest that chronic exposure of islets to elevated glucose and fatty acids can, independently, lead to changes
in gene expression consistent with a loss of beta-cell phenotype. Since both conditions lead to a loss of
glucose-responsive insulin secretion, these data support our theory that the dedifferentiation of beta-cells
underlies the insulin secretory defect in diabetes. Islets from db/db mice show an early loss of several genes
implicated in glucose sensing whereas transcript levels of beta-cell hormones are better maintained. We
showed that hyperglycaemia was a critical factor regulating the progression to β-cell decompensation in db/db
mice.
Expected future outcomes:
Fuure studies will be aimed to identify the transcription factors responsible for hyperglycaemia-induced betacell dedifferentiation and dysfunction.
Name of contact:
Ross Laybutt
Email/Phone no. of contact:
r.laybutt@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 210169
Start Year: 2002
CIA Name: Prof David James
End Year: 2004
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Project Grants
Main RFCD: Protein Targeting and Signal Transduction
Total funding: $468,300
Title of research award:
Molecular regulation of GLUT4 targetingMolecular regulation of GLUT4 targeting
Lay Description (from application):
Insulin resistance (the inability of ordinarily insulin-sensitive tissues such as muscle and adipose tissue to
respond to insulin) contributes to a number of diseases including diabetes and obesity. A key metabolic step in
these tissues is the uptake of glucose from the blood stream. This step is accelerated by insulin thus allowing
efficient clearance of glucose from the bloodstream after a meal. Our laboratory has played a major role in
showing that insulin regulates glucose uptake into muscle and adipose tissue by stimulating the movement of a
glucose transport protein from inside the cell to the cell surface (see http:--www.imb.uq.edu.au-groups-jamesglut4 for an animated description of this process). The purpose of this proposal is to dissect the molecular
mechanisms by which this glucose transporter can be held inside the cell in the absence of insulin and then
allowed to be released from this site moving to the surface in the presence of insulin. Our studies over the past
5 years have brought us much closer to understanding this process in detail. The identification of the molecules
responsible for this regulatory step will not only aid our understanding of this process but it will also provide a
valuable target for development of therapeutic agents that can be used to combat insulin resistance.
Research achievements (from final report):
Type 2 diabetes and obesity are increasing in our community at an alarming rate. One of the major
predisposing factors in these diseases is insulin resistance. The major goal of our studies is to conduct a
molecular study of the factors controlling normal insulin action. A major action of insulin is to control glucose
uptake in muscle and fat cells. This process is defective in Type 2 diabetes. We have begun to unravell the
steps that control this process in adipocytes. A major achievement during the garnt period was the development
of a novel assay for assessing insulin action in cells. We have patented this technology and are currently in
discussion with various Pharmaceutical companies to use this assay for drug screening purposes. We have also
used this assay to further dissect the basic mechanism of insulin regulated glucose transport. We have
identified multiple intracellular trafficking steps including the shuttling of the glucose transporter between
different compartments and this provides a much more detailed view of the process and provides new
opportunities for assessing how it may go awry.
Expected future outcomes:
1. The use of our novel assay to screen for compounds that override insulin resistance. This will be done using
compound libraries. 2. The use of our assay for screening known compounds that might modify insulin action
to determine their mode of action. 3. To further dissect the basic mechanism by which insulin regulates glucose
uptake in adipocytes
Name of contact:
David James
Email/Phone no. of contact:
d.james@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 210170
Start Year: 2002
CIA Name: Prof David James
End Year: 2004
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Project Grants
Main RFCD: Protein Targeting and Signal Transduction
Total funding: $451,980
Title of research award:
Identification of insulin specific signal transduction pathways in adipocytesIdentification of insulin specific
signal transduction pathways in adipocytes
Lay Description (from application):
Insulin resistance, which represents an inability of insulin to regulate metabolism in appropriate target tissues
such as muscle and adipose tissue, contributes to a number of diseases including diabetes and obesity. A key
metabolic step in these tissues is the uptake of glucose from the blood stream. This step is accelerated by
insulin thus allowing efficient clearance of glucose from the bloodstream after a meal. Our laboratory has
played a major role in showing that insulin regulates glucose uptake into muscle and adipose tissue by
stimulating the movement of a glucose transport protein from inside the cell to the cell surface (see http:-www.imb.uq.edu.au-groups-james-glut4 for an animated description of this process). In the present proposal
we will pursue a number of strategies to dissect the signal transduction pathways that connect the insulin
receptor to the movement of this glucose transporter. Identification of these molecules will provide the missing
pieces to this important puzzle. Once solved we will have at our disposal a novel set of targets for designing
drugs that will combat insulin resistant diseases.
Research achievements (from final report):
Type 2 diabetes and obesity are increasing in our community at an alarming rate. This is undoubtedly due to
increased food intake and reduced activity as a function of modernisation. To reverse this trend may not be
simple as exemplified by the lack of success achieved through diet and exercise regimes. Therefore, it is
necessary to continue to explore the molecular basis for obesity and diabetes in an effort to identify potential
tagets for therapeutic development. A major outcome from our research over the past 3 years was the
characterisation of a genetically modified mouse in which the gene encoding c-Cbl has been deleted. Metabolic
profiling of these animals revelaed that they eat 30% more food per day yet maintain 50% of the normal quota
of body fat as normal mice. This difference is due to increased energy expenditure. In other words rather than
storing the excess calories as fat these mice burn the food thus avoiding weight gain. Importantly this protects
the mice against the development of insulin resistance.
Expected future outcomes:
1. To understand the molecular mechanism by which Cbl controls energy homeostasis in mammals.
Name of contact:
David James
Email/Phone no. of contact:
d.james@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 210226
Start Year: 2002
CIA Name: Prof David James
End Year: 2006
Admin Inst: Garvan Institute of Medical Research Grant Type: Established Career Fellowships
Main RFCD: Protein Targeting and Signal Transduction
Total funding: $690,000
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
o Characterisation of mechanism of insulin action - this work has identified the major step regulated by insulin
in muscle and fat cells and has transformed the field in terms of how we think about this problem, o Discovery
of a new agent from Traditional Chinese Medicine that results in reduced body weight and improved insulin
action in animal models. , o Identification of a gene that controls energy expenditure in mice - this has resulted
in new knowledge about this important biological pathway and may lead to new therapeutic manipulations. , o
Development of a high throughput assay for one of insulin's major metabolic actions. This has already resulted
in several licence deals with the Pharmaceutical industry
Expected future outcomes:
o Discovery of new metabolic pathways regulated by insulin, o Dissection of the mechanism by which insulin
controls glucose transport in muscle and fat cells, o Discovery of mechanism of insulin resistance in muscle
and fat cells, o Identification of compounds for the treatment of human Type 2 diabetes
Name of contact:
David James
Email/Phone no. of contact:
d.james@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 230820
Start Year: 2003
CIA Name: A/Pr Amanda Sainsbury-Salis
End Year: 2005
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Project Grants
Main RFCD: Systems Physiology
Total funding: $329,625
Title of research award:
Investigation of the role of hypothalamic Y1 receptors in obesityInvestigation of the role of hypothalamic Y1
receptors in obesity
Lay Description (from application):
The worldwide prevalence of obesity alarming, and is a major risk factor for diseases such as type 2 diabetes.
Although the benefits of weight loss in overweight subjects are undisputed, there currently exists no effective
long-term treatment for obesity. Therefore pharmacological interventions for obesity could dramatically reduce
the burden of this disease. There is much interest in the development of treatments for obesity that prevent the
action of proteins in the brain that are thought to lead to increased food intake and gain of body fat, such as
neuropeptide Y and its receptor Y1, both of which are found in the hypothalamus in regions known to regulate
body fat. However, the true role of Y1 receptors in regulating body weight in the hypothalamus is currently
unclear, since there are no known pharmacological tools that can specifically block or activate this receptor in
order to demonstrate its function. To circumvent this problem we have developed genetically modified mice
that enable us to specifically delete the Y1 receptor from the hypothalamus of adult mice, and therefore
determine its role in regulating body weight. This project will demonstrate whether hypothalamic Y1 receptor
deletion can reduce food intake and body fat in mice in the long-term, and whether it can cause other changes
in metabolism that might also contribute to reducing body fat. We will also show whether the obesity that
results from either a high-fat diet, from an excess of the stress hormone corticosterone, or from genetic
mutation in mice, can be prevented or reversed by deletion of hypothalamic Y1 receptors. The results will be
instrumental in deciding whether developing medicines that specifically block Y1 receptors in the
hypothalamus will be of significant benefit for the long-term treatment of human obesity, which is caused by
multiple genetic and environmental factors.
Research achievements (from final report):
It is known that food restriction (e.g. dieting) leads to elevated expression of neuropeptide Y (NPY) in the
hypothalamus, contributing to increased hunger, reduced metabolic rate, and difficulty to attain and maintain a
healthy body weight. We know that NPY exerts these effects via a variety of different Y receptors, but we don't
know which one(s) is(are) the most important in mediating this NPY-induced "famine reaction". Using stateof-the-art technology to delete Y1 receptors specifically from the hypothalamus of the brain, we showed that
under normal conditions Y1 receptors are not involved in reguating food intake or fat storage, but contribute to
behaviours related to feeding, notably food grinding and aggression. However, under situations of increased
NPY levels in the brain (such as during food restriction), Y1 receptors are partly responsible for mediating the
increased propensity to store fat. Whereas deficiency of Y1 receptors resulted in a mild decrease in body fat
levels under some circumstances, we showed that deficiency of Y2 and Y4 receptors results in even greater and
synergistic reductions in body fat. These data show that strategies aimed at reducing the function of Y2 and Y4
receptors could help reduce the tenacity of the human "famine reaction", thereby increasing effectiveness of
lifestyle changes for weight loss.
Expected future outcomes:
These findings will provide valuable targets for pharmacotherapy for obesity.
Name of contact:
Dr Amanda Sainsbury-Salis
Email/Phone no. of contact:
a.sainsbury-salis@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 230842
Start Year: 2003
CIA Name: Prof David James
End Year: 2005
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Project Grants
Main RFCD: Protein Targeting and Signal Transduction
Total funding: $440,250
Title of research award:
Mechanism of action of Sec1p-like proteins in Membrane Trafficking.Mechanism of action of Sec1p-like
proteins in Membrane Trafficking.
Lay Description (from application):
One of the most important evolutionary changes that has occurred is the development of intracellular
compartments. All eukaryotic cells possess numerous membrane-encased structures which provide the basis
for intracellular specialisation. For example, in order to degrade unwanted components cells have developed
degradative enzymes. It is vital for the cell that these enzymes are sequestered away from other cellular
components to avoid destruction of valuable molecules. In addition, the cell has developed a complex
assembly line of modifications that are added to proteins in a specific order as they travel to their final
destination within the cell. This necessitates the accurate passage of molecules between compartments, a
process known as vesicle transport. To orchestrate the complex network of vesicular transport steps between
all of the various intracellular compartments it is necessary to employ complex machinery to guide and check
that these steps occur with high fidelity. The goal of our research proposal is to define the function of one of
the molecules involved in this control process, the so-called Sec1p proteins. The strength of our proposal lies
in the diversity of our approach. We intend to explore the molecular advantages of a relatively simple
eukaryotic organism, a yeast cell, and apply the findings obtained from this cell to a more complex but highly
related vesicular transport process; that of the insulin-regulated movement of a glucose transporter in
mammalian fat and muscle cells. While we intend to apply our findings to the treatment of patients with
diabetes, it is our ultimate goal to be able to learn more about this fundamental cell biological process so that
we can apply our knowledge to understanding many different disease states.
Research achievements (from final report):
The movement of proteins within the cell is fundamental to almost all biological processes. There are now
many diseases that appear to be due to disruptions in the process of protein movement within cells, including
Parkinson's disease, Huntington's disease, as well as various kinds of cancer. Although the function of proteins
within cells is very similar across all organisms, our understanding of the molecular machinery that governs
this function is very rudimentary. In this study, we have begun to unravel the workings of one of the proteins
that is involved in this process, which we believe will provide us with important clues to fundamental questions
about the relationship between protein movement and disease. .
Expected future outcomes:
In the future we hope to be able to define the function of the protein we have identified in much greater detail.
We hope to solve the atomic structure of this molecule, and then to use this information to pinpoint exactly
how it functions in the living cell and how this may relate to different disease states.
Name of contact:
Professor David E James
Email/Phone no. of contact:
d.james@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 230846
Start Year: 2003
CIA Name: Prof Edward Kraegen
End Year: 2007
Admin Inst: Garvan Institute of Medical Research Grant Type: Established Career Fellowships
Main RFCD: Medical Physiology not elsewhere classified
Total funding: $779,500
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
Obesity, the Insulin Resistance Syndrome and Type 2 Diabetes are major health care problems and are
reaching global epidemic proportions. Despite this there are few internationally competitive research teams
working in this area in Australia. We have built up an international reputation in the study of lipid-related
insulin resistance and research has focussed on this area, particularly on how fatty acids and other lipids could
interfere with insulin action in muscle, arguably the most important target for insulin in the body. There was a
need to develop new techniques to manipulate (overexpress or inhibit) individual target muscle proteins in
animal models to understand key factors in generating insulin resistance and suggesting new therapeutic
targets. This was achieved by the use of in vivo electrotransfer (IVE) techniques to locally introduce DNA
constructs to muscle, and since our publication the technique has generated widespread interest. Using this and
related techniques we have been able to clarify the role of several proteins in the insulin signalling pathway (eg
Akt isoforms). In a separate line of investigation we were the first to show the ability of the AMP-activated
protein kinase pathway to counteract lipid induced insulin resistance in a tissue-selective manner. We
established the importance of AMPK activation as a contributing mechanism to actions of thiazolidinediones
and metformin (common anti-diabetic drugs) in liver and muscle. In addition studies were started to identify
new anti-diabetic compounds based on traditional Chinese medicines. Collectively these open the way for
development of new anti-diabetic therapies that might help overcome limitations in current therapeutic
approaches.
Expected future outcomes:
We have development a number of unique methodologies for application to the preclinical area of new drug
development for diabetes and related metabolic disorders. These have helped clarified metabolic actions of
current "insulin sensitising" agents and should prove extremely valuable in the future to explore new
therapeutic approaches.
Name of contact:
Prof Edward Kraegen
Email/Phone no. of contact:
e.kraegen@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 244906
Start Year: 2003
CIA Name: Dr Jenny Gunton
End Year: 2007
Admin Inst: Garvan Institute of Medical Research Grant Type: Early Career Fellowships (Overseas)
Main RFCD: Gene Expression
Total funding: $373,780
Title of research award:
Gene expression profiles in adipose and liver tissue from insulin receptor substrateGene expression profiles in
adipose and liver tissue from insulin receptor substrate
Lay Description (from application):
Not Available
Research achievements (from final report):
The work identified genes which were altered in expression in the islets of people with type 2 diabetes. This
provides new understanding of the causes of beta-cell failure and thus the devleopment of diabetes. It has led to
studies currently underway to examine the effects of increasing levels of the transcription factors ARNT / HIF1a and the effects on diabetes. It is possible that this may lead to a new therapeutic agent for the treatment of
human type 2 diabetes.
Expected future outcomes:
There are further papers currently with journals for review, these will be published in due course. The patents
resulting from this work may lead to human type 2 diabetes clinical trials. We hope to start a human clinical
trial for the treatment of diabetes in the next year.
Name of contact:
Alison Heather
Email/Phone no. of contact:
a.heather@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 262013
Start Year: 2003
CIA Name: Dr Pablo Silveira
End Year: 2007
Admin Inst: Garvan Institute of Medical Research Grant Type: Early Career Fellowships (Australia)
Main RFCD: Autoimmunity
Total funding: $270,305
Title of research award:
B cell tolerance defects as a potential contributor to Type 1 diabetesB cell tolerance defects as a potential
contributor to Type 1 diabetes
Lay Description (from application):
Not Available
Research achievements (from final report):
A class of white blood cell in the immune system, termed T cells, are responsible for destroying the insulin
producing cells leading to Type 1 Diabetes (T1D). However, another class of immune cell, called B cells, also
play an important role in T1D as a mouse model made deficient in these cells no longer develops this disease.
B cells are one of the few cell types which are able to take up and present protein fragments from other cells in
a form recognizable to T cells. Normally, this only leads to the activation of T cells recognising foreign cells
such as viruses or bacteria, resulting in clearance of infection. We have identified an aberrant population of B
cells that arise in mice prone to T1D that specifically take up proteins from insulin producing cells. Using these
proteins, B cells can activate T cells that subsequently become armed to recognise and destroy insulin
producing cells. B cells that recognize the body's own cells such as those producing insulin are normally
eliminated or suppressed in healthy individuals. This project has identified faulty immune mechanisms that
allow T1D-promoting B cells to escape elimination and suppression. We have also identified sections of DNA
containing genes which control the generation of this T1D-promoting B cell population. By understanding how
dangerous B cells are generated in mice, we hope to form the basis of new therapies aimed at inhibiting these
cells from forming in T1D susceptible humans, thus preventing disease at an early stage.
Expected future outcomes:
In future, we hope to develop a more complete understanding the the faulty genes and proteins leading to the
development of diabetes promoting B cells. Such studies could potentially reveal new drug targets that could
avert diabetes by preventing the development of dangerous B cells.
Name of contact:
Pablo Silveira
Email/Phone no. of contact:
P.Silveira@garvan.org.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: 276419
Start Year: 2004
CIA Name: A/Pr Gregory Cooney
End Year: 2006
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Project Grants
Main RFCD: Nutrition and Dietetics
Total funding: $579,000
Title of research award:
The role of stress response and circadian genes in the link between excess lipid and muscle insulin
resistanceThe role of stress response and circadian genes in the link between excess lipid and muscle insulin
resistance
Lay Description (from application):
Obesity and its associated conditions of heart disease, reduced insulin action, fatty liver and type 2 diabetes are
increasing at an alarming rate worldwide. The epidemic of these conditions appears to be due to an interaction
between genetic background and changes in the environment such as reduced physical activity and increased
availability and consumption of high energy food. The relationship between genes and environment is very
complex but it seems clear that increased intake of high fat foods can cause body tissues to accumulate excess
fat. This interferes with the way that the hormone insulin controls body glucose utilisation although how this
happens has not been fully defined. This grant application will test two possible mechanisms that could help
explain the link between increased dietary fat intake and decreased insulin action in muscle. Using microarrays
to examine the activity of genes in normal and insulin resistant muscle, we have identified two groups of genes
that may be involved in how fat causes insulin resistance. One group of genes is normally associated with
stress and we will determine if fats control these genes directly or if fats increase other stress factors which
increase the activity of these genes. We will then use novel gene therapy techniques to see if these genes cause
insulin resistance in muscle of experimental animals. The second group of genes is related to the mechanisms
which regulate daily cycles in the body such as sleep/wake cycles, blood pressure, and eating behaviour. We
will examine the activity of these genes over a 24 hour period in muscle from normal animals and insulin
resistant animals to determine if disruption of these gene cycles contributes to insulin resistance. We will then
perform experiments to establish what processes these genes control. The successful outcome of this grant will
determine if these groups of genes can be targeted to help treat lipid-induced insulin resistance in muscle.
Research achievements (from final report):
Significant progress has been made in both parts of this project. , 1. We have undertaken microarray analysis of
gene expression in cultured L6 muscle cells treated overnight with fatty acid and shown that acute fatty acid
treatment up-regulates expression of several of the same stress genes up-regulated by fat-feeding in muscle. We
have established the utility of using siRNA constructs to reduce gene expression using electroporation in a
collaborative study in which siRNA for nurr77 was introduced into mouse muscle with the effect of reducing
genes of fatty acid oxidation. , 2. We have documented significant differences in the expression of circadian
rhythm and metabolic genes in muscle and liver of fat-fed rats. The circadian transcription factor dbp had
altered expression in liver and muscle from fat-fed rats. We have measured significant alterations in the
expression of metabolic genes in muscle and in the diurnal variation of plasma fatty acids and intracellular
lipids. These results indicate that the diurnal metabolism of glucose and lipid are significantly altered by a high
fat diet in a temporal fashion with key differences only evident at specific times of the 24 hour cycle. It is
possible that interventions at specific times of the day may have the most benefit for the treatment of metabolic
disease.
Expected future outcomes:
The outcomes of the work funded by this grant will be several journal articles documenting key differences in
the metabolism of glucose and lipid at specific times during the 24 hour cycle that are important in the
development of metabolic disease.
Name of contact:
A/Prof Greg Cooney
NHMRC Research Achievements - SUMMARY
Email/Phone no. of contact:
g.cooney@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 276430
Start Year: 2004
CIA Name: Prof Edward Kraegen
End Year: 2006
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Project Grants
Main RFCD: Endocrinology
Total funding: $481,500
Title of research award:
Role of impaired insulin signalling in fatty acid-induced muscle insulin resistance in vivoRole of impaired
insulin signalling in fatty acid-induced muscle insulin resistance in vivo
Lay Description (from application):
Type 2 diabetes represents an escalating global health problem. In Australia 7.5% of the population has
diabetes and another 16% insulin resistance (impaired action of insulin in tissues). As well as diabetes, insulin
resistance is closely associated with obesity, dyslipidaemia, hypertension and cardiovascular diseases
(Syndrome X). While genetic factors play a role, a high caloric intake (particularly with a high fat content) and
a sedentary lifestyle are extremely important environmental contributors to Syndrome X and diabetes. From
evidence that we and others have obtained over the last few years it is now evident that an important mediator
of insulin resistance is the quantity of fat molecules which accumulate in muscle and liver. This project
examines mechanisms whereby this fat accumulation can disrupt the signalling mechanism normally causing
increased glucose metabolism in response to insulin. While basic experiments in cell systems have identified
some candidates, a need exists to demonstrate whether they actually cause the insulin resistance in the whole
animal or human, or are merely associated with it. We will combine metabolic/physiological studies with a
novel technique we have recently established in our laboratory for introducing DNA into skeletal muscle of
laboratory animal models. We now aim to exploit this approach to obtain more definitive data about the
importance of insulin signalling changes to insulin resistance. Two major steps in insulin signalling will be
investigated, involving the insulin receptor substrate proteins and the kinase Akt/PKB, both strongly implicated
in lipid-induced insulin resistance. This knowledge will be invaluable in improving strategies to lessen or
prevent lipid-associated insulin resistance, a major contributor to the metabolic derangement in Type 2 diabetes
and Syndrome X.
Research achievements (from final report):
Our overall aim was to determine the in vivo mechanisms whereby accumulation of fatty acids and/or their
metabolites cause insulin resistance in muscle. We first established a new technique (in vivo electrotransfer
IVE) to alter local gene expression in skeletal muscle of rodents as a means of investigating the role of
signalling proteins in vivo. Extensive validation work was performed based on mechanisms which enhance
glucose transport in muscle and were published in Diabetes. We demonstrated that IVE combined with
appropriate methodology could be used to both enhance and diminish local muscle gene expression, thus
making it a powerful tool to establish important targets for insulin action in muscle in vivo. Our results
highlight the utility of IVE for the acute manipulation of muscle gene expression in the study of glucose
metabolism, led on to the signaling studies in this project as follows. We targetted a particular protein in insulin
signalling, namely Akt ; this has two isoforms whose respective roles in muscle were not clear. We overexpressed active forms of both isoforms (Akt1 and Akt2) in rat muscle using IVE and 1-2 weeks later assessed
responses. Both isoforms led to muscle hypertrophy but Akt-2 had a greater influence on glucose transport.
However insulin-stimulated glucose uptake was not altered by over-expression of either isoform despite
approximate 30% reductions in the upstream signalling protein IRS-1 These data indicate distinct roles for Akt1 and Akt-2 in muscle glucose metabolism and that moderate reductions in IRS-1 expression do not result in
the development of insulin resistance in skeletal muscle in vivo. Rather the results point to the likely
importance of steps in insulin signalling downstream of Akt in generating insulin resistance.
Expected future outcomes:
Novel techniques (in vivo electrotransfer) developed for manipulating muscle gene expression to study
metabolism have proved of considerable use to many groups. The new data on insulin signalling in skeletal
muscle in intact animals obtained using these novel techniques have implications for designing
pharmaceuticals targeting insulin signaling as a treatment of insulin resistance.
NHMRC Research Achievements - SUMMARY
Name of contact:
Prof Edward Kraegen
Email/Phone no. of contact:
e.kraegen@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 276431
Start Year: 2004
CIA Name: Prof Donald Chisholm
End Year: 2006
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Project Grants
Main RFCD: Endocrinology
Total funding: $335,800
Title of research award:
An examination of the contribution of visceral adiposity to insulin resistance in humans.An examination of the
contribution of visceral adiposity to insulin resistance in humans.
Lay Description (from application):
The worldwide epidemic of Type 2 diabetes is related to major nutritional and activity changes interacting with
a genetic predisposition. The two key defects in Type 2 diabetes are a reduced response to insulin (insulin
resistance) and relative failure of insulin production. Insulin resistance is the earliest defect and is closely
associated with cardiovascular risk. Obesity generates insulin resistance, but intraabdominal (visceral) fat has
particular importance. Visceral fat cells are different to other fat cells; they are very metabolically active and
'spill out' fatty acids indiscriminately contributing to insulin resistance in liver and muscle; they also produce
hormones which may modify the action of insulin. We will study people undergoing abdominal surgery.
Participants will be (1) normal weight and sensitive to insulin, (2) abdominally overweight and insulin
resistant, (3) insulin resistant with Type 2 diabetes. We will document abdominal fat, circulating lipid and
hormone levels and insulin action. At surgery fat biopsies will be obtained from (a) inside the abdominal
cavity, (b) the fat layer under the abdominal skin and (c) fat in the buttock. The activity of a large number of
genes in the fat tissue will be assessed in 8 subjects using DNA array (4 each from Groups 1 and 2). Then a
small number of genes will be selected on the basis of different activity in visceral fat from buttock fat, and
between insulin sensitive and insulin resistant people. The activity of these genes will be determined in all
subjects in the 3 groups. We anticipate identifying a few (perhaps 3) genes whose activity is closely associated
with insulin resistance and will examine their capability to block insulin action in a series of animal and
cellular studies. These studies should identify specific mechanisms by which visceral fat creates insulin
resistance. This would be an important step towards prevention and improved medication for Type 2 diabetes.
Research achievements (from final report):
The amount of visceral fat [fat inside the abdomen] is strongly associated with risk of Diabetes and
Cardiovascular disease.This research has examined the activity of a large number of genes in visceral and
peripheral [subcutaneous] fat and has demonstrated major differences in genes promoting inflammation and
regulating fat mobilisation [lipolysis] ,cortisol metabolism [11 B hydroxysteroid dehydrogenase] and metabolic
activity [Leptin].Major differences in genes controlling tissue development have also been found,indicating
that visceral fat is a different type of tissue to peripheral fat.Of most interest,it has been found for the first time
that an important developmental gene,Islet-1,is active in visceral but not peripheral fat -- this gene was
previously not thought to be active in any fat tissue.The expression [activity] of Islet-1 in visceral fat was
shown to be reduced with increasing obesity in both humans and rodents [mice fed a high fat diet or mice with
obesity due to deficiency of the Leptin gene] ;conversely expression was increased in mice with a genetic
manipulation [c-Cybl knockout] causing leanness and increased insulin sensitivity.Islet-1 was predominantly in
preadipocytes [the cells which develop into fat cells] suggesting it may play an important role in the
development and differentiation of visceral fat - which would be consistent with a role already established in
the pancreas,heart and nerve cells.This suggests Islet-1 could be a future target for drugs to reduce
accumulation of visceral fat and reduce risk of Diabetes and Cardiovascular disease.
Expected future outcomes:
This research has clarified major differences between abdominal fat and fat elsewhere in the body and has
identified a developmental gene,Islet-1,uniquely expressed in abdominal fat.This could lead the way to
modifying the adverse effects of abdominal fat,which include increased inflammation and increased release of
fats into the blood stream
Name of contact:
NHMRC Research Achievements - SUMMARY
Prof.Donald Chisholm
Email/Phone no. of contact:
d.chisholm@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 276440
Start Year: 2005
CIA Name: Dr Leonie Heilbronn
End Year: 2008
Admin Inst: Garvan Institute of Medical Research Grant Type: Early Career Fellowships (Australia)
Main RFCD: Endocrinology
Total funding: $276,447
Title of research award:
Intramyocellular lipid, oxidative stress and insulin resistanceIntramyocellular lipid, oxidative stress and insulin
resistance
Lay Description (from application):
Not Available
Research achievements (from final report):
The post-doctoral fellowhip enabled my return from a post-doctoral position overseas to the Garvan Institute in
Sydney. This funding contributed to 16 research publications as well as providing preliminary data for
successful 2007 NHMRC project grant funding and a 2008 Career Development Award.
Expected future outcomes:
This post-doctoral fellowship most likely contributed to my receiving a NHMRC Career Development Award
in 2008 and toghther this will enable me to become an independent researcher.
Name of contact:
Leonie Heilbronn
Email/Phone no. of contact:
l.heilbronn@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 325604
Start Year: 2005
CIA Name: Prof David James
End Year: 2007
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Project Grants
Main RFCD: Protein Targeting and Signal Transduction
Total funding: $469,500
Title of research award:
Molecular regulation of GLUT4 targeting.Molecular regulation of GLUT4 targeting.
Lay Description (from application):
Insulin resistance (the inability of ordinarily insulin-sensitive tissues such as muscle and adipose tisse to
respond to insulin) contributes to a number of diseases including diabetes and obesity. A key metabolic step in
these tissues is the uptake of glucose from the blood stream. This step is accelerated by insulin thus allowing
efficient clearance of glucose from the bloodstream after a meal. Our laboratory has played a major role in
showing that insulin regulates glucose uptake into muscle and adipose tissue by stimulating the movement of a
glucose transport protein from inside the cell to the cell surface. The purpose of this proposal is to dissect the
molecular mechanisms by which this glucose transporter can be held inside the cell in the absence of insulin
and then allowed to be released from this site moving to the surface in the presence of insulin. Our studies over
the past 5 years have brought us much closer to understanding this process in detail. The identification of the
molecules responsible for this regulatory step will not only aid our understanding of this process but it will also
provide a valuable target for development of therapeutic agents that can be used to combat insulin resistance.
Research achievements (from final report):
1. Tissue specificity. Conditional c-Cbl-/- mice have now gone germ line and mice are planned to be shipped to
the Garvan within the next month. , 2. The role of c-Cbl in the fat cell. We have studied insulin signalling
pathways in adipocytes from c-Cbl-/- mice and have found no significant difference compared to wild type
animals. We are currently developing fat cell transplantation techniques to examine the effects of c-Cbl fat
when transplanted into a wild type recipient. , 3. Energy expenditure. The activity of a series of oxidative
enzymes has been measured and we have found no significant difference in the oxidative capacity of muscle of
c-Cbl-/- mice compared to wild type controls. Furthermore, in high fat fed animals there was an equivalent
increase in oxidative capacity in muscle from knock out and wild type animals (Molero et al Casitas b-Lineage
Lymphoma-Deficient Mice Are Protected Against High-Fat Diet-Induced Obesity and Insulin Resistance.
Diabetes 55:708-15, 2006), 4. Domains in c-Cbl. Considerable progress has been made on this aim. We have
shown that knock in animals in which the Ubiquitin ligase domain in Cbl has been disarmed have a phenotype
resembling the knock out animals. This provides compelling evidence that the phenotype we have observed
relies to a great extent on the ubiquitinylation function of this protein. In combination with the tissue specific
knock out experiments (Aim 1) this should provide important information for target identification. This work
has now been published.
Expected future outcomes:
Once conditional mice have been received we will be in a strong position to map the tissue specificity for the cCbl metabolic phenotype by creating adipose tissue, muscle, liver and brain specific c-Cbl knock out mice.
Name of contact:
David James
Email/Phone no. of contact:
d.james@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 325614
Start Year: 2005
CIA Name: A/Pr Gregory Cooney
End Year: 2007
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Project Grants
Main RFCD: Protein Targeting and Signal Transduction
Total funding: $484,500
Title of research award:
Regulation of glucose homeostasis and insulin signalling by Grb10 and Grb14.Regulation of glucose
homeostasis and insulin signalling by Grb10 and Grb14.
Lay Description (from application):
The hormone insulin is a critical regulator of blood glucose levels. Defective insulin action, also known as
insulin resistance, underlies the development of Type 2 Diabetes, which is major health problem worldwide.
Understanding how insulin action is regulated may lead to new treatments for this disease. Insulin mediates its
effects by binding to a receptor on the cell surface that transmits signals to the interior of the cell. Depending
on the cell type, these signals can instruct the cells to take up glucose from the bloodstream (muscle and fat) or
decrease glucose production (liver). We have identified a new regulator of insulin signalling in cells, a protein
termed Grb14. This was accomplished by generating mice in which the Grb14 gene was removed, so that the
animals no longer produced Grb14. These animals responded better to insulin, indicating that Grb14 normally
inhibits insulin action. However, it is likely that another closely related protein, Grb10, functions alongside
Grb14 to regulate insulin signalling. Therefore, we will use mice in which the Grb10 and Grb14 genes have
been removed, singly and in combination, to define the roles of these two proteins in regulating blood glucose
levels and insulin signals inside the cell. We will also use cells isolated from the mice to analyse the molecular
events underlying the effects of Grb10 and Grb14 on insulin signalling. The significance of these studies is that
defining the functional role and mode of action of Grb10 and Grb14 may lead to novel therapeutic approaches
aimed at blocking their function. Such approaches could be used to overcome the insulin resistance associated
with Type 2 Diabetes.
Research achievements (from final report):
The major aim of this project were to define the effects of deleting the Grb10 gene on glucose metabolism in
mice. A secondary aim was to compare any effects with those previously described in a mouse model with a
gene deletion for the related adaptor protein Grb14 and to examine the metabolic phenotype of mice lacking
both Grb10 and Grb14. The investigation of the Grb10 gene-deleted mice revealed a novel phenotype of
increased muscle mass in the absence of any increase in other organ size (kidney, heart, liver, spleen). The
increased muscle mass was accompanied by a reduced amount of adipose tissue which suggested that, because
increased fat mass is normally associated with insulin resistance and poor glucose metabolism, the higher fat
free mass in Grb10 gene-deleted mice could be advantageous from a metabolic viewpoint. Grb10 gene-deleted
mice had improved glucose tolerance and the double knockout mice (Grb10 and Grb14) maintained the
phenotype of Grb10 mice having larger muscles and less fat tissue. These findings suggest that Grb10 might
have a negative effect on signalling pathways that control the growth of muscle tissue and that manipulating
the amount of Grb10 might be useful for increasing or maintaining muscle mass in elderly people. Other
experiments suggest that neither Grb10 or Grb14 deletion protect against the detrimental effects of a high-fat
diet but that the double knockout may have some beneficial effects.
Expected future outcomes:
Elucidating the pathways by which Grb10 influences muscle and fat depots could lead to new therapies to
combat excess fat tissue and reduced muscle mass which are both problems of an ageing population.
Name of contact:
A/Prof. Greg Cooney
Email/Phone no. of contact:
g.cooney@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 325618
Start Year: 2005
CIA Name: Dr David Ross Laybutt
End Year: 2007
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Project Grants
Main RFCD: Endocrinology
Total funding: $389,250
Title of research award:
Pancreatic beta-cell dysfunction in diabetesPancreatic beta-cell dysfunction in diabetes
Lay Description (from application):
In Australia over 7% of the population have type 2 diabetes. This epidemic represents a major health problem.
The majority of overweight individuals do not develop diabetes because their insulin-secreting pancreatic betacells adequately compensate with over-secretion. It is the failure of this so called, beta-cell compensation, that
is fundamental to the development of diabetes. We propose that in susceptible individuals, a gradual rise in
blood glucose levels resulting from obesity and insulin resistance leads to beta-cell failure and overt diabetes.
This project will investigate the mechanisms responsible for beta-cell failure in a mouse model with a similar
time-dependent progression to obesity and type 2 diabetes as that seen in humans. C57BL/KsJ db/db mice
progress from a pre-diabetic phase of insulin over-secretion, obesity and insulin resistance to a diabetic state
characterised by the appearance of high blood glucose and lipid levels and the loss of insulin secretory
capacity. With age, there are also a reduced number of beta-cells because of increased cell death. db/db mice
will be studied at different stages in their natural progression to diabetes to fully characterise the secretory
dysfunction and the changes in beta-cell phenotype over the time-course of diabetes development. The use of
laser capture microdissection will allow us to study selectively the actual beta-cells without contamination from
the other cells of the pancreas. The mice will also be treated with an agent that lowers blood glucose levels
without affecting lipids to test the influence of hyperglycaemia itself in the development of beta-cell
dysfunction. We will also test if the changes observed in the mice are regulated independently by high glucose
levels in cell culture systems. The role of one candidate protein called ID-1 will be investigated as a potential
link between hyperglycaemia and the development of beta-cell dysfunction.
Research achievements (from final report):
In Australia over 7% of the population have type 2 diabetes. This epidemic represents a major health problem.
The majority of overweight individuals do not develop diabetes because their insulin-secreting pancreatic betacells adequately compensate with over-secretion. It is the failure of this so called, beta-cell compensation, that
is fundamental to the development of diabetes. We proposed that in susceptible individuals, a gradual rise in
blood glucose levels resulting from obesity and insulin resistance leads to beta-cell failure and overt diabetes.
This project investigated the mechanisms responsible for beta-cell failure in a mouse model with a similar
time-dependent progression to obesity and type 2 diabetes as that seen in humans. db/db mice progress from a
pre-diabetic phase of insulin over-secretion, obesity and insulin resistance to a diabetic state characterised by
the appearance of high blood glucose and lipid levels and the loss of insulin secretory capacity., Our findings
suggest that chronic exposure of islets to elevated glucose and fatty acids can, independently, lead to changes
in gene expression consistent with a loss of beta-cell phenotype. Since both conditions lead to a loss of
glucose-responsive insulin secretion, these data support our theory that the dedifferentiation of beta-cells
underlies the insulin secretory defect in diabetes. Islets from db/db mice show an early loss of several genes
implicated in glucose sensing whereas transcript levels of beta-cell hormones are better maintained. We
showed that hyperglycaemia was a critical factor regulating the progression to β-cell decompensation in db/db
mice.
Expected future outcomes:
Fuure studies will be aimed to identify the transcription factors responsible for hyperglycaemia-induced betacell dedifferentiation and dysfunction.
Name of contact:
Ross Laybutt
NHMRC Research Achievements - SUMMARY
Email/Phone no. of contact:
r.laybutt@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 325624
Start Year: 2005
CIA Name: Prof David James
End Year: 2007
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Project Grants
Main RFCD: Protein Targeting and Signal Transduction
Total funding: $454,500
Title of research award:
Mechanistic studies of c-Cbl - a modulator of energy homeostasis.Mechanistic studies of c-Cbl - a modulator
of energy homeostasis.
Lay Description (from application):
Obesity has become one of the most serious health care problems in the world. It is a problem not just because
more people are getting fatter. It is a problem because obesity is a major risk factor for many other diseases
including Type 2 diabetes and heart disease. While many consider the solution to be straight forward, ie eat
less, this is obviously not an effective solution because the problem is accelerating at lightning speed around
the world. At the Garvan Institute we have recently identified a new mouse model bearing a disruption in one
single gene. This mouse eats 30% more food than its siblings but has half the body fat. This exciting discovery
constitutes the foundation for the present proposal.
Research achievements (from final report):
1. Tissue specificity. Conditional c-Cbl-/- mice have now gone germ line and mice are planned to be shipped to
the Garvan within the next month. 2. The role of c-Cbl in the fat cell. We have studied insulin signalling
pathways in adipocytes from c-Cbl-/- mice and have found no significant difference compared to wild type
animals. We are currently developing fat cell transplantation techniques to examine the effects of c-Cbl fat
when transplanted into a wild type recipient. 3. Energy expenditure. The activity of a series of oxidative
enzymes has been measured and we have found no significant difference in the oxidative capacity of muscle of
c-Cbl-/- mice compared to wild type controls. Furthermore, in high fat fed animals there was an equivalent
increase in oxidative capacity in muscle from knock out and wild type animals (Molero et al Casitas b-Lineage
Lymphoma-Deficient Mice Are Protected Against High-Fat Diet-Induced Obesity and Insulin Resistance.
Diabetes 55:708-15, 2006)4. Domains in c-Cbl. Considerable progress has been made on this aim. We have
shown that knock in animals in which the Ubiquitin ligase domain in Cbl has been disarmed have a phenotype
resembling the knock out animals. This provides compelling evidence that the phenotype we have observed
relies to a great extent on the ubiquitinylation function of this protein. In combination with the tissue specific
knock out experiments (Aim 1) this should provide important information for target identification. This work
has now been published.
Expected future outcomes:
Once conditional mice have been received we will be in a strong position to map the tissue specificity for the cCbl metabolic phenotype by creating adipose tissue, muscle, liver and brain specific c-Cbl knock out mice.
Name of contact:
David James
Email/Phone no. of contact:
d.james@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 325625
Start Year: 2005
CIA Name: Prof Edward Kraegen
End Year: 2007
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Project Grants
Main RFCD: Endocrinology
Total funding: $454,500
Title of research award:
Mechanisms of the insulin-sensitising effects of AMPK activation in liver and muscle.Mechanisms of the
insulin-sensitising effects of AMPK activation in liver and muscle.
Lay Description (from application):
Type 2 diabetes represents an escalating global health problem. In Australia 7.5% of the population has
diabetes and another 16% insulin resistance (impaired action of insulin). Insulin resistance is closely associated
with obesity, dyslipidemia, hypertension and cardiovascular diseases (Syndrome X) as well as diabetes. A high
caloric intake (particularly with a high fat content) and a sedentary lifestyle are extremely important
environmental contributors to Syndrome X and diabetes. One of the most exciting developments in the past
few years has been the discovery that an enzyme, AMP kinase (AMPK), normally activated by exercise, may
be involved in its beneficial effects. We have contributed to this exciting field by showing in an animal model
that one dose of AICAR, a chemical agent which can activate AMPK, ameliorates the effects of insulin
resistance in muscle and liver. Further very recent work has linked AMPK with various drugs (particularly
glitazones and metformin) and hormones which can enhance insulin sensitivity. The goal of the experiments in
this project is to determine the overall mechanism by which AMPK has ameliorating effects on counteracting
insulin resistance. We hypothesize that the mechanism for this involves an effect of AMPK to reduce fat
molecules accumulating within muscle and liver cells, and our studies will examine this hypothesis. Our
studies should lead to a better understanding of how exercise and pharmacological activators of AMPK help in
management of diabetes and insulin resistant states. In addition because AMPK activation enhances glucose
metabolism by a separate pathway to insulin, it offers promise of developing compounds able to bypass
metabolic steps impaired by insulin resistance. Our studies should help in the design of new therapeutic agents
which can counteract insulin resistance.
Research achievements (from final report):
There is a need to better understand factors that lead to reduced insulin potency in Type 2 diabetes and similar
metabolic states. The AMP-activated protein kinase K pathway may be involved in a bidirectional regulatory
system which influences the potency of insulin action, although the components of this system, the
mechanisms involved and the in vivo relevance are poorly defined. Our aim was investigate firstly the
mechanisms by which AMPK activation leads to enhanced insulin action, and secondly whether AMPK
activation is a major contributor to the beneficial effects of insulin sensitisers (thiazolidinediones TZDs). We
identified that the TZD rosiglitazone can potentiate AMPK activation and increase muscle glucose uptake. As
this pathway is normally activated by exercise our finding suggests that some of the beneficial effects of the
TZDs may be related to a potentiation of AMPK during exercise. Adiponectin is an endogenous AMPK
activator. We also overexpressed (in vivo by electroporation) muscle adiponectin receptors, plus APPL1, an
adiponectin interacting protein, to clarify their importance in influencing insulin action, and found that
increasing APPL1 can rescue the muscle from deleterious actions of excessive dietary lipids and oppose insulin
resistance. Conversely we have established that there is significant downregulation of adiponectin receptors in
skeletal muscle accompanying the onset of insulin resistance, suppression of AMPK activity and accumulation
of cytosolic lipid. Preventing the accumulation of cytosolic lipids (by enhancing mitochondrial transfer of
lipid) can increase insulin sensitivity in muscle. These findings have important therapeutic implications for
counteracting muscle insulin resistance.
Expected future outcomes:
The work has continued under a new NHMRC project (ID#481303) funded 2008-2010 to focus on adiponectin.
The new work is focussing on the precise steps in the insulin signalling pathway that are influenced by AMPK,
adiponectin and its signalling proteins such as Appl1. This has already led to a publication in 2009 (jointly with
collaborator Prof Aimin Xu) in Cell Metabolism.
NHMRC Research Achievements - SUMMARY
Name of contact:
Edward Kraegen
Email/Phone no. of contact:
e.kraegen@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 325631
Start Year: 2005
CIA Name: A/Pr Katherine Samaras
End Year: 2009
Admin Inst: Garvan Institute of Medical Research Grant Type: Career Development Fellowships
Main RFCD: Endocrinology
Total funding: $162,400
Title of research award:
Modulation of insulin resistance and metabolic syndrome.Modulation of insulin resistance and metabolic
syndrome.
Lay Description (from application):
Not Available
Research achievements (from final report):
As this was a Career Development Award, I am reporting achievements relative to objectives of , career
development, rather than scientific discovery., 1. A considerable research output, measured by a body of
original papers published, invited reviews and book chapters, invited plenaries and conference presentations. ,
2. Successful grant funding obtained through NHMRC and non-government funding bodies to , permit (most)
desired projects to come to fruition., 3. Establishment of a clinical database-biological tissue bank with
prospective data on a large , number of people with type 2 diabetes undertaking bariatric surgery., 4.
Establishing a presence or representation on government bodies or cooperatives defining or , influencing
policy, as a clinical science researcher ( for example, government treatment guidelines , on HIV, NSW Health
bariatric surgery guidelines, Federal Government Obesity Enquiry, American Heart Association Scientific
Consenus on cardiovascular risk in HIV, cardiovascular Research , Network-as part of 45 and Up)
Expected future outcomes:
N/A
Name of contact:
Katherine Samaras
Email/Phone no. of contact:
k.samaras@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 325638
Start Year: 2005
CIA Name: Dr Jerry Greenfield
End Year: 2008
Admin Inst: Garvan Institute of Medical Research Grant Type: Early Career Fellowships (Overseas)
Main RFCD: Endocrinology
Total funding: $384,870
Title of research award:
Detailed Phenotypic charaterisation of Human Melanocortin 4 Receptor Deficiency & Othr Monogenic Forms
of Severe ObesityDetailed Phenotypic charaterisation of Human Melanocortin 4 Receptor Deficiency & Othr
Monogenic Forms of Severe Obesity
Lay Description (from application):
Not Available
Research achievements (from final report):
During the research fellowship, I undertook a number of research studies examining the causes and metabolic
consequences of increased body fat in humans, particularly type 2 diabetes. Specifically, the studies performed
in the UK provided new information regarding the genetics of obesity and the abnormalities present in humans
who develop obesity due to defects in a single gene. This work was published in the New England Journal of
Medicine. A second groups of studies is being performed to investigate obese people who remain sensitive to
insulin despite having increased body fat. These individuals appear not to develop diabetes as commonly as
other obese people. We are studying the mechanisms of apparent protection from metabolic diseases in an
attempt to devise new therapies that may target these pathways. This paper will be sumitted to the Journal of
Clinical Investigation shortly. A third line of work, which started in the UK and is ongoing in Australia (funded
by an NHMRC Project Grant) is examining a novel therapy for treatment of high glucose levels. Glutamine, an
amino acid, appears to lower blood sugar levels in people with diabetes via a hormone secreted from the gut.
Two studies have been published from this work (in the American Journal of Clinical Nutrition and the Journal
of Nutrition).
Expected future outcomes:
The expected future outcomes relate to the discovery of new therapies for obesity and its metabolic
accompaniments, particularly insulin resistance and type 2 diabetes.
Name of contact:
Dr Jerry Greenfield
Email/Phone no. of contact:
j.greenfield@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 325644
Start Year: 2005
CIA Name: Dr Nigel Turner
End Year: 2008
Admin Inst: Garvan Institute of Medical Research Grant Type: Early Career Fellowships (Australia)
Main RFCD: Cell Metabolism
Total funding: $271,500
Title of research award:
The role of Dysfunctional Mucscle Mitochondria in Lipid-induced Insulin ResistanceThe role of Dysfunctional
Mucscle Mitochondria in Lipid-induced Insulin Resistance
Lay Description (from application):
Not Available
Research achievements (from final report):
This research involved an examination of the relationship between muscle mitochondrial metabolism and
insulin resistance. The major findings were 1) showing that an excess intake of calories does not cause obesity
and insulin resistance by reducing the capacity of muscle to burn fuel substrates; 2) demonstrating that a
number of anti-diabetic agents have their beneficial effects in part by influencing mitochondrial function; 3)
identifying that improved mitochondrial capacity is present in association with reduced fat mass and enhanced
insulin action in mice with a knockout of the c-Cbl gene. These results have provided novel insight into the
complex link that exists between mitochondrial function and insulin action, and indicate that targeted
manipulation of mitochondrial metabolism may be a fruitful approach for the treatment of insulin resistance
and diabetes.
Expected future outcomes:
The current study has identified mitochondrial pathways which appear to be associated with insulin action.
Future research will be aimed at testing whether specific manipulation of these pathways can improve insulin
action.
Name of contact:
Nigel Turner
Email/Phone no. of contact:
n.turner@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 358307
Start Year: 2005
CIA Name: Dr Cecile King
End Year: 2007
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Project Grants
Main RFCD: Autoimmunity
Total funding: $519,000
Title of research award:
The role of Interleukin-21 in the pathogenesis of autoimmune diabetesThe role of Interleukin-21 in the
pathogenesis of autoimmune diabetes
Lay Description (from application):
T cells are a component of our blood (white blood cells) and a major component of the body's defense system
against infection, known as immunity. Without T cells, we would fail to resist infection by foreign agents, such
as viruses, bacteria and fungi. Autoimmune (type 1) diabetes is a disease in which T cells attack our own
pancreatic islet self tissues as if they were foreign. T cells that react against the islets of the pancreas cause
destruction of the insulin producing beta cells so that the pancreas can no longer make insulin. Diabetes is a
life-threatening disease because insulin is a hormone that enables people to get energy from food. Type 1
diabetes is usually diagnosed in childhood and insulin must be administered daily by injection or through a
pump in order to survive. Unfortunately, taking insulin doesn t cure diabetes and people continue to suffer from
an extensive list of complications affecting most vital organs. Interleukin-21 (IL-21) is a soluble protein that is
produced by cells enabling them to communicate with other cells. IL-21 helps cells to produce factors that
cause inflammation and assist in clearance of viruses and bacteria from the body. However, our studies show
that IL-21 is a major factor in the development of the T cells that destroy beta cells and cause diabetes. Our
studies show that IL-21 is over-expressed in an important murine model of spontaneous type-1 diabetes. We
have isolated the T cells that cause diabetes and show that they are distinguished from other T cells by very
high levels of the receptor for IL-21. This project focuses on the IL-21-responsive T cells that cause diabetes
and aims to determine the mechanisms by which the cytokine IL-21 causes destructive immune responses and
ways to modulate its production. This project applies basic science to the important public health issue of type
1 diabetes for the development of therapeutic intervention strategies.
Research achievements (from final report):
The cytokine growth factor interleukin-21 (IL-21) has an important role in both immunity and autoimmunity.,
Our data has shown that IL-21 is a growth/survival factor for a specialised subet of cells known as T follicular
helper cells., T follicular helper cells orchestrate the production of high affinity antibodies by B cells in
specialised structures in lymphoid organds known as germial centers., Our data suggests that potentiating the
effects of IL-21 may improve vaccination protocols and inhibiting its actions may be useful in autoimmune
diseases that have dysregulated antibody production (such as Lupus)., Data obtained from this grant proposal
demonstrate that IL-21 is important in organ-specific autoimmune disease: the type-1 diabetes-susceptible
NOD mouse produces abnormally large amounts of IL-21., The abundance of IL-21 produced was due to a
mutation in thepromoter region IL-21 gene that ensured increased expression. , Production of IL-21 was
increased in T cells in the blood and pancreas just before the onset of diabetes. This suggests that the
measurement of IL-21 could be a predictive marker for the onset of T1D. , We have demonstrated for the first
time that short-term neutralization of IL-21 abolishes immune cell infiltration in the islets and prevents diabetes
in the NOD mouse. The ability of short-term blockade of a single cytokine to have this profound effect is very
impressive. , The inhibition of IL-21 signaling through its receptor starves diabetes-causing T cells of their
growth/surival factor IL-21. , Both the production of IL-21 by CD4+ T cells and receptiveness to IL-21 by
CD8+ T cells were found to be necessary for the destruction of insulin-producing islets and subsequent
diabetes. , These studies reveal a network in which IL-21 produced by CD4+ T cells provides a soluble helper
signal that ensures the survival of self-tissue destrcutive CD8+ T cells in non-lymphoid tissues.
Expected future outcomes:
IL-21 has equivalent effects on the immune system in mouse and humans. Therefore, we think that
neutralization of IL-21 has great therapeutic potential in humans for (1) the treatment of T1D and (2) the
NHMRC Research Achievements - SUMMARY
protection of transplanted islets. In addition (3) boosting IL-21's effects has potential application as a vaccine
adjuvant.
Name of contact:
Dr Cecile King
Email/Phone no. of contact:
c.king@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 376000
Start Year: 2006
CIA Name: Dr Jenny Gunton
End Year: 2008
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Project Grants
Main RFCD: Endocrinology
Total funding: $411,798
Title of research award:
The Role of ARNT in Beta-Cell Dysfunction and the Pathogenesis of Type 2 Diabetes Mellitus in Humans and
Animal ModelsThe Role of ARNT in Beta-Cell Dysfunction and the Pathogenesis of Type 2 Diabetes Mellitus
in Humans and Animal Models
Lay Description (from application):
The importance of type 2 diabetes research is clear, as we are in the midst of both a global and Australian
epidemic; 24% of Australian adults have increased blood sugar levels, and this already high rate will increase
rapidly over the coming years. The cost to the Australian economy will be enormous. Because diabetes does
not develop until -cell failure is present in the pancreas, and the mechanisms of -cell failure are not well
understood, more studies are needed, particularly using human samples. Until recently, these samples were
simply not available. The advent of reliable islet isolation techniques, and their availability in Sydney make
these studies feasible. My previous work identified a 90% decrease in ARNT in islets from people with type 2
diabetes, clearly making ARNT function and regulation an important question of relevance to human disease.
It is possible that understanding how ARNT works in -cells may lead to new treatments for -cell failure and
diabetes. The use of human islets will allow the important verification that substances having an effect in mice
and cell lines are actually relevant in normal humans.
Research achievements (from final report):
We have identified a decrease of a transcription factor called ARNT in the islets and livers of people with type
2 diabetes. Transcription factors are 'master regulators' of many things in living cells and decreased ARNT
causes changes in many other proteins needed for normal cell function. Decreased ARNT impairs insulin
release from the pancreas and insulin action at the liver, and increasing ARNT action may therefore provide a
possible therapeutic target for the treatment of type 2 diabetes.
Expected future outcomes:
We have 1 paper in press and 2 papers currently being considered for publication.
Name of contact:
Jenny Gunton
Email/Phone no. of contact:
j.gunton@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 376003
Start Year: 2006
CIA Name: Prof Ken Ho
End Year: 2008
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Project Grants
Main RFCD: Endocrinology
Total funding: $379,143
Title of research award:
The Metabolic Effects of Oestrogens and SERMs: Regulatory interactions with the GH-IGF-system in health
and diseaseThe Metabolic Effects of Oestrogens and SERMs: Regulatory interactions with the GH-IGF-system
in health and disease
Lay Description (from application):
This project extends work aimed at understanding how GH and sex hormones work together to optimise
physical health in women and men. It addresses the benefits and safety of oestrogen compounds in relation to
their effects on body fat and muscle (body composition). Oestrogen compounds are among the most widely
used medicines and include tradition oestrogens (female hormone) and synthetic oestrogens called SERMs.
Oestrogens are used in young women as oral contraception and in the postmenopause for replacement therapy.
Body composition is an important determinant of fitness and health. Obesity reduces fitness and increases the
risk of diabetes and heart attacks while muscle loss causes weakness and frailty. GH is a major regulator of
body composition; it acts by breaking down fat and building muscle mass. We discovered that oestrogens,
when taken as a tablet interferes with the action of GH and causes detrimental changes in body composition.
On the positive side, we have exploited the GH blocking action to treat acromegaly. This is a debilitating
disease of excessive GH production from a pituitary tumour and for which available drug treatments are very
expensive and require injection. The effects of SERMs on body composition are unknown. SERMs are
interesting compounds because they act like oestrogens in some but as oestrogen blockers in other tissues.
These are widely used in the treatment of breast cancer and osteoporosis. The extent to which they interfere
with the action of GH has not been studied. They may exert additional effects because they act on the pituitary
gland to reduce the secretion of GH. They may also prove to be effective in acromegaly which could extend
their usefulness to men. In summary, the work will provide important information on the long-term benefits of
SERMs in patient groups that tend to be frail. It may also prove to be a simple and inexpensive treatment for
acromegaly.
Research achievements (from final report):
This proposal addresses whether SERMs, commonly used oestrogen compounds affect the secretion and action
of growth hormone (GH), an important regulator of body metabolism, composition and function. This project
investigates whether SERMs which block the action of oestrogen, lead to a reduction in the release and in the
action of GH., , Our studies show that two synthetic oestrogen compounds, raloxifene and tamoxifen which
interfere with the action of natural oestrogens in the brain, markedly reduces GH secretion in both men and
women. Both these compounds also interfere with the ability of the liver to make a growth-promoting hormone
called IGF-1, which is normally produced in response to the action of GH. , , Our findings show unequivocally
that SERMs interfere with both the secretion and action of GH which in the longer term may be detrimental to
health. As these agents are used to treat a variety of conditions where alternatives are available, our findings
call for more judicious use of these compounds which are increasingly used for long periods in a frail and
aging population.
Expected future outcomes:
Future studies are expected to confirm the negative effect of these compounds on the ability of GH to burn
body fat and to build muscle which are currently being addressed in detailed metabolic studies.
Name of contact:
Professor Ken Ho
Email/Phone no. of contact:
k.ho@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 376008
Start Year: 2006
CIA Name: Prof David James
End Year: 2008
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Project Grants
Main RFCD: Protein Targeting and Signal Transduction
Total funding: $505,523
Title of research award:
The Role of AS160 in Insulin ActionThe Role of AS160 in Insulin Action
Lay Description (from application):
Obesity and diabetes are increasing in our community at an alarming rate. When one considers that Diabetes is
a major cause of heart disease, stroke and kidney disease these diseases represent one of the most threatening
for the future health of our nation. At the heart of these diseases is a disorder known as insulin resistance, or
the inability of insulin to function correctly. The explosion in biological outcomes over the past decade has
brought us closer than ever before to solving some of the key questions associated with this problem. This
proposal represents an exciting step forward in this area because our recent research combined with
information from our international colleagues have led us to propose a new concept concerning the mechanism
of insulin action. In this proposal we have formulated a series of molecular experiments to test this hypothesis
which if correct will both change the way we think about this problem and provide new prospects for
therapeutic design.
Research achievements (from final report):
This research has enhanced our understanding of how insulin regulates one of its fundamental steps namely the
import of glucose into muscle and fat cells. This step is considered to be one of the most important in
determining the removal of glucose from the bloodstream after a meal and indeed it becomes disrupted in
individuals who are at risk of developing type 2 diabetes. Over the period of the award we have identified
essential elements of how the protein AS160/TBC1D4 and its family members work in fat cells. AS160 is a
RabGAP that is phosphorylated by Akt. We have made the following achievements:, 1. Identified two Rabs
that specifically bind to AS160, 2. Established molecular mechanisms for AS160 dimerisation, 3. Developed
methods to show that phosphorylation and 14-3-3 binding per se are key to the function of AS160 in response
to insulin, 4. Performed systems analysis of AS160 combined with other key Akt substrstes to show that
AS160 is phosphorylated by Akt at the plasma membrane., 5. Used mass spectrometry to identify novel AS160
binding partners. , In a separate body of work we have begun to study the role of other TBC family proteins in
insulin action. Specifically we have found that another protein TBC1D13 binds to Rab10 and when over
expressed in adipocytes profoundly inhibits insulin dependent GLUT4 trafficking. , These studies have
provided novel insights into this important biological process.
Expected future outcomes:
Mutations in TBC1D4 and a related protein TBC1D1 have recently been identified in families with obesity and
Type 2 diabetes. However, the mechanism for this is not yet known. Our work will provide a deeper
understanding of this linkage and as to how the regulation of glucose transport in muscle and fat cells is so
closely linked to whole body energy homeostatsis and metabolism.
Name of contact:
Jacky Stoeckli
Email/Phone no. of contact:
j.stoeckli@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 376012
Start Year: 2006
CIA Name: A/Pr Gregory Cooney
End Year: 2010
Admin Inst: Garvan Institute of Medical Research Grant Type: Established Career Fellowships
Main RFCD: Cell Metabolism
Total funding: $607,101
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
This 5 year Fellowship Grant was used to pursue studies that have highlighted the importance of fuel
metabolism and energy expenditure in different tissues to the accumulation of fat and the development of
insulin resistance and type 2 diabetes. These studies have involved significant collaborations and publications
with other researchers interested in the regulation of metabolism in muscle. The studies supported by this
Fellowship have demonstrated tissues switch fuels to match energy demands and that changes in energy intake
or expenditure are necessary for fat loss. Other studies have determined that mice with a deletion of the Grb10
protein have greater muscle mass, less fat and better insulin action which is relevant to muslce loss with ageing
as well as type 2 diabetes. Finally there ahs been considerble focus on the circadian changes in metabolism that
regulate that we sleep at night and eat and work during the day. Studies have determined that making animals
eat when they normally sleep has significant effects on energy metabolism and can lead to metabolic
abnormalities similar to those now being reported ins hift workers. All thee studies have a major impact on
how to deal with the increasing incidence of obesity and its complications.
Expected future outcomes:
The successful research outcomes of this Fellowship Grant have resulted in a renewal of my Fellowship and
the next 5 years will be used to significantly contribute to understanding how obesity develops and causes
metabolic disease.
Name of contact:
Greg Cooney
Email/Phone no. of contact:
g.cooney@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 376020
Start Year: 2006
CIA Name: A/Pr Trevor Biden
End Year: 2008
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Project Grants
Main RFCD: Cell Metabolism
Total funding: $510,476
Title of research award:
Mechanisms of fatty-acid mediated destruction of pancreatic beta cellsMechanisms of fatty-acid mediated
destruction of pancreatic beta cells
Lay Description (from application):
Type 2 diabetes is associated with obesity, but not all obese individuals develop the disease. Non-diabetic
obese subjects are able to compensate for diminished sensitivity to insulin (a general feature of obesity) by
enhanced output of insulin from the pancreatic beta-cells of the islet of Langerhans. In diabetics this
compensatory mechanism is disrupted. Obesity and Type 2 diabetes are also associated with elevated levels of
fatty acids (FAs) in the bloodstream. These can be taken up by the beta-cells where they exert both short and
long-term effects. In the longer term FAs can be toxic to beta-cells and this is thought to be important in the
failure of beta-cell compensation. The project is aimed at a better understanding of the manner by which
different types of FAs influence the susceptibility of beta-cells to destruction. It builds on our preliminary
results suggesting that the capacity of the beta-cell to convert saturated FAs to unsaturated FAs helps protect
them from destruction. Our aim is to examine the mechanisms underlying this protection.
Research achievements (from final report):
The major achievements were the demonstrations that ER stress occurs in experimental models of Type 2
diabetes, and most importantly is present in beta cells of human subjects with the disease. We have additionally
shown that ER stress in necessary for full lipoapoptosis in our cellular model. On a more mechanistic level we
established that a slowing in the trafficking of sectory protein between the ER and golgi contributes to the
induction of ER stress.
Expected future outcomes:
In future studies we are focusing on the mechanisms whereby fatty acids disrupt protein trafficking and are
testing the hypothesis that compartalized increases in ceramide is a causative factor.
Name of contact:
Trevor Biden
Email/Phone no. of contact:
t.biden@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 376021
Start Year: 2006
CIA Name: A/Pr Amanda Sainsbury-Salis
End Year: 2008
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Project Grants
Main RFCD: Systems Physiology
Total funding: $569,282
Title of research award:
The role of dynorphins in energy homeostasisThe role of dynorphins in energy homeostasis
Lay Description (from application):
While it is clear that carrying excess body weight can jeopardize your health, and that losing excess weight is
good for you, attaining and maintaining a healthy body weight remains an elusive goal for more than 60 % of
Australian adults. There are many barriers that make permanent weight loss difficult. One of the main
biological barriers to weight loss is that humans aren t designed to diet. Instead, we vehemently conserve body
fat whenever food is scarce. This leads to a Famine Reaction that contributes to nagging hunger, lethargy, loss
of libido, reduced metabolic rate, plateaus, and rebound weight gain in response to weight loss programs of any
kind. In a new 3-year project funded by the National Health and Medical Research Council of Australia,
molecular scientists Dr Amanda Sainsbury-Salis and Associate Professor Herbert Herzog from the Garvan
Institute endeavor to get to the root of the problem. Using cutting-edge molecular, genetic, and metabolic
technology, Sainsbury-Salis and Herzog aim to identify the main culprits for the Famine Reaction. They
hypothesize that the natural brain molecules neuropeptide Y and the endogenous morphine-like peptide
dynorphin act together as major instigators of the Famine Reaction. Therefore they will determine whether
mice that are deficient in these molecules can lose more weight in response to dietary restriction than normal
mice. Moreover, they will determine whether dual deficiency of neuropeptide Y and dynorphin can not only
reduce the voracious appetite that occurs during caloric restriction (eg: dieting), but whether it can also speed
up metabolism and promote the loss of body fat. If their hypothesis proves correct, then it s likely that novel
pharmaceutical agents that block the effects of neuropeptide Y and dynorphin could dramatically increase the
do-ability and long-term effectiveness of lifestyle changes for permanent weight loss.
Research achievements (from final report):
This work demonsrated that dynorphins, one of the body's natural versions of morphine, plays a significant role
in regulating body weight. To test whether dynorphins play a significant role in weight loss, we generated mice
that were unable to produce any dynorphins. We found that these mice had significantly less body fat than the
normal group, and they lost 15-20% more weight than normal mice while eating the same amounts of food."
The Garvan study suggests that, for people genetically predisposed to produce higher levels of dynorphins, the
body will store more fat and lose less fat than for people with lower levels, even when they are placed on the
same calorie-restricted diet. This may help explain why some people find it harder to lose weight than others,
despite their best efforts at dieting.
Expected future outcomes:
This work is of potential relevance to the pharmaceutical sector, in the development of novel anti-obesity drugs
Name of contact:
Cate Smith
Email/Phone no. of contact:
c.smith@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 376022
Start Year: 2006
CIA Name: Dr Carsten Schmitz-Peiffer
End Year: 2008
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Project Grants
Main RFCD: Endocrinology
Total funding: $627,148
Title of research award:
Investigation of the Roles of Protein Kinase C epsilon in Insulin Secretion and Insulin ClearanceInvestigation
of the Roles of Protein Kinase C epsilon in Insulin Secretion and Insulin Clearance
Lay Description (from application):
The rise in blood insulin levels after a meal normally reduces blood sugar levels by increasing glucose uptake
and storage in certain tissues, especially muscle. Type 2 diabetes is characterized in part by a failure of the
pancreas to produce adequate insulin in response to increases in blood sugar. This loss of insulin secretion has
been strongly linked to increases in the availability of fat, although the reasons for this are not clear. We have
recently found that mice lacking a specific enzyme (protein kinase C epsilon) are much less susceptible to the
problems in dealing with blood sugar that are caused by a high fat diet. We showed that this is due partly to
improved insulin secretion, and also to a slower breakdown of insulin by the liver, which increases its
availability to target tissues. The aim of this project is to investigate the mechanisms occurring in the liver and
in the pancreas by which this enzyme contributes to improved insulin action. Firstly, we will examine insulin
uptake in liver cells, to investigate how the enzyme controls this process. Secondly, we will determine the
mechanism through which the activation of the enzyme, upon increased fat supply to pancreatic beta-cells,
reduces insulin secretion in response to glucose. Finally, will assess the relative importance of these two
actions of the enzyme in improving the control of blood sugar levels. This work will lead to a better
understanding of the mechanisms by which fat oversupply, and hence obesity, can play a role in the
development of Type 2 diabetes, so that they can be targeted both for the development of new and more
effective treatments for the disorder and for prevention of its onset.
Research achievements (from final report):
This project resulted in a high profile publication in a top scientific journal (Cell Metabolism), because the
work described a novel drug target for the treatment of Type 2 diabetes. We showed that the enzyme known as
protein kinase C epsilon (PKCe) plays an inhibitory role in the beta cells of the pancreas to reduce glucosestimulated insulin secretion in the face of increased fat accumulation, as occurs during obesity. Inhibition of
this enzyme improves glucose intolerance in mice fed a high fat diet. In addition, we found that PKCe reduces
the availability of insulin in the body by promoting its uptake and degradation by the liver. Thus drugs
designed to inhibit PKCe would enhance insulin secretion as and when needed as well as reduce its clearance.
These effects counteract the insulin resistance also occuring in Type 2 diabetes, improving blood glucose
levels. In addition to these key findings we also addressed the mechanisms involved in these actions of PKCe.
On the one hand, the enzyme affects lipid metabolism in beta cells to amplify their response to glucose and
thus enhance insulin secretion. On the other hand, PKCe affects the internalization of the insulin receptor in
liver cells which are responsible for insulin clearance. These findings are significant advances in our
understanding of the effects of PKCe, and also shed light on the regulation of glucose-stimulated insulin
secretion and insulin uptake.
Expected future outcomes:
Our work is the subject of an international patent application currently under examination. In addition we have
recently signed an agreement with a commercial partner to test PKCe inhibitory molecules in our models of
type 2 diabetes. The ensuing intellectual property may be licensed for development of PKCe inhibitors to treat
diabetes in humans.
Name of contact:
Carsten Schmitz-Peiffer
Email/Phone no. of contact:
NHMRC Research Achievements - SUMMARY
c.schmitz-peiffer@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 376024
Start Year: 2006
CIA Name: Dr William Hughes
End Year: 2008
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Project Grants
Main RFCD: Protein Targeting and Signal Transduction
Total funding: $509,268
Title of research award:
The Role of Phospholipase D in Regulating Insulin SecretionThe Role of Phospholipase D in Regulating
Insulin Secretion
Lay Description (from application):
Insulin, secreted appropriately by the b-cell of the pancreatic islets of Langerhans, regulates blood glucose
levels through its effects on various tissues throughout the body. Precise control of insulin secretion from the
pancreatic b-cell into the blood is therefore vital for accurate glucose homeostasis. Type II Diabetes Mellitus is
caused by the inability of pancreatic b-cells to respond adequately to changes in blood glucose. In the last 18
months we have determined that the enzyme phospholipase D (PLD) plays an essential role in distally
coordinating signals leading to accurately regulated insulin secretion from the pancreatic b-cell. Through this
proposal we now aim to define the signalling pathways upstream of PLD and identify the mechanism
downstream that allows PLD activity to regulate insulin secretion. We aim to use a combination of established
and novel, biochemical and cell biological, approaches to characterize the role PKC alpha and beta isoforms
and the small GTPase cdc42 may have in controlling PLD mediated insulin release. We will also use a variety
of cell biological approaches to identify why, where, and when PLD activation is required for appropriate
insulin secretion. We will also correlate these observations with the role the cell cytoskeleton may have in
mediating PKC, cdc42 and/or PLD effects. In particular we aim to use a state-of-the-art microscope facility
recently established at the Garvan Institute to achieve these aims. In doing this we will gain new insights into
the pathways determining how insulin is released into the bloodstream, further define cellular processes
common to all vesicular trafficking events and also identify potential targets for pharmacological intervention
in the disease Diabetes.
Research achievements (from final report):
The study was aimed at better understanding the mechanisms controlling the secretion of insulin from
pancreatic beta cells. The major achievement from the work is a the development of novel reagents and
techniques to image the insulin secretion process in live pancreatic beta cells. I have then either genetically or
pharmacologically stimulated or inhibited molecules implicated in regulating insulin secretion and have
visualized precicely which process in the secretory mechanism is defective.
Expected future outcomes:
A better understanding of insulin secretion and which molecules regulate which precise step in the process.
Name of contact:
William E. Hughes
Email/Phone no. of contact:
w.hughes@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 402727
Start Year: 2006
CIA Name: Dr Pablo Silveira
End Year: 2008
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Project Grants
Main RFCD: Autoimmunity
Total funding: $163,756
Title of research award:
Identifying the underlying mechanisms responsible for the generation of pathogenic B cells in Type 1
DiabetesIdentifying the underlying mechanisms responsible for the generation of pathogenic B cells in Type 1
Diabetes
Lay Description (from application):
Type 1 diabetes (T1D) occurs when the body's own immune system mistakenly attacks and destroys all the
beta cells of the pancreas which produce insulin, a hormone essential for regulating sugar levels in the blood.
The non-obese diabetic (NOD) mouse develops a form of T1D closely resembling the human disease, and as a
model, has led to numerous important insights into its cause. Based on studies in NOD mice, it is now well
accepted that a class of cell in the immune system, termed T cells, are responsible for most of the damage to
the beta cells in T1D. Recent work in this model, however, has demonstrated that another class of immune cell,
termed B cells, also play an important role in T1D as NOD mice made deficient in these cells no longer
develop disease. In addition to producing antibodies, B cells are one of the few cell types which are able to take
up and present protein fragments in a form recognizable to T cells. Normally, this only leads to the activation
of T cells recognising foreign insults, like viruses or bacteria, resulting in their destruction. We have shown that
a dangerous population of B cells can arise in NOD mice that can specifically take up beta cell proteins and
present them to the T cells, which subsequently become armed to recognise and destroy the beta cells. Just like
T cells, B cells that recognize the body's own proteins are normally eliminated in healthy mice and human
individuals. This research proposal aims to determine the faulty immune mechanisms that give rise to the beta
cell specific B cells in NOD mice. We have also set out to identify the diabetes susceptibility genes which
control the generation of this dangerous population of B cells in this model. By understanding how these
dangerous B cells are generated in NOD mice, we hope to form the basis for new therapies aimed at inhibiting
these cells from forming in T1D susceptible humans, thus preventing the disease at an early stage.
Research achievements (from final report):
Aim 1: We have performed experiments in which we have obtained complete genetic profiles of B cells from
diabetes-prone mice as well as non-diabetes prone mice at various stages of their development. By comparing
these genetic profiles, we have been able to identify new defective molecular pathways responsible for
generating self-reactive B cells that facilitate development of disease., , Aim 2:, We have produced genetically
engineered diabetes prone and non-diabetes prone mice in which all B cells recognize a transgenic pancreatic
beta cell protein. Using these mice we have been able to confirm that self-reactive B cells specific for beta cell
proteins are normally functionally inactivated and subsequently eliminated. However, in diabetes prone
animals, these self-reactive B cells can be rescued upon interaction with T lymphocytes, whereas those in nondiabetes prone backgrounds are not. This study provides an interesting insight into how self-reactive B cells are
able to be rescued and recruited into beta cell specific response in individuals predisposed to Type 1 Diabetes.,
, Aim 3:, We identified two genetic regions housing diabetes susceptibility genes in mice which control the
ability of B cells to participate in the autoimmune response against beta cells. We have revealed that the genes
in both of these regions increase the capacity of self-reactive B cells to escape being functionally inactivated in
diabetes susceptible mice. We are currently performing studies to identify the specific genes responsible for
these diabetes promoting B cell attributes.
Expected future outcomes:
Elucidation of the cellular and molecular basis for defective B cell tolerance in NOD mice will pave the way
for translational studies to determine whether dysregulation of similar pathways characterize Type 1 Diabetes
patients. These studies may yield novel targets in B lymphocytes for intervention protocols which may
ultimately prevent or reverse T1D in susceptible human subjects.
NHMRC Research Achievements - SUMMARY
Name of contact:
Pablo Silveira
Email/Phone no. of contact:
P.Silveira@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 427600
Start Year: 2007
CIA Name: Prof David James
End Year: 2011
Admin Inst: Garvan Institute of Medical Research Grant Type: Established Career Fellowships
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $765,883
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
I am a cell biologist studying the molecular mechanism of insulin action
Research achievements (from final report):
Type 2 Diabetes and obesity are major risk factors for most life threatening diseases of modern humans.
Because diabetes and obesity could be essentially eliminated by dietary restriction this places an enormous
emphasis on food as a public health risk. Our work has been attempting to define how food excess contributes
to life threatening diseases by studying systems as they transition from one dietary state to another. We have
been placing quite a bit of emphasis on intracellular stress pathways as we postulate that food intake is
intimately linked with these pathways. Another major area of interest is to examine not just the relationship
between absolute amounts of food and biological outcomes but also the time of exposure to food. We believe
that ultimately, research of this kind will lead to the development of personalized treatments for a range of
diseases based on individualized nutritional requirements. Such treatments may have broad impact on the onset
of a range of diseases that are now increasing in incidence throughout the world.
Expected future outcomes:
Over the next 5 years we aim to gather much more data that define system response to food and then using
sophisticated computational approaches we aim to decipher from these data those pathways that define long
term health of mammals.
Name of contact:
David James
Email/Phone no. of contact:
d.james@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 427610
Start Year: 2007
CIA Name: Prof Trevor Biden
End Year: 2011
Admin Inst: Garvan Institute of Medical Research Grant Type: Established Career Fellowships
Main RFCD: Protein Targeting and Signal Transduction
Total funding: $618,722
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
I am a biochemist/cell biologist primarily investigating pancreatic beta cell biology and diabetes as a function
of signal transduction pathways.
Research achievements (from final report):
Firstly, we have identified ER stress as a major and unexpected response, accounting for >20% of the total
alterations in gene expression occurring following exposure to palmitate but not oleate. Using a variety of
techniques we confirmed that ER stress does indeed occur, not only in vitro, but also in pancreatic islets of
db/db mice, a model of T2D. In addition, by performing immunohistochemistry on archival pancreatic tissue,
we showed for the first time that ER stress occurs in human T2D. Because only saturated FAs are cytotoxic,
whereas both unsaturated and saturated FAs cause secretory dysfunction, we believe that our results are
profoundly relevant to the processes whereby b-cell mass is decreased in T2D. This paper has received more
than 220 citations. Subsequent studies in this area demonstrated that a selective block in ER-to-golgi protein
trafficking contributed mechanistically to the induction of ER stress, and this was secondary to alterations in
sphingolipid metabolism as assessed via a comprehensive lipidomic screen. , With regard to secretory
alterations, we made the unexpected finding that ablation of PKCe reverses the effects of chronic lipid
exposure. These findings were made using in vivo, and ex vivo approaches, and were confirmed using a small
molecule inhibitor of PKCe in the db/db mouse model of T2D. This was a major discovery with implications
regarding both our understanding of the mechanisms underlying b-cell dysfunction, and the development of
new therapies to treat T2D. Subsequently we demonstrated that alterations in neutral lipid turnover
(esterification and lipolysis) contributed to the mechanism of action of PKCe deletion. , Other studies focused
on the mechanism of action of PKCd in both pancreatic islets in models of Type 1 diabetes, and in liver in
models of Type 2 diabetes. In both instances results suggest that inhibition of this PKC might be
therapeutically beneficial. ,
Expected future outcomes:
We are uniquely placed to elaborate defects in pancreatic beta cell dysfunction in the areas of both insulin
secretory failure and loss of beta cell mass. Firstly, we have generated mice for selectively deleting PKCe in
different tissues and will use these to further characterize underlying mechanisms. Secondly, we are pursuing
the nexus between sphingolipid metabolism, ER stress and apoptosis.
Name of contact:
Trevor Biden
Email/Phone no. of contact:
t.biden@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 427616
Start Year: 2007
CIA Name: Dr David Ross Laybutt
End Year: 2009
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Project Grants
Main RFCD: Endocrinology
Total funding: $537,110
Title of research award:
Mechanisms of beta-cell failure in diabetesMechanisms of beta-cell failure in diabetes
Lay Description (from application):
The current epidemic of type 2 diabetes represents a major global health problem, with over 7% of the
Australians suffering the disease. While there is a well-established relationship between obesity and insulin
resistance, the majority of overweight individuals do not develop type 2 diabetes because their pancreatic betacells compensate with enhanced insulin secretion. It is the failure of beta-cell compensation that is fundamental
to the development of diabetes. The beta-cell is a highly specialised cell with a unique metabolic profile and
differentiation specifically geared towards making these cells able to sense fluctuations in circulating glucose
levels and secrete insulin accordingly. We propose that in susceptible individuals, a gradual rise in blood
glucose (hyperglycaemia) and lipid levels resulting from increasing obesity and insulin resistance leads to a
loss of the unique expression pattern of genes necessary for appropriate insulin secretion. This exacerbates
hyperglycaemia, which causes further beta-cell dedifferentiation and eventually the death of beta-cells by
apoptosis. We have recently found evidence in several models of diabetes that supports this hypothesis. We
propose to use animal studies and cell culture systems to investigate the following hypotheses important for our
understanding of beta-cell failure and progression to diabetes: 1)Hyperglycaemia plays a critical role regulating
the progression to beta-cell dedifferentiation. 3) The overexpression of key candidate gene products play an
integral role linking hyperglycaemia to the loss of beta-cell secretion. 4) Endoplasmic reticulum stress is
necessary for beta-cell death in diabetes. Our studies will make a major contribution to our understanding of
why beta-cells fail in diabetes and aim to provide novel therapeutic targets in the treatment of diabetes.
Research achievements (from final report):
Diabetes occurs as a result of pancreatic beta cell failure. In both type 1 and type 2 diabetes, beta cell failure is
characterised by insulin secretory defects, loss of insulin content and beta cell destruction. In type 1 diabetes,
this is mediated by cytokines that are produced as a part of an autoimmune and inflammatory process. In type 2
diabetes, elevated lipid and glucose levels occurring as a result of high fat diets, obesity and insulin resistance
are thought to contribute. The beta cell is a highly specialised cell with a unique metabolic profile and
differentiation specifically geared towards making these cells able to sense fluctuations in circulating glucose
levels and secrete insulin accordingly. Our research showed that beta cell secretory defects in diabetes and in
islet transplants are associated with a loss of the specialised expression pattern of genes that optimises insulin
secretion. The molecular and cellular mechanisms responsible for this loss of beta cell differentiation were
investigated. Stress within the endoplasmic reticulum (ER) compartment of the cell was a focus of
investigation. Pancreatic beta cells possess a highly developed ER, which is required for the processing, folding
and export of vast quantities of newly synthesised insulin. We investigated ER stress as an exciting potential
mechanism for beta cell dysfunction and destruction in type 1 and type 2 diabetes.
Expected future outcomes:
We will further investigate potential mechanisms of beta-cell failure in type 1 and type 2 diabetes.
Name of contact:
Ross Laybutt
Email/Phone no. of contact:
r.laybutt@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 427629
Start Year: 2007
CIA Name: A/Pr Trevor Biden
End Year: 2007
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Development Grants
Main RFCD: Endocrinology
Total funding: $157,375
Title of research award:
Therapeutic Strategies and Screening Methods for PKC epsilon antagonists in the treatment of Type 2
diabetesTherapeutic Strategies and Screening Methods for PKC epsilon antagonists in the treatment of Type 2
diabetes
Lay Description (from application):
Type 2 diabetes is a chronic disease affecting over a million Australians and hundreds of millions of people
worldwide. Its prevalence is rising due to several factors such as an increase in caloric intake, the aging of the
population, and the common sedentary lifestyle of Western civilization. Type 2 diabetes occurs when the
pancreas is unable to produce enough insulin for the body to cope with rising blood glucose levels after a meal,
and has been strongly linked to obesity. We have now shown that an enzyme found in the pancreas becomes
inappropriately activated under conditions of fat oversupply, and plays an important role in the development of
defects in insulin release from the pancreas in response to glucose. Excitingly, we have also shown that
inhibition of this enzyme can partly reverse these defects once they have been established. We now intend to
further validate this enzyme as a drug target by determining the optimum dosing regimen for the treatment of
type 2 diabetes in a mouse model, and testing whether this approach can be used in conjunction with
previously-developed drugs which promote insulin action, to improve blood glucose handling better than either
treatment alone. This would promote the enzyme as a therapeutic strategy in the treatment of Type 2 diabetes.
We also plan to develop a high throughput screen to identify novel inhibitors of the enzyme, which will further
increase the attractiveness of the project to pharmaceutical companies, who are better able to implement full
commercialization of our findings.
Research achievements (from final report):
The major achievement of this grant was extension of knowledge on the mechanism of action of PKCe. We
made use of the peptide inhibitors to demonstrate a specific action of PKCe in the amplification pathway of
insulin secretion. This study was undertaken using islets of Langerhans isolated from mice, and now provides
us with the crucial baseline measurements for comparison with identical studies to be undertaken with human
islets. We also developed crucial reagents for undertaking the high throughput screen and demonstrated proof
of principle of the basis of our assay. This led us into extended discussions and potential collaborations with
industry partners. Unfortunately funding for the undertaking the screen was not forthcoming. More
productively, we have negotiated with a biotech firm for a joint investigation of their PKCe inhibitors in our
model systems. An agreement has now been signed.
Expected future outcomes:
We will perform the assays under the terms of our joint agreeement, and depending on outcomes, treatments
for Type 2 diabetes based around inhibition of PKCe will be developed clinically. Our partner has already
conducted trials for their inhibitors for other applications, so use with diabetes could be potentially fast-tracked.
Name of contact:
Trevor Biden
Email/Phone no. of contact:
t.biden@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 427639
Start Year: 2007
CIA Name: Dr Leonie Heilbronn
End Year: 2009
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Project Grants
Main RFCD: Endocrinology
Total funding: $417,197
Title of research award:
Short-term effects of overfeeding on metabolic risk in humansShort-term effects of overfeeding on metabolic
risk in humans
Lay Description (from application):
The prevalence of obesity is rapidly increasing in Australia and other parts of the world. Obesity is closely
associated with insulin resistance and plays a role in the development of type 2 diabetes. However, the effects
of short-term periods of over nutrition in humans remain unclear. In the proposed study, we will investigate the
effects of short-term weight gain by high fat feeding in lean subjects, in subjects who are overweight and in
subjects who are genetically more likely to develop diabetes (due to strong family history). The aims are to
distinguish physiological and endocrine characteristics of individuals who store more fat in response to
overfeeding. We will identify differences between these individuals and whether they have defects in
upregulating machinery involved in fat oxidation and energy production in skeletal muscle that may help them
adapt during to energy excess. We will look for changes in type 2 diabetes risk and we will have the potential
to identify defects in factors that are involved in this response. We will also re-examine indivudals again after
calorie restriction and weight loss. We also plan to confirm the role of the candidate genes involved in fat
oxidation that have been identifieid in human studies by in vivo gene transfer technology in rodents. This
study will determine whether overweight and lean subjects behave similarly when faced with an overfeeding
challenge. We expect that individuals with a genetic predisposition for T2DM will become more IR, due to
metabolic inflexibility and a decreased ability to upregulate machinery involved in fatty acid oxidation and
mitochondrial function. By characterising the physiological and endocrine responses to overfeeding, we will
establish quantifiable markers allowing us to distinguish those at risk and identify new targets for
pharmacological or lifestyle intervention.
Research achievements (from final report):
There are studies showing mitochondrial dysfunction and increased oxidative stress in human obesity and type
2 diabete. Furthermore, these studies suggest that these factors may be reversed by weight loss and induced by
lipids. However, an increasing number of rodent studies suggest that diet induced obesity increases, not
decreases mitochondrial function. It was unclear what will happen under these conditions. In this study, we
observed a transient increase in mitochondrial biogenesis indicating that mitocondrial dysfunction is not causal
in development of weight gain induced insulin resistance. Furthermore, we observed a significant increases in
systemic and muscle markers of oxidative stress. Further work is now required to determine whether increased
reactive oxygen species production in muscle causes insulin reistance in animal and human models.
Expected future outcomes:
We are using this high fat overfeeding model to now study individuals who were conceived through in-vitro
fertilisation. There is some animal evidence, and some cross-sectional studies to suggest that these individuals
are at increased risk of developing insulin resistance and type 2 diabetes. But this is has not been well studied
to date.
Name of contact:
Leonie Heilbronn
Email/Phone no. of contact:
leonie.heilbronn@adelaide.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 427642
Start Year: 2007
CIA Name: Prof David James
End Year: 2009
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Project Grants
Main RFCD: Protein Targeting and Signal Transduction
Total funding: $303,510
Title of research award:
Dissection of Insulin Regulated Phosphorylation in the AdipocyteDissection of Insulin Regulated
Phosphorylation in the Adipocyte
Lay Description (from application):
Obesity and diabetes are increasing at an alarming rate throughout the world. These diseases are part of a
constellation of disorders that includes cardiovascular disease and kidney disease, which are collectively
referred to as the metabolic syndrome. A disorder referred to as insulin resistance is at the heart of the
metabolic syndrome. This represents the inability of insulin to function correctly in target cells like muscle
and fat. In this project we are attempting to undertake a large scale effort to understand the complex circuitry
that gets turned on within cells when they become exposed to insulin. This project involves a collaboration
between the Garvan Institute and the University of New South Wales Mass Spectrometry Facility allowing us
to bring a combination of very sophisticated technologies to bear on this very significant health care problem.
This project will provide major new insights into our understanding of insulin action yielding new possibilities
for therapeutic development.
Research achievements (from final report):
The output of a biological system is an integrated response of numerous finely tuned regulatory events
involving millions of components. Large-scale studies have begun to define the components. The challenge is
to ascertain how they cooperate in a living cell and how they respond to perturbation. The metabolic system is
ideal as it adapts to environmental change and is relevant to many human diseases. Diabetes represents a
disease where this adaptive network becomes disrupted and the body is unable to cope with incoming nutrients
appropriately. The hormone insulin is at the heart of this regulatory circuit. It is secreted every time we eat to
coordinate the distribution of nutrients. One of the major facets of insulin's actions is to change the activity of
intracellular proteins by a modification called phosphorylation. To completely understand how this system
works it is essential to map all of these phoshorylation events. The goal of this proposal was to discover new
insulin regulated phosphoproteins in the hope of better understanding how insulin works. We developed novel
high resolution methods using a technique known as mass spectrometry to identify phosphoproteins. In
addition to identifying many of the known insulin regulated phosphoproteins we were able to identify 4 novel
proteins. We focussed our efforts on one of these known as Edc3 and this led us to unveil a completely new
pathway regulated by insulin. This will have major impact on future work in this area because this pathway
may have a lasting effect on the ability of cells to regulate metabolism.
Expected future outcomes:
Our work has revealed 4 new proteins phosphorylated by insulin. They control RNA repression, autophagy,
DNA methylation and cell movement. This will catalyse many new studies in each of these important areas.
Also we are now using this approach to map even more insulin-regulated events. This will lead to the most
comprehensive insulin regulated phosphomap.
Name of contact:
David James
Email/Phone no. of contact:
d.james@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 427644
Start Year: 2007
CIA Name: Dr Mark Cleasby
End Year: 2008
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Project Grants
Main RFCD: Endocrinology
Total funding: $340,400
Title of research award:
Role of Akt in insulin resistanceRole of Akt in insulin resistance
Lay Description (from application):
Type 2 diabetes represents an escalating global health problem. In Australia 7.2% of the population has
diabetes but an additional 16% have difficulty handling glucose, a problem which frequently precedes the
development of diabetes. Resistance of tissues to the action of insulin is an essential pre-requisite for type 2
diabetes but is also closely associated with the syndrome of obesity, dyslipidaemia, hypertension and
cardiovascular diseases (Syndrome X). Genetic factors combined with a high caloric intake and a sedentary
lifestyle are together responsible for the development of insulin resistance. From evidence that we and others
have obtained in recent years it is evident that an important mediator of insulin resistance is the amount of fat
which accumulates in muscle and liver. One way in which this abnormality seems to cause insulin resistance is
through interference with the normal signalling mechanism which causes increased glucose metabolism in
response to insulin. While experiments in cell systems have identified some candidate molecules that may be
involved, a need exists to demonstrate whether their dysregulation actually causes the insulin resistance in the
whole animal or human, or are merely associated with it. We will use novel techniques to manipulate the levels
of one of these candidate genes, protein kinase B/Akt, and its regulators in the muscle of rodents. We will then
examine the effects of these manipulations on insulin resistance using a combination of metabolic and
molecular tests. Building upon earlier work we will also determine how important different subtypes of this
molecule are for both normal and abnormal insulin-glucose metabolism, and whether these molecules or others
in the pathway are more important in insulin resistance. This knowledge will be invaluable in tailoring specific
novel treatment strategies or drugs for prevention or treatment of insulin resistance, and thus reducing the
burden of type 2 diabetes and Syndrome X.
Research achievements (from final report):
This NHMRC Project grant was terminated prematurely at the end of 2008 and was replaced by Program Grant
support (Grant 535921, "Pathways to Diabetes Prevention - Alleviating the type 2 diabetes burden in Australia"
James, D.E., Martin, J.L., Kraegen, E.W., Chisholm, D.J., Cooney, G.J., Ye, J.M, commencing in 2009).
Documentation regarding Research Achievments etc will be included in reporting for the Program Grant.
Expected future outcomes:
This Project Grant Support was a contributing factor to subsequent NHMRC Program Grant support from 2009
on., Documentation regarding Future Outcomes etc will be included in reporting for the Program Grant.
Name of contact:
Prof Edward Kraegen
Email/Phone no. of contact:
e.kraegen@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 427648
Start Year: 2007
CIA Name: Dr Shane Grey
End Year: 2009
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Project Grants
Main RFCD: Endocrinology
Total funding: $503,058
Title of research award:
The role of A20 in beta cell survivalThe role of A20 in beta cell survival
Lay Description (from application):
Diabetes mellitus is a disease reaching epidemic proprotions in the western world. Nearly one million
Australians have diabetes mellitus; many of these people will suffer debilitating secondary complications,
resulting in significant morbidity and mortality at considerable social and economic cost. Complications
include heart attack, stroke, kidney disaease, blindness and limb amputation. There are two forms of diabetes
(type I and type 2), and though there are considerable differences in their etiology, both forms result in an
inability of the body to control blood sugar levels. Beta cells release the hormone insulin, which regulates
blood sugar levels. Current knowledge suggests that a loss of beta cell mass is important for both diseases. For
type I diabetes the beta cells are destroyed by the immune system. Though for type 2 diabetes the causes are
less clear, it is apparent that the beta cells are dying. Our research is focused on understanding the molecular
pathways that control beta cell survival and regulate their death. Such knowledge would help us understand the
complex processes leading to the development of diabetes. Furthermore, we could use this knowledge in the
design of genetic engineering strategies to create 'death-defying' beta cells, as a potential therapeutic strategy
for the treatment of diabetes.
Research achievements (from final report):
Diabetes is an emerging health problem but still the causes and sequence of events leading to the development
of diabetes are poorly understood. Important in diabetes is the production of insulin by pancreatic beta cells.
Emerging evidence indicates that among other defects, a marked decrease in beta cell mass in conjunction with
an increased rate of beta cell death correlates with the development of type 2 diabetes mellitus (T2D). The how
and why of beta cell loss is not well understood. In this research we have uncovered some of the genetic clues
that govern the how and why of beta cell death. We hypothesize that loss of these genes may contribute to the
failure of beta cell compensation and the onset of T2D, conversely, enhancing the expression of these genes
may improve both beta cell survival and function - providing a possible new way to prevent or reverse diabetes
Expected future outcomes:
This research has contributed new understandings regarding the genes that control how beta cells die. Future
studies building upon this work may lead to new treatments for diabetes. One application for this research may
be to use the disovered genes to make beta cells resistent to dying and thus transplan these 'death-defying' beta
cells to treat diabetes - e.g. type 1 diabetes.
Name of contact:
Shane T Grey
Email/Phone no. of contact:
s.grey@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 427695
Start Year: 2008
CIA Name: A/Pr Shane Grey
End Year: 2012
Admin Inst: Garvan Institute of Medical Research Grant Type: International Collaborations
Main RFCD: Endocrinology
Total funding: $3,070,136
Title of research award:
Beta cell mass in Type 1 diabetes mellitus and islet transplantationBeta cell mass in Type 1 diabetes mellitus
and islet transplantation
Lay Description (from application):
This research program will examine the cellular and molecular mechanisms underlying the loss of Beta cell
mass and function: During the pathogenesis of Type 1 Diabetes Mellitus (T1D); and Following islet
transplantation. Though these processes have traditionally been considered to be purely immune-mediated, it is
now clear that the response of the beta cell is critical to the final outcome of the auto-immune process and
response to therapeutic interventions. Thus the complex interactions between the cellular and soluble
constituents of the immune system, plus the effects of a deregulated metabolic milieu, are integrated at the beta
cell. This in turn activates a series of complex transcriptional programs in the beta cell that together determine
the beta cells ultimate functional status and survival. We will use knowledge gained from studying these
processes to drive the development of novel therapeutic targets and strategies to improve the success of
immune-based and transplantation-based therapies.
Research achievements (from final report):
This research program was deliberately designed to focus on fundamental issues in contemporary T1D
treatment, where the expertise of the team was concentrated. It has shed new light on the processes of beta cell
failure and loss during the development of T1D and following islet transplantation. Knowledge gained from the
Program has direct relevance to clinically important areas, including the use of immuno-therapy and islet
transplantation for the treatment of T1D but also new discoveries that have enhanced our understanding of beta
cell failure in diabetes in general. As the work progresses towards clinical development in future programs,
considerable intellectual property (IP) is likely to emerge, particularly new IP related to stand alone or
adjunctive therapies for treatment of T1D.
Expected future outcomes:
Knowledge gained will be used to drive the development of novel therapeutic targets and strategies to improve
the success of immune-based and transplantation-based therapies.
Name of contact:
??Allison Heather???
Email/Phone no. of contact:
a.heather@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 481300
Start Year: 2008
CIA Name: A/Pr Jenny Gunton
End Year: 2010
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Project Grants
Main RFCD: Endocrinology
Total funding: $362,304
Title of research award:
The Role of Hypoxia Inducible Factor 1a in Beta-Cell Function and DiabetesThe Role of Hypoxia Inducible
Factor 1a in Beta-Cell Function and Diabetes
Lay Description (from application):
HIF1a is a gene which our preliminary data shows is needed for normal beta-cell function and insulin secretion.
When beta-cells cannot release enough insulin, blood sugar levels rise, and diabetes develops. This research
plan will look at the effects of deletion of HIF1a and of increasing HIF1a to see how this affects function of
beta-cells and / or diabetes development. This work may show that HIF1a is a potential therapeutic target for
the treatment of diabetes in humans.
Research achievements (from final report):
The ideas which led to the grant were confirmed. HIF-1a does appear to play an important role in beta-cell
function and insulin secretion in type 2 diabetes. , This led to a paper published in the Journal of Clinical
Investigation., We identified a drug which is a new therapeutic agent for the treatment of people with diabetes.
It is already in use in people with type 1 diabetes, and we are about to begin a trial in type 2 diabtes.
Expected future outcomes:
We expect at least 2 more papers from the grant in the near future, and will be starting a human clinical trial of
our drug for the treatment of type 2 diabetes.
Name of contact:
Jenny Gunton
Email/Phone no. of contact:
j.gunton@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 481303
Start Year: 2008
CIA Name: Prof Edward Kraegen
End Year: 2010
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Project Grants
Main RFCD: Endocrinology
Total funding: $604,793
Title of research award:
Adiponectin: key factors determining its metabolic actions and influences on insulin sensitivityAdiponectin:
key factors determining its metabolic actions and influences on insulin sensitivity
Lay Description (from application):
Diabetes and obesity are growing at alarming rates due to poor lifestyle and other factors. Adiponectin is a
complex molecule secreted by fat tissue that may help to burn fat in other tissues such as muscle and liver.
We investigate what are the main determinants of adiponectin action and how these might counteract defective
insulin action caused by excessive fat intake. This promises to provide new therapeutic targets to lessen the
metabolic derangement associated with diabetes and obesity,
Research achievements (from final report):
A hormone released from adipose tissue, adiponectin, has been implicated in counteracting insulin resistance, a
major perturbation in the Metabolic Syndrome and Type II Diabetes, although the mechanisms are not well
understood. One putative pathway influenced by adiponectin is the AMP kinase (AMPK) pathway. Our overall
objective was to determine the contribution of adiponectin oligimers, adiponectin receptors and adapter
proteins and AMPK in the ability of adiponectin to influence fuel metabolism and insulin action. Our work
focussed particularly on the role of the adiponectin receptors (AdipoR1 and AdipoR2), the important adaptor
protein APPL1, and on the extent of involvement of AMPK as a downstream component of adiponectin action.
Using in vivo gene manipulation techniques we demonstrated roles for AdipoR1 and APPL1 in skeletal muscle
glucose disposal, and their over-expression (OE) increased glycogen accumulation. APPL1 OE also increased
muscle glucose uptake and partially ameliorated high fat diet-induced insulin resistance. Furthermore insulin
signalling (IRS1) was activated by APPL1 OE and this finding provides a potential mechanism for the insulin
sensitising effect of adiponectin in muscle. Regarding liver, we demonstrated in collaboration with the AI
Assoc/Prof Aimin Xu, that APPL1 potentiates insulin-mediated inhibition of hepatic glucose production. These
studies, reported in Cell Metabolism, suggest that in liver APPL1 principally enhances insulin signalling by
blocking an inhibitory effect of Tribbles 3 (TRB3) on Akt activation. Thus, in both liver and muscle, our
studies of APPL1 suggest it is of physiological importance in enhancing insulin action.
Expected future outcomes:
Our findings provide potential mechanisms for the insulin sensitising effect of adiponectin in muscle and liver
and suggest the possibility of further insulin and AMPK-independent actions of adiponectin in regulating
glucose metabolism. This provides a positive impetus for investigating activation of adiponectin or its
downstream effectors in counteracting insulin resistance.
Name of contact:
Edward Kraegen
Email/Phone no. of contact:
e.kraegen@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 481315
Start Year: 2008
CIA Name: Prof Edward Kraegen
End Year: 2013
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Research Fellowships
Main RFCD: Endocrinology
Total funding: $944,892
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
I am a physiologist studying mechanisms of insulin resistance and investigating therapeutic approaches to
enhancing insulin action.
Research achievements (from final report):
Our aim was the development of a framework for understanding the pathogenesis of insulin resistance and for
optimising treatment. Specifically I continued to develop and use unique in vivo animal models to explore
mechanisms of insulin resistance. My contribution is based on pioneering in vivo methodologies (eg rodent
glucose clamps to quantitate tissue-specific glucose and fatty acid fluxes) and molecular techniques (eg in vivo
electroporation) to manipulate proteins to test hypotheses concerning insulin action in muscle. We have now
clarified roles of over ten key proteins and results published. For example the desirability of reducing muscle
cytosolic lipid accumulation to enhance insulin action was highlighted in this work. This opens the way for
new therapeutic approaches to counteract defective muscle insulin action., The AMPK molecule is involved in
muscle nutrient regulation particularly during exercise. We studied interventions leading to AMPK
suppression, implicated in defective muscle insulin action, using a model of nutrient oversupply to muscle
(chronic glucose infusion). This model was also applied to the sirtuins (eg SIRT1) that interact with AMPK in
some metabolic effects. Dr Amanda Brandon, a senior member of my group, has investigated effects of
silencing muscle SIRT1 and manuscripts are in preparation. Knowledge of muscle AMPK regulation could
lead to new therapeutic directions, based in part on simulating the beneficial effects of exercise. , Lastly we
pursued a productive Shanghai collaboration to identify antidiabetic drugs from traditional sources. We have
identified several molecules, (eg triterpenoid derivatives acting as novel AMPK activators) with possible
therapeutic potential.
Expected future outcomes:
It is expected that the research will open up new therapeutic possibilities for counteracting a major metabolic
disturbance of Type II diabetes, namely defective insulin action in muscle. This is at a time when there is a
pressing need for new drugs as problems have been found with a number of other commonly used clinical
drugs.
Name of contact:
Belinda Platzer
Email/Phone no. of contact:
b.platzer@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 481317
Start Year: 2008
CIA Name: Dr Carsten Schmitz-Peiffer
End Year: 2010
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Project Grants
Main RFCD: Endocrinology
Total funding: $504,097
Title of research award:
Dilinoleoyl phosphatidic acid as a novel mediator of insulin resistance in muscleDilinoleoyl phosphatidic acid
as a novel mediator of insulin resistance in muscle
Lay Description (from application):
We have identified a novel fat molecule in muscle which may play an important role in causing insulin
resistance during obesity, a major factor in the development of Type 2 diabetes. We will now examine whether
depletion of this molecule, dilinoleoyl-phosphatidic acid, can improve insulin action in muscles and in obese
mice, and investigate the mechanisms by which it may act. This work may indicate new strategies for the
treatment of diabetes.
Research achievements (from final report):
Insulin resistance in skeletal muscle is a major characteristic of Type 2 diabetes, and is strongly linked to
increased fat availability, although the mechanisms involved are not well understood. This project examined
the role of specific lipid mediators in the generation of insulin resistance caused by different high fat diets and
whether inhibition of enzymes involved in their accumulation in muscle could improve insulin action. We
showed that although different dietary fatty acids had been associated with distinct inhibitory mechansims in
cultered cells or acute in vivo models, oversupply of both saturated or unsaturated fatty acids in fat-fed mice
both caused the content of a particular intermediate, ceramide, to increase in muscle. Furthermore, ceramide
accumulation was best prevented using the anti-inflammatory agent lisofylline, rather than myriocin, an
inhibitor of ceramide biosynthesis, which agreed with the more potent effect of lisofylline in improving
gluucose homeostasis. This is the first indication that lisofylline could be used to treat Type 2 diabetes in
humans. Finally, lipidomic analysis of muscle by mass spectrometry revealed that changes in specific ceramide
species, rather than the most abundant forms, correlated ewith changes in insulin sensitivity, which suggests
that inhibition of specific ceramide synthases may represent a more targeted approach to the treatment of
insulin resistance. These findings were published in the specialist journal Endocrinology.
Expected future outcomes:
The potential use of lisofylline to treat diabetes has led to a research collaboration with Diakine Therapeutics,
Inc. which hold the IP on this drug and its orally-available derivatives. We will be investigating the use of these
compounds to improve insulin resistance in further studies. In addition we are determine the contribution of
different ceramide synthases which represent novel targets.
Name of contact:
Carsten Schmitz-Peiffer
Email/Phone no. of contact:
c.schmitz-peiffer@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 481329
Start Year: 2008
CIA Name: A/Pr Gregory Cooney
End Year: 2008
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Project Grants
Main RFCD: Endocrinology
Total funding: $169,695
Title of research award:
The role of muscle fatty acid oxidation in regulating intramyocellular lipid accumulation.The role of muscle
fatty acid oxidation in regulating intramyocellular lipid accumulation.
Lay Description (from application):
Obesity and the subsequent accumulation of fat in muscle leads to reduced insulin action and an increased risk
of type 2 diabetes. This project will investigate the metabolic processes that influence fat accumulation and
oxidation primarily in skeletal muscle, the tissue responsible for most fuel utilization in the body. This
information will help design therapeutic strategies to prevent the development of type 2 diabetes.
Research achievements (from final report):
The work conducted so far on this project clearly shows that increasing fat oxidation doesn't necessarily mean
that there will be fat loss from the body. Body fat can only be lost if energy expenditure exceeds energy intake.
Therefore an increase in fat oxidation without an increase in energy expenditure or decrease in energy intake
cannot lead to weight loss. Altering fat oxidation via AMPK activation might be beneficial to a particular tissue
but there is no evidence from this study that activation of AMPK leads to weight loss.
Expected future outcomes:
Understanding of the fact that increased use of fatty acids for energy is not necessarily linked to reduced fat
content (or weight loss).
Name of contact:
Gregory Cooney
Email/Phone no. of contact:
g.cooney@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 481330
Start Year: 2008
CIA Name: Prof David James
End Year: 2008
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Project Grants
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $265,970
Title of research award:
Regulation of Energy ExpenditureRegulation of Energy Expenditure
Lay Description (from application):
The incidence of obesity is increasing alarmingly throughout the world. In this proposal we aim to explore one
side of the energy equation - energy expenditure. We will conduct a series of detailed studies in genetically
modified mice to examine the role of the brain versus muscle in whole body energy expenditure. These
studies have significant implications for therapeutic management of Type 2 diabetes and obesity.
Research achievements (from final report):
We have recently obtained floxed c-Cbl mice from Ozgene and we are in the process of crossing them with
whole body Cre animals to verify the previously described phenotype. , We have already obtained ACC2
floxed animals and crossed these to whole body Cre's. These animals have been phenotyped and surprisingly
do not exhibit a lean phenotype. This is a very important observation that we have recently submited for
publication., We have recently obtained floxed ACC1 mice and are preparing to cross these to whole body
Cres.
Expected future outcomes:
These studies will provide a more detailed mechanistic view of how whole body energy is controlled and the
role of substrate switching in this phenomenon. .
Name of contact:
Greg Cooney
Email/Phone no. of contact:
g.cooney@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 481334
Start Year: 2008
CIA Name: Dr Jiming Ye
End Year: 2008
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Project Grants
Main RFCD: Therapies and Therapeutic Technology
Total funding: $115,155
Title of research award:
Therapeutical potential and mechanisms of action of new compounds from bitter melon for insulin resistant
statesTherapeutical potential and mechanisms of action of new compounds from bitter melon for insulin
resistant states
Lay Description (from application):
Type 2 Diabetes is a major disease with major economic and health implications. Current medications are
either insufficient or have serious adverse effects. Bitter melon is a vegetable in many countries including
Australia and it has been used as a traditional medicine to control blood sugar. This project intends to identify
the active ingredients from bitter melon for the treatment of type 2 diabetes. The results will indicate their
potential as new agents for this disease.
Research achievements (from final report):
Type 2 diabetes is a major disease which together with its complications of cardiovascular diseases, blindness,
kidney failure and amputation, causes significant burden for the public health and economy world wide
including Australia. This diseases is closely associated with insulin resistant states, particularly including
obesity and dyslipidaemia. However, current mediations for these diseases are either inadequte in their efficay
or have various adverse effects.This project was undertaken to identify anti-obese and anti-diabetic ingredients
and mechanisms involved from bitter melon, a vegetable which has been shown to possess benefits for diabetes
in traditional medicines in China and other Aisan countries. Our studies have idenditfied a number of active
compounds with potential anti-diabetic properties from bitter melon and some of these compounds were not
previously known. These newly-identified compounds are likely to have potential as new anti-diabetic drugs.
Additinally, they could be used as markers to indicate the sutiable type of bitter melon as a complementary
medicine/vegetable for the treatment of diabetes and obesity. Our data suggest that certain medicinal type of
bitter melon rich in these compounds can lessen body weight gain, lower hypertriglyceridemia and reduce fatty
liver in insulin resistant animal models. We believe that the research has considerable potential to eventually
lead to improved diabetes care.This grant has significantly faciliated the CI's capacity to extend our strategic
collaboration with Shanghai Institute of Materia Medica to explore additional new therapeutics for diabetes and
obesity.
Expected future outcomes:
Findings from this project grant are highly relevant to the trasnational research for new anti-diabetic
therapeutics now underway. For example, the information obained from this research has led us to explore
triterpenoids (~over 20,000 in the plant kingdom) for the development of new anti-obese and anti-diabetic
therapeutics.
Name of contact:
Dr. Jiming Ye
Email/Phone no. of contact:
j.ye@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 481335
Start Year: 2008
CIA Name: Prof Roger Daly
End Year: 2010
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Project Grants
Main RFCD: Protein Targeting and Signal Transduction
Total funding: $617,256
Title of research award:
Regulation of body composition and glucose homeostasis by the adaptor protein Grb10.Regulation of body
composition and glucose homeostasis by the adaptor protein Grb10.
Lay Description (from application):
Resistance to the hormone insulin underlies the development of Type 2 Diabetes. Loss of muscle mass in the
elderly contributes to insulin resistance. Recently we identified Grb10 as a new regulator of insulin action and
muscle mass. In this proposal, we aim to study how Grb10 affects development and growth of muscle and fat,
and the underlying molecular mechanisms. This may lead to new strategies for improving body composition
and treating the insulin resistance associated with Type 2 Diabetes.
Research achievements (from final report):
Skeletal muscle accounts for 40% of our body mass and is important not only for strength but also for
regulating our body glucose metabolism. Changes in muscle mass or the ability of muscle to respond
appropriately to circulating hormones contributes significantly to metabolic health. In obesity there is an
inappropriate 'spillover' of fats out of fat storage tissue and into muscle, as well as other tissues important for
insulin function. This leads to insulin resistance in the tissues and predisposes to diabetes. With ageing, there is
a loss of muscle mass and metabolic health is also compromised. Therefore, investigations into the mechanisms
regulating muscle mass are an important part of understanding whole body metabolism. This project examined
the role of a particular protein, Grb10, in reremained muscular throughout their life, and additionally possessed
reduced fat stores. This increase in muscle mass was due to an increase in muscle fibres. Furthermore, the
metabolic profile of the mice was improved. This work identifies Grb10 as a potential therapeutic target for
improving body composition and metabolism.
Expected future outcomes:
We expect to understand the mechanisms underpinning the muscle phenotype in Grb10-deficient mice and to
determine whether Grb10 regulates muscle wasting.
Name of contact:
Prof. Roger Daly
Email/Phone no. of contact:
r.daly@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 481340
Start Year: 2008
CIA Name: Prof Trevor Biden
End Year: 2010
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Project Grants
Main RFCD: Endocrinology
Total funding: $555,693
Title of research award:
Inhibition of glucose-stimulated insulin secretion by Protein Kinase C epsilonInhibition of glucose-stimulated
insulin secretion by Protein Kinase C epsilon
Lay Description (from application):
Type 2 diabetes is a chronic disease which occurs when the pancreas is unable to produce enough insulin for
the body to cope with rising blood glucose levels after a meal, and is strongly linked to obesity. We have
discovered that fat oversupply activates an enzyme in the pancreas causing defects in insulin release due to
glucose. Inhibiting this enzyme helps overcome diabetes, through poorly defined mechanisms that we aim to
clarify here. Our work could lead to new therapies for diabetes.
Research achievements (from final report):
We made great progress in identifying the mechanism of action of PKC? in ?-cells. We demonstrated that
PKC? acts mainly in the amplification phase, rather than initiation phase, of glucose-stimulated insulin
secretion. We have ruled out a host of potential mechanisms of action including alterations in pyridine
nucleotides and gating of calcium channels. Instead we found and published that PKC? impacted on the
deposition and subsequent mobilization of intracellular lipid stores. Technological investment in lipidomics
provided further breakthroughs in identifying the lipid stores involved, and revealed unexpected insights into
potential roles of PKC? in cholesterol metabolism. Our results provide a better understanding of the basic
mechanisms underlying glucose-stimulated insulin secretion as well as how these become dysregulated in Type
2 Diabetes. The second aim although initially delayed by technical issues, was also successfully accomplished.
We generated "floxed" PKC? mice and have mated these with CMV "Cre" mice to delete PKC? in all tissues of
the body. This was achieved but more important the phenotype of these animals, in terms of protection against
diet-induced glucose intolerance through enhanced insulin availability, completely recapitulated that of the
global knockout we had previously used. Not only does this confirm our hypothesis, but it also demonstrates
unequivocally that the "floxed" PKC? is working as intended and can now be used to investigate the role of
PKC? in specific tissues
Expected future outcomes:
Identification of the mechanism and site of action of PKCe and its evaluation as a therapeutic target for treating
Type 2 diabets
Name of contact:
Trevor Biden
Email/Phone no. of contact:
t,biden@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 481355
Start Year: 2008
CIA Name: A/Pr Amanda Sainsbury-Salis
End Year: 2011
Admin Inst: Garvan Institute of Medical Research Grant Type: Career Development Fellowships
Main RFCD: Medical Physiology not elsewhere classified
Total funding: $420,872
Title of research award:
Improving long-term weight loss by deactivating the famine reaction with molecular or lifestyle
meansImproving long-term weight loss by deactivating the famine reaction with molecular or lifestyle means
Lay Description (from application):
Dr Amanda Sainsbury-Salis’ research will clarify which hormones and natural brain chemicals interact in the
hypothalamus of the brain to control the famine reaction, the survival mechanism that slows your weight loss
when you are on a diet. By knowing precisely which natural chemicals mediate the famine reaction and how
they interact, it will be possible to weaken them by pharmaceutical and / or lifestyle means, thereby enabling
more people to reap the benefits of being lean and healthy.
Research achievements (from final report):
Non-surgical obesity treatments are ineffective for most, in part due to adaptive responses to energy restriction
that increase appetite & reduce metabolic rate. Not only do these adaptations oppose ongoing weight loss, they
may also adversely affect body composition via hormonal changes that favor abdominal fat accretion with loss
of muscle mass & bone. Thus, current obesity treatments may inadvertently increase the risk of metabolic
diseases such as atherosclerosis, as well as that of structural diseases such as sarcopenia & osteoporosis. My
long-term objective is to find ways to attenuate these adaptive responses so that more people can attain &
maintain a healthy body weight & composition. During this Career Development Award, my research team and
I identified brain pathways mediating these adaptive responses and their effects on fat, muscle & bone,
predominantly using transgenic mice at the Garvan Institute. For example - and as seen in the titles of
publications arising from this work - we demonstrated that Y4 receptors in the brain play a critical role in the
ability of the gut satiety hormone, pancreatic polypeptide, to reduce food intake in mice, as well as
demonstrating the pathways via which this occurs. This finding has important implications for the development
of anti-obesity treatments based on administration of agents that act similarly to pancreatic polypeptide. We
also demonstrated the role of a natural brain chemical called neuropeptide Y in the development of obesity in
response to estrogen deficiency. This has potential future implications for management of the weight gain that
many women experience in the peri-menopausal time of their lives.
Expected future outcomes:
I now hold 2 NHMRC project grants in order to apply this knowledge to clinical practice for more immediate
benefit to human health. Pending further NHMRC Research Fellowship funding, my team will determine the
consequences of adaptive responses to energy restriction on body composition in obese patients, and will also
test the utility of intermittent energy restriction for improved weight loss.
Name of contact:
Amanda Sainsbury-Salis
Email/Phone no. of contact:
amanda.sainsbury-salis@sydney.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 481356
Start Year: 2008
CIA Name: Dr Nigel Turner
End Year: 2011
Admin Inst: Garvan Institute of Medical Research Grant Type: Career Development Fellowships
Main RFCD: Cell Metabolism
Total funding: $380,559
Title of research award:
Mitochondrial Energy Metabolism and Insulin ActionMitochondrial Energy Metabolism and Insulin Action
Lay Description (from application):
Obesity and type 2 diabetes are two major health conditions associated with abnormal energy metabolism. In
this proposal I will investigate the role of important metabolic proteins in regulating energy expenditure and
insulin action in skeletal muscle and adipose tissue, two crucial tissues for whole-body energy metabolism.
These studies will provide critical insight into the factors leading to obesity and type 2 diabetes and will assist
in identifying possible therapeutic targets.
Research achievements (from final report):
The research conducted with the support of this award has further explored the relationship between
mitochondrial function and insulin action in different tissues. We have observed that specific types of dietary
fats have very different effects on metabolic pathways in different tissues, with medium chain fatty acids have
a particularly pronounced effect to increase nutrient oxidation in muscle. We have shown that directly
increasing the total capacity of mitochondria to oxidise nutrients can improve insulin resistance induced by a
high fat diet. Finally we have shown a potential role for a group of mitochondrial enzymes (sirtuins) in acutely
regulating mitochondrial function in response to alterations in nutrient availability.
Expected future outcomes:
Our investigations into the factors regulating mitochondrial nutrient oxidation in different tissues and have
identified a number of interesting proteins and pathways that may be potential drug targets for treating obesity
and type 2 diabetes.
Name of contact:
Nigel Turner
Email/Phone no. of contact:
n.turner@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 535917
Start Year: 2009
CIA Name: Dr Carsten Schmitz-Peiffer
End Year: 2011
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Project Grants
Main RFCD: Endocrinology
Total funding: $647,605
Title of research award:
The regulation of insulin action in liver and skeletal muscle by Protein kinase C epsilonThe regulation of
insulin action in liver and skeletal muscle by Protein kinase C epsilon
Lay Description (from application):
We have identified an enzyme, protein kinase C epsilon, which has a major negative impact on the control of
blood glucose levels. We will now examine the mechansisms by which it affects insulin action in liver and
muscle, two major target tissues of the hormone responsible for glucose disposal. This work is expected to
validate PKCepsilon or its downstream effectors as therapeutic targets in the treatment of the insulin resistance
which accompanies obesity and Type 2 diabetes.
Research achievements (from final report):
This project resulted in several novel findings regarding the role of the lipid activated enzyme protein kinase C
epsilon (PKC?) in generating the glucose intolerance associated with fat oversupply. Using mice lacking PKC?,
which were protected against the effects of a high fat diet, we demonstrated that this enzyme plays a key role in
liver in the initial adaptation to excess lipid availability and contributed to a reduction in insulin sensitivity. In
the longer term this enzyme also affects insulin secretion by the pancreas. Because insulin resistance defective
insulin release are key features of type 2 diabetes, this undescores the importance of targeting PKC? to treat the
disease. We also addressed the mechanisms by which PKC? affects insulin action and lipid metabolism in liver,
performing large scale protein and metabolic screens which identified downstream targets of the enzyme which
are now candidates for further research.
Expected future outcomes:
Examination of the candidate proteins identified in our mechanistic studies will lead to the further
identification of specific targets for intervention in Type 2 diabetes, as well as extend our understanding of the
mechanisms through which lipids interfere with normal insulin action.
Name of contact:
Carsten Schmitz-Peiffer
Email/Phone no. of contact:
c.schmitz-peiffer@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 535921
Start Year: 2009
CIA Name: Prof David James
End Year: 2013
Admin Inst: Garvan Institute of Medical Research Grant Type: Programs
Main RFCD: Endocrinology
Total funding: $11,200,494
Title of research award:
Pathways to Diabetes PreventionPathways to Diabetes Prevention
Lay Description (from application):
Type 2 diabetes (T2D) is threatening the health of this nation and if unchecked will cripple our health care
system. There are several problems: (1) The incidence of T2D is growing and we do not fully know why; (2)
T2D involves defective insulin action but how insulin works normally is still unclear; (3) much research in this
area is performed in laboratory cells or animals and the translation of this research to the human disease is yet
to be fully realised; and (4) current therapies and diagnostic markers for early disease prediction are
inadequate. Our goal is to make progress in each of these areas.
Research achievements (from final report):
This program enabled the team to branch into completely new areas and take risks that otherwise would not
have been possible through the Project scheme. Some of the achievements were , (1) Development of systems
biology approaches for examining metabolic disease. This involved establishment of new "omic" technology
particularly in proteomics for collecting very large data sets as cell and animal systems underwent transitions
from one state to another. As a function of this work we have established the most comprehensive maps of the
adipocyte phosphoproteome and the exercise regulated phosphoproteome in muscle and we are now
developing new methods to study the interaction between genes and the environment in the context of
metabolic disease. , (2) We solved the structures of key regulatory molecules that emanated from our systems
based analysis; , (3) We developed new methods for drug screening and target identification and have made
major inroads into identifying the mechanism of berberine action; , (4) We provided new insights into the
mechanism of insulin resistance by combining studies in cells, animals and humans. This has led us to question
current dogmas and branch into new terrain concerning the cause and possible approaches to thwart insulin
resistance. , (5) Finally we established valuable collaborations with a range of colleagues both in Australia and
overseas some of which, such as that with Steve Simpson at Sydney University have led to important insights
into the impact of nutrients on long term health.
Expected future outcomes:
Developing completely novel systems based approaches to study metabolic disease with a focus on identifying
signatures that define the gene-environment interaction ultimately leading to novel approaches for diabetes
prevention.
Name of contact:
David James
Email/Phone no. of contact:
d.james@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 535923
Start Year: 2009
CIA Name: Prof David James
End Year: 2012
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Project Grants
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $761,739
Title of research award:
The role of Rab GTPases and Rab GTPase activating proteins in Insulin ActionThe role of Rab GTPases and
Rab GTPase activating proteins in Insulin Action
Lay Description (from application):
Type 2 diabetes is one of the most rapidly growing diseases in the world. While lifestyle factors have
contributed to this we must understand how insulin works under normal circumstances to aid in the fight
against this disease. Our goal is to provide the molecular blueprint for one of insulin's major metabolic actions
that is disrupted in diabetes - glucose transport into muscle and fat cells. Over the past few years we have
begun to fill in the missing pieces to this puzzle.
Research achievements (from final report):
One of the major actions of insulin is to facilitate the delivery of nutrients like glucose to the appropriate places
in the body after a meal. This process is complex in part because glucose has to be ushered into cells via
specific transport proteins. While glucose transport occurs in all cells in the body, it is particularly unique in
muscle and fat cells because in between meals the glucose transporter here sits within the cell essentially
preventing glucose from entering. Insulin coordinates the delivery of the transporter to the membrane allowing
glucose to rush into the cell. This process is defective in type 2 diabetes. Our project focuses on a protein called
AS160 that plays an essential role in the switch that determines when the transporter should go to the
membrane. In between meals AS160 plays an active role in keeping the glucose transporter out of the
membrane. Insulin acts upon this molecule to switch off its negative effect allowing the transporter to move to
the membrane. Our recent findings indicate that AS160 also plays an important role in this process as well.
Expected future outcomes:
We will map how insulin brings about these molecular changes in AS160. Moreover, we will focus on what
role this molecule plays in disease. We have found that the level of this molecule is reduced in adipose tissue in
diabetes and this represents a new mechanism for impaired insulin action.
Name of contact:
David James
Email/Phone no. of contact:
d.james@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 535934
Start Year: 2009
CIA Name: Dr Cecile King
End Year: 2011
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Project Grants
Main RFCD: Autoimmunity
Total funding: $489,060
Title of research award:
The role of Interleukin-21 in the pathogenesis of autoimmune diabetesThe role of Interleukin-21 in the
pathogenesis of autoimmune diabetes
Lay Description (from application):
Interleukin-21 (IL-21) is a soluble protein that is produced by cells enabling them to communicate with other
cells. IL-21 helps cells to clear viruses and bacteria from the body. However, our studies show that IL-21 also
generates T cells that destroy beta cells and cause diabetes. IL-21 is produced at abnormally high levels in an
important murine model of spontaneous type-1 diabetes (T1D) and if we block IL-21 we prevent diabetes. This
projects' aims assess IL-21 as therapeutic target for T1D.
Research achievements (from final report):
Tissue types have their own individual molecular signatures. If tissue from one individual is transplanted into
another individual, the "mis-matched" tissue is rapidly rejected by the immune system. This process is known
as allograft rejection and along with existing autoimmunity, poses a huge hurdle for successful islet
transplantation. Our study demonstrated that preventing IL-21 from accessing immune CD8+ T cells prevented
both the allo-rejection of islet cells from other strains of mice as well as the recurrence of the existing
autoimmunity that destroyed the islets in the first place.The cells that make IL-21 in the inflamed lesion of the
pancreas are also increased in the blood of Sjogrens patients, suggesting that IL-21-producing T cells are
important for the development of autoimmune diseases that affect the accessory organs of the digestive
system., Thus, neutralizing the effects of IL-21 could prevent both autoimmunity and allograft rejection of
islets-the two major hurdles to successful replacement of islet tissue in type 1 diabetes. This reagent worked as
well in our model as drugs that are currently in clinical trials for islet transplantation. If this approach works in
people as it has in mice, then they would only have to take the drug for a brief time-window after surgery and
the transplant would be fine for life., , These findings are relevant to understanding the chronic inflammation in
autoimmune disease and to islet transplantation in human type 1 diabetes.
Expected future outcomes:
Neutralizing the effects of IL-21 could prevent both autoimmune and allograft rejection of islets-the two major
hurdles to successful replacement of islet tissue in type 1 diabetes. If this approach works in people as it has in
mice, then they would only have to take the drug for a brief time-window after surgery and the transplant
would be fine for life.
Name of contact:
Cecile King
Email/Phone no. of contact:
c.king@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 535949
Start Year: 2009
CIA Name: A/Pr Jerry Greenfield
End Year: 2012
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Project Grants
Main RFCD: Endocrinology
Total funding: $397,444
Title of research award:
Effect of oral glutamine on GLP-1 and insulin secretion and glycaemia in humans.Effect of oral glutamine on
GLP-1 and insulin secretion and glycaemia in humans.
Lay Description (from application):
Diabetes is an ever increasing problem with serious complications. We will investigate whether glutamine, one
of the most common amino acids (protein building blocks) in the body, has a beneficial effect on blood glucose
and insulin levels in the body in people who have type 2 (non-insulin dependent) diabetes. If so, glutamine
supplementation may represent a novel, cheap and palatable way of improving outcomes and preventing the
development of complications in people with type 2 diabetes.
Research achievements (from final report):
Insulin is secreted from the beta cells in the pancreas in response to a meal. In type 2 diabetes patients, the
insulin secretory response to a meal is impaired. Incretins are hormones secreted from the gut in response to a
meal that potentiate secretion of insulin from the pancreas. One such incretin is glucagon-like peptide-1 (GLP1). Increasing GLP-1 in the bloodstream in type 2 diabetes is a way of lowerring glucose levels. The amino
acid glutamine has been reported to increase secretion of GLP-1 from cells and, in a previous project, we
demonstrated that ingestion of glutamine increased GLP-1 release in obese and non-obese humans with and
without type 2 diabetes. Interestingly, the concentration of glutamine in the blood is low in type 2 diabetes
patients compared with healthy individuals. In one study, which has already been published, we found that
glutamine, when given with a low-fat meal to patients with type 2 diabetes (n = 15), decreased glucose
excursions in parallel with increases in insulin and GLP-1. In another study of 13 well-controlled type 2
diabetic patients, we demonstrated that glycaemic control was improved when glutamine was administered
twice daily for a month. This effect may be attributed to: (i) increasing the time to release nutrietnts from the
stomach to the blood stream; and/or (ii) a direct effect on the pancreas to secrete more insulin. We are currently
finalising a third study, in which we are investigating the effect of glutamine on insulin secretion in type 2
diabetes patients. In 2 other studies, performed with our collaborators in Adelaide, we have studied the effect of
glutamine on how fast the stomach empties and which part of the gut is important in mediating the effects of
glutamine in relation to GLP-1 secretion.
Expected future outcomes:
The expected outcome of the project is to demonstrate the naturally-occurring amino acid glutamine to be a
novel method of stimulating secretion of GLP-1 and perhaps, improving glycaemic control in type 2 diabetes.
Name of contact:
Jerry Greenfield
Email/Phone no. of contact:
j.greenfield@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 596802
Start Year: 2010
CIA Name: Dr Shu Lin
End Year: 2012
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Project Grants
Main RFCD: Neurosciences not elsewhere classified
Total funding: $461,598
Title of research award:
The role of pancreatic polypeptide in obesityThe role of pancreatic polypeptide in obesity
Lay Description (from application):
This study combines sophisticated molecular techniques with state-of-the-art biochemical and physiological
analyses to determine how gut hormones regulate satiety. By utilising unique conditional and germline KO
mice , this research will make highly original and internationally competitive contributions to the
understanding of the regulation of satiety and energy expenditure. Knowledge as to the causes of lack of satiety
will be of great benefit in the search for novel treatments for obesity.
Research achievements (from final report):
Obesity-associated cardiovascular diseases and diabetes are leading causes of death and are expected to
increase as the obesity epidemic worsens. A good understanding of the central integration of hunger and satiety
signals has been gained in recent times, however, therapies targeting modulation of food intake have not
proven effective in reducing body weight and benefits to weight loss are limited. The major scientific
achievements in the project provide valuable contributions to the development of potential therapeutics to
increase energy expenditure, likely being a more effective way for the treatment of obesity. I have successfully
mapped the neuronal pathway by injecting PP into brain, and then detect c-fos and related physiological
response in the animal models. Using several new developed neurological detective systems in our lab, I have
identified several neurotransmitters, such as POMC, BNDF and orexin in this pathway contributing to central
control of appetite and satiety. Finally, I have discovered these neurotransmitters expression in response to
different factors and p-ERK1/2 signalling transduction pathways involving in this regulative process. All of
these achievements related to this project and supported by this grant are evidenced in three publications as
bellows (one publication as the first author and two as a senior author):Lin S et al. PLOS One. 2009:
4(12):e8488Sainsbury A, … Lin S. Neuropeptides (2010) 44: 261-268.Yan-Chuan … Shu Lin. Obesity (2013
in press)
Expected future outcomes:
This project is to delineate the individual contributions of PP, PYY or PP/PYY in the coordinated regulation of
satiety and energy homeostasis, and to map the specific neuronal pathways involved to enable potential
identification of new drug targets for the development of novel anti-obesity agents.
Name of contact:
Dr Shu Lin
Email/Phone no. of contact:
s.lin@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 596828
Start Year: 2010
CIA Name: Prof Trevor Biden
End Year: 2012
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Project Grants
Main RFCD: Endocrinology
Total funding: $549,093
Title of research award:
Ceramide metabolism and ER stress in fatty-acid mediated destruction of pancreatic beta cellsCeramide
metabolism and ER stress in fatty-acid mediated destruction of pancreatic beta cells
Lay Description (from application):
The underlying cause of Type 2 diabetes is the failure of pancreatic beta cells to secrete sufficient insulin to
overcome the insulin resistance that is associated with obesity. Beta cell failre is associated with both defective
insulin secretion and loss of beta cell mass. This proposal focuses on the cellular mechanisms and stress
pathways whereby too much fatty acid promotes beta cell death.
Research achievements (from final report):
We elucidated fundamental mechanisms relating to the death of pancreatic beta cells in Type 2 Diabetes,
developing a link between alterations in certain forms of fatty acid metabolism and cellular stress pathways.
Expected future outcomes:
We have helped focus future research, particularly in indentifying novel lipid metabolites and mechanisms for
beta cell death.
Name of contact:
Trevor Biden
Email/Phone no. of contact:
t.biden@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: 1002514
Start Year: 2011
CIA Name: Prof Jenny Gunton
End Year: 2013
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Project Grants
Main RFCD: Medical Physiology not elsewhere classified
Total funding: $554,249
Title of research award:
The Role of Vitamin D in Beta-cell Function and DiabetesThe Role of Vitamin D in Beta-cell Function and
Diabetes
Lay Description (from application):
Vitamin D deficiency is common in Australia, with the success of the 'slip, slop, slap' campaigns. Low levels of
Vitamin D have been associated with diabetes. This grant aims to determine how vitamin D affects insulin
release and blood glucose levels.
Research achievements (from final report):
Vitamin D is important for the function and health of the pancreas, and of the insulin secreting cells in the
pancreas. Lack of vitamin D signalling in the pancreas increases damage to the pancreas. Lack of vitamin D
signalling in the beta-cells causes loss of normal insulin secretion and leads to diabetes in mice.
Expected future outcomes:
Further studies will follow to test whether vitamin D supplements improve beta-cell function.
Name of contact:
Jenny Gunton
Email/Phone no. of contact:
jenny.gunton@sydney.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1005819
Start Year: 2011
CIA Name: Dr Carsten Schmitz-Peiffer
End Year: 2013
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Project Grants
Main RFCD: Endocrinology
Total funding: $604,328
Title of research award:
Targeting ceramide metabolism to improve lipid-induced insulin resistanceTargeting ceramide metabolism to
improve lipid-induced insulin resistance
Lay Description (from application):
We have shown that the buildup of ceramide in muscle plays a key role in the inhibition of normal insulin
action when the body is exposed to excessive amounts of fat, which leads to poor control of blood sugar levels
and Type 2 diabetes. Using mass spectrometry we will now measure different ceramide types, to investigate
which contribute to defects in insulin action. We will also examine whether enzymes involved in ceramide
formation or degradation can be targeted to improve insulin responses.
Research achievements (from final report):
Our previous work indicated that obesity and fat oversupply to muscle cause defects in glucose metabolism due
to the accumulation of an inhibitory fat derivative known as ceramide. We tested whether the production of
ceramide could be changed in order to reverse the defects in glucose metabolism. We targeted the specific
enzymes which generate different subtypes of ceramide. Unexpectedly, blocking these enzymes did not
improve glucose handling but in some cases actually made it worse, indicating that they are not suitable targets
for therapy as commonly believed.
Expected future outcomes:
We and others will now examine different approaches to modulate ceramide production in order to improve
glucose metabolism.
Name of contact:
Carsten Schmitz-Peiffer
Email/Phone no. of contact:
c.schmitz-peiffer@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1009189
Start Year: 2011
CIA Name: Prof Trevor Biden
End Year: 2013
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Project Grants
Main RFCD: Endocrinology
Total funding: $555,893
Title of research award:
Mechanisms of PKCepsilon-dependent regulation of beta-cell lipid metabolism and insulin
secretionMechanisms of PKCepsilon-dependent regulation of beta-cell lipid metabolism and insulin secretion
Lay Description (from application):
Lipid loading of the insulin-producing beta cells of the pancreas contributes to the onset of Type 2 diabetes, but
the mechanisms are poorly understood. We have recently established that inhibiting the enzyme PKCe helps
restore insulin secretion. By better defining the cellular role of PKCe we will clarify how insulin secretion is
disrupted by fatty acids and cholesterol.
Research achievements (from final report):
We identified a completely unexpected role of the enzyme we were investigating, PKCe, in immune cells
which accounts for the beneficial effects of inhibiting this enzyme on insulin secretion. Thus the mechanism is
indirect, and not mediated by a function intrinsic to the pancreatic beta cells themselves. This was very
suprising, but now ties our work into a much broader area concerning how beta cell function is inhibited by the
immune system in the context of Type 2 diabetes. This work thus has relevence to elaborationg the
mechanisms underlying this dysfunction, and potentially also in identifying molecular targets for therapeutic
intervention in the disease.
Expected future outcomes:
Our myeloid studies will help define novel mediators of inflammatory beta cell dysfunction, as those currently
implicated do not appear to account for our phenotype. This has great future potential for identifying new
treatments for Type 2 diabetes. The lipase studies should elucidate novel intracellular pathways for amplifying
glucose-stimulated insulin secretion, and their physiological roles.
Name of contact:
Trevor Biden
Email/Phone no. of contact:
t.biden@garvanl.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1009794
Start Year: 2011
CIA Name: Prof Gregory Cooney
End Year: 2013
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Project Grants
Main RFCD: Endocrinology
Total funding: $624,961
Title of research award:
The role of Grb10 in the regulation of muscle metabolismThe role of Grb10 in the regulation of muscle
metabolism
Lay Description (from application):
Obesity increases the risk of metabolic diseases such as type 2 diabetes. Muscle is a key tissue for balancing
whether energy is used or stored as fat and as we age, muscle mass normally decreases making maintaining a
healthy metabolism even more difficult. We have discovered that removing the Grb10 gene from mice
produces bigger muscles. This project will investigate the mechanisms of this effect so that strategies can be
developed to regulate muscle mass and improve metabolic health
Research achievements (from final report):
Our work has highlighted for the first time a developmental role for Grb10 in regulating muscle formation. In
addition, we have identified that ours is the first described hypermuscular mouse model with hyperplasia but
not concurrent hypertrophy. Therefore, our model is of great value to the study of muscle formation in general,
and elucidating the mechanisms underlying this complex process. Published in FASEB J. 2012 and chosen for
illustration of front cover of Journal.
Expected future outcomes:
Closer invesitgations of the mechanisms via which Grb10 influences muscle fibre number and muscle insulin
action could lead to the development of agents that will influence muscle growth and metabolism for
therapeutic benefit.
Name of contact:
Gregory Cooney
Email/Phone no. of contact:
g.cooney@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1011388
Start Year: 2011
CIA Name: Dr Jae Ho Cho
End Year: 2013
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Project Grants
Main RFCD: Cellular Immunology
Total funding: $418,658
Title of research award:
Influence of TCR signals from contact with self-MHC ligands on naive T cell survivalInfluence of TCR signals
from contact with self-MHC ligands on naive T cell survival
Lay Description (from application):
A diverse repertoire of naive T cells constitutes a critical part of the adaptive immune system and protects hosts
from various infections and cancer. T cells are stably maintained at a constant number in the periphery by
mechanisms that are not clearly understood. This proposal will shed light on how the immune system preserves
a diverse naïve T cell pool able to respond against various foreign antigens, while preventing their harmful
auto-reactivity to self antigens.
Research achievements (from final report):
Generation of specific immunological memory leads to enhanced responses to pathogens but does not interfere
with tolerance to self components. For T cells, such self/non-self discrimination is established during thymic
selection directed to self peptides bound to major histocompatibility complex molecules (self-pMHC). As the
result of positive and negative selection plus T-cell receptor (TCR) "tuning", T-cell export from the thymus is
limited to cells with weak but significant TCR affinity for pMHC ligands. Especially for CD8 T cells, selfpMHC contact elicits low-level TCR signals which, together with IL-7, upregulates Bcl-2 and promotes longterm T cell survival in interphase. Since TCR affinity for self-pMHC ligands varies for naïve CD8 T cells,
naïve cells bearing high affinity TCR for self would potentially be dangerous in autoimmunity. This notion
similarly applies to memory CD8 T cells. One explanation for reducing the potential risk of autoreactivity by
these cells is to reduce their TCR sensitivity. As a main achievement of this research award, we discovered
that, after thymic selection, naïve and memory T cells display sequential TCR desensitisation. This finding
applies to various early TCR signalling events and as a mechanism, correlates with increase of a protein
tyrosine phosphatase, CD45, and reciprocal decrease of a TCR-proximal signalling molecule, activated LCK.
The inhibitory effect of high CD45 on naïve and memory T cells may reduce TCR reactivity to self-pMHC and
thereby guard against autoimmune disease, while enhanced sensitivity to cytokines, notably IL-2, these cells
give strong proliferative responses, thus ensuring robust responses to foreign antigens.
Expected future outcomes:
Our discoveries that specificity for self MHC ligands appears to change when naïve T cells switch to memory
cells through modulation of CD45 levels will provide better understanding how peripheral T cells maintain
their quiescence state to self ligands and have significant implications for designing effective approaches
against autoimmune diseases.
Name of contact:
Jae-Ho Cho
Email/Phone no. of contact:
j.cho@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1037540
Start Year: 2012
CIA Name: Dr Guang Yang
End Year: 2013
Admin Inst: Garvan Institute of Medical Research Grant Type: International Exchange Early Career
Fellowships
Main RFCD: Medical Biochemistry: Proteins and Peptides (incl. Medical Proteomics)
Total funding: $224,324
Title of research award:
A novel mechanism involved in the regulation of mTOR signaling by insulin in adipocytesA novel mechanism
involved in the regulation of mTOR signaling by insulin in adipocytes
Lay Description (from application):
I am a cell biologist with a major interest in insulin action and diabetes. I aim to determine the role of insulin as
a nutrient sensor in fat cells. This is very important as it is becoming evident that fat cells somehow sense the
amount of nutrients in the circulation and then relaying this information to other tissues including the brain.
This system may play an important role in the development of obesity. However, the molecular details of the
nutrient sensor remain poorly defined.
Research achievements (from final report):
The mechanistic target of rapamycin complex 1 (mTORC1) pathway can respond to diverse environmental
cues and controls many processes that generate or use large amounts of energy and nutrients. The deregulation
of mTORC1 occurs in many human diseases, including cancer, obesity, type 2 diabetes and neurodegeneration.
Our work revealed a novel mTORC1 regulatory pathway which can coordinate the effects of different stimulis
and it is the first time to identify a molecular acting as an intersection of growth factors and nutrients signalling
in mTORC1 regulatory pathway. This ambitious project will revolutionise our thinking about growth
factors/nutrients action in mTOR signaling and this novel understanding of the mTOR pathway will pave the
way for novel approaches to old diseases.
Expected future outcomes:
If we could figure out the detailed mechanism of this novel regulatory pathway, it could became a new
therapeutic target of mTOR related diseases in the future.
Name of contact:
Guang Yang
Email/Phone no. of contact:
g.yang@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 597439
Start Year: 2010
CIA Name: Prof Mark von Itzstein
End Year: 2012
Admin Inst: Griffith University
Grant Type: NHMRC Project Grants
Main RFCD: Structural Biology (incl. Macromolecular Modelling)
Total funding: $636,602
Title of research award:
Glycan specificity and dependence in rotavirus host cell invasionGlycan specificity and dependence in
rotavirus host cell invasion
Lay Description (from application):
Rotavirus is a global pathogen that causes acute gastroenteritis resulting in dehydration and high levels of
infant mortality. Annually, infections cause 138 million cases of infantile gastroenteritis and an estimated
average of 600,000 deaths. Within Australia ~10,000 children under 5 yrs old are admitted to hospital annually
with severe rotavirus-induced diarrhoea. This project will investigate the role of carbohydrates in rotavirus
infection to help design new vaccines and inhibitors.
Research achievements (from final report):
Through a systematic multi-technique investigation of ganglioside and other glycan-VP8* interactions at the
protein and virion level our aims were directed at the characterization of rotavirus (RV) specificity for host cell
carbohydrates and construct a RV VP8*-glycan interaction map (VP8* glycointeractome). Specifically we
used site-directed mutagenesis of VP8*, glycan array studies, structural biology techniques and cell-based
virological assays to: (1) Determine the exact binding sites on the carbohydrate-recognising domain (VP8*) for
natural oligosaccharide receptors, provide atomic details of these interactions and characterise glycan-binding
(2) Define the carbohydrate-recognising VP8* region(s) common to representative RV strains that are critical
for ligand binding, and assess their influence on RV host specificity and (3) Extend these glycointeractome
studies to analyse the role of sialylganglioside GM1 in determining the mode of human RV entry into cells.
Pleasingly our studies showed specific glycan recognition by human RV Wa VP8* and other RV VP8*.
Cholera Toxin B subunit (CTB) inhibited RV-3, RV-5 and UK infection. This function was mapped to RV
VP4 using reassortant rotaviruses. Most other animal rotaviruses were unaffected by CTB. These results have
enabled us to provide a structure-based hypothesis that accounts for rotavirus discrimination between Nacylneuraminic acid forms and shows that the determined carbohydrate specificities of these VP8* exhibit a
direct correlation with those demonstrated by infectious virus.
Expected future outcomes:
The outcomes of this project have now set the scene for an extended investigation into the importance of
ganglioside recognition in rotavirus infection. This extended study will further inform the discovery of novel
drugs and vaccines to treat and prevent rotavirus infection.
Name of contact:
Prof Mark von Itzstein
Email/Phone no. of contact:
m.vonitzstein@griffith.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 145702
CIA Name: Prof Patrick Sexton
Admin Inst: Howard Florey Institute
Main RFCD: Basic Pharmacology
Total funding: $392,037
Start Year: 2001
End Year: 2003
Grant Type: NHMRC Project Grants
Title of research award:
G-protein receptor interactionG-protein receptor interaction
Lay Description (from application):
The maintenance of optimum health and function of living cells, and consequently that of the whole organism,
depends on how cells respond to a multitude of physical and chemical stimuli that continually bombard them.
The majority of the chemical stimuli such as hormones and neurotransmitters impart their actions not by
directly entering the cell, but instead, by binding to a specific receiver protein at the cell surface called a
receptor. In one class of such receptors called G protein coupled receptors, the transmission of the message to
the interior of the cell involves yet another protein called G protein. It is extremely important to unravel how
each of these components, the stimulating agent, the receptor and G protein, works in order to understand how
the cells respond to various chemical signals. To make this process even more complex, it was recently shown
that another newly discovered group of proteins called receptor activity modifying proteins (RAMPs) too play
a critical role in some systems. Understanding what actually is the role of these new players, and how they
team-up with the other components to elicit a specific response to a chemical stimulus, forms the basis of this
proposal. Such knowledge is central to the unraveling of the processes involved in the maintenance of health,
abnormalities that lead to disease, and in the development of new treatments.
Research achievements (from final report):
This work led to new understanding on the importance of accessory protein interaction with G protein coupled
receptors (the major sites of pharmaceutical drug interaction). Further work will include examining the
mechanisms that underlie RAMP-induced changes in signalling. This work is important for understanding how
this important class of receptors function.
Expected future outcomes:
N/A
Name of contact:
N/A
Email/Phone no. of contact:
N/A
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: 1006517
CIA Name: Prof David Power
Admin Inst: Institute for Breathing and Sleep
Main RFCD: Nephrology and Urology
Total funding: $524,820
Start Year: 2011
End Year: 2013
Grant Type: NHMRC Project Grants
Title of research award:
Regulation of SPAK by AMPK links salt reabsorption to energy metabolismRegulation of SPAK by AMPK
links salt reabsorption to energy metabolism
Lay Description (from application):
Excessive salt and energy intake have emerged as major features of the unhealthy fast-food culture. Salt
promotes high blood pressure, whereas high energy intakes increase obesity and diabetes. In this study, we aim
to determine how energy availability and salt handling are linked in the kidney. This research will lead to new
ways to treat high blood pressure by limiting salt reabsorption in the kidney.
Research achievements (from final report):
High blood pressure, or hypertension, remains a significant health problems throughout the world. High salt
uptake by the kidney is one of the most important factors leading to high blood pressure. This uptake is done
through a series of salt transporters in the kidney. We have demonstrated that obesity leads to a change in the
activity of a kidney salt transporter called NKCC2, so increasing its ability to retain salt. The protein that
increases the activity of the salt transporter is known as a protein kinase. This new interaction between a
protein kinase and NKCC2 in the kidney leads to high blood pressure in obesity. We hope that further study of
this pathway will lead to new treatment approaches in people with high blood pressure, especially when it is
caused by obesity. Obesity can be viewed as a disorder of excess energy supply so, in another part of this
study, we have examined the effect of levels of energy on salt uptake by the kidney. We found that proteins
which sense energy levels in cells of the kidney also influence NKCC2, so providing a route for levels of
energy within the kidney to control salt uptake. These studies are helping to redefine the way that we view the
effect of energy metabolism and diseases of energy excess, especially obesity, on salt uptake and high blood
pressure.
Expected future outcomes:
These studies demosntrate that there are likely to be multiple pathways to high blood pressure. Identifying
these in the individual patient may lead to the use of specific therapy for each person who has high blood
pressure, rather than the trial and error approach that currently exists.
Name of contact:
David Power
Email/Phone no. of contact:
david.power@austin.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 233200
CIA Name: Prof Paul Zimmet AO
Admin Inst: International Diabetes Institute Inc
Main RFCD: Epidemiology
Total funding: $2,677,855
Start Year: 2003
End Year: 2007
Grant Type: NHMRC Project Grants
Title of research award:
A five year follow-up of people with Type 2 diabetes & other states of glucose intolerance and associated risk
factorsA five year follow-up of people with Type 2 diabetes & other states of glucose intolerance and
associated risk factors
Lay Description (from application):
The Australian Prospective Diabetes Study (APDS) is a 5 year follow-up study established to examine the
natural history of diabetes and its complications, as well as heart disease and kidney disease. It is a follow-up
to the recently completed AusDiab study and addresses some of the important gaps that exist nationally and
internationally in the understanding of the burden of Type 2 diabetes and related problems. AusDiab found
that 1 in 4 Australians aged 25 years and over has either diabetes or a condition of impaired glucose
metabolism (this condition is associated with substantially increased immediate risk of heart disease as well as
increased risk of diabetes in the future). This new study-APDS, will be the first Australian and indeed
international study of its type.We intend to invite 7000 out of the original 11,247 AusDiab sample to
participate. Participants who agree to take part in the follow-up study will be involved in 2 ways: 1. A 6-12
monthly contact with participants by telephone or mail to allow reporting of changes in health and utilisation of
health services.2. A 5 year biomedical follow-up survey. This will involve a survey team travelling around
Australia to test the participants for diabetes, heart and kidney disease and cardiovascular risk factors (e.g.
blood pressure and cholesterol). It will accurately define how many Australians are likely to develop diabetes
(as well as kidney and heart disease) in the future, and who is at highest risk. It is expected that outcomes from
this study will provide crucial information for both planning and testing public health policy and for the
appropriate allocation of resources including specific treatments of individuals and specific groups with or at
risk of Type 2 diabetes and its complications within the Australian population.
Research achievements (from final report):
This project (AusDiab) has had a major impact on our understanding of the burden of diabetes, obesity and
cardiovascular and kidney disease, as experienced across the population of Australia. In particular, it has
produced the first national estimates of the incidence of diabetes, obesity, chronic kidney disease and
hypertension. These figures have not only been described for the first time in Australia, but this study is one of
only a handful around the world to produce such figures for a national population. AusDiab has identified risk
factors for the development of diabetes, and described the pattern of weight change in the population over five
years. Furthermore, AusDiab has produced the first ever accurate figures relating pre-diabetes and diabetes to
the total burden of deaths due to cardiovascular disease, showing that two thirds of such deaths occur in people
whio had either diabetes or pre-diabetes within the previous five years. AusDiab has also allowed us to
estimate the risk of developing diabetes over a lifetime, and to examine how this might be affected in coming
decades by changes in the population's risk factor profile. Using the findings from AusDiab we have now
developed a screening tool (a 'tick test') that can be used by the general public and by health care professionals
to estimate an individual's risk of developing diabetes. This will allow people at risk of diabetes to be directed
into lifestyle programs aimed at preventing diabetes.
Expected future outcomes:
Further work will continue to be undertaken, examining the risk factors for diabetes, cardiovascular disease and
kidney disease, and looking at the impact that each of these conditions has on individuals and on society.
Name of contact:
Associate Professor Jonathan Shaw
Email/Phone no. of contact:
NHMRC Research Achievements - SUMMARY
jonathan.shaw@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 137811
CIA Name: Prof Alan Baxter
Admin Inst: James Cook University
Main RFCD: Autoimmunity
Total funding: $692,040
Start Year: 2001
End Year: 2005
Grant Type: NHMRC Project Grants
Title of research award:
Functional Genomic Analysis of NK and NKT Cell Immune Control of AutoimmunityFunctional Genomic
Analysis of NK and NKT Cell Immune Control of Autoimmunity
Lay Description (from application):
The major populations of white blood cells responsible for learned immunity to are the B cells, which make
antibody against microorganisms like bacteria, and the T cells, which kill virally infected cells and help B cells
produce antibody. The T and B cells occasionally attack the body s own tissues, resulting in autoimmune
disease. These diseases include type 1 diabetes, lupus, and anaemia, and collectively represent the third
commonest cause of morbidity and mortality in humans. The major reason why autoimmunity occurs is
thought to be due to a failure in the mechanisms responsible for controlling such unwanted responses. Two
other populations of white blood cells are involved in this regulation, termed NK and NKT cells, each of which
release important cell hormones. The current project is designed to test whether defects in NK and NKT cells
lead to autoimmune disease. For this purpose a special strain of mice (NOD mice) will be used. The reasons for
their selection are: 1) they are highly susceptible to a range of autoimmune diseases including diabetes, lupus
and anaemia, and 2) we and others have found that they are deficient in both NK and NKT cells. The
proposed experiments are divided into two groups, one designed to characterise the nature of the defects in
these cells and the other to identify the genes responsible for them. In this way it should be possible to shed
light on the genetic basis of autoimmune diseases in general. The approach to be used involves sophisticated
techniques of genetic analysis, which require production of special congenic lines of mice. These mice are
like NOD mice but carry in addition to NOD genes genetic regions from a non-autoimmune strain with the
potential to correct the defects in NK and NKT cells. In this way, it should be possible to pinpoint the disease
susceptibility genes involved in causation of autoimmunity and to work out how they affect NK and NKT cells.
Research achievements (from final report):
The aim of this project was to characterise the genes that control the numbers and function of lymphocytes of
the innate immune system, termed NK and NKT cells. A series of congenic mouse stocks were generated and
analysed. These studies provided an improved understanding of the regulation of these cell types and provided
the basis of ongoing studies to identify and sequence the genes involved.
Expected future outcomes:
Cloning and sequencing of immune control genes.
Name of contact:
Alan Baxter
Email/Phone no. of contact:
Alan.Baxter@jcu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 226911
CIA Name: Prof Alan Baxter
Admin Inst: James Cook University
Main RFCD: Immunogenetics
Total funding: $235,500
Start Year: 2003
End Year: 2005
Grant Type: NHMRC Project Grants
Title of research award:
Functional genomic analysis of the NKT cell control locus Nkt1 and the Bana3/Babs2 lupus susceptibility
locusFunctional genomic analysis of the NKT cell control locus Nkt1 and the Bana3/Babs2 lupus susceptibility
locus
Lay Description (from application):
The major populations of white blood cells responsible for "learned" immunity are the B cells, which make
antibody against microorganisms like bacteria, and the T cells, which kill virally infected cells and help B cells
produce antibody. The T and B cells occasionally attack the body's own tissues, resulting in autoimmune
diseases such as lupus, in which antibodies are deposited in the tissues causing inflammation in organs such as
the brain, skin and especially the kidneys. Another population of white blood cells, termed NKT cells, plays an
important role in keeping the T and B cells in check, and we have found that these cells are deficient in an
inbred mouse strain, NOD mice, which develop lupus after exposure to a particular type of bacteria, called
mycobacteria. We have found that one of the major genes conferring susceptibility to lupus in these mice lies
in the same genetic region as the major gene controlling NKT cell numbers, raising the possibility that the
deficiency in NKT cells in this strain predisposes it to developing lupus. The experiments proposed for this
project are divided into two groups. The first group test whether increasing NKT cell numbers by either
injecting them, or else transferring genes that allow more to develop naturally, can affect the risk of developing
lupus. The second group of experiments examine the potential roles of two specific genes which are in the
genetic region of interest, and which we think might control both NKT cell numbers and lupus susceptibility.
The approach to be used involves sophisticated techniques of genetic analysis, such as the use of mutant mice
which carry genetic mutations near the relevant genes, and congenic mice, which are like NOD mice, but carry
in addition to NOD genes, genetic regions from a non-autoimmune strain.
Research achievements (from final report):
Congenic and mutant mouse lines bearing genes affecting risk of developing diabetes and lupus were produced
and analysed.
Expected future outcomes:
Improved characterisation of genetic control of FasL expression, a factor that may affect disease susceptibility.
Name of contact:
Alan Baxter
Email/Phone no. of contact:
Alan.Baxter@jcu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 279402
CIA Name: Prof Robyn McDermott
Admin Inst: James Cook University
Main RFCD: Epidemiology
Total funding: $1,493,700
Start Year: 2004
End Year: 2007
Grant Type: NHMRC Project Grants
Title of research award:
Follow-up study of Indigenous adults in north Queensland: Chronic diseases and sexual healthFollow-up study
of Indigenous adults in north Queensland: Chronic diseases and sexual health
Lay Description (from application):
This study aims to follow up a cohort of Indigenous adults in rural and remote north Queensland communities
who participated in the "Well Persons Health Check" (funded by OATSIH) during 1998-2000. Out of the 2,862
Indigenous participants, 2,503 (87.5%) agreed to have another Check in a few years time. A follow-up study is
proposed for the consenting WPHC participants (any any other adults who wish to participate). This study will
have 5 main objectives: 1. Estimate the incidence rate of chronic disease conditions (diabetes, renal disease,
CVD) and the main determinants of these in the north Queensland cohort (It is expected that Torres Strait
Islanders will have different patterns to Aborigines), 2. Estimate the change over a 5 year period in risk
factors and complications (including hospitalisations) of those with existing chronic conditions 3. At a
community level, evaluate the effectiveness of local interventions aimed at health improvement (e.g. one
community has drastically changed rules about alcohol availability, other communities have significantly
improved the supply of fresh fruit and vegeta4. Estimate whether the early detection of chlamydia and
gonorrhoea (using routine urine PCR testing) has lowered the community prevalence of bacterial STIs, and
bles, still others have commenced family savings programs which improve the availability of money over the
week and enable savings to buy fridges etc). 5. Evaluate the effectiveness of local health promotion programs
(e.g. tobacco control initiatives, healthy weight programs). The study will be undertaken in collaboration with
Apunipima Cape York Health Council, the Torres Strait Health Council and relevant local community
organisations. It will involve skills development for local Indigenous researchers and practitioners. Results will
be given back to communities and individuals, with opportunities for further planning.
Research achievements (from final report):
The Adult Health Check+ was a study that followed up Indigenous adults in 19 remote communities that had a
health check under the Well Persons Health Check (WPHC) program between 1998-2000. The purpose of the
study was to look at changes in health status that occurred since the Well Persons Health check. The project
commenced in 2004 and was completed in 2007. A total of 719 people or 40% of the participants targeted for a
follow up had a health check. 8% or 178 people who participated in the WPHC screen have passed away since
the WPHC study and 712 or 32% of people had moved away from the area. The study found:, o Ninety-nine
(99) new cases of diabetes , o One hundred (100) new cases of high blood pressure., o Fifty-five (55) new cases
of renal disease. , o
Younger people gained more weight
and had a greater increase in waist size than did older people. , o
The rate of smoking in the Adult
Health Check+ cohort is more than twice the Australian rate., o Over half of the people who said they drank
alcohol were risky drinkers., o
People increased their intake of
vegetables, but on average are still eating much less fruit and vegetables than is recommended for good health.,
o
Overall people have increased their
physical activity but a only about half are doing enough physical activity for good health., , These results will
help the individual participants make decisions about their own health and inform planning for service
development.
Expected future outcomes:
o
This research evidence will continue
to inform Indigenous health policy and chronic disease strategies for Queensland's remote communities, o
Feedback to individuals enables their
active participation in prevention and management of chronic and communicable diseases., o Two Indigenous
PhD students will base their studies on this research data.
NHMRC Research Achievements - SUMMARY
Name of contact:
Professor Robyn Mcdermott
Email/Phone no. of contact:
robyn.mcdermott@unisa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 279408
CIA Name: Prof Jonathan Golledge
Admin Inst: James Cook University
Main RFCD: Surgery
Total funding: $299,250
Start Year: 2004
End Year: 2006
Grant Type: NHMRC Project Grants
Title of research award:
Role of osteoprotegerin in protecting the diabetic aorta from aneurysm formationRole of osteoprotegerin in
protecting the diabetic aorta from aneurysm formation
Lay Description (from application):
Between 5% and 10% of men over the age of 60 years develop weakening of their main abdominal artery
(aorta) leading to slow dilation of the vessel. If this process continues long term the artery can burst resulting in
sudden death. At present the only treatment available for this problem is surgery, either open or minimally
invasive. Both these forms of treatment are associated with significant complications and unsuitable for some
patients. Thus the development of a drug treatment which can slow or halt the weakening and dilation of the
aorta would have great patient benefits'. Surprisingly patients with sugar diabetes are less likely to develop this
form of artery weakening. This important negative association may form the basis of discovering a new
medication to protect arteries from rupture. In this study we investigate the role of a recently discovered
protein in protecting the main abdominal artery from weakening in diabetics. This protein is of particular
interest for the following reasons: 1. It comes from a group of proteins believed to be important in artery
calcium build-up. 2. Artery calcium is common in patients with diabetes who are relatively protected from
aortic weakening. 3. It is being used for the treatment of bone weakening, appears to be safe in patients and
therefore is a potential therapeutic agent. We believe this work is an important step towards the development
of a successful medical treatment for artery weakening.
Research achievements (from final report):
Abdominal aortic aneurysm affects approximately 5% of the middle aged and elderly population and can result
in sudden death due to rupture of the main abdominal artery. In this project we have investigated the role of a
bone protein in artery weakening. By examining human biopsies, serum samples and experimental models we
have demonstrated a significant association of this bone protein in the presence, growth and functional changes
seen in artery weakening. The project thereby suggests a potential target for medical therapy for this condition.
Expected future outcomes:
Therapies aimed at bone proteins may have a role in the medical therapy of abdominal aortic aneurysm. Future
studies involving treatments which interfere with the presence of bone proteins need to be examined in models
of aortic aneurysm.
Name of contact:
Professor Jonathan Golledge
Email/Phone no. of contact:
jonathan.golledge@jcu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 379608
CIA Name: Prof Alan Baxter
Admin Inst: James Cook University
Main RFCD: Immunogenetics
Total funding: $891,984
Start Year: 2006
End Year: 2010
Grant Type: NHMRC Project Grants
Title of research award:
Genetic control of thymic NKT cell numberGenetic control of thymic NKT cell number
Lay Description (from application):
Autoimmune diseases result from a complex interaction between multiple genes and environmental factors.
Attempts to identify the genes involved have been largely unsuccessful because of this complexity. This project
has chosen to focus on a particular subset of the genes that cause type 1 (autoimmune) diabetes - the subset that
control a small population of regulatory white blood cells, termed NKT cells. The applicants have previously
shown that a mouse strain prone to diabetes, the NOD mouse strain, is deficient in NKT cells and if they are
replaced by transfusion, the mice are protected from disease. In selective breeding experiments, they have been
able to show that the deficiency in NKT cell numbers is genetic, and have localised the chromosomal positions
of these genes. Furthermore, they have produced specially bred lines of NOD mice that have normal copies of
these genes and increased numbers of NKT cells. This project aims to identify the genetic coding sequences
responsible for controlling numbers of NKT cells. It will use a combination of genetic mapping, specific
breeding, gene analyses and the production of genetically modified organisms. The result of this study will be
the identification of at least one of the genes that control NKT cell numbers. These gene(s) will then be studied
in patients to determine if it plays a role in human disease.
Research achievements (from final report):
The Role of Slam in Nkt1 has been tested by congenesis and Slam transgenic mice have been generated and
phenotyped (Jordan et al, 2011)
Expected future outcomes:
N/A
Name of contact:
Alan G. Baxter
Email/Phone no. of contact:
Alan.Baxter@jcu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 379610
CIA Name: Prof Alan Baxter
Admin Inst: James Cook University
Main RFCD: Immunogenetics
Total funding: $607,101
Start Year: 2006
End Year: 2010
Grant Type: NHMRC Research Fellowships
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
Media Summary not available
Research achievements (from final report):
Autoimmune diseases are those in which the immune system attacks and damages the body's own tissues, and
include type 1 diabetes (T1D), gastritis and multiple sclerosis (MS). While it is known that both genes and
environmental factors contribute, it is far from clear how they interact, or how they can affect multiple tissues.
A better understanding of these issues would enable the prediction of disease and provide new therapeutic
opportunities. Over the 5 years of the Fellowship, Baxter's research group has shown that the effects of some
environmental risk factors are mediated through genes, such as the TLR genes, expressed by cells of the innate
immune system including monocytes, NK and NKT cells. Experimental achievements include: Completion of
an analysis of TLR in mouse model of multiple sclerosis (MS), a microarray analysis of NKT subsets,
confirmation of a role for SLAM in NKT development by transgenic complementation and identification of an
NK cell control locus on chromosome 1.
Expected future outcomes:
Major aims for the future include: dissection of the mechanism by which TLR control MS, dissection of the
mechanisms by which other NKT cell control genes operate and identification of MS susceptibility genes in
patients by expression-QTL analysis of peripheral blood subsets.
Name of contact:
Alan Baxter
Email/Phone no. of contact:
Alan.baxter@jcu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 487311
Start Year: 2008
CIA Name: Dr Hamsa Puthalakath
End Year: 2011
Admin Inst: La Trobe University
Grant Type: NHMRC Project Grants
Main RFCD: Cell Development (incl. Cell Division and Apoptosis)
Total funding: $558,189
Title of research award:
DETERMINING THE ROLE OF ER STRESS INDUCED APOPTOSIS IN THYMIC NEGATIVE
SELECTIONDETERMINING THE ROLE OF ER STRESS INDUCED APOPTOSIS IN THYMIC
NEGATIVE SELECTION
Lay Description (from application):
Apoptosis is an evolutionarily conserved mechanism for killing unwanted cells that are no longer needed,
damaged, infected with pathogens or dangerous. Defects in apoptosis can cause a number of diseases. For
example, abnormal survival of cells can cause cancer or autoimmune disease. Bim is a protein that induces
apoptosis and act as a barrier against cancer and autoimmune diseases. This work is aimed at understanding
how Bim acts as a barrier against the development of autoimmunity.
Research achievements (from final report):
This project was aimed at understanding the role of ER stress in thymic negative selection. Understanding the
molecular mechanism of this process would have profound implications for the wider understanding of how
auto-immunity develops. However, soon after the project started, our results clearly showed that ER stress did
not have any role in determining the outcome of thymic selection. Instead, we found that it was the
transcription factor c-Myc that regulated the cell death process during thymic selection. Subsequently, our
effort was focused towards understanding the molecular mechanism of c-Myc induced apoptosis. Our results
clearly demonstrate that c-Myc together with the co-factor CBP regulates the apoptosis process by inducing
epigenetic modifications at the bim locus which, in turn, regulates the apoptosis mechanism. To better
understand this in an in vivo system, we generated a knock-in mouse model where c-Myc biding sites on the
bim promoter are mutated. Analysis of the cells from these mouse showed that bim expression was muted in
these cells and they don't respond to stress hormones such as beta-adrenergic catecholamines. These findings
have implications for understanding the molecular basis of the stress-induced diseases in humans i.e.
cardiomyopathy and immune deficiency. Furthermore, we are in the process of designing a high throughput
screening strategy for developing drugs that can counter the apoptosis process.
Expected future outcomes:
Through this project, though we did not achieve the initial objective, we have been able to understand the
molecular basis of two major human diseases i.e. cardiomyopathy and immune deficiency. We are in the
process of validating our findings in in vivo models and developing therapeutic drugs against these.
Name of contact:
Hamsa Puthalakath
Email/Phone no. of contact:
h.puthalakath@latrobe.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 365225
Start Year: 2006
CIA Name: Prof David Power
End Year: 2008
Admin Inst: Macfarlane Burnet Institute for Medical Research and Public Health
NHMRC Project Grants
Main RFCD: Nephrology and Urology
Total funding: $401,523
Grant Type:
Title of research award:
AMP-activated protein kinase (AMPK) in acute renal failureAMP-activated protein kinase (AMPK) in acute
renal failure
Lay Description (from application):
Acute renal failure is a common complication of any severe illness. Generally, it is the lack of blood flow, or
"food" that leads to this problem. People who are ill are unable to provide adequate blood flow to their kidneys,
so the kidneys become diseased and fail to function. This can be fatal. There are, however, mechanisms in the
kidney that are designed to avoid this shortage of energy. The aim of these studies is to find out what these
protective mechanisms usually do in the kidney, and understand why they are not more active. We hope to find
ways to switch them on earleir, using drugs, so as to protect the kidneys from injury.
Research achievements (from final report):
We have identified a novel site for a protein that senses the amount of energy in the body, called AMPK. We
found that it helps to control the way that the body deals with salt; how it conserves and excretes it. This
research suggests that conserving salt should be seen as 'work' that the kidney performs to maintain a normal
blood pressure. The link between energy conservation and salt excretion by the kidney also suggests a new way
that blood pressure and metabolic diseases such as obesity might be linked. In a separate line of enquiry, we
have also found that this protein called AMPK can be bad when the kidney is stressed. Whether this has
anything to do with the ability of high blood pressure to damage the kidney is unknown, but something that we
are interested in studying.
Expected future outcomes:
We might be able to devise new ways to reduce blood pressure by ddsigning drugs acting on AMPK.
Name of contact:
David Power
Email/Phone no. of contact:
david.power@austin.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 490037
CIA Name: Prof Simon Foote
Admin Inst: Macquarie University
Main RFCD: Genetics not elsewhere classified
Total funding: $8,752,567
Start Year: 2008
End Year: 2013
Grant Type: Programs
Title of research award:
Genetic and Bioinformatic Analysis of Complex Human DiseasesGenetic and Bioinformatic Analysis of
Complex Human Diseases
Lay Description (from application):
Some human diseases are common in families; examples include prostate cancer, blood cancers, epilepsy and
diabetes. Therefore, close relatives of individuals with a disease have an increased risk of being affected by this
disease, implying a genetic basis. Finding the cause of these diseases is difficult, we will be developing novel
approaches to the identification of genes responsible for these diseases. This is the first step towards the
development of treatments for affected individuals.
Research achievements (from final report):
This program was based around the use of genetics and genomics techniques to find disease genes and to
describe disease processes. We have described the genetic basis of many new diseases. These include
epilepsies, mitochondrial disease and rare mendelian diseases. We have also worked with cancer biologists and
have determined breakpoints in myeloid leukaemias, analysed transcriptional differences in tumours. We have
also worked in malaria and have performed an ENU mutagenesis screen that has identified 80 malaria survival
mutants. We have implicated platelets in survival to malarial infection and delineated the functional molecular
basis., We also work on the development of statistical and genomic technologies. This has led to improvements
in the way metabolomics data is analysed. We improved the determination the ploidy of tissue and cell lines
using sequence data. We have also been involved in the statistical analysis of biological imaging, especially in
the field of malaria. Many studies on the construction and analysis of biological networks has been carried out
in cancer cells and micro-organisms., There has also been fundamental technology development that has
resulted in the production of statistical packages to further analyse microarray data. We have contributed to the
analysis of genomic sequence data and were involved in the wallaby sequencing project where the genomic
sequence of the wallaby was first produced. We have produced packages to analyse RNAseq data.
Expected future outcomes:
We will continue to contribute to the development of statistical analysis in biology, particularly genetics and
genomics, , continue working to identify genes and therapies for rare mendelian diseases. Our knowledge of
protective genes against malaria will be used to develop new antimalarial drugs that target the host, not the
parasite.
Name of contact:
Simon Foote
Email/Phone no. of contact:
simon.foote@mq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 457603
CIA Name: Prof Michael Clark
Admin Inst: Menzies Research Institute
Main RFCD: Endocrinology
Total funding: $433,973
Start Year: 2007
End Year: 2009
Grant Type: NHMRC Project Grants
Title of research award:
Central and peripheral actions of insulin for the control of muscle capillary recruitmentCentral and peripheral
actions of insulin for the control of muscle capillary recruitment
Lay Description (from application):
Type 2 diabetes is on the increase world wide and reflects the ever-increasing incidence of obesity. Whereas
the likely cause of type 2 diabetes includes low physical activity and high fat diet, the primary metabolic
abnormality is likely to be muscle insulin resistance. The cause of this resistance is controversial, but may stem
from microvascular dysfunction where muscle becomes poorly perfused and unresponsive to the action of
insulin to recruit capillary flow. In this project we will further extend our seminal discoveries that insulin
mediates capillary recruitment under normal circumstances and that in various models of insulin resistance
insulin's ability to increase the perfusion of muscle is markedly impaired. We will explore the hypothesis, that
insulin controls microvascular perfusion of muscle by a central neural mechanism ending at terminal arterioles
on the vasculature and endeavour to identify the details of this control. We will use in-house novel techniques
for examining both the role of central control mechanisms involving the brain as well as peripheral
mechanisms by local infusion of various agents likely to either enhance or block insulin's microvascular action.
A positive outcome will enhance our understanding of insulin action and the insulin resistance that precedes
type 2 diabetes. There is also the possible outcome that important clues will be obtained leading to new
therapeutic agents that could be used to treat type 2 diabetes.
Research achievements (from final report):
Type 2 diabetes is increasing worldwide in epidemic proportions and its associated morbidity and mortality not
only adversely affects the health and quality of life of the sufferer, but places a major burden on the health care
system. Insulin resistance is closely associated with the development of type 2 diabetes and may arise because
of altered blood flow within skeletal muscle. This project discovered that the recruitment of microvascular
blood flow in muscle in response to insulin was not due to a direct action of insulin in the brain. However
processes in the brain that depend upon nitric oxide signalling can impair the normal insulin-mediated
recruitment of blood flow in muscle and lead to insulin resistance. These outcomes may be relevant to the
underlying causes of stress related diabetes., The project also discovered that the local action of insulin to
recruit microvascular blood flow in skeletal muscle was dependent on nitric oxide production. Insulin action
also involved alterations in the rhythmical patterns of blood flow normally seen in muscle.
Expected future outcomes:
The discovery that insulin alters the rythmical variation of blood flow in muscle may provide new diagnostic
tests for insulin resistance and new avenues for therapeutic intervention to halt the progression of insulin
resistance to diabetes.
Name of contact:
Prof Steve Rattigan
Email/Phone no. of contact:
S.Rattigan@utas.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 544923
CIA Name: Prof Alison Venn
Admin Inst: Menzies Research Institute
Main RFCD: Epidemiology
Total funding: $360,326
Start Year: 2009
End Year: 2011
Grant Type: NHMRC Project Grants
Title of research award:
Inter-relationships between life-stage transitions, depression and cardio-metabolic health in young adultsInterrelationships between life-stage transitions, depression and cardio-metabolic health in young adults
Lay Description (from application):
This study will investigate how social transitions and depression in young Australian adults affect the
development of obesity and the adoption or persistence of behaviours that are associated with the risk of heart
disease and diabetes. These behaviours include smoking, poor diet, physical inactivity and alcohol
consumption. A better understanding of how psychosocial factors influence risk factors for heart disease and
diabetes is needed to improve prevention strategies.
Research achievements (from final report):
The Childhood Determinants of Adult Health (CDAH) study is a cohort study with follow-up of 8,498 chidlren
who participated in the 1985 Australian Schools Health and Fitness Survey (ASHFS) when aged 7 to 15 years.
This funding was used to conduct a second wave of follow-up, five years after the first follow-up. The study
aims were to investigate associations between life-stage transitions, depression and cardio-metabolic disease
risk in adults under 40 years of age., Overall, 58% of the 5,174 participants who provided some data in the first
wave of follow-up participated in the second wave. Of the 2,410 participants who completed the study clinics
in Wave 1, 78% completed the Wave 2 follow-up., Data cleaning is currently underway and the analyses will
be conducted in 2012-13.
Expected future outcomes:
This study will provide a better understanding of how social transitions and depression in young Australian
adults affect the development of obesity and the adoption or persistence of behaviours that are assoicated with
the risk of heart disease and diabetes. These behaviours include smoking, poor diet, physical inactivity and
alcohol consumption. This research will inform prevention strategies.
Name of contact:
Alison Venn
Email/Phone no. of contact:
Alison.Venn@utas.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 124319
Start Year: 2001
CIA Name: Prof Kerin O'Dea
End Year: 2004
Admin Inst: Menzies School of Health Research Grant Type: NHMRC Project Grants
Main RFCD: Indigenous Health
Total funding: $1,699,292
Title of research award:
Community-Based Interventions to Reduce the Risk of Diabetes and Cardiovascular Disease in Indigenous
AustraliansCommunity-Based Interventions to Reduce the Risk of Diabetes and Cardiovascular Disease in
Indigenous Australians
Lay Description (from application):
Poor nutrition is one of the main factors causing high rates of diabetes and heart disease in Aboriginal and
Torres Strait Islander people. Obesity is one of the main risk factors for diabetes and cardiovascular diseases
and it is associated with poor diet, lack of exercise and many social factors. Access to fresh vegetables and
fruit is often difficult for indigenous people , especially in remote areas. The aim of this project is to work with
indigenous communities in rural and remote areas to plan and run programs to lower the risk of diabetes and
heart disease. The programs will be designed by community members and involve health education, diet,
exercise and improving availability of healthy food choices in community stores. The programs will target
diabetic people and their families or, in most cases, the whole community. It is very difficult for overweight
adults to lose weight permanently, so school-based programs will be run to provide health education and
"healthy canteen" policies put in place to try and prevent excess weight gain in younger people. To see
whether these programs are effective, we will measure changes over time in risk factors for diabetes and heart
disease, nutrition and community support and involvement in the program. Where a community achieves even
modest improvements in diet and exercise, this is likely to lead to a much lower risk of diabetes and heart
disease. We will identify what factors make a program effective and sustainable over the long term. This
study will help us to set up a system for introducing and monitoring similar programs in other indigenous
communities. (1358 characters)
Research achievements (from final report):
Given the very high rates of premature type 2 diabetes and related conditions and risk factors (obesity,
cardiovascular disease, and renal failure) among Indigenous peoples, the major goals of this research program
were to work with Indigenous communities in rural and remote areas to plan, implement and evaluate
interventions to reduce the risk and/or severity of these conditions, and to develop a better understanding of the
barriers to, and enablers of, health promoting behaviour change at the community level - a PhD thesis due for
submission in 2006. We worked primarily with three communities: Galiwinku and Marthakal Homelands in
northeast Arnhem Land, NT; and Rumbalara community in Victoria (The Heart Health Project). The health
screenings in 2001-2 in the NT indicated the strong relation between biochemical markers of poor diet quality
and markers of inflammation and oxidation linked to vascular disease risk. Furthermore, relatively modest
increases in body weight greatly increased the risk of diabetes. These results provided the rationale for
community-driven interventions to improve the quality of the food supply. Included in the initiatives
undertaken was the establishment of home gardens (fruit trees and vegetables), and the establishment of a
partnership between a community organization and the major providers of food in the community (store, takeaways, school canteen, child care centre, meals-on-wheels) to develop a coordinated approach to improving the
quality of the food supply. Changes in the food supply have been monitored since 2001 using the store turnover
method.
Expected future outcomes:
We would like to report on the sustainability of the community-based interventions over the long term,
focussing onthe structural factors in the community (and outside) that support or hinder the sustainability of
improvements in diet and lifestyle at the community level. This follow up could be done as part of our Program
Grant.
Name of contact:
NHMRC Research Achievements - SUMMARY
Kerin O'dea
Email/Phone no. of contact:
kod@medstv.unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 236207
Start Year: 2003
CIA Name: A/Pr Joan Cunningham
End Year: 2004
Admin Inst: Menzies School of Health Research Grant Type: NHMRC Project Grants
Main RFCD: Indigenous Health
Total funding: $1,116,053
Title of research award:
The DRUID Study: Diabetes and related disorders in urban Indigenous people in the Darwin region.The
DRUID Study: Diabetes and related disorders in urban Indigenous people in the Darwin region.
Lay Description (from application):
Indigenous Australians suffer a high burden of ill health from diabetes and related conditions, but very little is
known about the burden of diabetes and its complications among Indigenous people in urban areas, and how to
reduce it. Unlike Indigenous people in rural and remote areas, Indigenous people in urban areas (the majority
of Indigenous Australians) have rarely been the subjects of health research and have even more rarely been the
drivers of such research. The DRUID Study (Diabetes and Related Disorders in Urban Indigenous People in
the Darwin Region) is a partnership between researchers and members of the Darwin Indigenous community
to: examine the health of adults aged 15 years and over; refer people with disease to appropriate health care and
related services; follow people over time to collect information on the state of their health and their use of
health services; and test the effectiveness of a program to improve dietary quality, increase physical activity
and reduce tobacco smoking among those at highest risk for diabetes. The results will be of significant value
to policy-makers, health practitioners, researchers, and, most importantly, Indigenous people and organisations.
The study will provide the first-ever data on the burden of diabetes and related conditions in an urban
Indigenous population. This information can be directly compared with recently collected national data from
the AusDiab study, and used to inform the development and implementation of strategies for reducing the
impact of diabetes and related conditions. The study will provide an important vehicle for the training and
development of Indigenous researchers, and the central involvement of Indigenous people in the study will
promote improved local awareness and understanding of diabetes among Indigenous people and increase the
capacity of Indigenous people and service providers to manage diabetes and related disorders.
Research achievements (from final report):
The DRUID Study was the largest research study to date on the health of urban Indigenous adults in Australia,
with over 1,000 Aboriginal and Torres Strait Islander adults participating. The Study provides new information
on the health and social circumstances of a group about which little information has been available and which,
as a consequence, has been easy to ignore. DRUID participants underwent an extensive health check, which
included a diabetes test, measurement of body size and blood pressure, several blood tests, a urine test, and a
test for heart disease. They also answered questionnaires about various topics including their health history,
health risk factors, psychosocial factors, and sociodemographic characteristics. People with diabetes, whether
previously known or newly diagnosed, had extra tests to see whether they had developed complications of
diabetes. All participants received feedback on their own results, plus specifically targeted health information,
and were referred to a health care provider as necessary. With permission, we also provided results to the
participant's own doctor or clinic, so they could discuss the results together. In addition to providing people
with important health information, the study also provided training, employment and educational opportunities
for 14 Indigenous staff members and one Indigenous PhD student, some of whom have continued on in
research. We have presented the preliminary results to partner organisations, community groups and
participants, and have begun extensive analysis of the data. We will work closely with health policy-makers
and service providers over the coming months and years to use the results of the study in a positive way to
improve the health and wellbeing of Indigenous people in the Darwin region and beyond.
Expected future outcomes:
Analysis of this extremely rich data set about the health and social circumstances of Indigenous adults in an
urban area is expected to yield increased understanding in a diverse range of areas, including chronic diseases,
women's reproductive health, discrimination and stress, health behaviours, etc. It also provides a platform for
targeted interventions in this population.
NHMRC Research Achievements - SUMMARY
Name of contact:
Joan Cunningham
Email/Phone no. of contact:
joanc@menzies.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 361617
Start Year: 2005
CIA Name: Prof Kerin O'Dea
End Year: 2005
Admin Inst: Menzies School of Health Research Grant Type: International Collaborations
Main RFCD: Indigenous Health
Total funding: $8,318
Title of research award:
Community and individual resilience for positive health in Indigenous populations at risk for diabetes and
cardiovasculaCommunity and individual resilience for positive health in Indigenous populations at risk for
diabetes and cardiovascula
Lay Description (from application):
Not Applicable
Research achievements (from final report):
We undertook activities involved in preparing the full application. These activities included visiting remote
Indigenous community partners for consultations on the proposal (flights accommodation, workshops),
teleconferences between chief investigators and co-principal investigators, and employment of a research
assistant (short term contract) to pull together all the necessary background information.
Expected future outcomes:
There were no outcomes as the proposal was not funded.
Name of contact:
Kerin O'dea
Email/Phone no. of contact:
kod@medstv.unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 436011
Start Year: 2007
CIA Name: Dr Gurmeet Singh
End Year: 2009
Admin Inst: Menzies School of Health Research Grant Type: NHMRC Project Grants
Main RFCD: Indigenous Health
Total funding: $505,213
Title of research award:
Aboriginal Birth Cohort Study: from childhood to adulthood.Aboriginal Birth Cohort Study: from childhood to
adulthood.
Lay Description (from application):
Aboriginal peoples have poor health at both ends of their life span. There are more low birth weight babies at
the beginning and more kidney, heart disease and diabetes at the end of the life spectrum. The Aboriginal Birth
Cohort study aims to examine the effect of early life events (such as low birth weight) on the risk of developing
chronic disease in later life with a view to early intervention. The "babies" of the study were last seen at 11
years and are now being seen again near their 18th birthday. Data available are weight, length and gestational
age of these babies at birth, the health and lifestyle of their mothers during pregnancy and the children's growth
and health. By 11 years of age, the low birth babies still remained shorter and thinner than their peers who were
normal size at birth, but importantly, markers of chronic disease were not higher in these children. The current
round of investigation, in addition to the tests done before, now includes non-invasive markers of heart disease,
such as heart rate variability, measures of arterial stiffness and the thickness of carotid intima media (lining)
and a dental examination looking at both teeth and gums. For the first time, the study will look beyond the
physical to examine the psychological wellbeing of these young adults using a specially designed questionnaire
(Strong souls). Little is known about this age group because they are relatively healthy and do not present to
clinics for treatment. The continuing life course study of this cohort, forming the oldest and largest birth cohort
of any indigenous population in the world, will help us understand the relationships between early life and the
sequential events that lead to chronic adult disease. This will help determine the most effective time for
intervention programmes, and will influence public health planning and policy directed towards the
improvement of the health of Aboriginal peoples.
Research achievements (from final report):
The study provides important information on the health of young adults which is often not available. At this
age, the participants were healthy with normal blood and urine tests. At 18 years the cohort participants
continue to have low body mass indices (BMI) and had low levels of abnormal markers of diabetes, heart and
kidney disease. , One major finding is that the low birth weight (LBW) babies weighed less and were shorter at
11 years and continued to be lighter and shorter even at 18 years. This is important as overweight and obesity
are the major predictors of adult chronic diseases such as diabetes, heart and kidney disease. This suggests that
there is still a window of opportunity to reinforce healthy lifestyle habits and emphasise the importance of
maintaining a healthy body weight., Gum and tooth disease were very common; 73 per cent had decayed teeth.
A mental health questionnaire revealed a self report of anxiety or depression in as many of 50 per cent of the
girls and only a slightly lower percentage of boys. , Iodine is an essential component of the thyroid hormones.
Low iodine affects many functions, particularly brain activity, temperature regulation and metabolic rates.
Levels of iodine in urine samples were found to be low in our participants. As these levels were collected
before the mandatory fortification of bread with iodine, we will be able to assess how effective this measure is
in improving the iodine status of our participants.
Expected future outcomes:
Analyses of various aspects are ongoing. Future plans include analysis of inflammatory markers and in-depth
analysis of wellbeing. Also planned are comparisons of anthropometry and chronic disease markers with agematched non-Aboriginal males and females living in Darwin.
Name of contact:
Gurmeet Singh
NHMRC Research Achievements - SUMMARY
Email/Phone no. of contact:
gurmeet.singh@menzies.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 545202
Start Year: 2009
CIA Name: A/Pr Louise Maple-Brown
End Year: 2012
Admin Inst: Menzies School of Health Research Grant Type: NHMRC Project Grants
Main RFCD: Nephrology and Urology
Total funding: $959,349
Title of research award:
To improve the accuracy and precision of estimated GRF (eGFR) measurements in Indigenous AustraliansTo
improve the accuracy and precision of estimated GRF (eGFR) measurements in Indigenous Australians
Lay Description (from application):
There is an overwhelming burden of chronic disease in Indigenous Australians. In order to attempt to improve
kidney disease in this high-risk population, it is vital that we are able to accurately measure kidney function.
This study will provide evidence to accurately assess kidney function in Indigenous Australians. This will then
enable development of appropriate clinical guidelines and more effective monitoring of future interventions to
slow progression of kidney disease.
Research achievements (from final report):
We have reported that the standard test of kidney function (estimated Glomerular Filtration Rate, eGFR) is
accurate in Indigenous Australians. In particular, the recently recommended formula to be used for eGFR
(known as the CKD-EPI formula) was found to be an accurate and reliable test of kidney function in
Indigenous Australians, similar to reports that it is accurate and reliable in non-Indigenous Australians. Thus,
health care providers can use the kidney function test across Australia with confidence and in addition, can now
more accurately track the progression of kidney disease. In the United States, the formula includes a correction
factor for African Americans, however we have reported that this correction factor should not be used in the
assessment of kidney function in Indigenous Australians. Further work is in progress to assess whether the
eGFR equation could be improved by incorporation of a measure of fat-free mass, and/or use of an alternative
biochemical measure such as creatinine.
Expected future outcomes:
The eGFR Study cohort of 600 Indigenous Australians was established by this grant and work is now in
progress to follow-up this cohort 2-4 years after baseline. Thus future outcomes include work assessment of
progression of kidney damage in this high risk population.
Name of contact:
Dr Louise Maple-Brown
Email/Phone no. of contact:
louise.maple-brown@menzies.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 143664
Start Year: 2001
CIA Name: Dr Marie Gibbs
End Year: 2003
Admin Inst: Monash University
Grant Type: NHMRC Project Grants
Main RFCD: Neurosciences not elsewhere classified
Total funding: $241,018
Title of research award:
Investigation of the mechanisms involved in consolidation of memory by beta 3
adrenoceptoragonists.Investigation of the mechanisms involved in consolidation of memory by beta 3
adrenoceptoragonists.
Lay Description (from application):
The inability to form new memories is a major and increasingly prevalent health problem for an aging
population. In addition to aging, the inability to form new memories is associated with serious medical
conditions including Alzheimer's Disease and diabetes. Common to these conditions is the inability to
consolidate memories. Memories are intact for a short while (30 minutes) after the event to be remembered,
but memory does not pass on into permanent storage. We have been able to achieve memory consolidation in
a particular learning task, which is not normally remembered, by injection of drugs acting on novel receptors
(beta 3 adrenoceptors) in the brain of day old chicks. These drugs mimic the action of noradrenaline at beta-3
adrenoceptors. There are a number of ways in which memory consolidation can be enhanced, and we will
compare the effects of beta-3 drugs with other potential drugs acting at other types of noradrenaline receptors.
One of the actions of beta-3 agonists is related to the uptake of glucose into cells in the brain. We will
investigate whether the mechanism of beta-3 enhancement of memory involves the uptake of glucose in brain
tissue and studies in cultures of individual cell types will show us which cells are involved. Although this work
is done using young chicks, there is no reason to suppose that the basic memory mechanisms at the level of the
nerve cell should be different in birds or mammals. There are distinct advantages to using chicks in this
research as they can form a long lasting memory for an experience lasting only 10 seconds, and they will
discriminate between different colours as part of their learning. This research is aimed at understanding the
processes involved in and influencing memory formation. If we are going to develop drugs to alleviate the
cognitive problems of old age and more serious cognitive diseases, we need to understand more about the basic
mechanisms of memory formation in the normal animal.
Research achievements (from final report):
One of the two major chemical transmitters in the body is noradrenaline. Noradrenaline is ubiquitous in its
distribution in the body with particularly high concentrations occurring in the brain. It has been known for
some years that there are many different types pf receptors for noradrenaline and we have been able to establsh
a role for many of these receptors in the different stages of memory. Our recent grant has focussed on the role
of a new receptor, the beta 3-adrenoceptor and we have elucidated its role in memory and the cellular effects it
is producing in the neurons and astrocytes (specialized brain cells). We have established the role of the beta 3receptor in relation to the other noradrenergic receptors and the location of the action in the brain. Although
this work has been carried out in the young chick, the results are proving to be very similar to the limited
knowledge of the mammalian systems with respect to nnoradrenaline and the adrenergic receptors. Memory
deficits occur in many diseases such as Alzheimer's disease and Parkinsons disease and this research opens up
the exciting possibility that some adrenoceptr drugs may be able to alleviate the memory deficits seen in these.
We have extended the work into understanding the cognitive disorders that may come about through hypoxia
before birth, and have shown that stimulation of the beta 3-adrenoceptor is able to alleviate the deficits caused
by prenatal compromise.
Expected future outcomes:
we hope that we will be able to extend this work at least to rodents to demonstrate the universality of our
findings and explore the usefulness of the beta 3-adrenergic receptor drugs in alleviating cognitive problems in
both neurodevelopmental and neurodegenerative diseases.
Name of contact:
NHMRC Research Achievements - SUMMARY
Dr Marie Gibbs
Email/Phone no. of contact:
marie.gibbs@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 143665
Start Year: 2001
CIA Name: Dr Tony Rowe
End Year: 2003
Admin Inst: Monash University
Grant Type: NHMRC Project Grants
Main RFCD: Protein Targeting and Signal Transduction
Total funding: $212,037
Title of research award:
Analysis of the Role of Vesicle Docking/Fusion Proteins in Trafficking of the Glut4 Glucose Transporter in
AdipocytesAnalysis of the Role of Vesicle Docking/Fusion Proteins in Trafficking of the Glut4 Glucose
Transporter in Adipocytes
Lay Description (from application):
The objective of these studies is to understand the molecular mechanisms that are involved in the control of
blood glucose levels by the hormone insulin. Elevated blood glucose levels following a meal stimulate the
pancreas to release insulin into the circulation. Insulin acts to reduce blood sugar levels by stimulating the
uptake of glucose into fat and muscle and suppressing glucose production by the liver. Defects in insulin action
in these tissues are the primary cause of Type II diabetes. The debilitating effects of Type II diabetes, the
dramatic increase its incidence, and the expense of treating the symptoms of diabetic complications have lead
to the realization that the disease represents a major health problem requiring substantial research and
development efforts. The project will focus on insulin regulation of glucose uptake in fat cells. Insulin
promotes glucose uptake into fat by activating an intracellular signaling pathway that triggers the translocation
of a unique glucose transporter protein (Glut4) from storage sites inside the cell to the cell surface. Glut4
translocation is mediated by small membrane vesicles that function to sequester the glucose transporter inside
cells in the absence of insulin, and to shuttle Glut4 to the cell surface in response to the hormone. Despite the
central importance of this event to the maintenance of normal blood glucose levels, it is poorly understood.
The studies will be directed towards investigating the cellular machinery involved in the latter stages of insulinstimulated glucose uptake- the vesicle-mediated delivery of Glut4 to the cell surface. The objective of these
studies is to better understand the molecular basis for Glut4 translocation, and regulation by the insulin
signaling cascade. Accomplishment of this goal may suggest potential drug intervention strategies aimed at
enhancing insulin-stimulated Glut4 translocation and promoting improved control of blood glucose levels in
Type II diabetes.
Research achievements (from final report):
The project focused on analysis of proteins that are involved in the movement of a glucose transporter protein
called Glut4 from the inside to the surface of fat cells (referred to as Glut4 translocation). This process is
defective in Type II diabetes, and therefore the proteins that mediate Glut4 translocation are potential
therapeutic targets for the disease. Three main achievements were made during the course of this research
award. First, a protein called Snapin was found to associate with another protein, SNAP23 that is involved in
Glut4 translocation. Second, a novel association was discovered between Sec15 (a component of a protein
complex called the exocyst), and another protein, Rab11. Rab11 belongs to a family of proteins (Rabs) that
cycle between active and inactive states, and thereby act as molecular switches controlling the movement of
proteins inside cells. We discovered that Sec15 interacts specifically with the activated form of Rab11. Since
the exocyst is implicated in Glut4 translocation, these results suggest that the interaction between Sec15 and
activated Rab11 is involved in this process. Third, a novel protein was discovered that interacts with a protein
known as VAMP2 that is also involved in Glut4 translocation. The novel protein was shown to promote the
conversion of certain Rabs (including Rab11) from the active to the inactive state. The identification of these
three novel interactions has led to an increased understanding of the molecular mechansisms that control Glut4
translocation. In addition to this potential benefit, students working on these projects gained valuable
experience in medical research science during the course of the award.
Expected future outcomes:
The achievements made during this award are anticipated to new research directions focusing on the potential
roles of the novel protein-protein interactions we have discovered in Glut4 translocation. These studies are
NHMRC Research Achievements - SUMMARY
likely to lead to publications in peer-reviewed scientific journals, as well as presentations at major international
conferences.
Name of contact:
Tony Rowe
Email/Phone no. of contact:
Tony.Rowe@biogenidec.com
NHMRC Research Achievements - SUMMARY
Grant ID: 219172
CIA Name: Prof Andrew Elefanty
Admin Inst: Monash University
Main RFCD: Endocrinology
Total funding: $4,260,000
Start Year: 2002
End Year: 2006
Grant Type: International Collaborations
Title of research award:
Creating b-cells to cure type 1 diabetesCreating b-cells to cure type 1 diabetes
Lay Description (from application):
They aim to create insulin-secreting B cells by identifying their progenitor cells and the moleculaes normally
required for their development, in order to restore B-cell function in the people with type 1 diabetes. Mouse
and human multipotent embryonic stem (ES) cells and fetal mouse panceas and adult pancreas duct cells will
be used as sources of progenitor B cells. Comparative studies will provide a more complete picture of human
B-cell ontogeny. Culture systems developed for ES cells/embryoid bodies (EB) / EB-derived cells, fetal
pancreas and adult pancreas duct cells, will be employed to screen for and identify novel growth/differentiation
factors and to optimise parameters for creating B cells in vitro or (re) generating B cells in vivo. Genetic
constructs allowing regulated expression of fluorescently-tagged marker genes and growth/transcription factors
will be introduced into cultured cells or transgenic mice to enable progenitor B cells to be tracked and isolated.
Progenitor B cells will be typed with panels of known novel markers molecules at the gene and protein level,
and gene expression profiles of tissue yielding B cells will be analysed across time to reveal further candidate
markers. Molecules and methods effective in mouse systems will be applied to human ES cell-derived or
pancreatic duct cells. The capacity to progenitor cells or insulin-secreting cells to ameliorate diabetes when
transplanted into the testis, under the kidney capsule or into the pancreas of mouse models would represent
proof-of-concept. Functional B cells derived from human ERS cells or pancreas duct cells, or growth factors
that regenerate B cells in vivo, could together with appropriate immunotherapy restore B-cell function in
people with type 1 diabetes.
Research achievements (from final report):
The aim of this grant was to create insulin-producing cells from several possible sources, with the long term
goal of restoring pancreatic insulin secretion in people with type 1 diabetes. The arms of the program
encompassed endeavours to grow these insulin producing cells from either mouse or human embryonic stem
cells or from stem cell populations present in the adult pancreas, again using the mouse as a model system., ,
Our studies with mouse embryonic stem cells utilised genetic engineering technologies that enabled us to
modify the stem cell lines such that we could visualise early pancreas cells by their green fluorescence and
more mature insulin producing cells by a red fluorescence. These powerful new tools enabled us to develop
growth conditions that allowed the mouse embryonic stem cells to turn into insulin producing cells in the
laboratory that had the ability to reduce the blood glucose when they were tranplanted into diabetic mice. If this
study can be recapitulated with human embryonic stem cells, the potential is there for a new therapy that could
benefit patients with diabetes. In fact, the development of precursor cells part of the way along the pathway to
pancreatic cells was already achieved in the more modest human embryonic stem cell component of this
program. , , Another area of achievement in this program related to improvements in the methods of identifying
and isolating stem cells from the adult pancreas with the eventual aim to direct these cells to making new
insulin producing cells for patients. As a result of our studies we were able to isolate and grow these cells more
successfully than previously., These results have provided the springboard for a second successful program
grant application that commenced in 2008 with the express aim of translating these results to human cells.
Expected future outcomes:
These studies have laid the groundwork for a currently funded program that will aim to translate the succeses
with the mouse embryonic stem cell experiments to human embryonic stem cell experiments with the long term
goal of making insulin producing cells to treat patients with diabetes.
Name of contact:
Andrew Elefanty
NHMRC Research Achievements - SUMMARY
Email/Phone no. of contact:
Andrew.elefanty@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 236824
Start Year: 2003
CIA Name: Prof Christina Mitchell
End Year: 2005
Admin Inst: Monash University
Grant Type: NHMRC Project Grants
Main RFCD: Protein Targeting and Signal Transduction
Total funding: $440,250
Title of research award:
SHIP-2 regulation of the actin cytoskeletonSHIP-2 regulation of the actin cytoskeleton
Lay Description (from application):
Following a meal glucose circulates in the blood and is taken up into cells via movement of an intracellular
glucose transporter from the inside of the cell to fuse with the cell membrane and subsequent transfer of the
glucose into the cell. This process is triggered by insulin. One of the commonest diseases resulting from a
failure of this cellular process is diabetes. A common form of diabetes which occurs in many adults in
Australia results from insulin resistance, whereby the effects of insulin are diminished and cells become
increasingly unable to uptake glucose. Recent studies have demonstrated that a novel enzyme known as SHIP2 may play a role in regulating insulin action in cells. Deletion of SHIP-2 in mice results in these animals have
increased sensitivity to insulin, low blood glucose levels, and a greatly enhanced ability to take up glucose in
cells in response to low dose insulin. Our laboratory has been working on the cellular mechanisms regulating
SHIP-2 function. We have recently revealed the intracellular location of SHIP-2 and also demonstrated how
SHIP-2 is localized in the cell. These studies have shown that SHIP-2, via interactions with other proteins,
regulates the actin cytoskeleton immediately beneath the cell membrane and this may be a mechanism for
facilitating cellular glucose uptake. This research proposal aims to determine how SHIP-2 facilitates glucose
uptake into cells. We will make cell lines and transgenic animals which express high levels of this enzyme and
determine the functional consequences on insulin stimulated glucose uptake. Collectively these studies in the
long term may facilitate better treatment strategies for diabetic patients.
Research achievements (from final report):
Cells respond to hormones, stress, growth factors and other enviromental stimuli resulting cell movement, cell
growth, cell division and other specialized functions. These cellular responses require the generation of a
multitude of signals including those generated on specific membrane compartments of the cell called
phosphoinositides. We have characterized the SHIP-2 5-phosphatase which regulates phosphoinositide signals
and have demonstrated that in fat cells this enzyme negatively regulates the glucose transporter protein
required for the uptake of glucose into cells. We have investigated two possible molecular mechnisms by
which SHIP-2 may regulate the glucose transporter. First, our results demonstrate that SHIP-2 regulates the
actin cytoskeleton which is essential for the transport of the glucose transporter to sites of glucose uptake into
cells. Secondly, we have demonstrated that SHIP-2 binds to, and inhibits the actions of a protein called SODD
which enhances the transport of the glucose transporter to the cell membrane, even in the absence of insulin.
These studies provide novel targets for the treatment of insulin-resisitant diabetes.
Expected future outcomes:
These studies provided identification of potential novel targets for the treatment of insulin-resistant diabetes.
Name of contact:
Christina Mitchell
Email/Phone no. of contact:
christina.mitchell@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 236869
CIA Name: A/Pr Tony Tiganis
Admin Inst: Monash University
Main RFCD: Endocrinology
Total funding: $425,250
Start Year: 2003
End Year: 2005
Grant Type: NHMRC Project Grants
Title of research award:
Protein tyrosine phosphatases in the regulation of insulin receptor signalling and glucose uptakeProtein
tyrosine phosphatases in the regulation of insulin receptor signalling and glucose uptake
Lay Description (from application):
The key pathological feature of type II diabetes is the lack of cellular response to normal levels of circulating
insulin. Insulin binding to its cell surface transmembrane receptor initiates a cascade of events known as
cellular signalling that results in amongst other things in the uptake of glucose. Protein tyrosine phosphatases
(PTPs) are key negative regulators of insulin-induced signalling events and their inhibition with broad based
chemical inhibitors can mimic several actions of insulin and lower blood glucose levels in both normal and
diabetic rats. This proposal will examine the roles of PTPs and in particular TCPTP and PTP1B in insulin
receptor-mediated signalling and glucose uptake. Moreover we will explore the role of TCPTP in alternate
insulin receptor-independent processes for glucose uptake. Our studies will shed light on processes important
for the regulation of glucose uptake. Moreover our studies may lead to the development of drugs capable of
inhibiting PTPs such as TCPTP, that may allow for enhanced glucose uptake and have therapeutic use in the
treatment of type II diabetes.
Research achievements (from final report):
Type 2 diabetes has reached epidemic proportions afflicting roughly 6% of the adult population in Western
society. Although the underlying genetic causes & the associated pathological symptoms are heterogenous, a
common feature is high blood glucose due to peripheral insulin resistance. The molecular basis of insulin
resistance is believed to be attributable to defects in insulin receptor (IR) signalling. Protein tyrosine
phosphatases (PTPs) that antagonise IR signalling might be important targets for therapeutic intervention in
type 2 diabetes; inhibition of specific PTPs may allow for enhanced IR signalling to alleviate insulin
resistance.Our studies have identified the roles of two key PTPs in insulin signalling.
Expected future outcomes:
N/A
Name of contact:
Tony Tiganis
Email/Phone no. of contact:
Tony.Tiganis@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 236872
CIA Name: Dr Sharyn Fitzgerald
Admin Inst: Monash University
Main RFCD: Systems Physiology
Total funding: $225,500
Start Year: 2003
End Year: 2005
Grant Type: NHMRC Project Grants
Title of research award:
Role of endothelial vasodilator mechanisms in cardiovascular control during diabetesRole of endothelial
vasodilator mechanisms in cardiovascular control during diabetes
Lay Description (from application):
Cardiovascular diseases such as stroke and heart attack are the greatest killers in developed societies such as
Australia. We now know that a number of metabolic disorders, and genetic and lifestyle factors, can increase
the likelihood of individuals developing cardiovascular disease later in life, such as obesity, diabetes, and
smoking. In many cases, individuals with these risk factors also have high blood pressure, which is a known
cause of stroke and heart attack. This seems to be a particular problem in patients with diabetes, a condition
that currently affects around 150 million people worldwide. Indeed, almost 70% of patients that develop
diabetes in later life, also develop high blood pressure. The aim of the studies outlined in this application is to
increase our understanding of the way diabetes affects blood pressure. High blood pressure often accompanies
established diabetes, but we have recent evidence that suggests that a gas (nitric oxide) made by the cells that
line blood vessels (endothelial cells) and in nerve cells, protects the cardiovascular system from hypertension
during the onset of diabetes. Our experiments will show whether the 'protective' nitric oxide comes from nerves
or the endothelial cells, and how it affects various blood pressure control mechanisms in diabetes. Our
experiments will also show whether this protective action of nitric oxide is eventually lost as the organ damage
that occurs in diabetes proceeds. This information should help in the design of new drug treatments and other
therapies aimed at reducing the occurrence of high blood pressure, and hence cardiovascular disease, in
diabetes.
Research achievements (from final report):
A facility to measure blood pressure and heart rate in 16 mice simultaneously has now been established, only a
few laboratories in Australia are currently capable of undertaking these types of studies. Hence, we can now
investigate the influence of a range of factors including disease state, genetic manipulation and drug treatment
on blood pressure and heart rate in mice, measured continuously 24 hrs/day. With the use of these techniques
we have now studied the influence of nitric oxide (an endogenous vasodilator) on blood pressure regulation in
normal and diabetic mice. Under both normal and diabetic conditions , nitric oxide does not appear to play a
major role in short- to medium-term control of blood pressure of mice. However, there does appear to be an
important role for nitric oxide in long-term blood pressure control in both normal and diabetic mice. A colony
of endothelial nitric oxide synthase (eNOS) knockout mice (with reduced nitric oxide activity) has now been
established at Monash University - one of only two colonies in Australia. These mice are now being used to
study the effect of diabetes on the cardiovascular system in the absence of a functional nitric oxide system and
also the relative roles of nitric oxide and other vasodilators on blood vessel tone.
Expected future outcomes:
Identifying the extent of involvement of nitric oxide and other endothelium-derived vasodilators in blood
pressure regulation during diabetes may lead to more appropriate therapies for blood pressure control in
diabetes. These studies may also greatly contribute to our understanding of the mechanisms responsible for the
organ damage observed in diabetes.
Name of contact:
Sharyn Fitzgerald
Email/Phone no. of contact:
sharyn.fitzgerald@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 237019
CIA Name: Dr Sharyn Fitzgerald
Admin Inst: Monash University
Main RFCD: Systems Physiology
Total funding: $166,421
Start Year: 2003
End Year: 2004
Grant Type: Early Career Fellowships (Australia)
Title of research award:
Cardiovascular control during diabetes: Role of endothelial vasodilator mechanismsCardiovascular control
during diabetes: Role of endothelial vasodilator mechanisms
Lay Description (from application):
Not Available
Research achievements (from final report):
A facility to measure blood pressure and heart rate in 16 mice simultaneously has now been established. With
the use of the this system we are able to investigate the influence of a range of factors including disease state,
genetic manipulation and drug treatment on blood pressure and heart rate in mice, measured continuously 24
hrs/day for up to two weeks. This is a very technically demanding model, involving an initial surgery to allow
implantation of the equipment needed to measure blood pressure and only a few laboratories in Australia are
currently capable of undertaking these types of studies. With the use of these techniques we have now studied
the influence of nitric oxide (an endogenous vasodilator) on blood pressure regulation in the normal and
diabetic mice. Under both normal and diabetic conditions , nitric oxide does not appear to play a major role in
short- to medium-term control of blood pressure of mice. However, there does appear to be an important role
for NO in long-term blood pressure control in both normal and diabetic mice. , A colony of endothelial nitric
oxide synthase (eNOS) knockout mice (with reduced nitric oxide activity) has now been established at Monash
University - one of only two colonies in Australia. These mice are now being used to study the effect of
diabetes on the cardiovascular system in the absence of a functional nitric oxide system and also the relative
roles of nitric oxide and other vasodilators on blood vessel tone.,
Expected future outcomes:
In these studies discovering the extent of involvement of nitric oxide and other endothelium-derived
vasodilators in blood pressure regulation during diabetes may lead to more appropriate therapies for blood
pressure control in diabetes. These studies may also greatly contribute to our understanding of the mechanisms
responsible for the organ damage observed in diabetes.
Name of contact:
Dr Sharyn Fitzgerald
Email/Phone no. of contact:
sharyn.fitzgerald@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 284273
CIA Name: Prof Christina Mitchell
Admin Inst: Monash University
Main RFCD: Enzymes
Total funding: $454,050
Start Year: 2004
End Year: 2006
Grant Type: NHMRC Project Grants
Title of research award:
Characterization of the 72 kDa inositol polyphosphate 5-phosphataseCharacterization of the 72 kDa inositol
polyphosphate 5-phosphatase
Lay Description (from application):
Cells respond to external signals and the enviroment to undergo cell growth, secretion and or other specialized
functions including control of cell death and or cell size. We have identified a new enzyme (72 kDa 5phosphatase) which resides inside the cell, which we have evidence plays a role in regulating both the
movement of intracellular vesicles and also lipid signals stimulated by insulin. We have characterised the
phospholipids that the enzyme cleaves and demonstrated the generation of new cell signals at specific
subcellular localizations on intracellular membranes. We predict the generation of these specific lipid signals
may play a significant role in controlling the transport of intracellular cargo to specific sites in the cell. In this
grant proposal we aim to examine the regulation of specialised cargo called the glucose transporter, which is
found in fat and muscle cells, and also the mannose 6-phosphate receptor, which regulates the trafficking of
specific enzymes which mediate digestion of proteins. These studies include the clarification of which
phospholipid signals the enzyme terminates and where in the cell this occurs. Secondly, we will examine the
movement of the glucose transporter GLUT-4 in unstimulated cells and in response to insulin and furthermore
how expression of the novel enzyme regulates its movement. We will also examine the movement of the
mannose 6-phosphate receptor and the specific phospholipid signals which control the route the receptor
traffics, using inhibitors of lipid signals and expression of lipid phosphatases and kinases. We will also
examine how our novel enzyme forms complexes with other molecules in the cell and characterise these novel
molecules using basic biochemical assessment of enzyme activity and function. Finally we will examine the
regulation of intracellular messages by our novel enzyme following insulin stimulation, which facilitates
glucose uptake into the cell.
Research achievements (from final report):
Phagocytosis is a biological process where specialised immune cells (macrophages) take up and remove
harmful particles such as bacteria or tumour cells from the circulation. We have shown a novel enzyme the 72
kDa 5-phosphatase is expressed in macrophages and plays a role in regulating phagocytosis and inhibiting the
uptake of particles and bacteria by macrophages. In addition we have shown this enzyme is also present in fat
cells where it may function to regulate glucose metabolism. In addition we have demonstrated that the 72 kDa
5-phosphatase regulates cancer cell proliferation and cell migration.
Expected future outcomes:
Future outcomes will characterise the molecular basis for the regulation of glucose metabolism and
macrophage function by this novel enzyme, the 72 kDa 5-phosphatase
Name of contact:
Christina MitchellEmail/Phone no. of contact:
christina.mitchell@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 299974
CIA Name: A/Pr Jennifer Wilkinson-Berka
Admin Inst: Monash University
Main RFCD: Endocrinology
Total funding: $481,500
Start Year: 2004
End Year: 2007
Grant Type: NHMRC Project Grants
Title of research award:
Vascular and neuro-glial dysfunction in diabetic retinopathyVascular and neuro-glial dysfunction in diabetic
retinopathy
Lay Description (from application):
The retina is responsible for sight. Vision occurs by interactions between blood vessels, neurons (cells that
transmit electrical signals for vision) and glia (cells that support the retina). In diabetes, high amounts of
glucose in blood increases certain factors within retinal cells. These factors slowly cause damage, such that
after 15 years of diabetes all patients will have some retinal disease and many will loose sight. Indeed, diabetes
is the leading cause of blindness in working people. The main treatment for diabetic retinal disease is to burn
away damaged blood vessels, however, this treatment has problems. Firstly, the burns destroy healthy retina
and the disease continues, secondly, the treatment is performed late in the disease and therefore does not
prevent the early changes in retinal cells, and thirdly, changes in neurons and glia are often not considered.
Therefore, there is an urgent need to understand how blood vessels, neurons and glia interact with each other to
threaten vision in diabetes, with the intention of developing safer and more effective treatments. This will be
the focus of the current project.Currently, there are no studies that have examined the sequential changes in
retinal blood vessels, neurons and glia in diabetes. This is mainly due to the lack of an experimental rodent
model that progresses from mild to severe diabetic retinal disease. In 2003, we established such a model in the
diabetic Ren-2 rat. In this project the diabetic Ren-2 rat will be used to study retinal cell changes and also to
identify the factors that damage these cells. We suggest that angiotensin, bradykinin and VEGF are involved.
These factors are present in the normal retina and are increased in diabetes. We will block these factors with
specific drugs with the intention of understanding how these factors affect retinal cells in diabetes, and also to
develop new drug therapies for the treatment of both early and late diabetic retinal disease.
Research achievements (from final report):
Retinopathy is the most feared complication of diabetes and is the leading cause of blindness in the working
population. Current treatments for diabetic retinopathy involve burning away damaged blood vessels with a
laser. This procedure although providing some benefits, is associated with damage to healthy retina and the
disease continues despite intensive treatment. New treatments for diabetic retinopathy are actively been sought.
One of these is blockade of a hormonal system called angiotensin. Our laboratory has played a key role in
establishing a role for angiotensin in diabetic retinal disease. This project grant is an extension of these studies
as we aimed to determine the relationship between blood vessels and neurons in diabetic retinopathy and
whether angiotensin affects the viability of these cell populations. Using blockers of the angiotensin system and
animal models of disease, we were able to report that this treatment improves overall retinal health in diabetes
and other retinal pathologies. These findings are directly relevant to diabetic patients, as currently a large
worldwide study comprising over 5000 patients is evaluating the effect of angiotensin blockade on the
progression of diabetic retinopathy (DIRECT study).
Expected future outcomes:
Our evaluation of how retinal blood vessels and neurons communicate in diabetes, and how abberations in
comunication leads to disease is a major focus. Using state-of-the-art microscopy (multiphoton) we will
evaluate how molecules such as angiotensin influence these cells in the living retina. This fundamental
knowledge will impact on future treatment strategies.
Name of contact:
Jennifer Wilkinson-Berka
Email/Phone no. of contact:
NHMRC Research Achievements - SUMMARY
Jennifer.Wilkinson-Berka@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 334032
Start Year: 2005
CIA Name: Prof John McNeil
End Year: 2009
Admin Inst: Monash University
Grant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $427,500
Title of research award:
Risk and Determinants of Fatal and Non-Fatal Coronary Heart Disease in the Melbourne Collaborative Cohort
StudyRisk and Determinants of Fatal and Non-Fatal Coronary Heart Disease in the Melbourne Collaborative
Cohort Study
Lay Description (from application):
Heart disease is the leading cause of death and ill-health in Australia. Accordingly, it also imposes a significant
cost burden to the community. The key to effective prevention is understanding of the roles of risk factors in
the development of heart disease. These are best defined through the use of large cohort studies, which are
those that follow up a group of individuals over time. Statistical analyses are used to develop prediction
equations to quantify the effects of multiple risk factors in terms of their contributions to risk of heart disease.
The current heart disease prediction equations most commonly used in Australia are based on older overseas
studies, such as the Framingham Heart Study. Other than having low relevance to the current Australian
population, they incorporate only a limited range of traditional risk factors. A spectrum of new risk factors is
emerging. This study aims to develop risk prediction equations for heart disease that are applicable to the
current Australian population, using contemporary data from the Melbourne Collaborative Cohort Study.
Results from this study will allow the future onset of heart disease to be predicted with accuracy and
confidence, which in turn will allow preventive strategies, including expensive drugs, to be utilised in a more
effective manner. Ultimately, the results will lead to a more efficient allocation of limited healthcare resources
in Australia.
Research achievements (from final report):
Using Medical Records, autopsy reports and adjudication, we have verified over 750 fatal cardiovascular
disease (CVD) events that have occurred in the Melbourne Collaborative Cohort Study (MCCS). A process for
linking the MCCS with the Victorian Admitted Episodes Dataset to determine non-fatal CVD events has also
been established. Both these achievements mean accurate ascertainment of CVD outcomes in the MCCS.
These outcomes can then be used to develop new risk prediction equations for Australia., Data on fatal CVD
events has been used in analysis of the relationships between CVD and dietary patterns, and CVD and alcohol
intake, demonstrating the importance of both factors on disease outcomes. Data has also been used in a study of
the association between socioeconomic status and CVD death. This analysis reinforced the signficant role of
both smoking and abdominal adiposity in the social gradient seen in CVD. Finally, baseline data from the
MCCS study has been used to calibrated the SCORE (Systematic Coronary Risk Evaluation) risk chart, which
estimates 10-year risk of cardiovascular death. Recalibration using contemporary risk factor data and national
mortality data enables this equation to be used in other populations other than that from which it was derived.
Expected future outcomes:
Fatal and non-fatal CVD outcomes occurring within the MCCS will be used to develop and validate new
cardiovascular risk prediction equations for Australia.
Name of contact:
Andrew Tonkin
Email/Phone no. of contact:
andrew.tonkin@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 334100
Start Year: 2005
CIA Name: Prof Andrew Elefanty
End Year: 2010
Admin Inst: Monash University
Grant Type: Established Career Fellowships
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $652,378
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
I am a stem cell scientist working on the biology of human embryonic stem cells and their differentiation into
cells of mesodermal (blood, endothelium and cardiomyocyte) and endodermal (pancreatic islet cells) lineages.
Research achievements (from final report):
Research in the laboratory that I jointly head with Prof Ed Stanley is focused on the study of human pluripotent
(hESC and hiPSC) stem cells. Our core interest lies in the regulation of human pluripotent stem cell
differentiation to mesoderm and endoderm lineages, as exemplified by blood and heart and pancreatic islet
cells, respectively. , In order to facilitate this work, our laboratory has generated genetically modified human
ES cell lines into which reporter genes have been inserted by homologous recombination in gene loci that are
expressed at specific developmental stages or in specific lineages. We have targeted approximately 10 different
genes in multiple hESC lines to date. Therefore, this has enabled us to more readily identify cells developing
into blood, heart, pancreas, lung, thymus and neural cell types. Our research has been published in high quality
scientific journals and we have successfully obtained ongoung research funding ofor our laboratory., We have
also devised a reproducible differentiation protocol for human ES cells ('spin EBs'), complemented with an
animal product free, recombinant human protein containing medium (APEL) that will facilitate optimisation of
human ES cell differentiation in the presence of appropriate growth factors. This cell culture medium has been
commercialised and is now being sold by a biotechnology company, STEMCELL Technologies., Our work has
generated unique opportunities for the study of early stages of human development, the generation of
laboratory models for human diseases, the testing of pharmaceuticals and other therapeutic products and
eventually we hope to be able to produce transplantable cells for tissue repair and regeneration. The ability to
genetically modify human ES cells may translate into an ability to correct genetic abnormalities in patient
derived iPS cells in some cases.
Expected future outcomes:
A major goal of our work is to realise some of the scientific and therapeutic potential that pluripotent cells
promise. We hope to continue to develop platforms for testing of therapeutic products and the generation of
cells for replacement therapies.
Name of contact:
Andrew Elefanty
Email/Phone no. of contact:
andrew.elefanty@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 334173
CIA Name: Dr Robyn Tapp
Admin Inst: Monash University
Main RFCD: Epidemiology
Total funding: $379,866
Start Year: 2005
End Year: 2009
Grant Type: Early Career Fellowships (Overseas)
Title of research award:
Epidemiology of Microvascular & Macrovascular Complications Associated with diabetes
MellitusEpidemiology of Microvascular & Macrovascular Complications Associated with diabetes Mellitus
Lay Description (from application):
Not Available
Research achievements (from final report):
In 2005 I was awarded the prestigious National Health and Medical Research Council Sidney Sax PostDoctoral Fellowship and as part of this award undertook post-doctoral training at the International Centre for
Circulatory Health, Imperial College London and INSERM France, returning to Australia at the start of 2007.
During this time, I developed extensive expertise in novel non-invasive methods for assessing both the retinal
microvasculature and cardiac structure and function. Additionally, I also developed expertise in life course
epidemiologic methods and the determinants of adult chronic disease. At the start of 2010 I returned to the UK
to further develop my research program 'Life course Epidemiology and Cardiovascular Physiology'. I maintain
strong collaborative links with Australia, but without career funding it has not been possible for me to remain
in Australia. A great disappointment to me.
Expected future outcomes:
Within the Australian context there is no future work, as I did not secure funding in Australia. Consequently I
am now based at the Imperial College London. Its nice to see that since lodging a formal complaint with the
NHMRC independent commissioner in 2009 that the CDF assessment process has been overhauled. It was
devistating to see fellows with limited experience being funded.
Name of contact:
Robyn Tapp
Email/Phone no. of contact:
r.tapp@imperial.ac.uk
NHMRC Research Achievements - SUMMARY
Grant ID: 384137
Start Year: 2006
CIA Name: Prof Christina Mitchell
End Year: 2008
Admin Inst: Monash University
Grant Type: NHMRC Project Grants
Main RFCD: Protein Targeting and Signal Transduction
Total funding: $505,523
Title of research award:
Characterization of the phosphoinositide 5-phosphatase SKIP.Characterization of the phosphoinositide 5phosphatase SKIP.
Lay Description (from application):
Growth factors and insulin stimulate a complex array of signals inside the cell, which are important for both
cell survival and metabolism. A central intracellular signaling enzyme that initiates lipid messages that promote
glucose uptake into the cell and promote cell survival is that generated by the PI3-kinase. This enzyme has
increased activity in many cancers, and is also important in diabetes when the enzyme may be suppressed. Our
grant proposes to investigate the function of another enzyme called SKIP which acts within the cell to oppose
the functions of the PI3-kinase. Several lines of evidence indicate SKIP may be important in both development
and cancer. SKIP has been identified as a putative candidate gene for a developmental disorder known as
Miller Dieker syndrome. This disease is associated with facial and significant brain abnormalities. In addition
the SKIP gene is located on a chromosome that is frequently deleted in breast and colon cancer. SKIP is an
enzyme that functions to remove phosphate molecules from PI3-kinase signaling molecules. SKIP has been
shown to prevent glucose uptake into the cell by breaking down PI3-kinase signals. We have recently
demonstrated SKIP phosphatase activity can be inhibited by binding to another protein called suppressor of
death domains (SODD). We plan to investigate the effects this complex has on SKIP enzyme activity, and how
this complex plays a role in regulating PI3-kinase signals that promote glucose uptake. Secondly, we plan to
investigate the function of SKIP in an intact animal by making mice which lack SKIP(knock out mice). Given
SKIP is implicated in a developmental syndrome and insulin signaling, we can delineate the functional
significance of SKIP and the molecular pathways regulated by this enzyme.
Research achievements (from final report):
This study has characterised a novel signal terminating enzyme called SKIP, that regulates the actin
cytoskeleton and thereby cell migration and in addition regulates insulin stimulated glucose uptake. The
inositol polyphosphate 5-phosphatase SKIP, opposes an important intracellular pathway generated by the PI3kinase. SKIP exhibits increased activity in certain cancers and may promote cancer cell migration and invasion.
SKIP is also implicated in a number of other human diseases including developmental defects of the human
cerebral cortex, perhaps as a result of abnormal cell migration. This grant has characterised the role SKIP plays
in regulating the actin cytoskeleton revealing it may function to regulate the migration and invasion of both
normal cells and tumours. In addition the grant has demonstrated that SKIP is essential for normal embryonic
development and mice which lack SKIP die mid gestation. These studies have identified a novel gene that is
important in human development.
Expected future outcomes:
We predict SKIP may play an important role in regulating the normal migration of brain cortex cells during
embryonic development and in future studies will develop mouse models with targeted and inducible deletion
of SKIP in specific tissues during embryonic development
Name of contact:
Prof Christina Mitchell
Email/Phone no. of contact:
christina.mitchell@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 384146
CIA Name: A/Pr Tony Tiganis
Admin Inst: Monash University
Main RFCD: Endocrinology
Total funding: $503,776
Start Year: 2006
End Year: 2008
Grant Type: NHMRC Project Grants
Title of research award:
Regulation of insulin signalling & glucose homeostasis by protein tyrosine phosphatasesRegulation of insulin
signalling & glucose homeostasis by protein tyrosine phosphatases
Lay Description (from application):
Type 2 diabetes has reached epidemic proportions afflicting roughly 6% of the adult population in Western
society. Although the underlying genetic causes & the associated pathological symptoms are heterogenous, a
common feature is high blood glucose due to peripheral insulin resistance. The molecular basis of insulin
resistance is believed to be attributable to defects in insulin receptor (IR) signalling. The IR is a protein
tyrosine kinase that phosphorylates itself & downstream substrates on tyrosine in response to insulin. Protein
tyrosine phosphatases (PTPs) that dephosphorylate the IR & its substrates might be important targets for
therapeutic intervention in type 2 diabetes; inhibition of specific PTPs may allow for enhanced insulin-induced
signalling to alleviate insulin resistance. This proposal will examine the roles of PTPs and in particular TCPTP
in IR signalling in vivo. Our studies will shed light on the molecular mechanisms of IR regulation & function
& may provide important insights into novel strategies for enhancing insulin sensitivity in type 2 diabetes.
Research achievements (from final report):
The liver is an important tissue for the control of blood glucose levels during periods of starvation and fasting.
The liver generates glucose during periods of starvation. This study has demonstarted that the enzyme TCPTP
acts in the liver to control glucose generation. Our studies suggest that inhibiting TCPTP in the liver in type 2
diabetes may provide a means by which to lower blood glucose levels and attenuate the fasting hyperglycemia
that characterises this disease.
Expected future outcomes:
Identify TCPTP as an important regulator of hepatic gluconeogenesis and as therapeutic target for the treatment
of type 2 diabetes
Name of contact:
Tony Tiganis
Email/Phone no. of contact:
Tony.Tiganis@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 384149
Start Year: 2006
CIA Name: Prof Tony Tiganis
End Year: 2010
Admin Inst: Monash University
Grant Type: Established Career Fellowships
Main RFCD: Protein Targeting and Signal Transduction
Total funding: $548,878
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
One of our key findings in the last five years has been in delineating the potential beneficial effects of reactive
oxygen species in insulin sensitivity and consequentially, the potentially detrimental effects of antioxidants in
the development of type 2 diabetes.
Expected future outcomes:
Delineating the precise nature by which reactive oxygen species can be both good and bad.
Name of contact:
N/A
Email/Phone no. of contact:
Tony.Tiganis@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 384215
CIA Name: A/Pr John Dixon
Admin Inst: Monash University
Main RFCD: Paediatrics
Total funding: $481,906
Start Year: 2006
End Year: 2008
Grant Type: NHMRC Project Grants
Title of research award:
A randomised control trial of medical treatment versus the placement of the Lap Band in severely obese
adolescents.A randomised control trial of medical treatment versus the placement of the Lap Band in severely
obese adolescents.
Lay Description (from application):
There has been a substantial rise in the number of overweight and obese adolescents in our community. While
prevention of obesity is the ultimate goal, effective stratagies for the management of obese adolescents must be
sought. Unfortunately there are few studies that have focused on this problem in adolescents and success has
been very limited. Modern obesity surgery is the only reliable method of achieving and sustaining major
weight loss in severely obese (body mass index > 35 kg/m2) adults and there are now several small studies that
demonstrate its effectiveness in adolescents. Modern obesity surgery involving the keyhole placement of an
adjustable band around the very upper part of the stomach has proven to be safe and effective and requires one
24 hr stay in hospital. In this collaborative study, involving the Monash University Centre for Obesity
Research and Education and the Royal Children's Hospital, we propose to formally test, for the first time, the
effectiveness of a weight loss program that includes adjustable band surgery, and compare this with a
comprehensive "best care" behavioral program, over a period of 2-years in severely obese adolescents. We
estimate that suitable subjects will come from the top 1% for body mass index in our community. After
thorough assessment 50 suitable candidates with ages ranging from 14 to 18 years will be randomly allocated
to one of the two treatment programs. The intensity of each program will be similar. A broad range of measues
including: weight, health status, physical disability, psychological status, body image and quality of life, will be
performed before and at completion of the 2-year programs. In addition we will compare the complications,
compliance and cost of the two programs. This study will help us assess and compare the effectiveness of the 2
programs and provide vital information regarding the role of modern keyhole obesity surgery for the
management of severely obese adolescents.
Research achievements (from final report):
Adolescent obesity is common and is associated with multiple health problems, poor quality of life and reduced
life expectancy. We performed a randomized controlled trial comparing laparoscopic adjustable gastric
banding (LAGB) with a program of behavioral therapy., 50 adolescents aged between 14 and 18 years with a
BMI>35. They were randomly allocated to a supervised behavioral intervention of the LAGB procedure and
followed for two years. 24 of 25 LAGB participants and 18 of 25 non-surgical patients completed the study.,
Outcomes - , - LAGB participants lost an average weight of 34.9kgs compared with an average of 3kgs for the
non surgical participants. , - At entry, the metabolic syndrome was present in 9 of the surgical group and 10 of
the non-surgical group. After 24 months, none of the surgical group had the metabolic syndrome, while 4 of the
18 completers in the non-surgical group still fullfilled the criteria for the metabolic syndrome., - The surgical
complication, gastric pouch dilitation, was more frequent in this population than expected in an adult
population , We concluded LAGB was more effective than the non-surgical program in achieveing weight loss
amd improving health. LAGB may be considered in the severely obese adolescent who have failed a
comprehensive non-surgical treatment program.
Expected future outcomes:
This study provides a strong level of evidence for the effectiveness of LAGB in adolescents with severe
obesity. This is the first demonstration by RCT of such an effect and should directly help clinicians determine
the best option for adolescents., Refinements to the surgical program may reduce complications.
Name of contact:
A/Prof John Dixon
NHMRC Research Achievements - SUMMARY
Email/Phone no. of contact:
john.dixon@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 400068
CIA Name: Prof Jennifer Wilkinson-Berka
Admin Inst: Monash University
Main RFCD: Endocrinology
Total funding: $636,288
Start Year: 2006
End Year: 2010
Grant Type: Established Career Fellowships
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
Diabetic retinopathy is the major cause of vision loss and blindness in people of working age. Almost all
people with type 1 diabetes and approximately 65% of people with type 2 diabetes will develop retinopathy,
with some individuals progressing to the severe form of the disease. The current treatments for diabetic
retinopathy are limited as they do not target the early stages of the disease, are invasive and may cause damage
to the retina. Research from our laboratory has established that in animal models of diabetic retinopathy that
blockade of a body hormonal system called renin-angiotensin is a potential treatment for diabetic retinopathy.
In particular, the role of prorenin, angiotensin, renin and aldosterone may play an important role in vascular
and nerve damage in the diabetic retina and hence be a target for treatment. This research fellowship identified
the cellular location of these renin-angiotensin system components in the retina of animals with retinopathy and
evaluated the cellular mechanisms by which they influence retinal cell injury. Using specific inhibitors of these
renin-angiotensin system components, it was identified that protection against retinal injury is possible. Some
of these inhibitors have or are under investigation in clinial trials to determine their relative utility as new
treatments for diabetic retinopathy.
Expected future outcomes:
Given our recent findings and new exciting developments in the area of the renin-angiotensin system and
diabetic retinopathy research, I have developed a research program that evaluates the immunological,
epigenetic and cellular mechansims that contriubte to this disease. This work is now funded by a renewed
NHMRC fellowship, and NHMRC project grants.
Name of contact:
Jennifer Wilkinson-Berka
Email/Phone no. of contact:
Jennifer.Wilkinson-Berka@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 401123
Start Year: 2006
CIA Name: Dr Stephanie De Dios
End Year: 2011
Admin Inst: Monash University
Grant Type: Early Career Fellowships (Australia)
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $327,334
Title of research award:
Endothelial Cell-Leukocyte Interactions: Atomic Force Microscopy StudiesEndothelial Cell-Leukocyte
Interactions: Atomic Force Microscopy Studies
Lay Description (from application):
Not Available
Research achievements (from final report):
The research project conducted during my training fellowship enhanced my knowledge and expertise in the
field of diabetes and cardiovascular disease. The knowledge and techniques acquired from this project has
contributed to the understanding of diabetes and its complications in basic research. The project contributed to
help my understanding of the microvascular complications of diabetes and the basic mechanisms which control
local microvascular haemodynamics. The results from the project indicate that high-density lipoproteins (HDL:
"good cholesterol") has a vasoprotective effect on vascular cells by inhibiting reactive oxygen species
generation. However once HDL is glycated, as in diabetes, its protective effects are reduced. Study results have
shown that albumin suppresses intracellular reactive oxygen species generation, but when modified by
advanced glycation end products, albumin's potency is suppressed. Ultimately, results will lead to further
research and provide rationale for the development of new pharmacological approaches that could be used as
an adjunct to currently used therapies to improve the lives of people with cardiovascular disease and diabetes.
The envisaged drugs are those that may reduce protein modifications, such as advanced glycation end products,
and/or increase vascular endothelial cell resistance to oxidative stress.
Expected future outcomes:
Further understanding of the mechanistic relationship between protein modification, diabetes and
cardiovascular disease.
Name of contact:
Stephanie de Dios
Email/Phone no. of contact:
stephdedios@hotmail.com
NHMRC Research Achievements - SUMMARY
Grant ID: 406620
Start Year: 2006
CIA Name: Dr Adam Hart
End Year: 2008
Admin Inst: Monash University
Grant Type: NHMRC Project Grants
Main RFCD: Cell Development (incl. Cell Division and Apoptosis)
Total funding: $491,768
Title of research award:
The regulation of pluripotency and self-renewal in embryonic and germline stem cells.The regulation of
pluripotency and self-renewal in embryonic and germline stem cells.
Lay Description (from application):
Regulation of self-renewal and developmental potential in embryonic and germline stem cells. The capacity of
some stem cells to self-renew and under specific conditions, give rise to all adult cell types, a property known
as pluripotency , is the key to unlocking the potential of cell based therapies. The development of stem cell
based therapies promises to revolutionize the treatment of many common human diseases. For instance, in
neurodegenerative conditions such as Parkinsons disease, normal embryonic stem cells grown in culture could
be used to replace the lost or disabled neurons in the patient. Many other conditions including diabetes, cystic
fibrosis, myocardial infarction (heart attack) and stroke could potentially be treated with stem cell based
therapies. Understanding the molecular regulators that govern establishment and maintenance in culture of
stem cell lines derived from embryos and from germ cells is the primary goal of this study. We will use wellestablished techniques to genetically manipulate mouse embryonic stem cells and embryos to examine the role
of a specific gene, NANOG. Named after the Celtic legend of Tir NaNog (land of the ever young). When
NANOG was forced to remain active, embryonic stem cells were able to grow in media deficient in factors
usually required for self-renewal and did not lose their pluripotency even when treated with chemical agents
that usually induce differentiation. Understanding the full capacity of NANOG to influence stem cell selfrenewal and elucidation of the underlying molecular pathways regulated by this gene will provide valuable
insights into the establishment and manipulation of stem cell lines from embryonic and adult tissues.
Research achievements (from final report):
The pluripotency homeobox gene NANOG was identified as an early genetic marker of human germ cell
tumors. This marker can be now be used to reliably diagnose the earliest forms of testicular and metastatic
germ cell tumor, enabling more rapid identification and treatment of this life threatening disease (Hart, AH., et.
al., 2005)., We investigated the role of the NANOG gene in normal development and cancer using genetically
manipulated cell lines and mice, demonstrating that this gene is essential for stem cell survival in the early
embryo. The genetically manipulated stem cells and mouse lines haveyielded an important insight into the
molecular basis of stem cell survival and self renewal. These tools will now enable further research into the
molecular regulation of embryonic and adult stem cells and the pathogenesis of germ cell tumours and some
other forms of cancer. , Identification and manipulation of nanog and other key stem cell genes will provide a
theoretical basis for the manipulation of embryonic and adult stem cell lines prior to application in cell based
therapies in a range of acute and chronic degenerative diseases., The genetically manipulated mice represent a
valuable resource for further investigation of the putative cancer stem cell that is thought to be the originating
cell of many tumor types, including mammary, colorectal, germ cell. leaukemias and lung cancer.
Expected future outcomes:
1. The germ cell tumor marker Nanog will be used in the clinical identification and classification of testicular
and metastatic tumours of germ cell origin. The Nanog mutant mice will be used to identify and analyse adult
stem cells.
Name of contact:
Adam Hart Phd
NHMRC Research Achievements - SUMMARY
Adam Hart
Email/Phone no. of contact:
adam.hart@med.monash.edu.au
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: 436634
CIA Name: Prof Richard Boyd
Admin Inst: Monash University
Main RFCD: Autoimmunity
Total funding: $5,554,618
Start Year: 2007
End Year: 2011
Grant Type: Programs
Title of research award:
Innovative stem cell-based strategies to establish immune tolerance and tissue repairInnovative stem cell-based
strategies to establish immune tolerance and tissue repair
Lay Description (from application):
Diseases such as autoimmune gastritis, multiple sclerosis and diabetes arise because a "rogue" immune system
has turned inwards to attack our organs. The organ destruction follows from recognition by the immune system
of specific molecules in these organs. These
"autoimmune" diseases are incurable and controlled mainly by long-term administration of substances that
suppress the immune
system, often with serious side-effects. A rational approach is to render the rogue immune system harmless by
removing the cells that
recognize these particular molecules. This can be achieved by a "Trojan horse" approach in which the
molecules are delivered to the
immune system such that that the immune cells that recognize them are removed. To deliver these molecules to
the immune system we
will genetically engineer bone marrow stem cells, or embryonic stem cells that generate these stem cells,
because they are precursors of
mature immune cells. Rejection of organ transplants arise in a similar way and also require long-term
immunosuppression. A similar
approach can therefore be taken to promote acceptance of foreign organ grafts. In the aged, we will combine
these approaches with
rejuvenation of the immune system by blockade of sex steroid production and/or by creation of a new immune
organ.
Research achievements (from final report):
One of the greatest challenges in the clinic is the treatment of autoimmune disease. Being the result of
abnormal immune responses, the clinical handling of these conditions is typically through a form of
chemotherapy. This has achieved some level of success but there are two major problems: by definition, the
level of chemotherapy or anti-inflammatory drugs necessary to stop disease progression almost by definition
creates a potentially even greater clinical problem- generalised immune suppression. This lack of immunity can
lead to outbreak of severe infections, which can be lethal. The secret to overcoming these issues is to hijack the
normal mechanisms of self-tolerance and apply them to the treatment of autoimmunity. This has at its essence
the thymus, which creates all T cells necessary for immune responses but eliminates those which are
potentially autoreactive. The reason it has not been manipulated to treat autoimmunity is because this organ
undergoes severe atrophy early in life. This program made a major advance to the field - it developed a means
of reactivating the seemingly dormant thymus and combined this with bone marrow transplantation and a very
low dose-conditioning regime. It also established the technology for identifying thymus stem cells and then
creating them from pluripotential stem cells as a means of growing a completely new thymus. By combining
these collective studies with that of intense research in neural development and disease, we now have a unique
platform for treating autoimmunity - particularly multiple sclerosis. The program also produced a number of
invaluable reagents and technologies for other studies on the immune and neural systems, and for the general
field of preventing rejection of donor transplants. We have thus established a unique platform for firstly
understanding how self tolerance is broken to allow development of disease and then exploring new ways of
treating autoimmunity.
Expected future outcomes:
NHMRC Research Achievements - SUMMARY
There are several very important application of this research, particularly clinically. We can trial restoration of
a functional thymus and immune capacity and combine this with donor haemopoietic and therapeutic stem cells
to generate new T cells which are both donor and self tolerant. The ability to create a thymus from stem cells
can be applied to many immunological diseases.
Name of contact:
Professor Richard Boyd
Email/Phone no. of contact:
richard.boyd@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 436740
CIA Name: Dr James Whisstock
Admin Inst: Monash University
Main RFCD: Enzymes
Total funding: $500,460
Start Year: 2007
End Year: 2009
Grant Type: NHMRC Project Grants
Title of research award:
Structural and Functional Studies on Glutamate Decarboxylase.Structural and Functional Studies on Glutamate
Decarboxylase.
Lay Description (from application):
This proposal aims to determine the molecular structure of the two known isoforms of Glutamate
Decarboxylase (GAD65 and GAD67). GAD in an essential human enzyme that is responsible for synthesising
the primary inhibitory neurotransmitter gamma-aminobutyric acid (GABA). GABA functions in the human
Central Nervous System (CNS) to "dampen down" excitatory signals. Proper control of GABA synthesis is
important and perturbations in GABA levels lies behind human diseases such as intractable epilepsy,
depression and schizophrenia. As a result of this role, numerous common therapeutics (for example
benzodiazepines) target proteins involved in the GABA neurotransmitter system. The goal of this proposal is
to use the molecular structures of GAD to understand how to achieve fine control of GABA production. In
addition to its role in the CNS, GAD is an important human autoantigen. Antibodies to one isoform of GAD,
GAD65, are found in most patients with type I diabetes as well as certain patients with the movement disorder
stiff person syndrome and related diseases of the CNS. It is suggested that the development of auto-antibodies
may play a key role in the pathophysiology of these conditions. Despite sharing >80% sequence similarity
with GAD65, autoantibodies to the other isoform of GAD, GAD67, are rarely found in patients with disease.
The aim of this grant is to characterise the region of GAD that is targetted by autoantibodes. These data will
allow us to understand why certain autoantibodes are able to inhibit GAD enzyme activity and why GAD65,
but not GAD67 is recognised by autoantibodes.
Research achievements (from final report):
We have determined the structure of both forms (GAD65 and GAD67) of the enzyme that in humans produces
the inhibitory neurotransmitter GABA. These data are the subject of a number of high quality publications
(including a paper in Nature Structural and Molecular Biology as well as a patent (PCT)). , , Perturbations in
GABA levels are linked to important diseases, including depression and anxiety disorders. Our structural data
suggest that it may be possible to modulate (increase) the activity of GAD65 with small molecule therapeutics
and that GAD65 may be an important drug target.
Expected future outcomes:
We have estabished a crucial assay that will permit us to screen for small molecule activtators of GAD65. We
have recently obtained funding to perform this screen with the long-term goal of developing a new class of
drugs for the treatment of anxiety disorders.
Name of contact:
James Whisstock
Email/Phone no. of contact:
James.Whisstock@med.monash.edu.au
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: 436781
CIA Name: Prof Patrick Sexton
Admin Inst: Monash University
Main RFCD: Basic Pharmacology
Total funding: $340,400
Start Year: 2007
End Year: 2008
Grant Type: NHMRC Project Grants
Title of research award:
Molecular characterisation of receptor activity modifying proteins (RAMPs)Molecular characterisation of
receptor activity modifying proteins (RAMPs)
Lay Description (from application):
The maintenance of optimum health and function of living cells, and consequently that of the whole organism,
depends on how cells respond to a multitude of physical and chemical stimuli that continually bombard them.
The majority of the chemical stimuli such as hormones and neurotransmitters impart their actions not by
directly entering the cell, but instead, by binding to a specific receiver protein at the cell surface called a
receptor. In one class of such receptors called G protein-coupled receptors, the transmission of the message to
the interior of the cell involves yet another protein called G protein. These receptors are the most abundant type
of cell surface receptors and form the targets for nearly 50% of currently used therapeutic drugs. It is, therefore,
extremely important to unravel how each of these components works. To make this process even more
complex, it was recently shown that another newly discovered group of proteins called receptor activity
modifying proteins (RAMPs) too play a critical role in some systems. We have shown that RAMPs interact
with many G protein-coupled receptors and that they have a wider range of actions than has previously been
appreciated. Moreover, it has been shown that the RAMP-receptor interface is a viable target for drug
development. Understanding the extent to which RAMPs interact with G protein-coupled receptors, how they
interact with the receptors and the consequences of this interaction forms the basis of the current proposal.
Such knowledge is central to the unraveling of the processes involved in the maintenance of health,
abnormalities that lead to disease, and in the development of new treatments.
Research achievements (from final report):
G protein-coupled receptors (GPCRs) are the largest family of cell surface receptors and form one of the most
important classes of drug targets. Receptor activity modifying proteins are a family of 3 accessory proteins that
interact with specific GPCRs to change their cellular location, spectrum of ligand interaction or how they are
regulated. In this work we have further explored the nature and extent of RAMP interaction with GPCRs to
reveal previously unknown GPCR-RAMP interactions plus also new knowledge on the potential consequence
of this interaction, specifically, the strength of coupling to different intracellular signaling pathways. This work
demonstrates increased breadth in the way that cells can respond to their environment, which may provide
novel opportunity for drug development. Additionally, we have demonstrated that PreProCT and ProCT,
circulating proteins that are highly elevated during sepsis, interact preferentially with RAMP-based receptors
with potential implication for mechanism of action of these peptides in the poor prognosis seen with sepsis.
Expected future outcomes:
Discovery of additional RAMP interacting receptors and elucidation of physiological consequence of these
interactions. This will provide new insight into GPCR diversity and potentially provide scope for new
therapeutic interventions, particularly in relation to diabetes/obesity and migraine.
Name of contact:
Prof. Patrick M. Sexton
Email/Phone no. of contact:
patrick.sexton@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 436797
CIA Name: Dr Velandai Srikanth
Admin Inst: Monash University
Main RFCD: Epidemiology
Total funding: $510,223
Start Year: 2007
End Year: 2009
Grant Type: NHMRC Project Grants
Title of research award:
A study of mechanisms of cognitive decline in Type 2 diabetes mellitusA study of mechanisms of cognitive
decline in Type 2 diabetes mellitus
Lay Description (from application):
Diabetes mellitus and dementia are major public health problems. Diabetes may increase the risk of dementia.
This study aims to uncover the mechanism by which diabetes may increase dementia risk. This may lead to
finding new ways to prevent or treat diabetes-related dementia and thus reduce the public health burden of
dementia.
Research achievements (from final report):
The primary aim is to study mechanisms of cognitive decline in Type 2 diabetes mellitus, postulating an
important role for cerebrovascular disease, neurodegeneration and advanced glycation endproducts
(AGEs).The recruitment of 300 people with Type 2 DM has been finally completed and measurements have all
been undertaken. Currently we are in the process of cleaning data, completing grading of carotid measurements
and beginning the analyses to answer the primary study hypotheses. The recruitment of the entire sample took
longer ~6-8 months longer than predicted. Hence the analytical phase and publication preparation will occur
this year. In the meanwhile there have been two articles published, an editorial comment and a review article
and 2 conference presentations in the final year of the grant.
Expected future outcomes:
Completion of data cleaning, analyses and publication are occurring this year (2010)
Name of contact:
A/Prof Velandai Srikanth
Email/Phone no. of contact:
velandai.srikanth@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 436866
CIA Name: Prof Andrew Forbes
Admin Inst: Monash University
Main RFCD: Epidemiology
Total funding: $188,538
Start Year: 2007
End Year: 2008
Grant Type: NHMRC Project Grants
Title of research award:
Fitness versus fatness: Disentangling their effects on disease outcomes and estimating the population burden of
diseaseFitness versus fatness: Disentangling their effects on disease outcomes and estimating the population
burden of disease
Lay Description (from application):
Overweight and physical inactivity are two of the major risk factors for cardiovascular disease and diabetes.
With increasing population levels of overweight, governments are increasingly advocating public health
measures aimed at increasing physical activity levels or otherwise decreasing weight. There has been much
research concerning which of these factors is the key prognostic factor for adverse health outcomes, but an
ongoing lack of clarity of research findings has led to uncertainty as to the direction of recommendations for
preventive health strategies and population lifestyle changes. In addition, the risks of overweight, in particular,
have been accused of being exaggerated in both the scientific and lay literature. This is often due to the
difficulty of dealing appropriately with time varying confounders which are also intermediate factors (such as
hypertension). To date, no studies have performed careful longitudinal modelling of the joint effects of
physical inactivity and overweight on cardiovascular events and diabetes while taking into account the effects
of factors, such as hypertension or atherosclerosis, that influence both physical activity and overweight as well
as disease, and simultaneously are consequences of these risk factors. Standard statistical methods are known
to produce biased estimates in these situations but we will apply more recently developed statistical techniques
to provide much improved estimation of these effects. After the statistical modelling stage, we will model the
burden of diabetes, cardiovascular disease and mortality associated with given levels of overweight and
physical inactivity. These will be combined with population levels of overweight and inactivity to identify the
fraction of the current and future burden of disease attributable to these risk factors.
Research achievements (from final report):
This project enabled estimation of the effects of physical activity on cardiovsacular disease that is free from
methodological problems of the relationship with obesity and other lifestyle factors or attributes that have
plagued prior studies. Although the finding that physical activity is beneficial for health is not new, the
research has identified how currency, recency and distant or lifetime activity inter-relate to risk.
Expected future outcomes:
These findings reinforce existing strategies for promoting health, and have provided a clearer evidence base for
this.
Name of contact:
Andrew Forbes
Email/Phone no. of contact:
Andrew.Forbes@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 443214
CIA Name: Prof Brian Oldenburg
Admin Inst: Monash University
Main RFCD: Preventive Medicine
Total funding: $708,607
Start Year: 2007
End Year: 2011
Grant Type: NHMRC Project Grants
Title of research award:
Using conversational computer technology to improve diabetes management: A randomised controlled
trialUsing conversational computer technology to improve diabetes management: A randomised controlled trial
Lay Description (from application):
The diabetes epidemic is a growing challenge for the Australian health care system with over 1 million
Australians living with diabetes. The impact on individuals' lives and the whole of Australian society is very
substantial indeed. There is very good evidence that this impact would be reduced by developing new
approaches to manage the disease and facilitate improved self-management. Recent developments in
information and communications technologies offer some promising new ways and tools for achieving this.
This research will evaluate a computer-controlled, interactive telephone system for improving the management
and self-management of Type 2 diabetes in addition to routine care. Patients with Type 2 diabetes will be
recruited from Brisbane and each patient will be randomly assigned to receive either this new program or just
their usual care from their doctor or Diabetes Clinic. The first group will call the system weekly for six months
using a regular phone or a mobile phone if they wish. During the call, they will answer questions by speaking
into the phone, listen to feedback and strategies for improving management of their diabetes and then "discuss"
their next targets and behavioural actions. They will receive systematic and tailored advice on blood glucose
testing, nutrition and physical activity, as well as medication taking and foot care. The system individualises
conversations according to the user s answers and responses over all the interactive sessions. The trial will
formally evaluate the clinical impact on blood glucose control and the adoption and maintenance of the
targeted health habits, as well as the intervention s cost-effectiveness and users satisfaction with the system.
This project s significance lies in the excellent potential of using this new technology to provide a 'low cost' but
effective program to help people better manage Type 2 diabetes.
Research achievements (from final report):
The impact of the diabetes epidemic on individuals and society is severe but can be reduced by improving
diabetes self-management. This research evaluated an automated interactive telephone system designed to
improve type 2 diabetes self-management. The system, called TLC diabetes, consists of a computer equipped
with speech recognition, pre-recorded conversation statements and a database in which users' answers are
stored to be used in future conversations. Adults with type 2 diabetes who accessed the TLC Diabetes
programme significantly improved their diabetes management compared to the group receiving routine care
only. The programme was also shown to improve quality of life. Importantly, user adoption was very good.
Users, of average age 58.4 years, found the system easy to use. They completed 75% of the expected weekly
calls. These results show that this information and communication technology provides a potential solution to
the increasing demand placed on the health systems by the growing number of people diagnosed with diabetes
every day. It can assist people better manage their condition from the comfort and the privacy of their home at
a time that is convenient for them. A large scale implementation of this type of teleheath could help address the
urgent need for effective, inexpensive and easily accessible resources for self-management of chronic
conditions.
Expected future outcomes:
Future work will concentrate on integrating this low cost and effective telephone-delivered program with other
information and communication technologies such as mobile and web applications and explore options to link
it to patients' electronic care plans. This will enhance the program's sustainaility and ability to complement
government efforts to improve the management of chronic conditions .
Name of contact:
Professor Brian Oldenburg
NHMRC Research Achievements - SUMMARY
Email/Phone no. of contact:
brian.oldenburg@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 465199
CIA Name: Prof Edouard Stanley
Admin Inst: Monash University
Main RFCD: Medical Biotechnology
Total funding: $2,968,051
Start Year: 2007
End Year: 2012
Grant Type: International Collaborations
Title of research award:
Derivation of Pancreatic Beta cells from embryonic stem cellsDerivation of Pancreatic Beta cells from
embryonic stem cells
Lay Description (from application):
People with type 1 diabetes require regular insulin injections because the organ that normally makes insulin,
the pancreas, no longer functions. The goal of this program is to derive human fetal pancreas tissues from
embryonic stem cells. Such tissue could be used to replace the missing insulin producing cells in people with
type 1 diabetes. The program brings together expertise in ES cell biology at Monash University and the leading
diabetes research at the Walter and Eliza Hall Institute.
Research achievements (from final report):
Insulin is a hormone that is needed to control the level of glucose in the blood stream. Type 1 diabetes is
caused by loss of insulin producing pancreatic beta cells. People with type 1 diabetes replace this lost insulin
by injecting insulin at least 3 times a day, a task that is very onerous. However, insulin injection does not fully
replace the function of lost beta cells, and as such, people with life long diabetes have a heightened risk of
developing conditions that effect their quality of life and ultimately, their longevity. These problems could be
remedied if the lost beta cells could be replaced by beta cells made from stem cells. The aim of this proposal
was to generate tools that enabled the analysis of beta cell production from stem cells and then to use these
tools to optimise beta cell production protocols. These tools came in the form of genetically modified cell lines
that glowed different colors as they underwent the process of changing from stem cells into beta cells. During
the course of this program we successfully generated a number of these lines and have distributed them to
several international laboratories that have similar aims. We also used these lines to learn how to coax the stem
cells towards becoming beta cells. These last studies enabled us to generate insulin producing cells that were
very close to functional beta cells. Our work has contributed significantly to knowledge concerning the way
beta cells are made and has provided valuable tools for others seeking to find a cure for type 1 diabetes.
Expected future outcomes:
The main future benefit of this work is that it has provided researchers around the world with new tools to
study how beta cells are made and how they work. This in turn will accelerate efforts to generate replacement
beta cells for people with type 1 diabetes.
Name of contact:
Ed Stanley
Email/Phone no. of contact:
ed.stanley@mcri.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 490938
CIA Name: Prof Susan Davis
Admin Inst: Monash University
Main RFCD: Endocrinology
Total funding: $690,082
Start Year: 2008
End Year: 2012
Grant Type: NHMRC Research Fellowships
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
I am an academic endocrinologist and clinician. I lead a large research program that investigates the links
between hormones and diseases of ageing in women. Thus my research program addresses the contribution of
changes in adrenal and ovarian steroids in
Research achievements (from final report):
I lead and published the largest and longest efficacy and safety study of the use of testosterone therapy for
women, a placebo-controlled RCT of 800 women recruited across 3 continents (NEJM Davis et al 2008). I
established the BUPA Health and Well Being After Breast Cancer Study which recruited 1684 women within
their 1st year of breast cancer (BC) diagnosis 2004-6. This is the largest longitudinal study to report on factors
substantially impacting BC survivors, ranging from sexual dysfunction through to determinants of wellbeing
and patterns of adherence to endocrine therapy. This study has resulted in 18 publications to date and a number
of manuscripts in preparation.My group has reported on the prevalence, incidence and risk factors for urinary
incontinence (UI) in women and the incidence of fecal incontinence in women. I conducted the first study of
UI in young women who have never been pregnant and showed that 1 in8 such women have UI. I developed
the PROSPECT tool for health practitioners to identify the women 70 + years most likely to have
osteroporosis/fracture. I also developed and validated a sexual function questionnaire now used by researchers,
and a menopause stageing questionnaire. I have completed several studies exploring the role of sex steroids on
cognitive performance in women. ?????
Expected future outcomes:
To document the prevalence and severity of menopausal symptoms and of depression in Australian women at
midlife, their use of prescribed and complimentary and alternative therapies, plus a range of other studies of
midlife women's health.
Name of contact:
Susan Davis
Email/Phone no. of contact:
Susan.Davis@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 490998
CIA Name: A/Pr Sophia Zoungas
Admin Inst: Monash University
Main RFCD: Endocrinology
Total funding: $143,661
Start Year: 2008
End Year: 2011
Grant Type: Early Career Fellowships (Australia)
Title of research award:
Glycaemia and cardiovascular disease outcomes in patients with diabetes and CKD: methodology, relationship
andGlycaemia and cardiovascular disease outcomes in patients with diabetes and CKD: methodology,
relationship and
Lay Description (from application):
Diabetes is increasing and now the primary cause of chronic kidney disease (CKD). At present the care of
people with diabetes and CKD aims to achieve normal blood glucose levels in the safest possible way in order
to prevent acute and chronic complications and improve outcomes and quality of life. In this project we will
examine the best means by which to measure, monitor and treat blood glucose levels in such people and
explore the effect of intensive blood glucose control.
Research achievements (from final report):
This research of people with type 2 diabetes sought to identify the optimum method by which to accurately
monitor blood glucose control in those with chronic kidney disease, to assess the effects of glucose lowering on
health outcomes and to determine the safest way to lower glucose levels. The results to date highlight the
importance of self-monitoring of blood glucose levels as well as HbA1c measurement in the day to day
management of people with chronic kidney disease, the important factors that predict vascular comnplications
and the separate and combined beneficial effects of glucose lowering and blood pressure control on vascular
disease and kidney outcomes.
Expected future outcomes:
Ongoing work is examinining the efficacy and safety of glucose lowering therapies in people with diabetes and
chronic kidney disease so that clear guidance on safe prescribing can be provided.
Name of contact:
A/Prof Sophia Zoungas
Email/Phone no. of contact:
sophia.zoungas@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 491031
Start Year: 2008
CIA Name: A/Pr Lisandra Martin
End Year: 2011
Admin Inst: Monash University
Grant Type: NHMRC Project Grants
Main RFCD: Pharmaceutical Sciences and Pharmacy
Total funding: $445,011
Title of research award:
Long acting Insulin: Drug design, in vitro activity through to animal model efficacyLong acting Insulin: Drug
design, in vitro activity through to animal model efficacy
Lay Description (from application):
This research will develop novel insulins that possess improved stability and activity for diabetic patients. The
improved pharmacological actions of the modified insulins offer increased treatment options for patients eg.
enabling less frequent or invasive medication. Our cross-disciplinary team will (i) design & synthesise insulin
derivatives, (ii) explore the activity of the modified insulins by biophysical activity profiles in vitro, (iii)
evaluate the in vivo stability and clinical effects.
Research achievements (from final report):
The new dicarba-insulin analogues generated and evaluated in this project possess superior metabolic:
mitogenic profiles, biostability and formulation stability to currently available insulin preparations and will
have immediate and significant impact on the global diabetes market, including the Australian population of
diabetes/pre-diabetes sufferers, estimated to be 3.2 million people. These analogues have been generated using
novel, state of the art catalytic and peptide chemistry and have been designed to cover fast and slow onset
formulations. The resultant novel dicarba insulins possess unrivaled metabolic-mitogenic profiles: Full
metabolic activity is observed in in vitro binding and activation studies and in vivo activity is also comparable
to human insulin preparations. The synthetic modifications, however, prevent activation of the IGF receptor, a
target that has long been associated with the potential for adverse mitogenic activity. Towards this end, we
have generated a dicarba glargine analogue, a long acting analogue with cancer concerns, with full metabolic
activity devoid of mitogenic activity mediated via the IGF receptor. The dicarba insulins have also been
assessed for their physical stability and shown to be stable without the need for refrigeration. This is a
significant finding which will facilitate the distribution of insulins to remote and under-resourced communities.
The dicarba substitution is also offering insight into the key determinants responsible for the activation of the
insulin receptor. Full knowledge of this elusive mechanism of action will provide much needed information for
the design of non-proteinogenic mimetics of human insulin.
Expected future outcomes:
More than 20 dicarba insulin analogues were synthesized and evaluated in this project. The molecules have
performed beyond all expectation. IP protection has been sought and several international pharmaceutical
companies are interested in the research. Publications were therefore delayed in order to file provisional
patents.
Name of contact:
Andrea J Robinson
Andrea Robinson
Email/Phone no. of contact:
Andrea.Robinson@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 491058
CIA Name: Prof Jennifer Wilkinson-Berka
Admin Inst: Monash University
Main RFCD: Opthalmology and Vision Science
Total funding: $733,841
Start Year: 2008
End Year: 2010
Grant Type: NHMRC Project Grants
Title of research award:
Receptor-mediated Actions of Prorenin in Diabetic RetinopathyReceptor-mediated Actions of Prorenin in
Diabetic Retinopathy
Lay Description (from application):
Despite improvements in patient care, the incidence of diabetic retinopathy is dramatically increasing. Recent
evidence suggests that a component of a hormonal system, called prorenin, may participate in the development
of diabetic organ disease. We will evaluate the role of prorenin in vascular and nerve damage in animal models
of diabetic retinopathy. We will determine if a new inhibitor of prorenin, prevents retinal injury and is a
potential treatment for diabetic retinopathy.
Research achievements (from final report):
Diabetic retinopathy is the major cause of vision loss and blindness in people of working age. Almost all
people with type 1 diabetes and approximately 65% of people with type 2 diabetes will develop retinopathy,
with many individuals progressing to the severe form of the disease. The current treatments for diabetic
retinopathy are limited as they do not target the early stages of the disease, are invasive and may cause damage
to the retina. Research from our laboratory has established that in animal models of diabetic retinopathy that
blockade of a body hormonal system called renin-angiotensin is a potential treatment for diabetic retinopathy.
In particular, the role of prorenin and its receptor, the (pro)renin receptor, may play an important role in blood
vessel and nerve damage in the diabetic retina and hence be a target for treatment. This research grant
identified the cellular location of prorenin and the (pro)renin receptor in the retina of animals with retinopathy
and evaluated the events by which they influence retinal cell injury. Recent evidence published in the highly
respected biomedical journal, Science, has identified further ways in which the (pro)renin receptor may
influence fundamental cell processes in the brain and the retina. This discovery together with our recent
findings has lead to a new avenue of study of prorenin and the (pro)renin receptor in diabetic retinopathy. It is
hoped that this new information will lead to the development of improved treatments for diabetic retinopathy
and possibly other retinal diseases.
Expected future outcomes:
Given our recent findings and new exciting developments in the area of (pro)renin receptor research we have
established a new research program to evaluate the signalling mechanisms by which prorenin and/or the
(pro)renin receptor influence blood vessel damage, inflammation, and neuronal damage in the developing and
diseased retina.
Name of contact:
Jennifer Wilkinson-Berka
Email/Phone no. of contact:
Jennifer.Wilkinson-Berka@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 491094
CIA Name: Prof Bryan Williams
Admin Inst: Monash University
Main RFCD: Autoimmunity
Total funding: $630,622
Start Year: 2008
End Year: 2010
Grant Type: NHMRC Project Grants
Title of research award:
Role of the IFN-induced helicase IFIH1 in type 1 diabetesRole of the IFN-induced helicase IFIH1 in type 1
diabetes
Lay Description (from application):
Type 1 diabetes (T1D) is presently the most common chronic disease of childhood and is increasing, with
incidence in children under five doubling over the last five years. Recent findings indicate the ifih1 gene is
important in T1D. Our research aims to establish the contribution of this gene to the disease. It is hoped that
recognition of relevant pathological molecules will allow identification of risk factors for disease development
and, ultimately, targets for therapeutic intervention.
Research achievements (from final report):
We have demonstrated that IFIH1 mediates the immune response to rotovirus, which is considered an
etiological agent for the development of type-I diabetes. In addition, we show that genetic polymorphisms
associated with the risk of developing type-I diabetes affect the function of IFIH1, thereby establishing a
potential innate immune mechanism in defects that may lead to autoimmunity. We show that impaired IFIH1
function affects the induction of type-I interferons in response to rotavirus, implicating this cyokine as part of
the mechanism of autoimmunity. We also recognised that gene polymorphisms associated with the risk of
developing type-I diabetes do not simply translate to lost protein function, as initially presumed, but to
regulation of protein activity. This alters the manner in which it had been envisaged that mutations in IFIH1
might induce autoimmunity.
Expected future outcomes:
Our findings indicate an alternative consequence to IFIH1 function to that anticipated, changing our perception
of how this gene product modulates autoimmune disease. In addition, we believe we have identified a novel
antiviral activity that may be important in lentivirus infections.
Name of contact:
Professor Bryan Williams
Email/Phone no. of contact:
bryan.williams@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 491123
CIA Name: Prof Leon Bach
Admin Inst: Monash University
Main RFCD: Endocrinology
Total funding: $493,221
Start Year: 2008
End Year: 2010
Grant Type: NHMRC Project Grants
Title of research award:
The role of ezrin-radixin-moesin proteins, novel binding proteins for advanced glycation endproducts, in
kidney cellsThe role of ezrin-radixin-moesin proteins, novel binding proteins for advanced glycation
endproducts, in kidney cells
Lay Description (from application):
High glucose levels in diabetes react with proteins to form AGEs and it is thought that this reaction may lead to
kidney damage, which is one of the complications of diabetes. However, how this damage occurs is not
completely understood. Cells need to maintain their shape and position for an organ to stay healthy. We have
shown that AGEs affect kidney cells by interacting with and disturbing the function of proteins that maintain
cell shape. We now want to study how this occurs.
Research achievements (from final report):
We have defined the nature of an interaction between proteins that are modified by the high glucose levels in
diabetes and another protein that regulates important cellular functions in kidney cells. Glucose-modified
proteins interfere with the actions of the regulatory protein and increase its breakdown. This interaction may
contribute to kidney damage caused by diabetes.
Expected future outcomes:
If the role of the above interaction in diabetic kidney disease is confirmed, it may lead to new treatments for
this condition.
Name of contact:
Leon Bach
Email/Phone no. of contact:
leon.bach@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 491169
CIA Name: Dr Dana Hutchinson
Admin Inst: Monash University
Main RFCD: Basic Pharmacology
Total funding: $105,590
Start Year: 2008
End Year: 2008
Grant Type: NHMRC Project Grants
Title of research award:
Understanding the mechanisms used by G-protein coupled receptors to regulate insulin-independent glucose
transportUnderstanding the mechanisms used by G-protein coupled receptors to regulate insulin-independent
glucose transport
Lay Description (from application):
In type 2 diabetes, stimulation of glucose transport in fat cells and skeletal muscle by insulin is impaired. As a
result there is great interest in identifying insulin-independent mechanisms that increase glucose transport.
Several G-protein coupled receptors (GPCRs) regulate glucose transport independently of insulin but the
mechanisms involved in these effects are largely unknown. This project investigates how GPCRs regulate
glucose transport for potential as treatments.
Research achievements (from final report):
Obesity and type 2 diabetes is increasingly more prevalent in our society and at present there is no definite
treatment for either disease. Insulin is an important mediator for the regulation of glucose homeostasis and
glucose uptake, but these processes can be regulated independently of insulin by activation of G proteincoupled receptors. This work has identified novel targets activated by adrenergic stimuli in skeletal muscle,
adipose tissue and brain that will assist in the understanding of mechanisms likely to be important for the
development of novel treatments for type 2 diabetes and obesity. This work has advanced our understanding of
how adrenoceptors and other G protein-coupled receptors affect glucose metabolism in tissues important for
glucose homeostasis.
Expected future outcomes:
This work has advanced our knowledge of the mechanisms whereby adrenoceptors stimulate glucose uptake in
cells. This work has the potential to identify novel ways of treating obesity and type 2 diabetes by G proteincoupled receptor activation.
Name of contact:
Dr Dana Hutchinson
Email/Phone no. of contact:
dana.hutchinson@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 491171
Start Year: 2008
CIA Name: Prof Lenore Manderson
End Year: 2012
Admin Inst: Monash University
Grant Type: NHMRC Strategic Awards
Main RFCD: Complementary-Alternative Medicine not elsewhere classified
Total funding: $663,577
Title of research award:
Care-seeking, use of CAM, and self-management among people with Type 2 Diabetes andCare-seeking, use of
CAM, and self-management among people with Type 2 Diabetes and
Lay Description (from application):
Chronic disease and related health problems are increasing in prevalence in Australia. Recent estimates suggest
that Type 2 diabetes and heart disease cost the Australian community almost $9 billion in direct costs per
annum. People with chronic conditions follow medical and behavioural prescriptions variably, however, while
also using complementary and alternative (CAM) therapies, practitioners, vitamins and herbs. We will explore
the reasons for presentation to and use of CAM practitioners and therapies by people diagnosed with and under
treatment for two of the most commonly diagnosed chronic conditions - cardiovascular disease and diabetes in order to establish the relationship with adherence to their prescribed treatment. The focus is on what is
described as the “drivers, costs and benefits” of the use of CAM, and how the practical interaction of CAM and
conventional health care approaches may support adherence. This research program will have very important
implications for the control of these diseases and individual wellbeing. Using an innovative interdisciplinary
approach and a mix of research methods, the research will provide a unique evidencebase on community
approaches to and use of complementary and alternative medicine, and the significance of this to current and
future health needs. The program will take advantage of the interdisciplinary skills in novel ways to explore
areas of health and society that have so far received limited attention. By including two PhDs, we will
strengthen Australia’s research capacity in health social sciences and public health in this field, generating new
skills important to population health practice and policy in this country.
Research achievements (from final report):
Our research data indicated that 43% of older Australians with diabetes or heart disease used CAM in the
survey year, including 11.9% to manage these two conditions. Among CAM users, 86.4% used vitamin,
mineral or other nutritional supplements, with 42.3% having these prescribed by a medical doctor; followed by
massage or manipulative therapies (45.9%); western herbal medicine (26.9%); meditation, prayer or spiritual
healing (22.1%); Chinese, oriental medicine or acupuncture (14.5%); homeopathy (10.4%); and so on. Most
people used multiple modalities and combined CAM and medical treatments. However, many people used
CAM without supervision of a complementary, alternative or medical practitioner, 20.2% had never discussed
CAM use with their medical doctor(s), and 37.7% only sometimes discussed it. There were demographic
differences between CAM non-users, CAM practitioner users, and CAM product only users, although rather
than the expected tendency for middle-aged middle-class women to dominate, CAM use tended to be
associated with the presence of co-morbidities and chronic and complex health problems. Cost factors
prevented 25.8% of all respondents from accessing CAM. People indicated that doctor's recommendations and
government subsidization of CAM would increase their use of CAM.
Expected future outcomes:
We will conduct further study on the relationship of CAM use and chronic complex health problems, while
disseminating our findings to enhance quality of care.
Name of contact:
Lenore Manderson
Email/Phone no. of contact:
lenore.manderson@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 491181
Start Year: 2008
CIA Name: Prof Christopher Porter
End Year: 2011
Admin Inst: Monash University
Grant Type: NHMRC Project Grants
Main RFCD: Pharmaceutical Sciences and Pharmacy
Total funding: $398,157
Title of research award:
Recognition of macromolecular complexes by cell surface receptors: A novel mechanism of lipid and drug
absorptionRecognition of macromolecular complexes by cell surface receptors: A novel mechanism of lipid
and drug absorption
Lay Description (from application):
A clear understanding of the mechanisms by which orally ingested materials are absorbed from the
gastrointestinal tract is critical in areas such as nutrition, drug development and toxicology. The current project
aims to evaluate the role of specific receptor types in the intestine in the absorption of both dietary lipids and
drug molecules, with a view to providing a means to better regulate lipid absorption and to more effectively
facilitate the design of improved drug delivery systems.
Research achievements (from final report):
Despite the discovery of many drug candidates with great potential, relatively few successfully progress
through clinical trials and become marketed medicines. There are myriad reasons for this failure- but one
common problem is that the molecules that are most active are often very poorly soluble in water. Since
molecules must pass into solution in fluids of the gastrointestinal tract prior to being absorbed, this is a
significant problem for drugs that are intended to be given orally (by mouth). To combat this, ourselves and
others have shown that effective absorption (and therefore treatment) can be supported by administering drugs
with small quantities of lipids (fats). However, not all types support absorption and the mechanisms by which
different lipids facilitate absorption are not well understood. In the past this has limited the ability to 'tailor' the
design of formulations such that good exposure can be maintained. In this project a number of novel
mechanisms by which lipids and drugs are absorbed have been uncovered. In particular, we have confirmed
that high concentrations of drugs and lipids may be incorporated into lipid complexes inside the intestine, that
the nature of these complexes is critical and that depending on structure, maximal absorption is attained by
lipid complexes that are able to specifically release the drug near the intestinal membrane, ready for absorption.
Subsequently, proteins within intestinal cells aid in cellular transport and promote drug and lipid uptake into
the body via two pathways: the intestinal blood supply and the intestinal lymphatic capillaries. Better
understanding of these mechanisms has the potential to facilitate more efficient delivery of new drugs and also
the 'recovery' of old drugs that previously failed to have an impact due to low absorption.
Expected future outcomes:
Improved elucidation of the mechanisms by which lipids promote drug absorption will allow the rational
design of formulations that promote drug absorption for compounds that otherwise might never have been
usable. Identifying novel mechanisms of lipid absorption in this project might also provide the first steps
towards identifying new drug targets for diabetes, obesity, and/or heart disease.
Name of contact:
Chris Porter
Email/Phone no. of contact:
Chris.Porter@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 502607
CIA Name: Prof Matthew Watt
Admin Inst: Monash University
Main RFCD: Cell Metabolism
Total funding: $323,453
Start Year: 2008
End Year: 2010
Grant Type: NHMRC Project Grants
Title of research award:
Adipose triglyceride lipase: regulation and implications for the aetiology of insulin resistanceAdipose
triglyceride lipase: regulation and implications for the aetiology of insulin resistance
Lay Description (from application):
Obese individuals have elevated fat levels in the blood and muscle, which contributes to the development of
other diseases such as type 2 diabetes. A newly discovered protein named adipose triglyceride lipase (ATGL)
is essential for fat breakdown. This project aims to identify how ATGL operates and determine whether
defective ATGL function leads to type 2 diabetes. These studies will assist in the development of strategies
aimed at reducing fatty acids in blood and muscle.
Research achievements (from final report):
We have shown that the protein adipose triglyceride lipase (ATGL) is important for fatty acid metabolism in
skeletal muscle and liver. Specifically, ATGL breaks down triacylglycerol, resulting in reduced hepatic
steatosis (fatty liver) and mild improvement of liver insulin sensitivity, an effect that is sufficient to improve
whole-body insulin resistance. Thus, ATGL may be a viable therapeutic target to reverse fatty liver disease. ,
We have also identified novel phosphorylation sites in ATGL, which result in activation of ATGL. This
fundamental information is important for understanding how the protein works and ways in which it could be
manipulated to increase fat break down.
Expected future outcomes:
These studies contribute to understanding how ATGL works and will provide insight into designing therapies
aimed at activating ATGL to enahnce fat breakdown.
Name of contact:
Matthew Watt
Email/Phone no. of contact:
matthew.watt@monash.edu
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: 519502
CIA Name: Prof Edouard Stanley
Admin Inst: Monash University
Main RFCD: Endocrinology
Total funding: $540,075
Start Year: 2008
End Year: 2010
Grant Type: NHMRC Project Grants
Title of research award:
Expansion, Differentiation and Functional Analysis of In Vitro Derived Pdx1+ Pancreatic
ProgenitorsExpansion, Differentiation and Functional Analysis of In Vitro Derived Pdx1+ Pancreatic
Progenitors
Lay Description (from application):
Type 1 diabetes is a condition that arises when the body's immune system destroys insulin-producing beta cells
within the pancreas. Recent studies have shown that normal glucose control can be restored by replacing the
missing beta cells by transplantation of cells from deceased donors. However, the demand for transplant
material outweighs supply. The work described in this application seeks to define how insulin-producing beta
cells can be derived in the laboratory from embryonic stem cells .
Research achievements (from final report):
Type 1 diabetes is an autoimmune disease characterised by loss of β cell mass, compromised insulin production
and persistent high levels of blood glucose. Despite the success of insulin control regimes, people with type 1
diabetes suffer complications which result from deficiencies in the fine control of blood glucose levels afforded
by exogenously administered insulin. This fine control can be corrected by islet transplantation, although the
availability of this treatment option will always be limited by the scarcity of donor-derived islets. Pancreatic β
cells derived from the in vitro differentiation of human embryonic stem cells (ESCs) potentially represent an
inexhaustible supply of therapeutically effective cells for the treatment of type 1 diabetes. However, before
such cells can be used, further understanding of the processes by which these cells are generated is required. In
our project we used mouse embryonic stem cells as a model system to examine characteristics of the precursors
that give rise to pancreatic β cells. We correlated the results of gene expression studies, morphological analyses
and growth characteristics with the ability of progenitors to generate branching pancreatic organoids. We found
only specific progenitors were able to generate organoids that resembled those arising from fetal pancreatic
explants. Our studies provide additional criteria for classifying pancreatic progenitors made from ESCs and
will facilitate strategies for generating insulin producing β cells for the treatment of type 1 diabetes.
Expected future outcomes:
Results obtained with mouse embryonic stem cells (ESCs) will be applied to our human ESC experiments.
Specifically, this work provides valuable clues as to how to determine if pancreatic cells made in the laboratory
from human ESCs represent a genuine and functional insulin producing β cells.
Name of contact:
Ed Stanley
Email/Phone no. of contact:
ed.stanley@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 545846
CIA Name: Prof Tony Tiganis
Admin Inst: Monash University
Main RFCD: Endocrinology
Total funding: $542,462
Start Year: 2009
End Year: 2011
Grant Type: NHMRC Project Grants
Title of research award:
Regulation of insulin signalling and glucose homeostasis by protein tyrosine phosphatasesRegulation of insulin
signalling and glucose homeostasis by protein tyrosine phosphatases
Lay Description (from application):
A common feature of type 2 diabetes is high blood glucose due to peripheral insulin resistance. Protein tyrosine
phosphatases (PTPs) that antagonise insulin signalling might be important targets for therapeutic intervention
in type 2 diabetes; inhibition of specific PTPs may allow for enhanced IR signalling to alleviate insulin
resistance. This proposal will examine the roles of PTPs and in particular TCPTP in insulin signalling and
glucose homeostasis.
Research achievements (from final report):
Type 2 diabetes has reached epidemic proportions in both developed & developing nations afflicting some 220
million people worldwide. Insulin resistance (diminished cellular response to circulating insulin) is a key
pathological feature of type 2 diabetes. Inhibiting protein tyrosine phosphatases (PTPs) that antagonize insulin
signaling may provide a means for promoting insulin sensitivity and alleviating insulin resistance. This
proposal examined the role of the PTP known as TCPTP in insulin sensitivity and glucose homeostasis. We
generated mice lacking the protein in eithet muscle, liver, fat or brain, the principal tissues that response to
insulin in teh control of glucose homeostasis. Our studies identified TCPTP as a key regulator of glucose
homeostasis and body weight in liver and the brain. Our studies have identified TCPTP as a potential
therapeutci target for the treatment of obesity and type 2 diabetes.
Expected future outcomes:
Our ongoing studies will define the molecular mechanisms by which PTPs regulate body weight and contribute
to the development of obesity and type 2 diabetes.
Name of contact:
N/A
Email/Phone no. of contact:
Tony.Tiganis@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 545878
CIA Name: A/Pr Peter Tipping
Admin Inst: Monash University
Main RFCD: Nephrology and Urology
Total funding: $487,067
Start Year: 2009
End Year: 2011
Grant Type: NHMRC Project Grants
Title of research award:
The role of the cytoplasmic domain of tissue factor in maintenance of the glomerular filtration barrier.The role
of the cytoplasmic domain of tissue factor in maintenance of the glomerular filtration barrier.
Lay Description (from application):
This research aims to understand mechanisms of normal kidney function and the development of chronic
kidney damage associated with diseases such as nephritis and diabetes. These diseases represent a significant
burden of illness in Australia.
Research achievements (from final report):
Leakage of protein into the urine (albuminuria) is an early sign of kidney in a number of human diseases (eg,
diabetes, hypertension, glomerulonephritis). The presence of albuminuria accelerates kidney damage and
development of chronic kidney failure. These studies explored novel roles for a protein (tissue factor: known to
be critical for blood clotting) in kidney filtering functions that prevent protein leakage under normal conditions.
Theses demonstrated that tissue factor helped to maintain of the functional and structural integrity of cells
(podocytes) that are crucial to normal filtering function. In the absence of tissue factor, albumin leakage and
production of potentially injurious chemicals (cytokines) such as tumor necrosis factor was increased. This
knowledge may assist in understanding the mechanisms and preventing the development of albuminuria in the
future.
Expected future outcomes:
Improved knowledge of mechanisms of albuminuria may lead to more effective therapy of this adverse
influence on renal function in common diseases such as diabetes and hypertension.
Name of contact:
In The Absence Of Tissue Factor, Podopeter Tipping
Email/Phone no. of contact:
peter.tipping@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 545888
CIA Name: Prof Helena Teede
Admin Inst: Monash University
Main RFCD: Endocrinology
Total funding: $227,333
Start Year: 2009
End Year: 2012
Grant Type: Career Development Fellowships
Title of research award:
The prevention and optimal treatment of Type II DiabetesThe prevention and optimal treatment of Type II
Diabetes
Lay Description (from application):
Lifestyle related metabolic disease including obesity and diabetes, represent a disease continuum and present
an increasing public health challenge. This research focuses on mechanisms underpinning lifestyle diseases and
on prevention and treatment covering the spectrum from health related behaviours (barriers to change and
behavioural modification), to mechanisms of action of exercise-diet and medications, to public health
interventions to improve prevention and treatment of lifestyle diseases.
Research achievements (from final report):
This CDA fellowship enabled me to progress my career to the stage of being successful at obtaining an
NHMRC Practitioner Fellowship commencing in 2013. It has enabled me to have leadership roles across
research, clinical service, education, translation and community/ policy interaction. I hold a 0.4EFT position as
Head of Diabetes at Southern Health, Victoria's largest Health Service, encompassing 5 acute hospital sites.
Concurrently I hold a 0.6 position as Professor of Women's Health Monash University. In 2010 I was
appointed as the Monash Site Director for the School of Public Health and Preventive Medicine. Having
established my new research group in 2005, I have nurtured it from 2 staff to ~50 staff, students and affiliates
with 6 clinical research programs now established. Grant successes since 2009 include 4 NHMRC project
grants (CIA x2, CIB x 2) and a partnership grant with > 90 publications and many HDR student supervision
completions. Also I have senior representation at national NHRMC committees, policy forums as well as an
increasingly successful national and international research profile exemplified by invited speaking
engagements. I have made significant contributions to research in high risk metabolic conditions, especially in
PCOS. Contributions sit across mechanistic research on the causes of PCOS, interventional research to improve
outcomes, epidemiological research on clinical outcomes including in diabetes and metabolic diseases. I also
led the first evidence based guidelines internationally on PCOS and these have been approved by the NHMRC.
Expected future outcomes:
Moving forward I will progress my career aiming for a CRE in PCOS to build on the National PCOS Alliance I
have bought together to progress research in this area and build greater international collaborations. I will
increase my engagement with government and other stakeholders to progress translation of research into
practice.
Name of contact:
Helena Teede
Email/Phone no. of contact:
helena.teede@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 545944
CIA Name: A/Pr David Nikolic-Paterson
Admin Inst: Monash University
Main RFCD: Nephrology and Urology
Total funding: $641,678
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 an immunologist-nephrologist determining molecular mechanisms of inflammation and fibrosis in acute
and chronic forms of kidney disease
Research achievements (from final report):
My studies have examined the role of a number of enzymes (called kinases) in experimental models of
different types of kidney disease. I have demonstrated that the development of rapidly progressive
glomerulonephritis and of diabetic nephropathy can be halted by preventing the infiltration of blood monocytes
(a type of white blood cell) into the kidney via inhibition of an enzyme called c-fms. In addition, inhibiting cfms was also protective against kidney transplant rejection, identifying that blocking this enzyme may have
promise as a new therapy, particularly in acute forms of kidney injury. Overlapping with this finding, I
identified that the enzyme JNK is critical for how monocytes cause renal injury once they have entered the
kidney. In addition, JNK activation in the tubular cells of the kidney is an important factor in the progression of
kidney disease. Our drug-based studies showed that blockade of JNK can suppress kidney inflammation and
fibrosis in several disease models. Indeed, our studies played a key role in the development of a clinical trial of
this JNK inhibitor drug in patients with idiopathic pulmonary fibrosis. Most recently, my work has identified
another kinase enzyme (Syk) as playing an important role in acute antibody-dependent types of kidney injury.
Finally, we have identified a role for antibody in the induction and progression of human and experimental
diabetic nephropathy.
Expected future outcomes:
I anticipate that the results of our experiments will lead to clinical studies to evaluate the potential of drugs that
inhibit specific kinase enzymes (JNK, c-fms and Syk) in different types of kidney disease.
Name of contact:
Dr David Nikolic-Paterson
Email/Phone no. of contact:
david.nikolic-patetrson@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 545945
CIA Name: Prof Jennifer Wilkinson-Berka
Admin Inst: Monash University
Main RFCD: Endocrinology
Total funding: $511,295
Start Year: 2009
End Year: 2011
Grant Type: NHMRC Project Grants
Title of research award:
Aldosterone inhibition and diabetic retinopathy: Treatments and mechanisms of actionAldosterone inhibition
and diabetic retinopathy: Treatments and mechanisms of action
Lay Description (from application):
The World Health Organization predicts that by 2030, more than 360 million people will have diabetes.
Despite almost all patients developing retinopathy, current treatments do not prevent disease progression. One
strategy being evaluated is blockade of a hormone called angiotensin II. We have new evidence that a related
system called aldosterone exists in retina and contributes to damage. This project will determine if aldosterone
blockade is a potential treatment for diabetic retinopathy.
Research achievements (from final report):
We made the novel discovery of a local aldosterone system in the retina, and that nhibition of this system at
various levels including the mineralocorticoid receptor and aldosterone production reduced retinal vascular
pathology. These findings may be important for the development of improved treatments for retinopathy which
involve blockade of the renin-angiotensin aldosterone system. We have also evaluated the mechanisms by
which aldosterone influenced retinopathy and have on-going studies in this area.
Expected future outcomes:
The expected future outcomes of this work is to identify the various actions of aldosterone in the retina which
are likely to include both physiological and pathophysiological processes. Whether inhibition of aldosterone or
the mineralocorticoid receptor is a useful adjunct treatment for retinal vasculopathy is still to be fully
understood and is being evaulated in on-going studies.
Name of contact:
Jennifer Wilkinson-Berka
Email/Phone no. of contact:
jennifer.wilkinson-berka@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 546018
CIA Name: E/Pr Paul O'Brien
Admin Inst: Monash University
Main RFCD: Indigenous Health
Total funding: $600,855
Start Year: 2009
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
THE CONTROL OF TYPE 2 DIABETES THROUGH WEIGHT LOSS IN INDIGENOUS AUSTRALIANS:
THE FEASIBILITY AND ACCEPTABILITY OF LAGBTHE CONTROL OF TYPE 2 DIABETES
THROUGH WEIGHT LOSS IN INDIGENOUS AUSTRALIANS: THE FEASIBILITY AND
ACCEPTABILITY OF LAGB
Lay Description (from application):
Our recent clinical trial showed that 3 out of every 4 obese people with type 2 diabetes who undergo substantial
weight loss have their diabetes go into remission. In this project we recognise in the Indigenous people
specific cultural and socio-economic factors and family and community approach to health care and seek to test
if the Lap-Band procedure is acceptable to them and if it is feasible to achieve substantial weight loss and
control of diabetes as was seen in a European population.
Research achievements (from final report):
The central aim of this study is to achieve a substantial and durable weight loss. The primary outcome is the
frequency of remission of type 2 diabetes in response to this weight loss., 30 candidates were entered into the
study. They had a mean BMI of 44.3 kg/m2 and they had a mean duration of diabetes of 4.3 years., All patients
had placement of a Lap-Band at the Goulburn Valley hospital as an outpatient or with an overnight stay, A
mean weight loss of 28.2kg was achieved. BMI reduced from 44.3 to 34.3 kg/m2, a change of 10 BMI units.
Diabetes remission had occurred in 20 (77%) of the 26 who completed the follow up and final assessments.
When calculated on the basis of intention to treat, so including the four who have not completed final
assessment, 66% of study participants are known to be in remission., The involvement and education of the
local Aboriginal Health service enabled the continuation of medical care following the 2 year period.
Expected future outcomes:
The study has been completed according to the protocol and has shown that this approach to therapy is equally
effective in a rural Indigenous population as it was in an urban Western population. It will provide a strong
endorsement of the value of direct efforts at weight loss as a path to better control of diabetes for Indigenous
Australians
Name of contact:
Prof Paul O'brien
Email/Phone no. of contact:
paul.obrien@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 546027
CIA Name: Prof Matthew Watt
Admin Inst: Monash University
Main RFCD: Cell Metabolism
Total funding: $358,319
Start Year: 2009
End Year: 2011
Grant Type: NHMRC Project Grants
Title of research award:
Circulating ceramides, inflammation and insulin resistanceCirculating ceramides, inflammation and insulin
resistance
Lay Description (from application):
Ceramides are a type of fat that are stored in the body. When people store too many ceramides in their muscles
and liver they no longer respond normally to insulin, which leads to the development of type 2 diabetes.
Ceramide levels are increased in the blood of people with type 2 diabetes. The aim of the this project is to
determine whether ceramides in the blood contribute to type 2 diabetes and whether reducing ceramide levels
in the blood improves health.
Research achievements (from final report):
We have shown that a type of lipid (or fat) called ceramide circulates in the blood. Ceramide is elevated in the
low-density lipoporteins (LDL) of blood of patients with type 2 diabetes compared with lean or obese people
without diabetes. When ceramide is infused into lean, healthy mice, these mice developed hallmarks of type 2
diabetes including resistance to the actions of insulin and low grade inflammation. In addition, we have shown
that the liver is a major source of this ceramide. These newly identified roles of blood ceramide suggest that
strategies aimed at reducing liver ceramide production or reducing ceramide packaging into LDL may improve
some features of diabetes pathologies.
Expected future outcomes:
Ongoing work will examine how to reduce blood ceramide production and also to validate whether ceramides
contained in high density lipoproteins a detrimental to health.
Name of contact:
Matthew Watt
Email/Phone no. of contact:
matthew.watt@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 546087
CIA Name: Dr Marianne Tare
Admin Inst: Monash University
Main RFCD: Basic Pharmacology
Total funding: $771,295
Start Year: 2009
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
Understanding local and regional determinants of EDHF and NO dysfunction in resistance arteries in
diabetesUnderstanding local and regional determinants of EDHF and NO dysfunction in resistance arteries in
diabetes
Lay Description (from application):
Diabetes is a serious and increasing health burden worldwide. Most of the sickness and death associated is due
to complications arising in the blood vessels. The inner lining of blood vessels in small arteries uses several
different mechanisms to ensure proper blood flow, and in diabetes these are impaired. This study will reveal
the cellular mechanisms involved and identify pathways for therapeutic intervention to alleviate the debilitating
effects of small artery disease.
Research achievements (from final report):
Vascular complications are the leading cause of sickness and death associated with diabetes, and disease in the
smaller arteries is relatively resistant to current therapies. The focus of this project was to elucidate the
mechanisms regulating small blood vessel function in diabetes, and regional susceptibility to complications. A
landmark finding was that small arteries where the lining cells of the inside of the blood vessel (the
endothelium) make physical and electrical contact with the underlying muscle cells in the wall, developed
complications earlier and to a greater extent than arteries where these connections are absent. In arteries where
the two cell types make contact, we determined that the inability of the muscle to relax in diabetes is due to
dysfunction of two types of channels (intermediate- and small- conductance calcium-activated K+ channels) on
the endothelial cells, not due to failure of the electrical signal to get to the muscle. We identified two transient
receptor potential channel types that facilitate the activity of these K+ channels, and the effect of diabetes on
their activity. The regional effects of diabetes on vascular function were reflected in region-dependent
differences in the upregulation of oxygen radical generation by NADPH oxidases. The in vitro findings were
reflected in the effects of diabetes on regional blood flow in vivo. Similar mechanisms were identified in
arteries from women with gestational diabetes. We established the role of a novel endothelial vasodilator,
HNO, in the regulation of endothelium-dependent relaxation and determined that its contribution is sustained
or upregulated in diabetes. Its therapeutic value is the focus of future investigation.
Expected future outcomes:
The results of this project provide significant new insight into the mechanisms regulating small artery function
in diabetes. This new knowledge will facilitate development of new therapies to alleviate complications in
small arteries and improve the quality of life in individuals with diabetes.
Name of contact:
Marianne Tare
Email/Phone no. of contact:
Marianne.Tare@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 546131
CIA Name: Dr Zane Andrews
Admin Inst: Monash University
Main RFCD: Central Nervous System
Total funding: $400,885
Start Year: 2009
End Year: 2011
Grant Type: NHMRC Project Grants
Title of research award:
Ghrelins novel neuroprotective effects in Parkinsons disease are mediated by AMP-activated protein kinase
(AMPK).Ghrelins novel neuroprotective effects in Parkinsons disease are mediated by AMP-activated protein
kinase (AMPK).
Lay Description (from application):
Studies show that body mass index, midlife adiposity and diabetes are associated with Parkinson's disease
(PD). During obesity there is a dramatic change in nutritional information, such as hormones, sugars and fats,
carried in the blood. This proposal explores how this altered nutritional information in obesity kills the brain
cells associated with PD. It will examine how ghrelin, a metabolic hormone inversely related to obesity,
influences and protects brain cell activity in models of PD.
Research achievements (from final report):
Ghrelin is a hormone that stimulates appetite and body weight under conditions of low food avavilability. We
discovered that ghrelin also prevents degeneration of dopamine brain cells associated with Parkinson's disease.
It is well known that mild calorie restriction improves behavioural and cognition fucntion in humans and in
animal models of Parkinson's disease. In this grant we discovered that ghrelin mediates the beneficial effects of
calorie restriction in Parkinson's disease. Further, we showed that diet-induced AMPK activation prevents
degeneration of dopamine brain cells. These discoveries have significant implications for human treatment of
Parkinson's disease. Since starting this grant i have joined the Cure Parkinson's Trust as an advisor and we are
currently conducting feasibility analyses for a human trial for Parkinson's disease
Expected future outcomes:
We expect to show that ghrelin activates AMPK in dopamine neurons to induce neuroprotection. Further we
hope to show that ghrelin improves quality of life in human Parkinson's disease patients.
Name of contact:
Zane Andrews
Email/Phone no. of contact:
zane.andrews@moansh.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 586698
CIA Name: Dr Clinton Bruce
Admin Inst: Monash University
Main RFCD: Cell Metabolism
Total funding: $403,541
Start Year: 2010
End Year: 2013
Grant Type: Career Development Fellowships
Title of research award:
Molecular mechanisms of lipid-induced insulin resistanceMolecular mechanisms of lipid-induced insulin
resistance
Lay Description (from application):
Media Summary not available
Research achievements (from final report):
Obesity is an escalating global health problem and is associated with a number of disorders including insulin
resistance and type 2 diabetes. The prevalence of these metabolic diseases has increased dramatically over the
last two decades reaching epidemic proportions. In fact, metabolic diseases are among the most significant
health issues in Australia. Although the pathogenesis of insulin resistance is well-investigated, the precise
interplay between the pathways that lead to this disorder are not fully understood. In the series of studies
supported by this fellowship, we have advanced the understanding of how defects in lipid metabolism
contribute to the development of insulin resistance. Firstly, we identified that defects in insulin action in
multiple tissues (liver, muscle, adipose) coincindes with the build up of lipids in these tissues. With this
knowdedge we began targeting pathways to prevent lipid accumulation with the aim of improving insulin
sensitvity. We identified an enzyme, that once activated, can improve lipid handling in skeletal muscle and as a
result prevent insulin resistance. More importantly, we discovered that a drug which can act on aspects of this
pathway can amelioriate insulin resistance in a rodent model of type 2 diaetes. This is particularly exciting as
this drug has been approval for human used in the treatment of an unrelated disease, thus these results may
provide new strategies for the treatment of type 2 diabetes.
Expected future outcomes:
Our intial findings indicate that we may have identified a novel therapy for the treatment of insulin resistance
and type 2 diabetes. In-depth studies are now being carried out to examine mechanisms of action with the
ulimate goal of translating these finding to the clinic.
Name of contact:
Clinton Bruce
Email/Phone no. of contact:
clinton.bruce@deakin.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 606453
CIA Name: A/Pr Robyn Slattery
Admin Inst: Monash University
Main RFCD: Autoimmunity
Total funding: $484,301
Start Year: 2010
End Year: 2013
Grant Type: NHMRC Project Grants
Title of research award:
The Role of MHC Class I Expression on Pancreatic Ductal Lineage Cells in the Pathogenesis of Type I
Diabetes (TID).The Role of MHC Class I Expression on Pancreatic Ductal Lineage Cells in the Pathogenesis
of Type I Diabetes (TID).
Lay Description (from application):
MHC molecules act as traffic lights to the immune system telling it whether to stop or go, so that only when
there is an infection does the immune system receive the signal to destroy target cells. However, the immune
system in Type 1 Diabetes patients receives signals to destroy the insulin-producing cells when there is no
apparent infection. We aim to determine where the faulty traffic signal occurs and so be in a better position to
design intervention strategies to prevent Type 1 Diabetes.
Research achievements (from final report):
Type 1 Diabetes (T1D) is one of the most common autoimmune diseases of the childhood. Understanding the
early pathogenesis of T1D is important to design immunoregulatory strategies to prevent disease in genetically
susceptible individuals. Our studies have shown that transgenic mice lacking MHC class I molecules on beta
cells were protected from developing T1D.To understand the reasons underlying this protection, we analysed
the pancreatic histological samples and found that the degree of insulitis was restricted only to the pancreatic
ducts leaving the beta cells free from immune invasions. As pancreatic ductal cells were the progenitors for
beta cells, we decided to explore the role of MHC class I in ductal cells of the pancreas. , The cre-lox system
was used to remove MHC class I from ductal and neuronal cells. GFAPcre mice were generated on the NOD
background, then phenotyped and found to have appropriate neuronal expression of cre. CAIIcre transgenic
mice were generated however both lines phenotyped expressed ectopically in myeloid and lymphoid cells.
After sequential transmission of the transgene via female and male germlines, and persistence of ectopic
expression we have concluded that the human CAII promoter naturally expresses ectopically. Therefore to
achieve the original aims a new approach was taken i.e. to generate radiation bonemarrow chimeras that have
derived myeloid and lymphoid cells from WT donors and therefore do not express cre. The chimeric CAIIcre
mice will be used to achieve the original aims.
Expected future outcomes:
By conducting irradiation chimera experiments we will be able to test whether it is the ductal progenitor cell or
the beta cell that is the primary target for CD8 T cells. Understanding the primary auto antigen in T1D will
help us to design therapeutic strategies to treat T1D in humans.
Name of contact:
Robyn Slattery
Email/Phone no. of contact:
robyn.slattery@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 606544
CIA Name: A/Pr Velandai Srikanth
Admin Inst: Monash University
Main RFCD: Haematological Tumours
Total funding: $394,460
Start Year: 2010
End Year: 2013
Grant Type: Career Development Fellowships
Title of research award:
Cerebrovascular Disease and Dementia in Ageing PopulationsCerebrovascular Disease and Dementia in
Ageing Populations
Lay Description (from application):
Media Summary not available
Research achievements (from final report):
This award has enabled me to be very successful in areas of research in stroke, dementia, gait and falls with an
emphasis on the interface between cerebrovascular disease and dementia. It has led to significant research
translation in the management of transient ischaemic attack (TIA) for which a novel hospital pathway was
developed and evaluated resulting in an effective and cost-saving program. In addition, several cerebrovascular
markers of future risk of falls and gait disability in older people were identified. Finally, a major program of
research examining the relation between type 2 diabetes mellitus and dementia was begun, with some key
findings relating DM to brain atrophy generated. These findings may lead to new ways to treat/prevent
dementia.
Expected future outcomes:
The above research has ste the platform for further innovation particularly in the field of diabetes and dementia
which will be a major focus for the next 5 years.
Name of contact:
Velandai Srikanth
Email/Phone no. of contact:
velandai.srikanth@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 606553
CIA Name: Prof Helena Teede
Admin Inst: Monash University
Main RFCD: Reproduction
Total funding: $416,116
Start Year: 2010
End Year: 2011
Grant Type: NHMRC Project Grants
Title of research award:
Insulin resistance in Polycystic Ovary Syndrome and the role of skeletal muscle and adipose tissueInsulin
resistance in Polycystic Ovary Syndrome and the role of skeletal muscle and adipose tissue
Lay Description (from application):
11% of women have polycystic ovarian syndrome(PCOS), characterised by insulin resistance, irregular periods
and infertility. These women are prone to obesity, diabetes and potentially, heart disease. Treatments include
lifestyle modifications +/- medical therapy. Lifestyle is first line, yet the best diet/exercise prescription is
unclear. This study will provide insights into the cause of PCOS, will inform on the role of exercise in therapy
and may identify targets for future therapies.
Research achievements (from final report):
The research award has afforded us the opportunity to take a multidisciplinary approach to address a number of
important clinical and scientific questions surrounding a major Australian health issue, Polycystic Ovary
Syndrome (PCOS) that impacts as many as 1 in 5 young Australian women. PCOS is a complex condition with
cardio-metabolic (insulin resistance and a 4-7 fold higher risk of cardiovascular disease and type 2 diabetes),
reproductive (anovulatory infertility) and psycho-social problems. In this project we focused on insulin
resistance (IR) due to the potential central role of insulin in PCOS. Specifically we looked at potential
mechanisms of insulin resistance in PCOS and the role of exercise in alleviating it. We studied 4 groups of
women, lean with and without PCOS, and overweight to obese women with and without PCOS, examining
insulin sensitivity by insulin clamp, body composition, mitochondrial biogenesis/ function, and insulin
signalling in skeletal muscle to determine if women with PCOS were intrinsically more IR. We also exercise
trained the overweight groups for 3 months. The results show that women with PCOS do have an intrinsic
PCOS related IR which does not appear to be related to mitochondrial biogenesis/function but more likely to
body lipid storage and or insulin signalling. Furthermore, in the overweight women exercise improved but did
not completely alleviate their IR when compared to matched controls. This work provides important advances
in understanding the aetiology of IR in PCOS and informs clinical practice on the impact of exercise in PCOS
with inclusion in national evidence based guidelines.
Expected future outcomes:
This work has provided a number of new hypothesis-driven clinical and basic science research questions and
projects in PCOS, new multidisciplinary national and international collaborations, has informed practice and
with completion and analysis of insulin signalling data, should provide greater ins9ights itno IR in obesity
generally and in PCOS.
Name of contact:
Prof Helena Teede
Email/Phone no. of contact:
helena.teede@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 606557
Start Year: 2010
CIA Name: Prof James Whisstock
End Year: 2013
Admin Inst: Monash University
Grant Type: NHMRC Project Grants
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $876,679
Title of research award:
Structural, Biochemical and Biophysical Studies on PerforinStructural, Biochemical and Biophysical Studies
on Perforin
Lay Description (from application):
This proposal focuses upon understanding the structure and mechanism of perforin, a protein that performs a
crucial role in human immunity. We will investigate how certain mutations in perforin cause deficiency and
disease. Our work will also seek to understand how potential therapeutics act to modulate perforin function.
Finally, through a combination of biochemical and structural studies we will elucidate the details of perforin
mechanism.
Research achievements (from final report):
All aspects of this grant were successfully achieved. A major achievement of this project was determining the
structure of perforin as well as the the low resolution structure of the perforin pore. This work was published in
Nature (Law et al., 2010, Nature) and has contributed to a seeding drug discovery program funded by the
Wellcome Trust (CIs Trapani, Hill, Denny and Whisstock). Perforin inhibitors are anticipated to be of
therapeutic utility in improving the success of bone marrow transplantation (a therapy used to treat a range of
haematological malignacies).
Expected future outcomes:
The development of perforin inhibitors of utility in treating a range of different immune driven diseases, as
well as in improving the success of bone marrow transplantation.
Name of contact:
James Whisstock
Email/Phone no. of contact:
James.Whisstock@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 606561
CIA Name: Prof Matthew Watt
Admin Inst: Monash University
Main RFCD: Cell Metabolism
Total funding: $361,638
Start Year: 2010
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
Identifying a novel role for pigment epithelium-derived factor in obesity-related metabolic
dysfunctionIdentifying a novel role for pigment epithelium-derived factor in obesity-related metabolic
dysfunction
Lay Description (from application):
Obesity is an important factor contributing to insulin resistance and type 2 diabetes; however, the factors
linking these disorders are not well defined. A protein called PEDF is elevated in obesity and type 2 diabetes.
This project will examine how PEDF causes insulin resistance and whether blocking PEDF's actions prevents
insulin resistance. Successful completion of this project may lead to therapeutics that reduce the risk of
developing type 2 diabetes.
Research achievements (from final report):
We have shown that the protein pigment epithelium-derived factor (PEDF) is secreted from fat cells and causes
insulin resistance and inflammation, two events that underpin the development of type 2 diabetes. These
defects were reversed in obese mice when we blocked the actions of PEDF. We have also shown that PEDF
acts with another protein called adipose triglyceride lipase to increased fat breakdown in fat cells, resulting in
the inappropriate release of fat into the blood. This can also contribute to insulin resistance development. We
have developed a mouse that over-produced PEDF in fat cells- this mouse has increased fat breakdown but did
not become diabetic suggesting that other tissues may secrete PEDF to cause insulin resistance. Finally, in
collaborative work, we have shown that PEDF is evelvated in the fat tissue of obese humans but that exercise
training is insufficient to reduce the PEDF levels in obesity.
Expected future outcomes:
We will create a monoclonal antibody against PEDF and test when this prevent diabetes development in obese
mice. This could lead to clinical trials.
Name of contact:
Matthew Watt
Email/Phone no. of contact:
Matthew.watt@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 606604
CIA Name: Prof Tony Tiganis
Admin Inst: Monash University
Main RFCD: Endocrinology
Total funding: $564,644
Start Year: 2010
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
Regulation of insulin sensitivity by reactive oxygen speciesRegulation of insulin sensitivity by reactive oxygen
species
Lay Description (from application):
In morbid obesity and type 2 diabetes chronic levels of reactive oxygen species (ROS) are detrimental and
diminish insulin's ability to maintain normal blood glucose levels. Paradoxically, ROS also promote insulin
action by inhibiting enzymes known as protein tyrosine phosphatases (PTPs). This proposal will determine
whether the promotion of ROS for the inhibition of PTPs early in the progression of type 2 diabetes may be of
therapeutic benefit.
Research achievements (from final report):
Oxidative stress in obesity can contribute to the development of insulin resistance, a primary feature of type 2
diabetes. Although antioxidants have been touted as therapeutics, there is evidence that reactive oxygen species
(ROS) such as H2O2 can also promote insulin signalling. Hence it is possible that antioxidants might subvert
the physiological roles of H2O2. In this proposal we established that insulin promotes H2O2 generation in
skeletal muscle in vivo to enhance insulin signalling by inactivating protein phosphatases. We found that
general antioxidant administration to lean mice prevented insulin-induced H2O2 generation and signalling and
increased postprandial blood glucose levels. Our studies have established the importance of H2O2 in the
physiological insulin response in vivo and have highlighted the importance of targeted antioxidant approaches
in combating obesity-related diseases.
Expected future outcomes:
N/A
Name of contact:
N/A
Email/Phone no. of contact:
Tony.Tiagnis@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 606662
CIA Name: Prof Michael Cowley
Admin Inst: Monash University
Main RFCD: Endocrinology
Total funding: $617,531
Start Year: 2010
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
Does loss of melanocortin glucose sensing contribute to obesity induced diabetes?Does loss of melanocortin
glucose sensing contribute to obesity induced diabetes?
Lay Description (from application):
Diabetes is a failure to properly regulate blood glucose levels. Escalating rates of diabetes are a major health
problem. Melanocortin neurons in the brain detect blood sugar levels and usually regulate glucose production
and utilization, but in obese animals they do not. We have developed a possible therapeutic, which appears to
reverse the glucose insensitivity, and rapidly reduces blood glucose in diabetic mice. This project will
determine how melanocortins act to regulate glucose levels
Research achievements (from final report):
We have developed a potential drug target for treatment of congenital or acquired hypopituitism, and also for
some metabolic diseases, especially in combination with a phoshpodiesterase 4b inhibitor, such as
rolipram.This would offer the potential of better metaboilic health to those who lack a functional pituitary, but
more significantly, may be a adjunctive therapy in diabetes.
Expected future outcomes:
We expect to continue to advance alpha MSH as a drug development opportunity. We are seeking funding for
human studies of the drug. We expect to test if alpha MSH is a safe and effective drug for lowering blood
glucose levels.
Name of contact:
Michael Cowley
Email/Phone no. of contact:
michael.cowley@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 634469
CIA Name: Prof Paul McMenamin
Admin Inst: Monash University
Main RFCD: Ophthalmology
Total funding: $435,590
Start Year: 2010
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
Do activated retinal microglia mediate neurotoxicity in background diabetic retinopathy?Do activated retinal
microglia mediate neurotoxicity in background diabetic retinopathy?
Lay Description (from application):
Diabetic retinopathy, a frequent complication of Type 1 and Type 2 diabetes, is the commonest cause of
blindness in working age individuals. Prior to the growth of blindness-causing new vessels in the eye we now
know that there is a gradual loss of neurons in the retina. This project will investigate whether the resident
immune cells in the retina, which are normally neuroprotective, become neurotoxic during episodes of systemic
inflammation (e.g. bacterial or viral infections).
Research achievements (from final report):
N/A
Expected future outcomes:
N/A
Name of contact:
Prof Paul Mcmenamin
Email/Phone no. of contact:
paul.mcmenamin@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 1002180
CIA Name: Prof Patrick Sexton
Admin Inst: Monash University
Main RFCD: Basic Pharmacology
Total funding: $681,954
Start Year: 2011
End Year: 2013
Grant Type: NHMRC Project Grants
Title of research award:
Molecular characterisation of the glucagon-like peptide 1 receptorMolecular characterisation of the glucagonlike peptide 1 receptor
Lay Description (from application):
The glucagon-like peptide 1 receptor is a major target for treatment of Type 2 diabetes and obesity. However,
the development of drugs for this receptor is challenging due to limited understanding of potential sites of drug
interaction and how individual drugs may differentially change signalling from the receptor. This project will
address these critical knowledge gaps, which may allow for improved therapeutic outcomes.
Research achievements (from final report):
We have demonstrated distinct signalling patterns of 6 non-peptidic receptor agonists and modulators across a
range of signalling assays and assays of receptor regulation (Wootten et al, 2011, 2013; Savage et al, 2013).
We have also demonstrated distinct consequences of naturally occurring polymorphisms on peptide versus
small molecule interaction with the receptor, including the ability of small molecule compounds to
allosterically rescue loss of function mutations (Koole et al, 2011). We have also carried out extensive sitedirected mutagenesis that includes alanine scanning of each of the extracellular loops (Koole et al, 2012a,
2012b), as well as polar residues of the transmembrane domain (TM) that are likely important for activation
transition of the receptor (Wootten et al, 2013). This work is providing insight into the distinct role of loop
regions of the receptor in ligand binding and also in activation of the receptor. We have demonstrated that the
GLP-1R undergoes dimerization via a TM4 interface, and that dimerization is critical for efficient receptor
signalling but in a biased manner such that intracellular calcium signalling is virtually abolished, with only
~10-fold attenuation in cAMP or pERK signalling. Furthermore, this work demonstrated that activation of the
receptor, but not allosteric modulation, by allosteric agonists absolutely required receptor dimerization
(Harikumar et al, 2012). Finally, we have used data from photoactive cross-linking (Miller et al, 2011) and the
mutational studies described above to help build improved molecular models of the GLP1R, both with respect
to peptide binding and the packing of the TM bundle.
Expected future outcomes:
This work has formed the basis of new studies examining the physiological role of ligand-directed signal bias
as well as novel insight into the structural basis for bias at the level of the ligand-receptor interface.
Name of contact:
Patrick Sexton
Email/Phone no. of contact:
patrick.sexton@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 1002235
Start Year: 2011
CIA Name: Prof Jennifer Wilkinson-Berka
End Year: 2013
Admin Inst: Monash University
Grant Type: NHMRC Project Grants
Main RFCD: Medical and Health Sciences not elsewhere classified
Total funding: $486,825
Title of research award:
Evaluating the link between the GPR91 receptor and renin in the pathogenesis of diabetic
retinopathyEvaluating the link between the GPR91 receptor and renin in the pathogenesis of diabetic
retinopathy
Lay Description (from application):
Diabetic retinopathy is the leading cause of blindness in people of working age. A hormonal system called
renin-angiotensin is implicated in the development of diabetic retinopathy, and new evidence indicates that its
blockade improves aspects of the disease. This project will examine if succinate/GPR91 mediates the over
production of renin and represents an additional target for the treatment of diabetic retinopathy.
Research achievements (from final report):
A particular type of nerve cell, called a ganglion cell, influences the development of blood vessel disease in the
retina of the eye. This occurs by the ganglion cell producing increased amounts of a factor called, VEGF, in
response to stress. We determined that a molecule involved in cell metabolism, called succinate, stimulates the
production of VEGF in ganglion cells. Furthermore, succinate also increases the production of an enzyme
called renin. These three molecular players, are linked together, and may play an important role in the
development of retinal disease, due to the potent role of VEGF on blood vessel damage in the retina. We
explored the utility of inhibiting particular receptors in these systems to reduce the ability of succinate and
renin to increase VEGF in ganglion cells. Some of these inhibitors were more successful than others, due to the
complex interactions between the succinate system and the renin system. The potential benefits of the research
are a better understanding of how these inhibitors can be applied to patients who suffer from blinding retinal
disease such as diabetic retinopathy.
Expected future outcomes:
We anticipate evaluating in more detail the complex interactions between the metabolic and blood pressure
systems involved in diabetic retinopathy in order to develop improved treatments for various ischemic
retinopathies.
Name of contact:
Jennifer Wilkinson-Berka
Email/Phone no. of contact:
jennifer.wilkinson-berka@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 1006348
CIA Name: A/Pr David Nikolic-Paterson
Admin Inst: Monash University
Main RFCD: Nephrology and Urology
Total funding: $555,893
Start Year: 2011
End Year: 2013
Grant Type: NHMRC Project Grants
Title of research award:
Distinct pathogenic roles for JNK signalling in glomerular and interstitial injury in kidney disease.Distinct
pathogenic roles for JNK signalling in glomerular and interstitial injury in kidney disease.
Lay Description (from application):
Our studies have identified a stress-activated mechanism (the JNK signalling pathway) as a therapeutic target
in the treatment of kidney disease. The current project will define the role of JNK signaling in individual cell
types in the development of different types of kidney disease. These studies will provide new insights into the
pathogenesis of kidney disease, and will be highly relevant to other diseases, including atherosclerosis, lung
fibrosis and arthritis.
Research achievements (from final report):
We have used a combination of drug-based inhibition and genetic targetting to define the role of an enzyme
(JNK) in different aspects of acute and chronic kidney disease. We demonstrated that a lead clinical compound
is effective in halting an experimental model of rapidly progressive glomerulonephritis. The same compound
was also effecting in suppressing a model of infection-associated acute kidney injury. Genetic studies identified
that activation of the JNK enzyme in some types of white blood cells (macrophages) and in tubular cells of the
kidney are the key sites at which this enzyme causes kidney injury. These studies support the use of JNK
inhibitor drugs in acute forms of kidney disease.
Expected future outcomes:
We anticipate that the results of our experiments will lead to clinical studies to evaluate drugs that inhibit JNK
activation in different types of kidney disease.
Name of contact:
Dr David Nikolic-Paterson
Email/Phone no. of contact:
david.nikolic-paterson@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 1008860
CIA Name: Prof Jennifer Wilkinson-Berka
Admin Inst: Monash University
Main RFCD: Endocrinology
Total funding: $580,042
Start Year: 2011
End Year: 2013
Grant Type: NHMRC Project Grants
Title of research award:
Prorenin and the prorenin receptor in diabetic retinopathy: involvement of the Wnt pathway and
inflammationProrenin and the prorenin receptor in diabetic retinopathy: involvement of the Wnt pathway and
inflammation
Lay Description (from application):
Diabetic retinopathy is the leading cause of blindness in people of working age. The World Health
Organization predicts that by 2030 more than 300 million people will have diabetes. Given the prevalence of
diabetic retinopathy and the lack of effective treatments, there is an urgent need to identify the factors that
contribute to its development. This project will determine the role of components of a hormonal system,
prorenin and its receptor, in diabetic retinopathy and whether they are new targets for its treatment.
Research achievements (from final report):
The research identified that a protein called prorenin elicits potent effects on cells within the retina of the eye.
This includes promoting the abnormal growth of blood vessels and the increased produciton of damaging
factors from inflammatory factors. These damaging effects of prorenin may influence the health and survival of
other cell populations in the retina and contribute to the development of retinal diseases such as diabetic
retinopathy. , A major finding was that the renin-angiotensin system, a hormonal system in the body, influences
the adaptive immune system, a pathway that has a major role in regulating inflammation in the body. In
particular, components of the renin-angiotensin system are produced in inflammatory cells called T cells and
increased in a specialized T cell called a FoxP3+ Treg. We determined that modulation of particular parts of
the renin-angiotensin system influenced the amount of FoxP3+ Tregs in retinopathy and improved retinal
vascular disease.
Expected future outcomes:
To further understand how modulation of the renin-angiotensin system influences the adaptive immune system
in diabetic retinopathy and other ischemic retinopathies in order to develop improved treatments for patients.
Name of contact:
Jennifer Wilkinson-Berka
Email/Phone no. of contact:
jennifer.wilkinson-berka@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 1011274
CIA Name: Dr Zane Andrews
Admin Inst: Monash University
Main RFCD: Cell Physiology
Total funding: $411,735
Start Year: 2011
End Year: 2013
Grant Type: NHMRC Project Grants
Title of research award:
Diet-induced obesity causes ghrelin resistanceDiet-induced obesity causes ghrelin resistance
Lay Description (from application):
Diet-induced obesity is the foremost health concern in today’s society and causes many metabolic problems
that lead to type diabetes and cardiovascular disease. This grant identifies ghrelin resistance, as a novel
metabolic adaptation during obesity. Ghrelin is a hormone that normally stimulates food intake and body
weight gain, however during obesity ghrelin does not stimulate food intake. Artificial induction of ghrelin
resistance will restrict the development of diet –induced obesity.
Research achievements (from final report):
Diet-induced obesity has profound effects on the body's ability to maintain healthy weight. In this grant we
examined how diet-induced obesity made the brain resistant to hormone message (ghrelin) that carries
information about body weight from the body to the brain. This hormone ghrelin actually increases food intake
and body weight gain so the fact that we become resistant to this hormone represents a physiological adaptation
to limit excess body weight. Despite this ghrelin resistance, subjects still continue to put on weight on a high
fat diet. This begs the question - what is the physiological relevance of ghrelin resistance if its actually not
restricting body weight gain on a high fat diet. Our research is the first to describe ghrelin resistance we believe
the ghrelin resistance is a physiological mechanism designed to protect a higher body weight to provide
adequate energy during times of food shortage. This means when obese subjects undergo diet-induced weight
loss, ghrelin resisatnce is reversed in order to promote food intake and body weight gain back to levels before
weight loss. We believe that this is one mechanism that makes it so hard to keep weight off after dieting.
Essentially, even though the body has enough energy stored on it, the brain thinks it need more and reverses
ghrelin resistance. This presumably represents one way in which we have evolved to maximise fat stores on our
bodies, as energy reservoirs, in order to sustain periods of low food availability
Expected future outcomes:
We are yet to publish on work showing that diet-induced obesity also affects the reward system and dampens
the effects of ghrelin reward-based feeding.
Name of contact:
Zane Andrews
Email/Phone no. of contact:
zane.andrews@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 334354
Start Year: 2005
CIA Name: A/Pr Fergus Cameron
End Year: 2007
Admin Inst: Murdoch Childrens Research Institute Grant Type: NHMRC Project Grants
Main RFCD: Endocrinology
Total funding: $416,000
Title of research award:
Insights into the acute cerebral lesion of childhood diabetes and it's neuropsychological sequelaeInsights into
the acute cerebral lesion of childhood diabetes and it's neuropsychological sequelae
Lay Description (from application):
Type 1 diabetes in childhood is a major cause of morbidity with an Australian prevalence of approximately 20
per 100,000 children under 15 years of age. The leading cause of death in type 1 diabetes in children and
adolescents is diabetic ketoacidosis complicated by cerebral oedema (brain swelling), the origins of which
remain unknown. This research is aimed at providing an insight into changes in the brain of children with
diabetic ketoacidosis (DKA) and the relationship of these brain changes to short and long term
neuropsychological functioning. The major aim of this project is to provide an insight into brain changes of
children with diabetic ketoacidosis (DKA) and the relationship of these brain changes to subseuqent brain
function. This is a study where we will simply observe differences between newly diagnosed type 1 diabetic
patients with no ktoacidosis, ketoacidosis or ketoacidosis with brain swelling over 6 months. We will measure
brain function using various techniques includiung: magnetic resonance imaging (MRI), magnetic resonance
spectroscopy (MRS), electrophysiology (EEG) and neuropsychological tests. The significance of this project is
that it will provide insight into the brain impairment of diabetic patients with and without DKA, and with brain
swelling in the context of DKA. By further clarifying the nature of brain impairment we will provide early
intervention strategies to improve psychological development of the young patients with diabetes. In addition
to this we hope to better understand the origins of brain swelling during DKA and design treatment protocols
that will prevent this devastating complication.
Research achievements (from final report):
The sample recruited between 2004 and July 2008 includes 58 children aged between six and 18 years of age,
presenting to the RCH with newly diagnosed type 1 diabetes. , Preliminary neuropsychology subset data
analyses have been conducted on 13 DKA and 21 non-DKA children. We found a trend for poorer intellectual
functioning in the DKA group compared with the non-DKA group. All children exhibited disrupted mental
status, learning, attention and inhibitory control in the acute phases of diagnosis. Some improvements in
cognitive functions were observed over the first 6 months, although not always to age expected levels. A
pattern of persisting deficits in complex skills such as divided attention was observed., Preliminary
electroencephalographic subset data analyses have been conducted acutely on 6 DKA and 10 non-DKA
children. Reversible encephalopatic changes were evident on both the DKA and non-DKA group with higher
degree of disruption in the DKA group. Epileptiform discharges were identified in 2 of 6 DKA patients and 1
of 10 non DKA patients, persisting in all cases on follow up EEGs. This finding is unrelated to DKA and most
likely indicate a genetic or developmentally determined predisposition to seizures. Further correlation analysis
is on the way and until such takes place we are unable to further comment in details, Preliminary analysis of
spectroscopy on 33 completed subset studies shows some significant differences in metabolite concentration
between non-DKA and DKA subjects. In particular frontal grey matter, N-acetylaspartate, myoinositol and
taurine are increased in DKA, relative to non-DKA, at 28 days but not at other time points. In DKA subjects,
frontal white matter taurine and glycerophosphocholine were decreased at day 1 and increased at 6 months
follow up, relative to non-DKA subjects. Further correlation analysis is essential on the whole cohort of
patients upon completion of data collection.
Expected future outcomes:
Ongoing clinical recruitment and further correlation data analysis to be done.
Name of contact:
A/Professor Fergus Cameron
NHMRC Research Achievements - SUMMARY
Email/Phone no. of contact:
fergus.cameron@rch.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 546425
Start Year: 2009
CIA Name: Prof Anne-Louise Ponsonby
End Year: 2011
Admin Inst: Murdoch Childrens Research Institute Grant Type: NHMRC Project Grants
Main RFCD: Epidemiology
Total funding: $342,795
Title of research award:
Investigating low sun exposure and other possible early life determinants of type 1 diabtes
mellitusInvestigating low sun exposure and other possible early life determinants of type 1 diabtes mellitus
Lay Description (from application):
Type 1 diabetes mellitus is becoming more common among Australian children. The project explores aspects
of the modern child's environment that may increase the risk of type 1 diabetes. In particular it aims to assess
whether very low sun exposure in early life is adverse. Low sun exposure may be adverse because sun
exposure -derived vitamin D is vital for the developing child's immune system. We need to know what level of
sunlight and vitamin D children need to prevent disease.
Research achievements (from final report):
The achievements for the Early Environment and Type 1 Diabetes Prevention Project so far are the publishing
of two papers. For the first paper, the sample consisted of children with T1DM and their sibling (n = 42). Cases
were significantly more likely to have lighter skin pigmentation at the upper arm (AOR 0.69 [95% CI: 0.52,
0.90]; P = 0.01). Low infant sun exposure was imprecisely associated with a two-fold increase in T1DM risk
(AOR 2.43 [95% CI: 0.91, 6.51]; P = 0.08 for under 1 hour of winter sun exposure per leisure day). The VDR
gene promoter was completely unmethylated in both cases and siblings. The previously demonstrated
association between light skin pigmentation and T1DM risk was evident even in this comparison across sibling
pairs. The second paper assessed levels of glutamic acid decarboxylase 65 islet cell antigen (GADA) and antiinsulin antibodies (IAA) in 247 incident T1DM cases presenting <15 years of age. 58.9% (142/241) of cases
were GADA seropositive and 42.3% (94/222) were IAA seropositive. Factors associated with elevated IAA
antibodies included younger age and red hair phenotype. Factors associated with elevated GAD antibodies
included lower birthweight and recent eczema. Intriguingly, low recent or past sun exposure was only
associated with elevated GADA levels among children presenting at age <5 years, not older (difference in
effect, p<0.05 for 4 of 5 associations). These findings show that environmental and phenotypic factors are
associated with autoantibody levels at time of presentation for T1DM.
Expected future outcomes:
This ultimate goal is to improve public health guidelines on lifestyle or environment to prevent the
development of T1DM. This project aims to investigate the role of early life risk factors for T1DM onset in
childhood, with an emphasis on the role of low sun exposure.
Name of contact:
Anne-Louise Ponsonby
Email/Phone no. of contact:
anne-louise.ponsonby@mcri.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1002033
Start Year: 2011
CIA Name: Prof Kathryn North
End Year: 2013
Admin Inst: Murdoch Childrens Research Institute Grant Type: NHMRC Project Grants
Main RFCD: Genetics not elsewhere classified
Total funding: $624,355
Title of research award:
The influence of a-actinin-3 on muscle structure, metabolism, performance and response to diet and diseaseThe
influence of a-actinin-3 on muscle structure, metabolism, performance and response to diet and disease
Lay Description (from application):
We have identified a common genetic variant that results in absence of the fast muscle fibre protein a-actinin-3
in more than one billion humans worldwide. Loss of a-actinin-3 influences elite athletic performance, muscle
bulk and strength in the general population, response to diet and exercise, and susceptibility to developing type
2 diabetes. We will now study mice and humans to determine how this gene influences variations in human
performance, metabolism and severity of muscle disease.
Research achievements (from final report):
The human ACTN3 gene encodes ?-actinin-3, a component of the contractile apparatus in fast, skeletal muscle
fibres. We have identified a common null polymorphism in ACTN3 (R577X) that, has undergone strong
positive selection during recent human evolution and results in absence of ?-, actinin-3 in ~18% of the world's
population. We have established that ACTN3 genotype, influences skeletal muscle athletic performance,
susceptibility to muscle damage, and regulation of, muscle mass and metabolism., We have made several
exciting new discoveries:, 1. ?-actinin-3 deficiency enhances response to exercise, and protects against muscle
wasting., 2. Differential expression of the sarcomeric ?-actinins regulates calcineurin signalling, providing, for
the first time a mechanistic explanation for some of the effects of ACTN3 genotype on skeletal, muscle
performance in elite athletes and the general population., 3. ACTN3 genotype influences glucose homeostasis
and weight gain in response to high fat diet, 4. The sarcomeric ?-actinins are also expressed in brown adipose
tissue (BAT) and the presence, or absence of ?-actinin-3 influences BAT activity, 5. ACTN3 genotype is a
genetic modifier of Duchenne muscular dystrophy.
Expected future outcomes:
There is emerging evidence that ACTN3 genotype affects metabolic efficiency and adaptation to changes in
diet, with potential public health implications for genetic susceptibility to diabetes and obesity. We will
determine how the metabolic and structural phenotypes associated with ?-actinin-3 deficiency influence human
health and disease.
Name of contact:
??Kathryn North???
Email/Phone no. of contact:
kathryn.north@mcri.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 169010
Start Year: 2001
CIA Name: Prof Evan Simpson
End Year: 2003
Admin Inst: Prince Henry's Institute of Medical Research
Grant Type: NHMRC Project Grants
Main RFCD: Endocrinology
Total funding: $408,055
Title of research award:
Lipid metabolism in the Aromatase Knock-out Mouse (ArKO)Lipid metabolism in the Aromatase Knock-out
Mouse (ArKO)
Lay Description (from application):
Studies of humans with natural mutations in aromatase, the enzyme responsible for oestrogen biosynthesis,
have revealed a number of unexpected roles for oestrogens in both males and females. These discoveries even
challenge the definitions of oestrogens and androgens as we now know them. We have created a mouse model
of oestrogen insufficiency by targetted disruption of the aromatase gene. These mice display a number of age
dependent phenotypes including both male and female infertility, undermineralisation of the bones, intraabdominal obesity, hypercholesterolaemia and insulin resistance. We are addressing the mechanisms of all of
those phenotypes but in the present application we focus on the abnormalities in lipid metabolism. Thus we
will seek to understand the increase in adiposity by examining the role of oestrogen in lipid synthesis, oxidation
and breakdown in adipose tissue from intra-abdominal sites. We will also examine the role that oestrogen
plays in cholesterol uptake, synthesis and catabolism by the liver as well as fatty acid synthesis and oxidation
by the liver. These studies will be correlated with whole body parameters such as feeding behaviour, physical
activity, energy expenditure, glucose and fat oxidation rates. We will also examine the effect of feeding a
high cholesterol or a high fat diet on lipid metabolism in the oestrogen deficient animals, and we will
determine the effect of oestradiol and isoflavone replacement on the phenotype. In this way we aim to reach a
better understanding of the multiplicity of roles that oestrogens play in the regulation of lipid and cholesterol
metabolism in both males and females. The results of such studies will be the development of better strategies
to deal with pathologies resulting from disturbances in cholesterol and lipid metabolism.
Research achievements (from final report):
Our work demonstrated that oestrogens have a number of unforeseen roles in the physiology and
pathophysiology of both males and females. Using the ArKO mouse as a model, we showed that oestrogen
insufficiency in mice leads to increased intra-abdominal obesity, increased hepatic lipid accumulation,
hypercholesterolaemia and insulin-resistance. In humans these are associated with such disorders as
cardiovascular disease, diabetes, and increased risk of cancer. Our work illustrated that where in
postmenopausal women and in men, the role of oestrogen as a circulating hormone is minimal, its actions are
important at local levels. Thus oestrogens produced in specific tissues have an important role to play in their
normal physiology and in the prevention of these conditions. Dietary isoflavones attenuated the ArKO
phenotype, suggesting that such compounds also could be efficacious in ameliorating these conditions., We
observed striking effects of oestradiol replacement achieved through the use of implants. These resulted in a
loss of fat, accompanied by a decrease in lipoprotein lipase expression and an increase in factors involved in
fatty acid B oxidation such as CPT1, UCP1 and long chain fatty acid dehydrogenase. These findings would
suggest that the major sites of oestrogen action in terms of the regulation of adiposity are at the level of
lipoprotein lipase on the one hand and fatty acid B oxidation on the other. , We observed that male, but not
female, ArKO mice develop hepatic steatosis, due primarily to an increase in intra-hepatic triglycerides and is
accompanied by elevated serum cholesterol and triglycerides. The molecular mechanisms regulating this
process included a significant up-regulation of hepatic fatty acid synthase expression coupled with elevated
levels of the fatty acid transporter adipocyte differentiated regulatory protein. Cholesterol dietary challenge to
ArKO mice revealed a sexually dimorphic regulation of hepatic homeostasis.
Expected future outcomes:
Knowledge resulting from this study makes possible the concept of pharmaceutical development of Specific
Aromatase Modulaters (SAMs). Such compounds could act to inhibit aromatase expression in a tissue-specific
NHMRC Research Achievements - SUMMARY
fashion, for example in a tumourous region of the breast, and at the same time leave unaffected aromatase
expression in other sites where it has important physiological roles.
Name of contact:
Professor Evan Simpson
Email/Phone no. of contact:
Evan.Simpson@phimr.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 198712
Start Year: 2002
CIA Name: Dr Greg Tesch
End Year: 2004
Admin Inst: Prince Henry's Institute of Medical Research
Grant Type: NHMRC Project Grants
Main RFCD: Nephrology and Urology
Total funding: $451,980
Title of research award:
Macrophages in diabetic nephropathy.Macrophages in diabetic nephropathy.
Lay Description (from application):
Kidney disease occurs in up to 50% of patients with insulin-dependent (type 1) and non-insulin-dependent
(type 2) diabetes. The increasing rate of diabetes in our community has made it a major cause of kidney disease
and a growing health problem. Despite clinical attempts to control blood glucose and blood pressure levels,
kidney disease in most diabetic patients progresses towards a complete loss of kidney function. In severe
cases, the survival of the patient is dependent upon lifelong dialysis or transplantation, which are costly and
complicated treatments. Therefore, there is an urgent need to improve treatment stategies in diabetic patients to
avoid kidney failure. Recent evidence in human and experimental models of diabetic kidney disease has
indicated that macrophages infiltrate the kidney during the disease process. Our previous knowledge from other
inflammatory kidney diseases suggests that macrophages play an important role in promoting the progression
of disease and, in some of these diseases, treatment strategies which block macrophage function and
accumulation have been shown to be effective in inhibiting the disease. The overall aim of these studies will
be to determine the importance of macrophages in the pathogenesis of diabetic kidney disease and identify the
mechanisms regulating their recruitment and activation within the diabetic kidney. This will be achieved by
examining the progression of kidney disease in type 1 and type 2 diabetic mice which have been genetically
modified to prevent macrophage accumulation and activation within the kidney. These studies will provide
valuable information into the pathogenesis of diabetic kidney disease and will identify whether therapeutic
strategies targeting macrophages can help prevent kidney loss in diabetes.
Research achievements (from final report):
In this project, we examined the importance of macrophages to the development of diabetic nephropathy, the
major cause of end-stage renal failure., , In conclusion, the findings of this project provide substantial evidence
that macrophages promote the progression of type 1 and type 2 diabetic nephropathy. Dr Fiona Chow was
awarded the 2004 ANZSN Young Investigator Award for her contribution to the studies.
Expected future outcomes:
These findings have helped identify potential mechanisms by which macrophages may contribute to the
development of renal fibrosis during diabetic nephropathy.
Name of contact:
N/A
Email/Phone no. of contact:
N/A
NHMRC Research Achievements - SUMMARY
Grant ID: 338500
Start Year: 2005
CIA Name: Prof Chen Chen
End Year: 2007
Admin Inst: Prince Henry's Institute of Medical Research
Grant Type: Established Career
Fellowships
Main RFCD: Endocrinology
Total funding: $350,250
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
I have established and sustained a strong international profile in endocrine cell biology and expanded our
research into cardiology and cancer research during this fellowship support. I have made a substantial
contribution to my working field, having published 27 papers in high quality journals including J Physiol,
Endocrinology, Am J Physiol, Human Mol Genet, etc. It should be noted that this support was only for 3 years
with an early promotion to Principal Research Fellow starting 2008. A number of published papers have been
seminal contributions with impact beyond my specific field, e.g. demonstration of FFA's action on receptor and
ion channels in beta cells, role of oestrogen in pituitary GH cells, effect of ghrelin on cardiac myocytes, role of
ghrelin in endometrium, etc. This substantial body of high-quality work is clearly continuing to make an
international impact in my discipline, confirmed by the high impact factor of journals in which I published, the
frequent citation of my papers, frequent invitations to give plenary lectures, symposium chair and presentation,
and to be in the organizing committees of several scientific conferences and societies. It is also reflected in the
number of invitations to join the Editorial Boards of international journals, including leading endocrine journal,
Endocrinology. I have also been invited to review grant proposals for a number of funding agencies. I was
offered a Professorship title by the University of Queensland with significant start-up funds to relocate my
laboratory to Brisbane early 2008.
Expected future outcomes:
In the next 5 years, my group is expanding into several new researdch areas including diabetes research, single
cell exocytosis with multiple photon microscope, single cell contraction and signal image analysis, and cancer
development. Our research will be related to type 2 diabetes, heart failure, obesity, and endometrium cancer.
Name of contact:
Chen Chen
Email/Phone no. of contact:
chen.chen@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 338501
Start Year: 2005
CIA Name: Prof Chen Chen
End Year: 2007
Admin Inst: Prince Henry's Institute of Medical Research
Grant Type: NHMRC Project Grants
Main RFCD: Cell Physiology
Total funding: $256,500
Title of research award:
Regulation of pancreatic beta-cell number and function by adipocyte-released hormones, free fatty acids and
ghrelin.Regulation of pancreatic beta-cell number and function by adipocyte-released hormones, free fatty
acids and ghrelin.
Lay Description (from application):
The disease diabetes mellitus comprises a heterogeneous group of disorders all characterised by high blood
glucose levels. Beta-cells in the pancreas, which secrete insulin, are central to the pathophysiology of the
disease. Type 1 or insulin-dependent diabetes mellitus results from an absolute deficiency of insulin due to auto
immunological destruction of the pancreatic beta cell, and accounts for 5-10% of total diabetes mellitus. In the
more common type 2 or non-insulin-dependent diabetes mellitus, liver, muscle and fat cells are resistant to the
action of insulin and compensatory mechanisms that are activated in the beta-cell to increase insulin secretion
are not sufficient to maintain normal blood glucose levels. In Western countries including Australia, type 2
diabetes currently affects around 2% of the whole population and about 6% of adults (10% of over 60-y) and
continues to grow at around 6% per annum. Type 2 diabetes often occurs in obese patients and a direct link
between obesity and type 2 diabetes has been strongly suggested by research to date. It has also been found that
a progressive loss of beta-cell function throughout the course of the disease results in the reduction of insulin
secretion. The contribution of excessive fat tissue in obese patients to the progress of type 2 diabetes is not
clear. Certain hormones from fat cells, metabolic regulatory hormone, and fatty acids have been demonstrated
to influence the function of beta-cells in previous studies, including our own. We now aim to investigate in
detail the effect of these on cultured beta-cells with molecular and cell biology techniques. We expect to
identify a factor or factors which stimulate or inhibit the progress of beta-cell dysfunction, with the potential to
identify therapeutic targets in the treatment of type 2 diabetes.
Research achievements (from final report):
Diabetes mellitus is a heterogeneous group of disorders characterised by high blood glucose levels. The
pancreatic beta-cell and its secretory product insulin are central in the pathophysiology of the disease. Type 2
diabetes counts for 90-95 % of total diabetes. In type 2 or non-insulin-dependent diabetes mellitus, liver,
muscle and fat cells are resistant to the action of insulin and compensatory mechanisms that are activated in the
beta-cell to secrete more insulin are not sufficient to maintain blood glucose levels within a normal
physiological range. Type 2 diabetes occurs often in obese patients and a direct link between obesity and type 2
diabetes has been strongly supported. The contribution of excessive adipose tissue in obesity patients to the
progress of beta-cell dysfunction has been studied in this project. Adipocyte-derived hormones and free fatty
acids have been demonstrated to damage the function of beta-cells in insulin synthesis and secretion.
Membrane ion channels and signalling systems have been studied. We found that FFA influenced beta cell
function through both membrane receptor and intracellular metabolism pathways. We also found that insulin
resistance in beta cells was responsible for beta cell dysfunction. These new discoveries lead to a new project
proposal submitted for further investigation.
Expected future outcomes:
The results from this study lead to a further study on cell function of pancreatic islet cells under the influence
of FFAs through receptor and metabolite pathways. It will clarify the mechanism of FFA-induced beta cell
dysfunction and will also lead to new ways to delay the process of diabetes.
Name of contact:
Chen Chen
Email/Phone no. of contact:
NHMRC Research Achievements - SUMMARY
chen.chen@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 338510
Start Year: 2005
CIA Name: Dr Margaret Jones
End Year: 2007
Admin Inst: Prince Henry's Institute of Medical Research
Grant Type: NHMRC Project Grants
Main RFCD: Cell Metabolism
Total funding: $361,200
Title of research award:
THE METABOLIC SYNDROME, RISK FACTORS AND ESTROGENTHE METABOLIC SYNDROME,
RISK FACTORS AND ESTROGEN
Lay Description (from application):
The Metabolic Syndrome is a group of closely related risk factors that contribute to the onset of diabetes and
heart disease. The risk factors include obesity, (especially when fat accumulates around the waist), insulin
resistance and high blood pressure. There is an important but as yet not fully understood relationship between
estrogen and the development of these risk factors. The Metabolic Syndrome has been estimated to affect some
20-30% of the middle-aged population and prevalence appears to be increasing in the world population with
increasing obesity and sedentary lifestyle. Therefore it is of great importance to be able to understand the
mechanisms regulating the development of, and the interrelationships between, the risk factors of the
syndrome, particularly the integral role played by estrogen. By utilising a mouse model that cannot make its
own estrogen, we are able to study how estrogen contributes to maintaining the body's balance of fat tissue,
sensitivity to insulin and a healthy heart. We will be looking at how genes important to these systems are
affected when estrogen is not available and what the downstream consequences of any gene changes are. We
also plan to monitor the mouse's sensitivity to insulin in the absence of estrogen, then again when estrogen is
given back. Similarly, we will study the mouse's cardiovascular system, checking blood pressure, heart health
and sensitivity to salt (which can affect blood pressure). By completing this body of work, we will better
understand how estrogen can best be used as a therapy to prevent the development of the risk factors for the
Metabolic Syndrome.
Research achievements (from final report):
Estrogen has an important role to play in energy homeostasis in both men and mice. Lack of estrogen results in
the development of a metabolic syndrome in humans and rodents, including excess adiposity, hepatic steatosis
(in male but not female Aromatase Knockout (ArKO) mice) and insulin resistance. Estrogen replacement
results in a prompt reversal of the energy imbalance symptoms associated with estrogen deficiency. A corollary
to the perturbed energy balance observed in the ArKO mouse is the death by apoptosis of dopaminergic
neurons in the hypothalamic arcuate nucleus of male ArKO mice, an area of the brain pivotal to the regulation
of energy uptake, storage, and mobilisation. An extension of our work exploring the relationship between
estrogen and adiposity has been to examine the role played by androgens in energy balance. We have
demonstrated that an increased androgen to estrogen ratio can promote visceral fat accumulation in the rodent
by inhibiting AMPK activation and stimulating lipogenesis. Therefore understanding the regulation of energy
homeostasis is becoming an increasingly fascinating challenge, as the number of contributors, their
communications, and the complexity of their interactions, involved in the preservation of this equilibrium
continues to increase. Models of aromatase deficiency, both naturally occurring and engineered, will continue
to provide valuable insights into energy homeostasis.
Expected future outcomes:
Features of the Metabolic Syndrome, including 1) abdominal obesity and dyslipidemia, 2) insulin resistance
and 3) hypertension, constitute significant risk factors for Type 2 diabetes and cardiovascular disease. Our
research is continuing to make significant inroads into understanding the role of estrogen in the development of
these features.
Name of contact:
Dr Margaret Jones
Email/Phone no. of contact:
NHMRC Research Achievements - SUMMARY
Margaret.Jones@princehenrys.org
NHMRC Research Achievements - SUMMARY
Grant ID: 338517
Start Year: 2005
CIA Name: Dr Greg Tesch
End Year: 2007
Admin Inst: Prince Henry's Institute of Medical Research
Grant Type: NHMRC Project Grants
Main RFCD: Nephrology and Urology
Total funding: $454,500
Title of research award:
Role of JNK and p38 MAPK signalling in diabetic nephropathyRole of JNK and p38 MAPK signalling in
diabetic nephropathy
Lay Description (from application):
Renal failure is a major health problem in our community. Patients who progress to end-stage renal failure are
dependent upon lifelong dialysis or transplantation (an expensive and complex treatment). The past decade has
seen a dramatic increase in the number of patients developing end-stage renal failure, mainly due to increasing
rates of diabetic kidney disease. Indeed, the recent AusDiab nationwide survey that identified diabetes or
glucose intolerance (a precursor to diabetes) is now present in up to 25% of the adult Australian population.
Around 50% of diabetics develop kidney disease and, despite recent advances in better control of blood
glucose and blood pressure, kidney disease in most diabetic patients will inexorably progress to end-stage renal
failure. Therefore, there is an urgent need to improve treatment strategies in diabetic patients to avoid kidney
failure. We have identified a group of proteins (enzymes called JNK and p38) within cells that play a causal
role in the development of non-diabetic forms of kidney disease. Most recently, we have shown that an
increase in the activity of these proteins (JNK and p38) is associated with the development of human and
experimental diabetic kidney disease. Therefore, this project will block the action of JNK and p38 using two
complementary approaches (pharmaceutical drugs and genetically modified mice) to determine whether
targeting these proteins can suppress the development of diabetic kidney disease. In addition, there is evidence
to suggest that blockade of these proteins may have a beneficial impact upon insulin resistance and elevated
blood glucose in type 2 diabetes. If these postulates are proven, this will provide a well-defined therapeutic
target for the treatment of diabetic kidney disease, and perhaps diabetes itself. Furthermore, since inhibitors of
these proteins are already in clinical trials for other indications, targeting this mechanism in diabetic kidney
disease is a realistic goal.
Research achievements (from final report):
This project has shown that intracellular signalling via JNK1 or MKK3 promotes the development of
pancreatic injury, islet destruction and hyperglycaemia in the multiple-low dose model of streptozotocininduced type 1 diabetes in mice. Furthermore, we have identified that signalling via JNK1 or JNK2 is critical
for the development of type 2 diabetes in obese db/db mice. In contrast, MKK3 signalling was not required for
the induction of type 2 diabetes in db/db mice, but was important for the subsequent development of diabetic
nephropathy in these animals. These studies indicate that therapeutic targeting of the JNK or MKK3 signalling
pathways may be beneficial in the treatment of diabetes or diabetic nephropathy.
Expected future outcomes:
Our findings provide the foundation for future research examining how JNK signalling contributes to the
development of type 2 diabetes and may also lead to the development of specific kinase inhibitors which target
these signalling pathways in order to suppress the development of diabetes or diabetic nephropathy.
Name of contact:
Dr Greg Tesch
Email/Phone no. of contact:
greg.tesch@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 388902
Start Year: 2007
CIA Name: Dr David Nikolic-Paterson
End Year: 2008
Admin Inst: Prince Henry's Institute of Medical Research
Grant Type: NHMRC Project Grants
Main RFCD: Nephrology and Urology
Total funding: $425,921
Title of research award:
Lefty - a novel anti-fibrotic molecule for the treatment of kidney diseaseLefty - a novel anti-fibrotic molecule
for the treatment of kidney disease
Lay Description (from application):
Patients with progressive forms of kidney disease go on to develop end-stage renal failure which requires
intensive medical support of dialysis or organ transplantation. This is an increasingly common condition in
Australia, and the Western world in general. It is devastating for the individual and it places an enormous
economic strain upon our healthcare system. In addition, renal failure is a strong and independent risk factor
for cardiovascular disease. Current treatments can at best slow the rate of progression of kidney disease, but
cannot prevent the relentless progression to end-stage renal failure. Thus, there is a major medical need to be
able to halt, and hopefully reverse, this relentless disease. Scarring of the kidney (termed fibrosis) is the
common final pathway leading to end-stage renal failure regardless of the nature of the underlying kidney
disease. Our preliminary studies have shown that a naturally occurring protein called Lefty can act to inhibit
renal fibrosis in cell culture and animal studies. These very promising results have lead to the hypothesis that
Lefty can halt, and perhaps even reverse, scarring of the kidney in progressive kidney disease. We will test this
hypothesis by using Lefty as a treatment in animal models of renal fibrosis. Further cell culture studies are also
planned to examine the mechanisms by which Lefty modulates renal fibrosis. If successful, these studies will
provide critical data to support the development of Lefty as a clinical treatment for patients with progressive
forms of kidney disease.
Research achievements (from final report):
These studies have examined the mechanisms involved in fibrosis (or scarring) of the damaged kidney, a
process generally considered to be the final pathway leading to complete loss of kidney function that requires
treatment by dialysis or kidney transplantation. We have identified a novel, naturally occurring protein that
appears to have potential anti-fibrotic actions when used in cell culture studies and has indicated some promise
in animal studies. This anti-fibrotic molecule appears to operate via a novel mechanism and represents a
potential therapy for the treatment of chronic kidney disease. However, much work remains to be done before
this molecule could be used in clinical trials.
Expected future outcomes:
We hope that these exciting findings can be translated into clinical trials in patients with renal disease, although
this possibility is still some time away.
Name of contact:
David Nikolic-Paterson
Email/Phone no. of contact:
david.nikolic-paterson@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 388930
Start Year: 2006
CIA Name: Dr Greg Tesch
End Year: 2010
Admin Inst: Prince Henry's Institute of Medical Research
Grant Type: Career Development
Fellowships
Main RFCD: Nephrology and Urology
Total funding: $462,290
Title of research award:
Macrophage-mediated injury - potential therapeutic targets for preventing diabetic nephropathy and insulin
resistance.Macrophage-mediated injury - potential therapeutic targets for preventing diabetic nephropathy and
insulin resistance.
Lay Description (from application):
Not Available
Research achievements (from final report):
During this fellowship, I have performed genetic mutation and pharmacological studies in animal models of
disease which have demonstrated that tissue accumulation of a particular type of inflammatory cell, known as a
macrophage, is a major contributor to the development of obesity-related diabetes and diabetic kidney injury.
These studies have determined some of the critical molecular mechanisms by which macrophages cause tissue
injury during obesity and diabetes. They have also identified specific molecules that can be blocked
therapeutically to prevent the tissue injury caused by macrophages, and have shown that this strategy can be
used to prevent the progression of kidney damage during diabetes. However, the therapeutic strategies
identified for blocking macrophages so far are not ideal for clinical use in chronic disorders such as obesity or
diabetes. Therefore, more investigations are required to identify better strategies for macrophage blockade that
will be more appropriate for potential use in patients.
Expected future outcomes:
The findings made during my CDA have facilitated the development of new research projects and
collaborations with pharmaceutical companies. These ongoing studies aim to identify molecules that are better
therapeutic targets for selectively preventing the development of inflammatory responses which cause obesityrelated diabetes or diabetic nephropathy.
Name of contact:
Dr Greg Tesch
Email/Phone no. of contact:
greg.tesch@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 441102
Start Year: 2007
CIA Name: Prof Vincent Harley
End Year: 2011
Admin Inst: Prince Henry's Institute of Medical Research
Grant Type: Established Career
Fellowships
Main RFCD: Genetic Development (incl. Sex Determination)
Total funding: $618,722
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
I am a molecular biologist investigating the role of SRY/SOX transcription factors in the formation and
function of the gonad, and to a lesser extent, of bone, the brain and the pancreas. I also identify and
functionally characterise other factors causing
Research achievements (from final report):
A COMMON FAILURE IN SEVERAL FORMS OF 46XY DSD Human mutations in the SRY (sex
determining region on Y), SOX9 (SRY-related HMG box 9) or SF1 (steroidogenic factor 1) genes cause DSDs.
These factors function during gonadal development around SOX9 as a hub gene, with different genetic causes
of 46,XY DSD due to a common failure to upregulate SOX9 transcription., ATRX, AN IMPORTANT
REGULATOR OF SPERMATOGENESIS Infertility affects about one in 20 Australian men, and is a common
experience for men with DSDs. Studies of the molecular action of the ATRX gene are providing a better
understanding of some underlying causes of male infertility. We have discovered that the ATRX protein is an
important regulator of androgen actions, as well as playing a key role in the survival of testicular cells. ,
THREE NOVEL CAUSES OF DSD IDENTIFIED 1. Whole-genome analysis of a 46,XY DSD patient that
identified the WWOX gene, supporting a role for WWOX in human gonad development. 2. Genomic
rearrangements within the SOX3 regulatory region are a relatively common cause of XX DSD in cases lacking
the SRY gene. 3. A testis enhancer region of the SOX9 gene was identified where gain or loss of this region
was associated with 46,DSD or 46, XY DSD, respectively., ROLE OF SRY IN THE HUMAN MALE BRAIN
We have recently has demonstrated that SRY protein also co-localises with dopamine neurons in the ventral
tegmental area in human males. This challenges the dogma in brain sex differentiation that hormones control
sex differences., GENETICS OF GENDER IDENTITY DISORDERS Our genetic study of male-to-female
transsexuals was the first to link a gene, androgen receptor with this condition. This has stimulated genetic
research worldwide.,
Expected future outcomes:
We will have identified causative genes in DSD and their normal functions in gonadal development. , We will
have demonstrated that SRY, a gene found only in males, plays key roles in the regulation of dopamine in the
normal brain and its misregulation in men with Parkinsons disease is a symptom. Moreover, agents that lower
SRY expression have a protective effect.
Name of contact:
Vincent Harley
Email/Phone no. of contact:
vincent.harley@princehenrys.org
NHMRC Research Achievements - SUMMARY
Grant ID: 494822
Start Year: 2008
CIA Name: A/Pr David Nikolic-Paterson
End Year: 2010
Admin Inst: Prince Henry's Institute of Medical Research
Grant Type: NHMRC Project Grants
Main RFCD: Nephrology and Urology
Total funding: $537,704
Title of research award:
TAK1 - a novel regulator of renal inflammation and fibrosis.TAK1 - a novel regulator of renal inflammation
and fibrosis.
Lay Description (from application):
Renal failure is a major health problem in our community. Recent in vitro studies have identified a protein that
plays a critical role in the induction of inflammation and fibrosis - processes central to the progression of
kidney disease. This project will use a genetic-based approach to determine if this regulator plays a critical role
in the pathogenesis of experimental kidney disease. If successful, these studies will identify a new therapeutic
target for the treatment of kidney disease.
Research achievements (from final report):
We have examined the function of a specific gene, called TAK1, in the development of inflammation, fibrosis
and cell death in experimental kidney disease. Using mice in which that TAK1 gene has been deleted in
different cell populations, we have been able to define several distinct functions of the TAK1 gene. Specific
deletion of the TAK1 gene from particular white blood cell populations (macrophages and neutrophils) showed
that this gene is not required macrophage development. As postulated, we found that TAK1 deficient
macrophages exhibit a severely diminished response to various pro-inflammatory stimuli. In vivo, these mice
were partially protected in a model of endotoxin-induced acute renal injury (albuminuria). In a separate study,
general deletion of the TAK1 gene in adult mice was shown to protect against fibrosis in a model of kidney
scarring, although the lack of TAK1 did enhance cell death in the kidney which limits the potential usefulness
of blocking TAK1 function as a treatment of kidney scarring. Finally, deletion of TAK1 in a key cell type in
the glomerulus (the filtering unit of the kidney) called the podocyte demonstrated that TAK1 is not required for
normal kidney development; however, TAK1 deletion made these mice more susceptible to immune-mediated
podocyte injury resulting in more severe kidney disease. In summary, we have identified TAK1 as a key
regulator of inflammation, fibrosis and cell death in kidney disease. However, our studies indicate that TAK1 is
not a suitable therapeutic target in kidney disease because TAK1 exhibits both protective and detrimental
functions in kidney disease depending upon the nature of underlying renal injury.
Expected future outcomes:
Our studies have indicated that two of the three key signalling pathways activated by TAK1 (called p38 and
JNK) are potential therapeutic targets in kidney disease, whereas the third major pathway activated by TAK1
(called NF-kB) plays an important role in protecting the kidney from cell death. We anticipate that these
findings will shape the design of future clinical trials.
Name of contact:
Dr David Nikolic-Paterson
Email/Phone no. of contact:
david.nikolic-paterson@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 494823
Start Year: 2008
CIA Name: Dr Greg Tesch
End Year: 2010
Admin Inst: Prince Henry's Institute of Medical Research
Grant Type: NHMRC Project Grants
Main RFCD: Endocrinology
Total funding: $519,715
Title of research award:
Therapeutic targetting of MIF in type 2 diabetesTherapeutic targetting of MIF in type 2 diabetes
Lay Description (from application):
In this study, mouse models of disease will be used to determine the mechanisms by which the
proinflammatory molecule called MIFpromotes the development of insulin resisitance and type 2 diabetes. We
will also test whether therapeutic blockade of MIF can prevent the progression of disease in mice with
established type 2 diabetes. Studies on tissue samples obtained from human patients will be used to confirm the
human relevance of these findings.
Research achievements (from final report):
This project has identified a role for a circulating pro-inflammatory molecule (macrophage migration inhibitory
factor - MIF) and two types of intracellular signaling molecules (JNK1 and JNK2) in the development of type 2
diabetes in obese db/db mice. Our studies showed that MIF was increased in the abdominal fat and liver of
obese db/db mice and was inducible in cultured fat cells by increasing levels of free fatty acids, which are
present during obesity. Genetic deficiency of MIF protected db/db mice from inflammation of the fat tissue,
loss of insulin sensitivity and the development of type 2 diabetes without reducing obesity. We also examined
the role of intracellular JNK signaling as a downstream mediator of MIF-induced inflammation and insulin
resistance. Genetic deficiency of either JNK1 or JNK2 were found to protect db/db mice from the development
of obesity-related type 2 diabetes. JNK1 deficiency resulted in improved insulin sensitivity in db/db mice. In
contrast, JNK2 deficiency had no clear effect on insulin sensitivity but altered fat distribution in db/db mice.
These findings indicate that blockade of MIF or JNK signaling with specific inhibitors has significant
therapeutic potential for preventing the development of insulin resistance and type 2 diabetes in obese patients.
Expected future outcomes:
Our analysis of 3 animal model studies is approaching completion and we expect to publish these studies
within the next 12 months. These studies are expected to identify mechanisms by which MIF, JNK1 and JNK2
promote the development of type 2 diabetes.
Name of contact:
Dr Greg Tesch
Email/Phone no. of contact:
greg.tesch@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 496688
Start Year: 2008
CIA Name: A/Pr Naomi Wray
End Year: 2010
Admin Inst: Queensland Institute of Medical Research
Grant Type: NHMRC Project Grants
Main RFCD: Preventive Medicine
Total funding: $269,371
Title of research award:
Accurate prediction of individual risk to disease from genome-wide association studiesAccurate prediction of
individual risk to disease from genome-wide association studies
Lay Description (from application):
Risk for many complex diseases (such as psychiatric disorders or heart disease) has a substantial genetic
component, however few specific high risk variants have been identified. Evidence is mounting that there are
likely to be hundreds of risk loci each individually conferring a very low increase in relative risk for disease.
We aim to develop methods that utilise information from multiple genetic risk variants simultaneously to create
a 'genomic profile' of risk.
Research achievements (from final report):
, We have made significant developments in the methodology for using genome-wide genotype data for
prediction of genetic risk to disease. At the moment, accurate prediction is not possible because effect sizes at
individual loci are small and very large sample sizes are required to detect them with accuracy. In the long run
it it is highly likely that clinically useful predictors based on genome-wide genotypes will be available for some
complex disorders, but probably not others. This will depend on the true genetic architecture of the disorders
(i.e., number or risk loci, distribution of effect sizes of risk alleles, distribution of frequency of risk alleles). The
methods we have developed can be used to understand and quantify the genetic architecture of complex genetic
disease. Our analyses applied to schizophrenia and bipolar data sets provide direct empirical evidence for a
shared genetic etiology between these disorders. Our methods have been used to determine the proportion of
variance that is tagged by SNPs, and we have partitioned this variation by chromosome, by minor allele
frequency of the genotyped SNPs and by function. Results of these analyses have considerably enhance our
understanding of the genetic architecture of complex disorders and contribute to planning of future research.
We have developed methodologies for quantifying the efficacy of a genomic predictor, these methods account
for the oversampling of cases into case-control studies compared to the general population., Prediction of
genetic risk for common complex genetic disorders could provide a valuable screening tool allowing early
intervention strategies to reduce the risk of onset of disease. These predictors will be probabilistic rather than
deterministic but could contribute to life choice options.
Expected future outcomes:
The progress we have made in this 3 year grant has been recognised by having secured an NHMRC project
grant supporting two full-time post-doctoral researchers. We hope to extrapolate our methods to more complex
data and situations and ultimate to provide clinically useful predictors of genetic risk.
Name of contact:
Naomi Wray
Email/Phone no. of contact:
naomi.wray@qimr.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 496739
Start Year: 2009
CIA Name: Prof Nicholas Martin
End Year: 2013
Admin Inst: Queensland Institute of Medical Research
Grant Type: International
Collaborations
Main RFCD: Quantitative Genetics
Total funding: $921,225
Title of research award:
Validation and Replication of Genes Associated with Common Human Disease Using Australian Twin
FamiliesValidation and Replication of Genes Associated with Common Human Disease Using Australian Twin
Families
Lay Description (from application):
The European Network for Genetic and Genomic Epidemiology (ENGAGE) aims to translate the wealth of
data emerging from large-scale research efforts in molecular epidemiology into information of direct relevance
to future advances in clinical medicine. ENGAGE will do this through the integration of very large datasets
already available from a substantial number of large and well-characterised samples. The resulting ENGAGE
resource will represent a research investment >€100M (>AU$160M) and provide unprecedented power to
discover disease and trait susceptibility genes. QIMR will contribute 12,000 twins for ENGAGE joint analyses
and provide analytical expertise in the analysis of disease and genetic data related to lifestyle and metabolic
traits, with particular emphasis on cardiovascular disease, type 2 diabetes and migraine risk factors. Our
laboratory will also perform vital further genetic studies to establish the causal relationship between the genetic
variants concerned and the traits of interest. Most importantly, our direct participation will allow the translation
of these findings into the Australian population and clinical arena.
Research achievements (from final report):
The European Network for Genetic and Genomic Epidemiology (ENGAGE) aimed to translate the wealth of
data emerging from large-scale research efforts in molecular epidemiology into information of direct relevance
to future advances in clinical medicine. , QIMR Berghofer contributed data from over 16,000 twin family
individuals for ENGAGE joint analyses and provided analytical expertise in the analysis of disease and genetic
data related to lifestyle and metabolic traits, with particular emphasis on cardiovascular disease, type 2 diabetes
and migraine risk factors. Our laboratories also performed vital further genetic studies to establish the causal
relationship between the genetic variants concerned and the traits of interest. Most importantly, our direct
participation allowed the translation of these findings into the Australian population and clinical arena.
Expected future outcomes:
Through continued integration of new and larger datasets we will continue to discover genetic risk factors for
common human disease.
Name of contact:
Nick Martin
Email/Phone no. of contact:
Nick.Martin@qimrberghofer.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 339718
Start Year: 2005
CIA Name: A/Pr Gavin Turrell
End Year: 2006
Admin Inst: Queensland University of Technology Grant Type: NHMRC Project Grants
Main RFCD: Public Health and Health Services not elsewhere classified
Total funding: $429,000
Title of research award:
A multilevel study of socioeconomic position and physical activity: environmental and individual-level
determinantsA multilevel study of socioeconomic position and physical activity: environmental and individuallevel determinants
Lay Description (from application):
Regular physical activity offers many health benefits, whereas inadequate activity is a leading cause of
premature death and disability and a major contributor to the increasing prevalence of overweight and obesity.
Socioeconomically disadvantaged groups are least likely to be physically active, and they experience higher
rates of death and morbidity for conditions directly linked to inactivity. Currently, our understanding of why
socioeconomic groups differ in their physical activity is limited, and very little research has investigated this
issue. This study will investigate why socioeconomic groups differ in their physical activity, by examining the
influence of neighbourhood and individual-level factors. Neighbourhood factors include people's access to
recreational facilities such as swimming pools, tennis courts, golf clubs, gyms, local parks, walking and bicycle
paths; prices for entry to recreational facilities and opening hours; physical characteristics of the
neighbourhood including public transport, presence of footpaths and street lighting, speed limits on local
streets, availability of local services such as shops and schools, and; aesthetic characteristics, such as the
presence and size of parks and green spaces, and traffic density. Individual factors include personal enjoyment,
knowledge, confidence, type of occupation and hours worked, family responsibilities, age, health status, and
whether other family member or friends engage in physical activity. A major aim of the study is to determine
whether environmental or individual factors are more important in influencing participation in physical
activity. The study will produce new knowledge to inform future public health strategies directed at increasing
physical activity among socioeconomically disadvantaged groups, and these will have the potential to reduce
socioeconomic health inequalities, as well as contribute to an overall reduction of the disease burden
attributable to chronic conditions.
Research achievements (from final report):
The HABITAT study is unique internationally and has a number of strengths including its multilevel design
and its focus on area- and individual-level socioeconomic determinants of physical activity (PA). The new
knowledge generated will inform public health strategies directed at increasing PA among socioeconomically
disadvantaged groups, and these will have the potential to reduce health inequalities, as well as contribute to an
overall reduction of the disease burden attributable to chronic conditions. Also, this research will inform the
development of intervention trials with different socioeconomic groups. Preliminary output from the project
has been presented at a number of national conferences.
Expected future outcomes:
The HABITAT Project (baseline) was completed in 2007. Currently we are writing manuscripts for publication
in international journals. Future collections of HABITAT data will occur in May 2009 and 2011.
Name of contact:
Gavin Turrell
Email/Phone no. of contact:
g.turrell@qut.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 497230
Start Year: 2008
CIA Name: Prof Nathan Efron
End Year: 2011
Admin Inst: Queensland University of Technology Grant Type: NHMRC Project Grants
Main RFCD: Endocrinology
Total funding: $540,372
Title of research award:
A longitudinal study of nerve morphology in diabetic neuropathy using novel non-invasive ophthalmic
surrogate markersA longitudinal study of nerve morphology in diabetic neuropathy using novel non-invasive
ophthalmic surrogate markers
Lay Description (from application):
This research project will use two new ophthalmic instruments - the corneal confocal microscope and noncontact corneal aesthesiometer - to directly monitor changes in corneal nerves and corneal sensitivity, over a 5
year period, in diabetic patients suffering from a painful condition of the arms and legs known as diabetic
neuropathy. This study will generate important new information that could allow diabetic doctors to more
accurately monitor the progression of the disease.
Research achievements (from final report):
Diabetic peripheral neuropathy is a debilitating condition that affects about 50% of diabetic patients. The
symptoms of neuropathy include numbness, tingling or pain in the arms and legs. If left untreated, patients with
numbness may develop foot ulcers which may ultimately require foot amputation. Currently the only method of
directly examining peripheral nerves is to conduct skin punch biopsies, which are uncomfortable and invasive.
Indirect methods include quantitative sensory testing (assessing responses to heat, cold and vibration) and
nerve electrophysiology. This project has demonstrated the utility of using ophthalmic markers to assess
diabetic neuropathy. Specifically, it has been demonstrated that corneal nerve structure and function can be
assessed using corneal confocal microscopy and non-contact corneal aesthesiometry. Using these techniques, it
has been demonstrated that diabetic neuropathy - assessed using conventional techniques - is associated with
altered morphology of corneal nerves and reduced corneal sensitivity. Initial findings of this study establish
these ophthalmic markers as rapid, painless, non-invasive, sensitive, reiterative and cost-effective means of
screening for early detection and diagnosis of diabetic peripheral neuropathy, and for monitoring the
progression and quantifying the severity of this debilitating condition.
Expected future outcomes:
Corneal confocal microscopy and non-contact corneal aesthesiometry could be employed in diabetes clinics as
simple screening tests of diabetic neuropathy and/or for ongoing monitoring of this condition.
Name of contact:
Professor Nathan Efron
Email/Phone no. of contact:
n.efron@qut.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 535930
Start Year: 2009
CIA Name: Prof Jiming Ye
End Year: 2012
Admin Inst: RMIT University
Grant Type: NHMRC Project Grants
Main RFCD: Therapies and Therapeutic Technology
Total funding: $574,076
Title of research award:
Investigation of Novel Triterpenoids as New Potent AMPK Activators for the Treatment of Insulin Resistant
StatesInvestigation of Novel Triterpenoids as New Potent AMPK Activators for the Treatment of Insulin
Resistant States
Lay Description (from application):
Type 2 Diabetes has major economic and health implications. Current medications are inadequate or have
serious adverse effects. Triterpenoids have been used in traditional medicines for various diseases. This project
builds on our recent discovery of novel triterpenoids with antidiabetic properties to investigate their efficacy
and mechanisms of action. The results will provide valuable information about this class of molecules as
potential new therapeutics for Type 2 diabetes.
Research achievements (from final report):
This Project has made a number of significant achievements in three aspects. At the scientific level, our studies
have identified CaMKK as the upstream mechanism leading to the activation of triperpenoids on AMPK. This
finding indicates that the triterpenoid has the potential as a new class of anti-diabetic compounds by a
mechanism which is different from other AMPK activators including metformin, TZD and berberine.
Furthermore, we have demonstrated that one triperpenoid (oleanolic acid) exerts sustained effect in maintaining
reduced hyperglycemia far beyond the treatment period by suppressing hepatic gluconeogenesis. This exciting
finding may provide a clue to develop strategies to overcome the current problem of the loss of the therapeutic
effects for most anti-diabetic drugs. Finally, we also found that treatment with a triterpenoid can protect against
the morphological damage in kidney associated with diabetes. , This project has enabled us to consolidate our
strategic collaboration with the Shanghai Institute of Materia Medica, one of top research institute in the world
in drug discovery research. During the period of this grant, we have held three joint symposia to promote the
exchange of researchers from RMIT, Shanghai Institute of Materia Medica and Garvan Institute. This
collaboration is part of our ongoing study on the new triterpenoids discovered from bitter melon which is listed
as one of the most successful scientific collaborations between Australia and China in the past 30 years.
Expected future outcomes:
Continuing collaboration with Shanghai Institute of Materia Medica for the research in Shanghai to optimize
the triterpenoid lead as possible drug candidate doe the treatment of type 2 diabetes. Follow-up study on the
mechanism of the sustained the anti-hyperglycemia effects of triterpenoids. These studies are likely to generate
additional publications.
Name of contact:
Jiming Ye
Email/Phone no. of contact:
jiming.ye@rmit.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 251558
Start Year: 2003
CIA Name: Prof Mark Febbraio
End Year: 2005
Admin Inst: Royal Melbourne Institute of TechnologyGrant Type: NHMRC Project Grants
Main RFCD: Cell Physiology
Total funding: $330,375
Title of research award:
Muscle derived interleukin-6: signalling pathways and biological rolesMuscle derived interleukin-6: signalling
pathways and biological roles
Lay Description (from application):
Over the past few years work from our research group has identified that the cytokine interleukin-6 (IL-6) is
produced by skeletal muscle during contractions. Moreover, we have demonstrated that IL-6 performs entirely
novel functions that have major ramifications for diseases such as type 2 diabetes and obesity. We have
demonstrated that IL-6 is a potent factor in increasing the breakdown of fatty acids in the human body. We
have also demonstrated that IL-6 down-regulates the cytokine tumour necrosis factor alpha (TNF-a), which
impairs glucose uptake and promotes insulin resistance. The proposed work will extend upon these findings.
Discovering that IL-6 produced during exercise contributes to fatty acid utilisation will have profound
ramifications for what we know about energy breakdown. If we find that the function of IL-6 produced by
muscle is to down-regulate TNF-a and lead to enhanced glucose uptake in type 2 diabetics, it may lead to IL-6
being used as a possible therapeutic aid in the treatment of type 2 diabetes. In summary, this project will have
major significance for not only our fundamental knowledge of the processes involved in maintaining metabolic
homeostasis, but also for our understanding of the major health problem of obesity related diseases.
Research achievements (from final report):
Firstly, we have identified that the cytokine interleukin (IL-6) is one of only two cytokines produced by
skeletal muscle during contraction. Moreover, we have demonstrated using in situ hybridization and
immunohistochemistry that the myocytes themselves, not other cells within the muscle (eg fibroblasts,
macrophages etc), are responsible for the increase in IL-6 within muscle seen with contraction. In addition, we
have demonstrated that p38 MAPK is phosphorylated at the nucleus of muscle cells and acts on a downstream
transcription factor to induce IL-6 transcription. We have also demonstrated that the upstream signal appears to
be calcium since it is the calcium ionophore ionomycin that activates IL-6 in muscle. In exciting final
experiments, we have identified a novel signalling pathway for the gene transcription of IL-6 in skeletal muscle
cells. , We have identified IL-6 as a mediator of endogenous glucose production during exercise showing that
skeletal muscle is an endocrine organ capable of releasing biologically active compounds. We have
demonstrated that contrary to dogma, IL-6 is not associated with insulin resistance and in fact increases fatty
acid turnover while enhancing insulin sensitivity as measured by the homeostatic model assessment (HOMAIR). This has led us to determine if IL-6 actually increases insulin sensitivity. We have performed studies in
cells to show that IL-6 increases insulin stimulated glucose transport via activation AMP kinase and by
increasing the translocation of glucose transporter 4. We then performed experiments in humans to show that
IL-6 increases glucose infusion rate during a maximal insulin clamp. We have also performed a chronic
experiment in rats demonstrating that IL-6 improves glucose tolerance. These data demonstrate that targeting
the receptor for the IL-6 family of cytokines provides a realistic therapeutic target for the treatment of obesity
related disorders such as type 2 diabetes
Expected future outcomes:
We are currently working on designing ligands that bind to the IL-6 receptor complex to activate the metabolic
master switch AMP kinase and to increase fat oxidation. It is anticipated that these ligands will act to mimic the
effects of exercise and ultimately therapies will be developed from this work
Name of contact:
Mark A Febbraio Phd
Email/Phone no. of contact:
NHMRC Research Achievements - SUMMARY
mark.febbraio@rmit.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 345439
Start Year: 2005
CIA Name: Dr Andrew Carey
End Year: 2008
Admin Inst: Royal Melbourne Institute of TechnologyGrant Type: Early Career Fellowships
(Australia)
Main RFCD: Protein Targeting and Signal Transduction
Total funding: $279,906
Title of research award:
Transcriptional targets for the AMP-activated protein kinaseTranscriptional targets for the AMP-activated
protein kinase
Lay Description (from application):
Not Available
Research achievements (from final report):
The studies conducted under this award revealed mechanisms that are pertinent to the actions of novel
molecules that are important in the eitiology and potential therapy for obesity and type 2 diabetes. Knowledge
gained from these studies paves the way for further investigation into these molecular mechanisms, that might
eventually lead to effective treatments for obesity related diseases.
Expected future outcomes:
Additional experiments are currently in progress that will further our knowledge in this area, and results will be
published in coming months.
Name of contact:
Andrew Carey
Email/Phone no. of contact:
andrew.carey@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 445314
Start Year: 2007
CIA Name: Prof Emilio Badoer
End Year: 2009
Admin Inst: Royal Melbourne Institute of TechnologyGrant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $454,692
Title of research award:
Contribution of the central nervous system to peripheral neural control in obesity and diabetes.Contribution of
the central nervous system to peripheral neural control in obesity and diabetes.
Lay Description (from application):
Obesity and diabetes are becoming major worldwide public health problems. A characteristic of human obese
diabetes is a marked increase in sympathetic nerve activity to the kidneys and to the muscle. The cause of this
overactivity is unknown, but undoubtedly involves the central nervous system. Within the brain are a select
group of regions that are able to directly influence the activation of the sympathetic nervous system. We
suspect these areas to play a critical role in the overactivity of the sympathetic nerve activity in obese diabetics.
Indeed, we believe that there are specific chemical messengers in these select brain areas that are normally
finely balanced. In obesity / diabetes, this balance is disturbed. Finally, we hypothesise that exercise, which is
known to have beneficial effects for obesity / diabetes, restores the balance of the neurochemicals and this
contributes to the positive outcomes of exercise.
Research achievements (from final report):
The aim of the work was to identify the role of specific brain regions (hypothalamic PVN and RVLM) in the
abnormally elevated sympathetic nerve activity to the muscle vasculature in obesity. This project required
considerable preparation work involving a high fat feeding regime for over three months. We compared normal
rats with a group of high fat (ie 30% by weight high fat) fed rats. The high fat fed rats increased body weight
and had increased fat deposits. We found that inhibiting neuronal function in the PVN dramatically reduced
sympathetic nerve activity in both high fat fed rats and rats fed a normal chow diet. The reduction, however,
was significantly greater in the high fat fed rats. This suggested that the PVN, a key integrative region in the
brain, was over activated in obesity. We subsequently investigated whether the overactivity of the PVN was
due to a change in the balance between the inhibitory and excitatory influences in the PVN. We found that
blocking the actions of GABA, the major inhibitory neurotransmitter in the brain, resulted in increased
sympathetic nerve activity in high fat fed rats. Interestingly, the response in the normal chow fed rats was not
significantly different from that observed in the high fat fed group. Thus, the results suggest that in obesity
there is a tonic inhibitory input into the PVN that influences sympathetic nerve activity of the muscle, however,
the contribution this inhibitory input makes to sympathetic nere activity is not altered by obesity.
Expected future outcomes:
Our data suggests that in obesity there is a shift in the role of specific premotor regions in the regulation of
sympathetic nerve activity. The mechanisms that underlie these changes require investigation. Future work will
highlight the mechanisms.
Name of contact:
Professor Emilio Badoer
Email/Phone no. of contact:
emilio.badoer@rmit.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 456049
Start Year: 2007
CIA Name: Prof Philip Poronnik
End Year: 2009
Admin Inst: Royal Melbourne Institute of TechnologyGrant Type: NHMRC Project Grants
Main RFCD: Nephrology and Urology
Total funding: $346,603
Title of research award:
Two-photon microscopy of albumin handling by the intact kidneyTwo-photon microscopy of albumin handling
by the intact kidney
Lay Description (from application):
The clinical association between protein loss in the urine and retention of salt, resulting in high blood pressure
and progressive decline in kidney function, is well known. Under normal conditions, the kidneys filter 180
litres of water and reabsorb 1.7 kg of salt per day, a function which is principally performed by the kidney
tubules in the kidney. Similarly the kidney tubule cells reabsorb and break down up to 3 grams of albumin per
day. In the past, it has been considered that excessive protein loss in the urine is primarily due to problems in
the filtering units of the kidneys, rather than due to abnormalities in the reabsorption of protein in the kidney
tubules. However, we consider that common abnormalities in the processes within the kidney tubules that
regulate both the reabsorption of salt and the excretion of acid may result in concomitant high blood pressure
and increased protein loss in the kidney. Thus the overall aim of the project is to investigate the mechanisms by
which the complex responsible for protein uptake determines the interrelationship between protein reabsorption
and catabolism and the ion transporting proteins in the membrane of the proximal tubule. This project will use
cutting-edge microscopic imaging technology to investigate the mechanisms of protein uptake in the intact
kidney. This information will be integrated with data obtained from our molecular physiology experiments to
define how the kidney handles protein. As persistent proteinuria is the most important predictor of
tubulointerstitial pathology and progressive decline in renal function in almost all renal disease, the
understanding of the precise mechanism by which this occurs is essential in the design of renoprotective
therapies.
Research achievements (from final report):
This project developed new methods for visualising how the intact kidney handles protein and undertsanding
how these pathways are disrupted in disease. In addition to the imaging work we have identified some new
protein-protein interactions that shed further light on the molecular basis for albumin uptake. This work
represents advances in basic science and our fundamental understanding of kidney function that may in time
lead to new diagnostic or therapeutic strategies for renal disease.
Expected future outcomes:
This work underpins further studies that will develop new methods for examining how the increased urinary
protein relates to renal and cardiovascular disease.
Name of contact:
Philip Poronnik
Email/Phone no. of contact:
philip.poronnik@rmit.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 499321
Start Year: 2008
CIA Name: A/Pr Arnan Mitchell
End Year: 2009
Admin Inst: Royal Melbourne Institute of TechnologyGrant Type: NHMRC Development Grants
Main RFCD: Instruments and Techniques
Total funding: $191,599
Title of research award:
Development of a Prototype Production System for Optical Fibre Diagnostic ProbesDevelopment of a
Prototype Production System for Optical Fibre Diagnostic Probes
Lay Description (from application):
Advances in nanotechnology have led to new techniques for the precise fabrication of nanometre scale
structures. A recent breakthrough by the applicants now allows high-quality nanostructures to be "stamped"
onto the tip of low-cost optical fibre probes. When coated with silver, these sensitive probes can be used for
continuous monitoring of blood glucose in diabetics and in critical care situations. This project aims to develop
a prototype manufacturing system for optical fibre glucose probes.
Research achievements (from final report):
This project has demonstrated a capability for industrial scale manufacturing of nano-imprinted optical fibre
diagnostic probes. At the project onset, our proof of concept device took 40 minutes to fabricate. At the
conclusion of this project we have developed technology that allows a single operator to repeatably fabricate
over 1000 fibre probes a day. , To achieve this outcome we separated the fabrication process into a sequence of
modular 'production line' steps and parallelized the fabrication process allowing fibre probes to be processed in
batches of 40. We have automated many of the steps such that all of the fabrication steps could be managed in
parallel by a single operator., This refined process has significantly improved both quality and repeatability of
the fibre probes. We have successfully replicated nano-textures with features on the scale of 15nm and
demonstrated fabrication of samples of 50 fibre probes which are functionally identical., The outcomes of this
project have paved the way for the development of optical fibre probes which use nano-photonic elements to
detect trace chemicals. These sensors, realized entirely on the tips of fibres, are compact enough that they can
be integrated within hypodermic needles to monitor chemicals within the blood stream in-vivo. , The findings
of this project have been featured on the cover of the prestegious technology journal 'Advanced Materials' [1].
Expected future outcomes:
Having demonstrated fabrication of fibre probes on an industrial scale, we are now designing 'smart' textures
for selective and sensitive detection of specific chemicals. Continuous monitoring of glucose within blood is a
major objective. Application of this technology in other contexts, such as monitoring water contaminants, is
also under investigation.
Name of contact:
Professor Arnan Mitchell
Email/Phone no. of contact:
arnan.mitchell@rmit.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 446201
Start Year: 2007
CIA Name: Prof Annemarie Hennessy
End Year: 2012
Admin Inst: Royal Prince Alfred Hospital
Grant Type: NHMRC Enabling Grants
Main RFCD: Medical Physiology not elsewhere classified
Total funding: $632,700
Title of research award:
The National NHMRC Baboon ColonyThe National NHMRC Baboon Colony
Lay Description (from application):
The National NH&MRC Baboon colony provides access to large non-human primates to support Australia’s
research efforts in diverse scientific areas around the country. These include diabetes research (kidney
involvement and prevention of kidney damage, nerve damage and eye damage); treatment options inlcuding
gene therapy of blood/bone-marrow cancers; understandng pregnancy changes in blood pressure and the causes
of hypertension (high blood pressure) in pregnancy; identification of new techniques for analyis of brain
function; the effects of aging on liver function especially with regards to drug metabolism; new therapies for
transplantation which would allow more rational and lower/safer drug use for transplant patients; breaking
down the barriers to animal-to-human transplantation through assessment of safety and development of new
techniques; behavioural aspects of fertility management; vaccine development; development of oral
vaccination; the nature of wound healing.
There is diverse and wide access to the National NHMRC Baboon colony from research interests around
Australia. The use of the animals is at all times approved by the Animal welfare Committee governing the
colony, as well as that which governs the researchers involved. All approved projects have been given access to
the animals required. The need for non-human primate use as opposed to other animals or other techniques not
involving animals is justified to the relvant committees before any project proceeds. The use of the animals
therefore adds a dimension to Australian research due to animal similarity to humans physiology or size
comparisons.
Contributions made by the colony in the last 20 years are listed in the attached references, but understanding
physiology at a depth not possible with other animals has changed our thinking about the human condition as a
result of primate -based research.
Research achievements (from final report):
The provision of a colony of healthy, higher-order, non-human primates to the Australian biomedical research
community has allowed highly relevant research to be carried out in multiple national health priority areas.
Research into cardiovascular disease, diabetes, transplantation, pregnancy complications and other areas has
been facilitated by the provision of NHMRC funding. Research groups from 18 different institutions have been
supported by access to the NBC.
Expected future outcomes:
The ANBC will continue to meet its objectives of providing a healthy colony of non-human primates for
scientifically and ethically justified biomedical research in Australia. The maintenance of the highest standard
of animal welfare is a key priority.
Name of contact:
The Director
Email/Phone no. of contact:
RPAH.NBC@sswahs.nsw.gov.au
NHMRC Research Achievements - SUMMARY
Grant ID: 156713
Start Year: 2001
CIA Name: Prof Bruce Kemp
End Year: 2003
Admin Inst: St Vincent's Institute of Medical Research
Grant Type: NHMRC Project Grants
Main RFCD: Genetic Technologies: Transformation, Site-directed Mutagenesis, etc.
Total funding: $351,110
Title of research award:
Physiological effects of manipulating AMP-activated kinase genesPhysiological effects of manipulating AMPactivated kinase genes
Lay Description (from application):
The AMP-activated protein kinase is a metabolic stress sensing protein kinase responsible for matching the
supply of energy to the body's functions. During vigorous exercise it senses metabolic stress (reduction in
energy) caused by muscle contraction and stimulates glucose uptake and burning of fat to provide energy. The
AMP-activated protein kinase also regulates the production of nitric oxide that is important in controlling blood
pressure and blood clotting. Reduced caloric intake activates the AMP-activated protein kinase to suppress
energy consuming activities and modify the expression of genes. Many of the conditions that activate the
AMP-activated protein kinase (exercise, reduced caloric intake) are associated with a healthy life style,
increased longevity and resistance to age onset diseases including cardiovascular disease (atherosclerosis,
hypertension), obesity, neurodegeneration and diabetes. By manipulating the gene for the AMP-activated
protein kinase in mice we expect to learn more about its key physiological roles and give new insight into the
control of age onset diseases.
Research achievements (from final report):
The AMPK is a key enzyme in the control of metabolism in response to exercise that is involved in regulating
many physiological events. Our overall goal is to track down how exercise prevents development of many age
onset diseases. AMPK appears to be a key enzyme in these protective molecular mechanisms. The
development of drugs that activate AMPK may have benefits people with sedentary life styles or otherwise
incapable of getting adequate exercise. Since out knowledge of AMPK is incomplete we have modified two of
the genes involved in AMPK in mice in order to determine how they are affected. In yeast removal of a
corresponding gene called sip2 causes the yeast to rapidly age.
Expected future outcomes:
N/A
Name of contact:
N/A
Email/Phone no. of contact:
N/A
NHMRC Research Achievements - SUMMARY
Grant ID: 219168
Start Year: 2001
CIA Name: Prof Thomas Kay
End Year: 2006
Admin Inst: St Vincent's Institute of Medical Research
Grant Type: International
Collaborations
Main RFCD: Not Allocated
Total funding: $3,095,000
Title of research award:
T-cell mechanisms of B-cell destructionT-cell mechanisms of B-cell destruction
Lay Description (from application):
In type 1 diabetes the body becomes deficient in insulin production from pancreatic b cells because the immune
system mistakenly attacks and destroys b cells as if they were an invading infection. Recurrence of
autoimmune destruction of b cells also occurs following transplantation of whole pancreas or islet cells and
may occur in the future when other engineered insulin producing cells are transplanted. The focus of this
program is to better understand how b cells are killed by the immune system and to test ways of protecting beta
cells from these mechanisms. Because of the inaccessibility of the pancreas to study (particularly biopsy) in
humans with diabetes, much of the proposed work will be carried out in b cells derived from non-obese
diabetic (NOD) mice, the best available mouse model of type 1 diabetes. It is clear from the literature that a
molecule called perforin found in cytoxic T lymphocytes (CTL) is a major, if not the major, mechanism the
immune system uses against b cells. For this reason we will try to better understand the interaction between b
cells and perforin and ultimately design ways of them from perforin-mediated cell death. It is equally clear that
there are other mechanisms besides perforin that can cause b cell death and the program will also address
discovery of these mechanisms and new ways to block them. Beta cells in NOD mice will be protected from
perforin or other mechanisms by the addition of protective genes or removal of harmful genes using transgenic
knockout technology. Addition or removal of genes involved in cell death can be done systematically and
each protocol tested using NOD mouse model. The process of cell death that b cell undergo in type 1 diabetes
is called apoptosis. Apoptosis is a general mechanism by which cells of all types die. Experts in the biology of
apoptosis and perforin are important members of the program, providing the opportunity to translate the latest
advances in cell death research to diabetes. This research addresses several of the specific research areas of
interest to JDRF. It focuses on the prevention of b cell death in individuals with type 1 diabetes receiving islet
transplants. It may be applicable in the future to protection of stem or precursor cells that have been
differentiated into b cells or even to devising strategies to prevent the development of diabetes.
Research achievements (from final report):
Our group has made significant contributions to understanding mechanisms of beta-cell destruction. We have
clarified the mechanisms of beta-cell killing by CD8+ T cells (CTL) showing that the perforin-granzyme
pathway is the main mechanism used in several different models of type 1 diabetes and allogeneic beta-cell
transplant rejection. Further, the susceptibility of beta cells to perforin and granzymes was studied in detail.,
Major achievements of the Program include:, - Demonstrating the effect of blocking the Fas, TRAIL and
TNFR1 pathway by dominant negative FADD on progression of diabetes., - Identifying that suppressor of
cytokine signalling 1 blocks both perforin and Fas-dependent beta cell death., - Using a high-throughput screen
to identify small-molecule perforin inhibitors and development of in vitro systems to measure perforindependent killing of β cells., - Identifying the role of Bim in abnormal thymic deletion in NOD mice
Expected future outcomes:
Beta-cell apoptosis is one of the major pathologic steps in progression to type 1 diabetes. Understanding the
mechanisms of this and developing inhibitors that may be clinically applicable is highly significant to future
treatment of type 1 diabetes or islet transplant rejection.
Name of contact:
Professor Tom Kay
Email/Phone no. of contact:
NHMRC Research Achievements - SUMMARY
tkay@svi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 292917
Start Year: 2004
CIA Name: A/Pr Matthew Watt
End Year: 2007
Admin Inst: St Vincent's Institute of Medical Research
Grant Type: Early Career Fellowships
(Australia)
Main RFCD: Endocrinology
Total funding: $216,494
Title of research award:
Cellular basis of cytokine-mediated fat metabolism and insulin resistanceCellular basis of cytokine-mediated
fat metabolism and insulin resistance
Lay Description (from application):
Not Available
Research achievements (from final report):
Work from this grant identified the protein ciliary neurotrophic factor (CNTF) as a potential anti-obesity factor.
Mice treated with CNTF lost weight due to a decrease in food intake and an increase in fat metabolism.
Importantly, this effect was maintained in obese mice and also partially reversed diabetes in these mice. This
work was published in the prestigious journal Nature Medicine.
Expected future outcomes:
Compounds that activate the CNTF receptor but do not cause the production of inhibitory antibodies are being
tested for their anti-obesity effects.
Name of contact:
Matthew Watt
Email/Phone no. of contact:
matthew.watt@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 345402
Start Year: 2005
CIA Name: Prof Bruce Kemp
End Year: 2007
Admin Inst: St Vincent's Institute of Medical Research
Grant Type: NHMRC Project Grants
Main RFCD: Protein Targeting and Signal Transduction
Total funding: $582,000
Title of research award:
Regulation of Protein Kinases and their SubstratesRegulation of Protein Kinases and their Substrates
Lay Description (from application):
Western communities are experiencing an obesity epidemic with up to half the population being overweight.
Sedentary life styles and high caloric intake are the cause and will contribute to the development of age onset
diseases including obesity, diabetes, cardiovascular disease, stroke and neurodegeneration. This project is
investigating an enzyme that plays a pivotal role in controlling the body s response to exercise and diet. The
key enzyme involved in this process is called the AMP-activated protein kinase. This work will increase our
understanding of the health benefits of diet and exercise. This new knowledge will play a vital role in
developing new therapies for promoting exercise and mitigating the effects of diet that will improve health
during the ageing process.
Research achievements (from final report):
This research is concerned with an enzyme called AMPK that may mediate the health benefits of diet and
exercise. AMPK is also important in the control of appetite and whole body energy metabolism. We have
obtained structural information on AMPK that may contribute to the development of activating drugs. We have
identified components of the mechanisms that control the activity of AMPK and several new substrates which
contributes to our knowledge on how AMPK controls genes important for glucose uptake. We have also shown
that activation of AMPK in mice by genetic changes can increase exercise capacity. This research is relevant to
cardiovascular disease, obesity, type 2 diabetes and maintaining health during ageing.
Expected future outcomes:
Research on AMPK will contribute to our understanding of the underlying mechanisms that mediate the health
benefits of diet and exercise. It may be possible to develop drugs that activate AMPK and improve metabolism
to facilitate exercise and protect against obesity and age onset diseases
Name of contact:
Bruce E. Kemp
Email/Phone no. of contact:
bkemp@svi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 345426
Start Year: 2009
CIA Name: Prof Bruce Kemp
End Year: 2009
Admin Inst: St Vincent's Institute of Medical Research
Grant Type: Established Career
Fellowships
Main RFCD: Protein Targeting and Signal Transduction
Total funding: $153,250
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
In terms of potential significance to Australia's Health Care system the study of the metabolic stress sensing
enzyme, AMPK provides a path to understanding the molecular basis of the health benefits of diet and
exercise. The indications are that activation of AMPK by diet and exercise plays an important part in
prevention of age onset diseases that include, obesity, diabetes, hypertension, stroke, neurodegeneration, cancer
and cardiovascular disease. These areas of disease are the major cost items for the Australian Health budget.
The study of the AMPK family of enzymes is of enormous fundamental and commercial importance. It has
been found that several drugs used to treat age onset diabetes (metformin, rosiglitazone) activate the AMPK as
well as the adipocyte hormones, adiponectin and leptin. Since exercise and weight control prevent the
development of diabetes it seems likely that AMPK is a critical regulator in the health benefits of diet and
exercise. Our work has opened up a very large vista of opportunities. For example, AMPK controls both
triglyceride and cholesterol synthesis as well as the oxidation of fatty acids, drugs that activate AMPK may
have major therapeutic potential for treating obesity and cardiovascular disease in addition to type II diabetes.
The rest of the world has recognized this potential and there are now an average of three publications per day
on AMPK.
Expected future outcomes:
Our key major goals are to develop activating drugs for AMPK that will mimic the health benefits of diet and
exercise. We are studying the natural mechanisms of activation of AMPK and the physiological roles of this
signaling pathway.
Name of contact:
Bruce E. Kemp
Email/Phone no. of contact:
bkemp@svi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 345433
Start Year: 2005
CIA Name: Dr Helen Thomas
End Year: 2009
Admin Inst: St Vincent's Institute of Medical Research
Grant Type: Career Development
Fellowships
Main RFCD: Cellular Immunology
Total funding: $453,500
Title of research award:
Mechansims of T cell-dependent pancreatic ¿ cell destructionMechansims of T cell-dependent pancreatic ¿ cell
destruction
Lay Description (from application):
Not Available
Research achievements (from final report):
The major aim of this project was to discover a strategy for preventing loss of insulin-producing cells in the
pancreas (called beta cells) from being destroyed by cells of the immune system. To do this, it was necessary to
understand the death signals that the immune cells use to kill beta cells, and the pathways inside the beta cell
that are switched on in response to these cell death signals. We identified the pathways activated in beta cells in
response to immune cells and their toxic products. We also determined that immune cells are capable of
delivering several different death signals in type 1 diabetes, and that all of these need to be inhibited to prevent
diabetes. Knowledge of cell death pathways in beta cells will allow us to identify how we can prevent them
from being killed in type 1 diabetes or after islet transplantation. In addition, we successfully began
transplanting human islets isolated from cadaveric organ donors into patients with type 1 diabetes. At the
completion of this grant, we had performed 10 transplants into 6 recipients in Victoria and South Australia
Expected future outcomes:
It is expected that some of this research will be translated to human islets by preventing their death in type 1
diabetes and after islet transplantation. The Tom Mandel Islet Transplant program is a platform on which to
apply knowledge gained from this research.
Name of contact:
Dr Helen Thomas
Email/Phone no. of contact:
hthomas@svi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 395507
Start Year: 2006
CIA Name: Prof Bruce Kemp
End Year: 2008
Admin Inst: St Vincent's Institute of Medical Research
Grant Type: NHMRC Project Grants
Main RFCD: Protein Targeting and Signal Transduction
Total funding: $478,776
Title of research award:
Regulation of Lipid Metabolism by AMP Activated Protein KinaseRegulation of Lipid Metabolism by AMP
Activated Protein Kinase
Lay Description (from application):
Western communities are experiencing an epidemic of overweight and obesity that is contributing to diabetes,
heart disease, and premature death. This project is investigating an enzyme, called AMP-activated protein
kinase, that plays a pivotal role in controlling how our bodies control energy metabolism in response to
exercise. Improved understanding about how this enzyme regulates the body's storage and breakdown of fat
and responsiveness to insulin will enable the development of new medicines for the treatment of obesity and
the prevention of diabetes.
Research achievements (from final report):
This project is concerned the regulation of fat (triglyceride) synthesis in the body. The first step in fatty acid
synthesis is catalysed by an enzyme acetyl CoA-carboxylase (ACC), which is regulated in multiple ways and
can be inhibited by exercise. Triglycerides contain three fatty acid linked to glycerol and provide the major
form of fat storage in the body. An enzyme called glycerophosphate acyl transferase or abbreviated GPAT is
responsible for the first step of adding a single fatty acid to glycerol in the synthesis of triglycerides.
Understanding the regulation of lipid metabolism has important implications for several diseases.
Dysregulation of fatty acid metabolism in obesity results in the accumulation of intramuscular lipid that is
central to the development of insulin resistance, which in turn may lead to age onset diabetes. In the present
study we set out to examine whether the regulation GPAT involves direct control by another enzyme AMPK,
which is activated by exercise and is responsible for phosphorylating ACC and GPAT. By studying how
exercise is able to suppress fatty acid and triglyceride synthesis we may gain greater insight into the health
benefits of exercise. We found that AMPK phosphorylated GPAT at multiple sites and inhibited the enzyme. In
ongoing work we are attempting to determine which phosphorylation site is responsible for this inhibition. In
the case of ACC we prepared a genetically engineered mouse that contained a mutation in the site
phosphorylated by AMPK and are continuing to evaluate the impact of this on lipid metabolism and insulin
sensitivity.
Expected future outcomes:
It is hoped our ongoing research will identify how AMPK regulates GPAT and controls the synthesis of
triglycerides. Our study of the ACC genetically modified mice will indicate how important AMPK regulation
of this enzyme is and whether blocking this regulation leads to increase fat deposition and or alterations in
appertite.
Name of contact:
Bruce Kemp
Email/Phone no. of contact:
bkemp@svi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 395522
Start Year: 2006
CIA Name: Prof Bruce Kemp
End Year: 2010
Admin Inst: St Vincent's Institute of Medical Research
Grant Type: NHMRC Strategic Awards
Main RFCD: Genome Structure
Total funding: $1,222,500
Title of research award:
Phosphoproteomics: Metabolic and Exercise Signalling Markers for Sedentary and Trained
IndividualsPhosphoproteomics: Metabolic and Exercise Signalling Markers for Sedentary and Trained
Individuals
Lay Description (from application):
It is widely recognized that diet and exercise have a major influence on the health and fitness. Sedentary
lifestyles predispose people to obesity and the early development of age onset diseases. In the past decade we
have gained considerable insight into the regulatory links between exercise and metabolism particularly
involving the AMPK signalling pathway. This project is concerned with the "phosphoproteome" of trained and
untrained skeletal muscle, fat and erythrocytes as a marker of fitness.
Research achievements (from final report):
This Medical Bioinformatics Genomics Proteomics Program was concerned with developing technology for
studying protein phosphorylation which is an important regulatory mechanism for controlling protein function.
The bioinformatics aspects of the program were run by Professor Bostjan Kobe at the University of Queensland
and the experimental work in mass spectrometry by Professor Bruce Kemp at the St Vincent's Institute
University of Melbourne. Two of the great challenges in understanding regulation by protein phosphorylation
is being able to assign which protein kinases are responsible for the phosphorylation of specific residues on
target proteins and the identification of changes in protein phosphorylation at specific under physiological
conditions. The key achievements in the program were the development of the Predikin system at the
University of Queensland for predicting substrate specificity of protein kinases and the establishment of a mass
spectrometry facility at St Vincent's Institute for the analysis of phosphorylation sites. Both of these
developments will have eduring benefits to medical research in Australia
Expected future outcomes:
In bioinformatics the Predikin system is contributing to understanding the function of over 500 protein kinases
identified in the human genome. The mass spectrometry facility will contribute to the identification of
physiologically important phosphorylation sites and the mapping of cellular signalling processes
Name of contact:
Bruce E Kemp
Email/Phone no. of contact:
bkemp@svi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 448326
Start Year: 2007
CIA Name: Prof Bruce Kemp
End Year: 2009
Admin Inst: St Vincent's Institute of Medical Research
Grant Type: NHMRC Project Grants
Main RFCD: Endocrinology
Total funding: $512,065
Title of research award:
Cytokine signalling and insulin resistance in obesity.Cytokine signalling and insulin resistance in obesity.
Lay Description (from application):
Western communities are experiencing an epidemic of obesity that is contributing to diabetes, heart disease,
and premature death. This project is investigating why being overweight and obese causes diabetes. Improved
understanding about how hormones regulates the body's storage and breakdown of fat and responsiveness to
insulin will enable the development of new medicines for the treatment of obesity and the prevention of
diabetes.
Research achievements (from final report):
1. The metabolic sensor AMP-activated protein kinase (AMPK) is activated by the drug metformin and
exercise. We have shown that in obesity AMPK is reduced in immune cells and that genetic deletion of the
protein results in low-grade inflammation the accelerates the development of insulin resistance in obesity.
These data suggest that by activing AMPK in immune cells we may be able to treat inflammatory diseases., 2.
A genetic mutation in humans in which the protein SOCS1 is activated results in improvements insulin
sensitivity. We show that the reason for this may be because SOCS1 prevents inflammation in immune cells
and by doing so prevents the development of liver insulin resistance. These data suggest that strategies aimed at
increasing SOCS1 expression in immune cells may be beneficial for the treatment of type 2 diabetes., 3. The
protein SOCS3 is elevated in obesity. Increased levels of SOCS3 in the liver is believed to be a contributing
factor to the development of insulin resistance in obesity. However, we have shown that increases in liver
SOCS3 may actually help protect the liver from becoming infiltrated with fat.
Expected future outcomes:
We intend to examine the role of SOCS3 in adipose tissue and skeletal muscle.
Name of contact:
Gregory Steinberg
Email/Phone no. of contact:
gsteinberg@mcmaster.ca
NHMRC Research Achievements - SUMMARY
Grant ID: 502602
Start Year: 2008
CIA Name: Prof Michael Parker
End Year: 2010
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: $526,703
Title of research award:
Structure-function studies of insulin-regulated membrane aminopeptidaseStructure-function studies of insulinregulated membrane aminopeptidase
Lay Description (from application):
Memory loss can occur as a result of injuries or disease such as Alzheimer's disease, the fourth biggest killer in
developed countries. Currently there is no effective treatment for memory loss. This proposal concerns the
biochemical investigation of a protein involved in memory and possibly diabetes. This work is expected to
provide an understanding of how this protein functions in the body and will form the basis for the design of
drugs for the treatment of memory loss.
Research achievements (from final report):
We constructed a three-dimensional model of a brain protein called insulin-regulated aminopeptidase and then
computationally screened the model against a database of 2 million potential drug-like molecules. The most
promising molecule was tested in animals and shown to enhance memory. We plan to develop these molecules
into drugs that could be used to treat a range of cognitive impairments such as Alzheimer's disease.
Expected future outcomes:
To maximise the drug development opportunities both Institutes involved in the discovery have enlisted a
commercial partner, Bio-Link, to seek out international biopharmaceutical companies to help develop our
molecules into drugs that can used to treat cognitive impairment such as Alzheimer's disease
Name of contact:
Professor Michael W Parker
Email/Phone no. of contact:
mparker@svi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 502605
Start Year: 2008
CIA Name: A/Pr Helen Thomas
End Year: 2010
Admin Inst: St Vincent's Institute of Medical Research
Grant Type: NHMRC Project Grants
Main RFCD: Autoimmunity
Total funding: $535,333
Title of research award:
Apoptotic pathways in pancreatic beta cells leading to type 1 diabetes and transplant rejectionApoptotic
pathways in pancreatic beta cells leading to type 1 diabetes and transplant rejection
Lay Description (from application):
The destruction of insulin-producing beta cells in the pancreas by immune cells leads to the need for daily
insulin injections in patients with type 1 diabetes. This project aims to understand how beta cells are destroyed.
A knowledge of the process by which this occurs will indicate ways we can protect these cells. Our previous
work has suggested strategies that may protect beta cells, and we aim to test these. Such protection may
eventually allow beta cell replacement by transplantation.
Research achievements (from final report):
We demonstrated that a molecule called Bid is required for killing of insulin-producing beta cells in the
pancreas by one particular pathway thought to be used by immune cells in type 1 diabetes. When we assessed
the contribution of this molecule to development of type 1 diabetes in a mouse model, we showed that it is
dispensable, indicating that this pathway of killing is not important. We also tested the importance of another
killing pathway used by the immune system, called granzymes. We made mice that spontaneously develop
diabetes that lack important granzymes, granzyme A and granzyme B. We discovered interesting changes in
development of diabetes in both these mouse models. Mice lacking granzyme B had a delay in the onset of the
immune process leading to diabetes, while mice lacking granzyme A developed faster diabetes. We used cells
from these mice to study how killer cells of the immune system develop, and determined that these cells
become killer cells only after they have entered the pancreas, even though they have already begun to expand
in number while they are still in the lymph node next to the pancreas. These findings are significant discoveries
about how insulin-producing cells are killed in type 1 diabetes, which we anticipate will lead to prevention of
human beta cell killing in transplantation or type 1 diabetes.
Expected future outcomes:
Our work remains to be tested in human systems, and that is a future aim of our work. We have identified ways
to inhibit these pathways in human islets, and have human immune cells to test killing of islets with these
pathways disabled.
Name of contact:
Helen Thomas
Email/Phone no. of contact:
hthomas@svi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 502610
Start Year: 2008
CIA Name: Prof Bruce Kemp
End Year: 2010
Admin Inst: St Vincent's Institute of Medical Research
Grant Type: NHMRC Project Grants
Main RFCD: Cell Metabolism
Total funding: $553,197
Title of research award:
Regulation of protein kinases and their substratesRegulation of protein kinases and their substrates
Lay Description (from application):
Our research is concerned with the control of the body's energy metabolism via an enzyme called AMPK. This
enzyme is at the hub of metabolic control in response to diet and exercise. AMPK controls energy expenditure
in response to demand as well as appetite. It is well recognized that diet and sedentary life-styles are major
contributors to obesity and cardiovascular disease. We are testing how a new drug activates AMPKand how
energy expenditure can be increased.
Research achievements (from final report):
Phosphorylation of AMPK α subunit on Thr172 is essential for activity and this is catalyzed by either upstream
kinase LKB1 or CaMKKβ. During metabolic stress the reduction in ATP levels and increase in ADP and AMP
levels is accompanied by increased phosphorylation of AMPK α Thr172. Up until 2010 the consensus in the
field was that AMP binding to the γ subunit inhibited dephosphorylation of AMPK and allowed for the
accumulation of pThr172 and that there was no AMP regulation of the phosphorylation step by the upstream
kinases. We found that AMP did stimulate α Thr172 phosphorylation but this form of regulation depended
entirely on the β subunit being myristoylated. Importantly once AMPK is phosphorylated on Thr172 the AMP
allosteric activation of the enzyme and protection against dephosphorylation does not depend on β-subunit
myristoylation. Our view of the regulation now is that the β subunit myristoyl group anchors the kinase in a
conformation protecting it against phosphorylation and activation by the upstream kinases unless AMP is
present. In addition to solving a 15-year problem in the field our study also raises the possibility that AMP
triggers a β subunit myristoyl switch and that this serves in subcellular targeting of AMPK to membrane
anchored substrates. , The second important discovery involving the β subunit was that the thienopyridone
AMPK activating drug A769662 developed by the Abbott Laboratories was specific for AMPK αβγ
heterotrimers containing the β1 isoform and that it did not act on β2 containing heterotrimers.
Expected future outcomes:
The discovery that β-subunit myristoylation was essential for AMP regulation of AMPK activation by
phosphorylation paved the way for us to show that ADP also activated AMPK in a similar manner. The drug
screening protocols in the Pharmaceutical Industry have been modified by our work.
Name of contact:
Bruce E Kemp
Email/Phone no. of contact:
bkemp@svi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 526694
Start Year: 2009
CIA Name: Dr Stephen Tonna
End Year: 2013
Admin Inst: St Vincent's Institute of Medical Research
Grant Type: Early Career Fellowships
(Australia)
Main RFCD: Genetics not elsewhere classified
Total funding: $332,141
Title of research award:
Epigenetic hyperglycemic cell memory causes vascular complications in type 1 diabetesEpigenetic
hyperglycemic cell memory causes vascular complications in type 1 diabetes
Lay Description (from application):
This project seeks to identify how epigenetic change in response to hyperglycemia can cause vascular
complications of diabetes, and how this contributes to “hyperglycemic memory”; a phenomena where cells
may undergo gene modifications which increase risk to further complications later in a patients life. These
studies are the first of their kind and will characterize the types of epigenetic change that can cause human
disease.
Research achievements (from final report):
During the duration of this fellowship, I established that for bone forming cells, osteoblasts, to survive and
form bone of maximal strength without undergoing early cell death, they need to express the protein, ephrinB2.
Without it, mice that lack ephrinB2 specifically in the bone forming cells suffer from early osteoblast
apoptosis, resulting in adult skeletons that are mechanically compromised. The softer bones formed when
ephrinB2 is lacking occurs because osteoblasts lacking ephrinB2 secrete poor quality collagen and the bone
that they produce is poorly mineralized. I also established that it is signalling through ephrinB2, not through
any other receptor, that is most important for bone strength. In addition, although others have suggested this is
the case, I showed that the cells that destroy bone in normal skeletal maintenance and in diseases, including
rheumatoid arthritis, and the spread of breast cancer to bone do not depend on ephrinB2 for their action.
Finally, I showed that ephrinB2 plays a role in the development of the skeleton - when it is absent, young mice
demonstrate a syndrome called osteopetrosis. These findings indicate that therapies currently being developed
to inhibit of ephrinB2 in the context of cancer and neurodegeneration may have significant detrimental effects
on the skeleton, and conversely, that stimulating ephrinB2 signalling in these cells may promote the formation
of stronger bone.
Expected future outcomes:
Improved therapy for osteoporosis, and development of appropriate monitoring of patients that may use
ephrinB2 inhibitors in the future.
Name of contact:
Natalie Sims
Email/Phone no. of contact:
nsims@svi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 559007
Start Year: 2009
CIA Name: Dr Stuart Mannering
End Year: 2011
Admin Inst: St Vincent's Institute of Medical Research
Grant Type: NHMRC Project Grants
Main RFCD: Autoimmunity
Total funding: $404,400
Title of research award:
A T-cell based approach to identifying islet antigens in human type 1 diabetesA T-cell based approach to
identifying islet antigens in human type 1 diabetes
Lay Description (from application):
Autoimmune diseases arise when the immune system, which protects us from infections and cancer, attacks
healthy tissues. Nobody knows why the immune system mistakes healthy for unhealthy tissue. The immune
system's T cells are prime suspects because they play a central role in controlling the immune response. Hence,
the aim of this work is to understand what human T cells see in healthy tissues that may lead them to cause
autoimmune diseases like type 1 diabetes.
Research achievements (from final report):
Our original aim was to use an 'array' of islet proteins associated with nitrocellulose particles. Further work
with this approach confirmed that T cell responses to islet proteins prepared in this manner were found in the
blood of people with T1D, but not those without T1D. However, we found that T cells from people with T1D
also responded to spleen proteins prepared in a similar manner. These data indicated that the responses were
not specific for islet proteins and may be directed against proteins that are modified during electrophoresis and
transfer to nitrocellulose. For this reason we developed a new method for extracting proteins from human
tissues in a format that is compatible with T cell proliferation assays. We published a paper describing this
approach (Moon et al, 2010). Our new protein extraction protocol avoids the use of detergents which are toxic
to the cells in proliferation assays. Using this protocol we have prepared extracts from human islets, spleen, and
acinar tissues. These extracts have been used to stimulate T-cell responses from the blood of T1D patients and
HLA matched controls. Surprisingly we found that extracts from human spleen suppressed T-cell responses in
vitro. Upon further investigation we found that the suppression was due to residual prednisolone (prednisolone
is given to the organ donors prior to organ collection). Islet and acinar tissue extracts are also being used to
develop an assay to measure human T cell responses against beta cells and to examine the specificity of human
islet-infiltrating T-cell clones that we have isolated. , In light of these results we changed strategy and
developed methods for isolating T cells from within the residual pancreatic islets of deceaed organ donors who
suffered from type 1 diabetes. We are the first group in the world to isolate human T cells from the islets of
people who had type 1 diabetes. To date we have over 380 CD4+ T-cell clones and >260 CD8+ T cell clones
from five donors.
Expected future outcomes:
The analysis of T cells that infiltrate the islets of people with type 1 diabetes is powerful new approach to study
the autoimmune response that causes type 1 diabetes in humans. Our future work will identify the antigens
'seen' by these T cells and support the development of new therapies for type 1 diabetes.
Name of contact:
Stuart Mannering
Email/Phone no. of contact:
smannering@svi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 559013
Start Year: 2009
CIA Name: Prof Bruce Kemp
End Year: 2011
Admin Inst: St Vincent's Institute of Medical Research
Grant Type: NHMRC Project Grants
Main RFCD: Exercise Physiology
Total funding: $540,973
Title of research award:
The Role of the AMPK-ACC2 Signaling Axis in Metabolic Control During Exercise and ObesityThe Role of
the AMPK-ACC2 Signaling Axis in Metabolic Control During Exercise and Obesity
Lay Description (from application):
Australian society is experiencing an epidemic of obesity that is contributing to diabetes, cardiovascular
disease and premature death. This project is investigating how exercise might prevent obesity and type 2
diabetes by examining the major pathways that regulate fat metabolism.
Research achievements (from final report):
The goal of this project is to study the role of AMPK signaling in the regulation of fatty acid metabolism and
insulin sensitivity in response to muscle contractions and exercise utilizing two unique mouse genetic models
deficient in different aspects of AMPK signalling. These models will assess whether AMPK signalling is
required for the stimulation of fatty acid oxidation during exercise but will not delineate the pathways involved.
β2 KO mice have reduced AICAR stimulated muscle glucose uptake but contraction stimulated glucose uptake
and fatty acid oxidation and ACC phosphorylation are not impaired. During treadmill running β2 KO mice
have reduced maximal and endurance exercise capacity, which is associated with lower starting levels of
muscle and liver glycogen. When challenged with a high-fat diet, β2 KO mice are more susceptible to the
development of insulin resistance. Overall these data show that deletion of AMPK β2 reduces AMPK activity
in skeletal muscle resulting in impaired exercise capacity and exacerbation of obesity induced insulin
resistance. AMPKβ1β2 null mice mice have a profound reduction in both spontaneous exercise and treadmill
running exercise capacity. They exhibit muscle fatigue and reductions in exercise dependent glucose uptake.
These results show that AMPK is extremely important for maintaining exercise capacity.
Expected future outcomes:
This work has contributed to our understanding of the physiological roles of AMPK in maintaining energy
balance and exercise capacity. At present we consider AMPK a potentially important target for the therapeutic
treatment of Type 2 diabetes, obesity and cardiovascular disease.
Name of contact:
Bruce E. Kemp
Email/Phone no. of contact:
bkemp@svi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 575552
Start Year: 2009
CIA Name: Dr Thomas Brodnicki
End Year: 2011
Admin Inst: St Vincent's Institute of Medical Research
Grant Type: NHMRC Project Grants
Main RFCD: Medical Genetics
Total funding: $732,439
Title of research award:
Genomic and functional analyses of a novel gene implicated in type 1 diabetesGenomic and functional
analyses of a novel gene implicated in type 1 diabetes
Lay Description (from application):
We have recently discovered a novel gene that contributes to the development of juvenile diabetes.
Unfortunately, very little is known about the function of this gene. To better understand how this gene affects
the immune system and contributes to disease, we have generated a unique mouse strain that has a
dysfunctional copy of this gene. These mice will enable us to characterise this gene and potentially establish a
new area of research in diabetes prevention.
Research achievements (from final report):
Autoimmune diseases are a major cause of morbidity and mortality in developed countries. In this project we
focused on type 1 diabetes, an autoimmune disease that results in the destruction of insulin-producing beta cells
found in the pancreas. More than 120,000 Australians have type 1 diabetes, and ~6 new cases are diagnosed
every day. While the cause of T1D is still not known, genetic analyses of families and animal models for this
disease have provided important insights about the genes that increase one's risk for developing this disease. In
particular, we performed genetic studies using the NOD mouse strain, which develops type 1 diabetes similar
to children, and discovered a novel gene that contributes to the development of this disease. Unfortunately,
very little was known about the function of this gene. To better understand how this gene affects the immune
system and contributes to disease, we determined that this gene is expressed in certain cells of the immune
system that participate in the destruction of the pancreatic beta cells. We next generated a unique mouse strain
that has a dysfunctional copy of this gene and discovered that this gene is important for regulating certain
immune responses associated with infection and autoimmune diseases. Thus this gene appears to act as a
molecular switch to help turn off immune cells once an infection has been clear and prevent them from
initiating autoimmune diseases, such as type 1 diabetes.
Expected future outcomes:
We anticipate that we will identify the human version of the mouse diabetes susceptibility gene that we have
discovered. Further characterization of the mouse and human gene will help identify cellular mechanisms that
may be targeted by drugs to increase protection against the development of autoimmune disease.
Name of contact:
Thomas Brodnicki
Email/Phone no. of contact:
tbrodnicki@svi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 620232
Start Year: 2010
CIA Name: A/Pr Helen Thomas
End Year: 2012
Admin Inst: St Vincent's Institute of Medical Research
Grant Type: Career Development
Fellowships
Main RFCD: Autoimmunity
Total funding: $324,353
Title of research award:
Prevention of pancreatic beta cell destruction in type 1 diabetesPrevention of pancreatic beta cell destruction in
type 1 diabetes
Lay Description (from application):
Media Summary not available
Research achievements (from final report):
This fellowship studied the hypothesis that blocking cell killing pathways in beta cells, combined with
inhibition of immune cell activation and migration can prevent diabetes and improve survival of islet grafts
after transplantation. Several cell death pathways were studied, and we identified that blocking a molecule
called perforin remains the most effective way to prevent beta cell death in type 1 diabetes. Future work is
focused on using small molecule inhibitors of perforin in type 1 diabetes. We found that loss of the cell death
molecules Bim and Puma prevents beta cell death in response to high concentrations of glucose, such as might
be seen in type 2 diabetes. Inhibition of these molecules may help preserve beta cell function in type 2 diabetes.
We also studied immune cell function in type 1 diabetes. We found that immune cells are stimlated by beta
cells themselves, leading us to study how beta cells contribute to their own demise in type 1 diabetes. This
work has led to new funding from the NHMRC and international funding agencies. It is hoped that outcomes
from this work will lead to new therapies for type 1 and type 2 diabetes.
Expected future outcomes:
It is expected that the progress to date will be leveraged through further grant funding from NHMRC and other
funding bodies. The collaborative links established during this fellowship will be preserved, remain productive
and be augmented in the future.
Name of contact:
Helen Thomas
Email/Phone no. of contact:
hthomas@svi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1006062
Start Year: 2011
CIA Name: Prof Bruce Kemp
End Year: 2013
Admin Inst: St Vincent's Institute of Medical Research
Grant Type: NHMRC Project Grants
Main RFCD: Signal Transduction
Total funding: $524,820
Title of research award:
An AMPK myristoyl switch controls AMP mediated metabolic stress signalingAn AMPK myristoyl switch
controls AMP mediated metabolic stress signaling
Lay Description (from application):
This project is investigating an enzyme called AMP-activated protein kinase that plays a pivotal role in
controlling how our bodies regulate energy metabolism in response to exercise and diet. Improved
understanding of how this enzyme is regulated may provide new therapeutic methods for mimicking the
beneficial effects of diet and exercise to treat multiple metabolic diseases including obesity, Type 2 diabetes
and cardiovascular disease.
Research achievements (from final report):
The AMP-activated protein kinase (AMPK) is a key regulator of cellular and whole-body energy homeostasis
that co-ordinates metabolic pathways to balance nutrient supply with energy demand. AMPK protects cells
from physiological and pathological stresses that lower cellular energy charge (increase AMP/ATP ratio)
including nutrient starvation, hypoxia/ischemia, and exercise. AMPK acts to conserve energy by directing
metabolism towards ATP production while inhibiting ATP consuming pathways. This is achieved by
phosphorylation of key enzymes in major branches of metabolism including fat synthesis, protein synthesis and
carbohydrate metabolism. AMPK regulates whole-body energy homeostasis, food intake and body weight in
response to a variety of hormones including leptin, adiponectin and ghrelin. Animal studies have shown that
activating AMPK in peripheral tissues leads to a lean body mass and increased exercise capacity. In lower
organisms such as yeast and worms AMPK homologues have a potentially important role in regulating ageing
and longevity. We found that ADP as well as AMP regulates the activation of AMPK in response to metabolic
stress. AMPK activation is dependent on ADP-controlled phosphorylation of Thr172 on its activation loop, a
mechanism of protein regulation that represents an example of an allosterically regulated modification.
Expected future outcomes:
AMPK is thought to be an important mediator of the health benefits of diet and exercise. By understanding the
detailed molecular mechanisms controlling AMPK we may reveal new strategies to develop therapeutics for
the treatment of age onset diseases including type 2 diabetes, cardiovascular disease, neurodegeration and
cancer.
Name of contact:
Prof Bruce E Kemp
Email/Phone no. of contact:
bkemp@svi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1009821
Start Year: 2011
CIA Name: Dr Suzanne Rogers
End Year: 2013
Admin Inst: St Vincent's Institute of Medical Research
Grant Type: NHMRC Project Grants
Main RFCD: Endocrinology
Total funding: $593,888
Title of research award:
Mechanisms regulating nutrient stimulated glucose disposal - linking diet and diabetesMechanisms regulating
nutrient stimulated glucose disposal - linking diet and diabetes
Lay Description (from application):
Type 2 diabetes causes significant health problems. The fundamental reasons underlying this disease are not
fully known and will require molecular analysis of proteins critical to blood glucose control. This work aims to
define a novel pathway that responds to circulating nutrients. The research will enhance our understanding of
the links between diet and metabolic disease, with potential to reveal much needed therapeutic targets and/or
dietary interventions for the treatment of Type 2 diabetes.
Research achievements (from final report):
This research has furthered our understanding about the regulation of blood glucose levels, particularly in the
insulin resistant state. It has utilised animal and cell models to study insulin-independent blood glucose
clearance into muscle and how this is regulated following a meal.
Expected future outcomes:
It is expected that in the future this work will continue to further our understanding of the pathogenesis and
treatment of type 2 diabetes.
Name of contact:
Suzanne Rogers
Email/Phone no. of contact:
suzanne.rogers@rmit.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1011486
Start Year: 2011
CIA Name: Prof Bruce Kemp
End Year: 2013
Admin Inst: St Vincent's Institute of Medical Research
Grant Type: NHMRC Project Grants
Main RFCD: Medical Biochemistry: Proteins and Peptides (incl. Medical Proteomics)
Total funding: $555,893
Title of research award:
Understanding the importance of lipid metabolism in mediating the anti-diabetic effects of
metforminUnderstanding the importance of lipid metabolism in mediating the anti-diabetic effects of
metformin
Lay Description (from application):
Obesity is a major cause of adult onset Type 2 diabetes. This project is investigating the mechanism of action
of the glucose lowering drug metformin on fat metabolism. We are investigating whether the regulation of two
enzymes, involve in fat synthesis and the burning of fat respectively that are important for metformin’s action.
Through this research we hope to improve on the treatment of Type 2 diabetes and cardiovascular disease.
Research achievements (from final report):
Metformin is the most commonly prescribed therapeutic for the treatment of type 2 diabetes with over 100
million patients worldwide using it. The mechanisms by which metformin is able to prevent and treat type 2
diabetes are not fully understood but recent data suggest that a reduction in liver and skeletal muscle lipid may
be an important component. Our study indicates that metformin doesn't directly reduce sugar metabolism, as
previously suspected, but instead reduces fat in the liver, which in turn allows insulin to work effectively. The
breakthrough in pinning down how metformin functions began with our making generic mutations to the genes
of two enzymes, ACC1 and ACC2, in mice, so they could no longer be controlled. The mice had fatty livers
and a pre-diabetic condition. When we put the mice on a high fat diet they became fat, but unlike normal mice
metformin no longer lowered the blood sugar levels of the mutant mice.
Expected future outcomes:
The findings are expected to now help researchers better target type 2 diabetes and with this new knowledge go
beyond just diabetes and potentially be used to treat other medical conditions, such as cancer. Low doses of
metformin have also been shown to extend the lives of animals.
Name of contact:
Professor Bruce E Kemp
Email/Phone no. of contact:
bkemp@svi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 448610
Start Year: 2008
CIA Name: Dr Paul Stoddart
End Year: 2008
Admin Inst: Swinburne University of Technology Grant Type: NHMRC Development Grants
Main RFCD: Instruments and Techniques
Total funding: $385,151
Title of research award:
Spectrometer Module for Surface Enhanced Raman Scattering Spectroscopy in Glucose
AnalysisSpectrometer Module for Surface Enhanced Raman Scattering Spectroscopy in Glucose Analysis
Lay Description (from application):
Scientists have developed a number of incredibly powerful and sophisticated techniques to identify chemicals
and measure their concentrations in the laboratory. However, it remains a major challenge to perform these
measurements under everyday circumstances. For example, surface-enhanced Raman scattering (SERS) has
gained widespread recognition as a technique for trace chemical detection, but it remains confined to a small
number of specialist laboratories. For this reason, Dr Paul Stoddart at Swinburne University of Technology
recognised a need for more practical SERS probes for field applications. His team has now developed a
proprietary SERS probe, based on an optical fibre that is little thicker than a hair. These optical fibres can form
the core element of field-portable SERS spectrometers. This work has recently been boosted by the discovery
in the United States that SERS can be used to monitor glucose in blood. The development of a continuous
glucose monitor has long been a "holy grail" of sensor research, because of the millions of diabetes sufferers
who regularly perform the painful "finger prick" test. For SERS to provide a practical solution to glucose
monitoring, it is recognised that SERS optical fibres are needed for minimally invasive probes. With support
from Biopharmica and the Diabetes Australia Research Trust, Dr Stoddart's team has now demonstrated that
sensitive SERS probes can be produced in large quantities. The next objective is to develop a prototype lowcost SERS spectrometer for use as part of a continuous glucose monitoring system. This will require the
development of a laser source and spectroscopic system that can interface to the SERS probes. It is proposed to
use an Australian designed and manufactured laser system based on a low-power narrow-linewidth laser diode.
The project plans to bring together Swinburne University, OptoTech and Grey Innovation in order to develop a
commercially scaleable and robust device.
Research achievements (from final report):
Following a technology demonstration phase, prototype spectroscopic glucose monitoring devices have been
developed. These include compact optics modules for interfacing the optical fibre glucose sensors with four
different laser light sources and a spectrometer module. A technique for mounting the optical fibre probes in a
narrow guage hypodermic needle was also developed. In parallel with this, significant improvements to the
optical fibre probes were undertaken, as the initial fabrication method could not be scaled up to commercial
levels. This process led to the development of an innovative molding technique and a very robust vapour
deposition technique for sensor fabrication. Each of these methods offers advantages under certain
circumstances and the sensors are expected to support a great deal of further research and application
development. Efforts to integrate the system for glucose measurements were unsuccesful, pointing to the need
for systematic improvement of the sensor surface chemistry. Initial efforts to improve the surface chemistry
have met with some success. The optoelectronic technologies developed for the demonstrator units are
expected to assist in the development of other new devices, including an advanced pulse oximeter for use with
critically ill patients.
Expected future outcomes:
The prototype devices developed and knowledge achieved in this project will underpin future work to develop
a more effective surface chemistry for the sensor. This technique remains one of the most promising candidates
for continuous in vivo glucose monitoring, which would help to improve the management of diabetes.
Name of contact:
Dr Paul Stoddart
NHMRC Research Achievements - SUMMARY
Email/Phone no. of contact:
pstoddart@swin.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 219128
CIA Name: Prof Steven Boyages
Admin Inst: Sydney West Area Health Service
Main RFCD: Not Allocated
Total funding: $92,375
Start Year: 2002
End Year: 2003
Grant Type: SRDC - Research
Title of research award:
An evidence based capacity building approach to improving vascular health in an Aboriginal CommunityAn
evidence based capacity building approach to improving vascular health in an Aboriginal Community
Lay Description (from application):
Not Available
Research achievements (from final report):
A primary health care team approach and a community development approach were taken to making changes
needed to improve the prevention, detection and management of diabetes related illness in the local Indigenous
community., An important achievement was the development of community members' and staff members'
knowledge, attitudes and behaviours conducive to achieving the above aims. , The insights gained into client
and family members' experience living with diabetes were of particular value in planning support and
interventions. The insights gained into community members' information needs has informed the development
of health education and promotion resources and activities., Management systems were improved for detecting,
monitoring and managing existing diabetic illness. These included the development of policies, procedures and
protocols; improvements to computerised diabetes registers, records and recall systems; the introduction of
point of care testing for HbA1c (a key indicator of blood glucose control) and ACR (a key indicator of kidney
damage) which enabled immediate feedback to clients from the treating medical practitioner; and the
introduction of the Aboriginal adult health check for detection of diabetes risk or illness., There has been
improved client access to some relevant allied health services (podiatry, optometry, dietetics, diabetes
education) through improved advocacy and collaboration with other organisations., Staff received relevant
education, training and resources to assist the team to effectively engage in assisting clients to manage their
diabetes and in educating family and community members about diabetes., There is enhanced competence and
confidence (within the organisation as a whole) in relation to health education and promotion and in relation to
participating in primary health care research.
Expected future outcomes:
A booklet detailing the outcomes of interviews and focus groups with clients, family members and staff will be
used in community health education and promotion. , The service strives to fully implement early detection in
the face of competing acute care priorities., An article is to be prepared for publication.
Name of contact:
Maree Keogh
Email/Phone no. of contact:
project@rivmed.org
NHMRC Research Achievements - SUMMARY
Grant ID: 249403
Start Year: 2003
CIA Name: A/Pr Karen Waters
End Year: 2005
Admin Inst: The Children's Hospital at Westmead Grant Type: NHMRC Project Grants
Main RFCD: Paediatrics
Total funding: $320,375
Title of research award:
Metabolic complications of obstructive sleep apnea during early developmentMetabolic complications of
obstructive sleep apnea during early development
Lay Description (from application):
Adults with OSA are known to have increased risk for heart disease. We will study children with OSA, and an
animal model of the disease during early development, to help clarify how this disease of adulthood actually
has its origins in childhood. We have already shown that obese children with obstructive sleep apnea (OSA)
are more prone to diabetes (metabolic problems) than those without OSA. More recently, we found that this is
also true for children who are not overweight. This early diabetes is known to be to show a future risk for heart
disease. This study will examine why OSA in children is linked to metabolic problems. First, we will continue
our study in children who are not overweight. We need to study more children to be sure that OSA is truly
linked to metabolic problems - whether or not a child is overweight, because this means that children with OSA
are at risk for metabolic and future cardiac problems, whether they are overweight or not. Since weight does
not usually change after treatment of OSA, we will also study children again, after they have been treated for
OSA. We expect to show that treatment of OSA resolves the metabolic problems. Since hypoxia (low oxygen)
occurs in OSA we believe that this is the fundamental cause of the metabolic problems. To test whether this is
true, we will look for metabolic problems in piglets exposed to similar, low levels of oxygen as those seen in
children with OSA, comparing them to piglets that have not been so exposed. We believe that the tendency to
develop OSA and diabetes is inherited. To test this, we will study the genes of a very large family whose
members have OSA and/or diabetes, and try to find which genes are associated with OSA and with diabetes.
This will help determine if the two genes are linked in some way.
Research achievements (from final report):
Additional funding from the NIH allowed completion of all 5 aims of this large project. Results have been
presented at international conferences. Three post-doctoral fellows, one clinical trainee, and 4 honours students
participated in the project. Collaborations were extended with the Philippines. We examined (1) Associations
between obstructive sleep apnea (OSA) and the metabolic syndrome in at least 210 children. A manuscript was
is being revised, for 184 out of 216 children who underwent overnight sleep studies and blood collection. (2)
Mechanistic links beteween OSA and metabolic syndrome. A manuscript examining inflammatory markers has
been accepted for publication with the Journal of Pediatrics and Child Health. (3) Restudy at least 50 children
after treatment of OSA. A mansucript describing results for 69 children out of 213 families contacted, is under
revision with the International Journal of Pediatric Otorhinolarngology. A separate component of the follow-up
is under revision with the American Journal of Respiratory and Critical Care Medicine. (4) Early markers of
metabolic syndrome were studied in 13 piglets and this manuscript is in preparation for Pediatric Resea. An
examination of inflammatory markers was undertaken in 14 piglets and this manuscript is in preparation. (5)
Physiologic and genetic material were collected from 58 members of a large family in the Philippes spanning 4
generations for linkage analysis. Those data are currently undergoing complex statistical analyses. The
information obtained from this study has clarified how examination of metabolic and inflammatory markers
should be incorporated into the management of Pediatric OSA.
Expected future outcomes:
Several manuscripts have been written and are either under revision or re-submission. It is anticipated that at
least 3 manuscripts will have been accepted for publication by the end of the current year.
Name of contact:
Karen Waters
NHMRC Research Achievements - SUMMARY
Email/Phone no. of contact:
karenw2@chw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 219109
Start Year: 2002
CIA Name: Prof Robyn McDermott
End Year: 2003
Admin Inst: The Dr Edward Koch Foundation Limited
Grant Type: SRDC - Research
Main RFCD: Indigenous Health
Total funding: $414,600
Title of research award:
Sustainability & Transferability of an effective community based management system for diabetes in remote
indigenous comSustainability & Transferability of an effective community based management system for
diabetes in remote indigenous com
Lay Description (from application):
This project aims to improve systems for secondary prevention of CVD among Indigenous adults in remote
communities in NW Queensland and ultimately to improve patient outcomes in this high risk group. The
intervention is aimed at the three domains of health systems: the community and client group, clinical services
and health management systems. The intervention is centred around increasing the capacity of Indigenous
health Workers (IHW's) to manage recall and reminder systems for CHD in communities, supported by
appropriate training and systems changes. The project will liaise closely with the client and community groups
and aim to improve capacity for effective self-management of cardiovascular disease among clients. The study
will evaluate the effectiveness of this complex intervention in 3 sites over two years, with 2 control
communities
Research achievements (from final report):
This work built upon a successful collaboration between the University and the Health Service in the Torres
Strait (north Queensland) which proved, in a randomised cluster trial, that a community-based system of
managing basic diabetes care in remote communities, led by properly supported local Indigenous Health
Workers, improved diabetes care processes and significantly reduced preventable hospitalisations from
complications of diabetes. The current project evaluated the sustainability of the chronic care model over 4
years, looking at 3 domains of policy and resources, clinical systems (including registers, recall and reminder
systems) and community and patient perceptions of quality of care. The project showed that, given a supportive
policy environment and clinical systems (including workforce development), a sustained improvement in
diabetes care processes and outcomes could be achieved across the whole health service (population
approximately 10,000) ina high risk remote Indigenous population.
Expected future outcomes:
This work has contributed to the evidence base supporting the chronic disease strategy in north Queensland. It
has been used in developing an Evaluation Framework for the Chronic Disease Strategies in NQ and the NT.
Name of contact:
Robyn Mcdermott
Email/Phone no. of contact:
robyn.mcdermott@unisa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 158007
CIA Name: A/Pr Michael DAVIES
Admin Inst: University of Adelaide
Main RFCD: Obstetrics and Gynaecology
Total funding: $449,073
Start Year: 2001
End Year: 2003
Grant Type: NHMRC Project Grants
Title of research award:
Fetal and genetic origins of Polycystic Ovary Syndrome (PCOS) in young womenFetal and genetic origins of
Polycystic Ovary Syndrome (PCOS) in young women
Lay Description (from application):
Polycystic ovary syndrome (PCOS) is a common hormonal condition which emerges at puberty and afflicts up
to 10% of women. The cause of PCOS is uncertain. Symptoms include menstrual disorders, acne, obesity, and
excess body hair. PCOS is of great significance for women because of the high incidence of infertility and the
high risk of other serious diseases, including diabetes mellitus and endometrial cancer. PCOS is probably the
most common hormonal condition among young women. The cause of PCOS is unknown and the
relationship between PCOS and the more common condition of polycystic ovaries, which often features in
PCOS, is uncertain. There is evidence that genetic factors contribute to PCOS, but cannot explain certain
aspects. There is also striking new evidence that abnormal growth in the womb can alter the metabolism of the
baby for life, resulting in increased risks of adult disease, including diabetes and cardiovascular disease. PCOS
may be another consequence of abnormal fetal growth, a suggestion that is supported by two recent studies of
closely related conditions.
To investigate the origins of PCOS, we propose to establish the first international
study of the relationships between fetal growth, genetic factors and the presence of PCOS. In this study, we
shall trace 3,260 women born in one maternity ward during 1973-75. These women, now young adults, will be
invited into our study for an interview, physical examination, and a blood test. We expect 2,200 women will
participate. Of this group, some 220 women with PCOS will receive further tests to investigate a range of
metabolic problems. The study has the potential to illuminate the path from genetic predisposition and fetal
growth, to the emergence of an important reproductive disorder with serious associated diseases in a woman s
later life.
Research achievements (from final report):
N/A
Expected future outcomes:
N/A
Name of contact:
Dr Michael Davies
Email/Phone no. of contact:
michael.davies@adelaide.ed.au
NHMRC Research Achievements - SUMMARY
Grant ID: 158012
CIA Name: Prof Gary Wittert
Admin Inst: University of Adelaide
Main RFCD: Nutrition and Dietetics
Total funding: $208,055
Start Year: 2001
End Year: 2003
Grant Type: NHMRC Project Grants
Title of research award:
The role of dietary protein on weight loss and body composition in men and women with insulin resistanceThe
role of dietary protein on weight loss and body composition in men and women with insulin resistance
Lay Description (from application):
Obesity is an increasing problem in the community and is associated with an increased incidence of high blood
pressure, high cholesterol and triglycerides, diabetes, heart disease and cancer. Although conventional dietary
advice for weight loss is a low fat high carbohydrate and high fibre diet there is a very strong interest in the
media and the general population in alternative diets that feature reduced carbohydrate with the remainder of
the diet either protein or a mixture of protein and fat. Unfortunately there is very little published data to guide
the decisions of health professionals in this area and there is a strong demand for such information. We plan to
perform 2 large weight loss studies which focus on high protein diets with one exchanging protein for
carbohydrate and keeping fat constant and the second exchanging protein for fat keeping carbohydrate
constant. We will assess whether the high protein diets blunt the decrease in metabolic rate that occurs with
weight loss, and whether it spares some of the inevitable loss of muscle mass. We will also measure whether
high protein diets improve glucose metabolism in people already at risk of diabetes and heart disease because
of their obesity and high insulin levels.
Research achievements (from final report):
The outcomes of this research provided a better understanding of the role of protein in a healthly, nutritionally
balanced diet for weight loss, weight maintenance and the improvement of risk factors associated with the
metabolic syndrome. Although we found that without active ongoing dietary advice, long-term adherence to
the dietary patterns invetsigated is poor, they all resulted in net weight loss and improvements in cardiovascular
risk factors. That the increased protein diets confered several benefical effects over the standard protein
(control) diets without causing detrimental effects, warrants that they be given consideration by health
professionals as an effective dietary choice for treating obesity and the metabolic syndrome.
Expected future outcomes:
All work is complete and published
Name of contact:
Professor Gary Wittert
Email/Phone no. of contact:
gary.wittert@adelaide.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 250335
CIA Name: Prof Michael Horowitz
Admin Inst: University of Adelaide
Main RFCD: Gastroenterology
Total funding: $393,750
Start Year: 2003
End Year: 2005
Grant Type: NHMRC Project Grants
Title of research award:
Gastroduodenal motility and glycaemic control in diabetes mellitusGastroduodenal motility and glycaemic
control in diabetes mellitus
Lay Description (from application):
The recent application of novel techniques to evaluate gastrointestinal motor function has established that the
rate which the stomach empties food is abnormally slow in ~50% of people who have insulin-dependent (type
1) or non-insulin dependent (type 2) diabetes. Delayed stomach emptying was thought to be an infrequent
complication in diabetes; much less common than damage to the eyes, kidneys or nerves. Abnormal stomach
emptying may contribute to a number of problems in diabetes, including symptoms such as nausea and
bloating, and poor control of blood glucose concentrations. It is now recognised that the blood glucose level
itself has a reversible effect on both stomach contractions and symptoms. For example, when the blood
glucose is abnormally high (hyperglycaemia), the rate at which the stomach empties food into the intestine is
slower and symptoms, such as fullness, are greater. The rate of stomach emptying and the absorption of
glucose from the intestine affect the rise in the blood glucose level after a meal; this is an important issue
because it is desirable to maintain blood glucose levels within the normal range to minimise the risk of both the
development and progression of the complications of diabetes. In many people with diabetes eating a meal
results in a substantial fall in blood pressure, which may cause fainting and falls. By slowing gastric emptying
the magnitude of the fall in blood pressure is minimised. Our group has been the recipient of ongoing support
from the NH&MRC for approximately 18 years to conduct research in this area. As a result we have
performed the most comprehensive studies to date and developed new methods to evaluate stomach and
intestinal function in people with diabetes, resulting in international recognition. The studies proposed in the
current application represent a logical development from our previous work and have important implications
for the management of diabetes.
Research achievements (from final report):
Our group has conducted research in this area for some 20 years and have performed the most comprehensive
studies to date, resulting in international recognitiion. The studies that were performed represented a logical
development from our previous work and have important implications for the management of diabetes. This
research capitalised on novel techniques (eg scintigraphy, ultrasound and manometry) developed in many cases
by members of our group to study gastric emptying and its mechanics, gastrointestinal symptoms, intestinal
carbohydrate absorption, hormonal responses to nutrient delivery and the impact of the blood glucose
concentration on gastrointestinal motor and sensory function. The central role of gastric emptying, and
probably small intestinal motility, to blood glucose homeostasis has only recently been widely appreciated and
is of major importance to the effective management of diabetes. The grant was highly productive (as attested to
by the publication record) and the outcome of this work will have a substantial impact on patient management.
It has also consolidated our position as arguably the world leaders in this area.
Expected future outcomes:
We propose to continue our research programme in this area with an increasing focus on the capacity to
modulate gastric and small intestinal motility, by dietary and pharmacological means, to optimise glycaemic
control in diabetes mellitus
Name of contact:
Prof Michael Horowitz
Email/Phone no. of contact:
michael.horowitz@adelaide.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 250403
CIA Name: A/Pr William Hague
Admin Inst: University of Adelaide
Main RFCD: Obstetrics and Gynaecology
Total funding: $257,400
Start Year: 2003
End Year: 2005
Grant Type: NHMRC Project Grants
Title of research award:
Gestational diabetes: treatment with metformin compared to insulinGestational diabetes: treatment with
metformin compared to insulin
Lay Description (from application):
Gestational diabetes (GDM) is diagnosed when women have elevated blood sugar levels detected in pregnancy.
Treatment aims to keep the mother's blood sugar normal and to prevent extra sugar transferring to the baby, as
this can lead to elevated insulin levels, and subsequent complications, in the baby. Initial treatment is by diet,
but more than 30% of women need further treatment with insulin injections. Metformin, which can be taken by
as a tablet, is an alternative to insulin that is used widely outside pregnancy for people with diabetes. There are
good data to support the safety of metformin in pregnancy. We plan to test that metformin is not only safe but
also an effective alternative to insulin for women with GDM. Metformin works by reducing resistance to
insulin, which is a key factor for the development of GDM and also for high blood pressure complications. We
hope to demonstrate a reduction in these complications with metformin treatment. Metformin is associated with
less weight gain than insulin and we hope to demonstrate an associated reduction in the risk of diabetes
following pregnancy in women with GDM treated with metformin. It is likely that metformin crosses the
placenta, and if so, it may reduce elevated insulin levels in the baby. The study will measure insulin levels in
the cord blood, hoping to demonstrate that more babies have normal insulin levels in pregnancies treated with
metformin
Research achievements (from final report):
We have demonstrated in an adequately powered randomised clinical trial that, in women with gestational
diabetes who require more than lifestyle adjustment to control hyperglycaemia, an oral medication metformin
is safe and effective with similar perinatal outcomes when compared with insulin which needs to be given by
injection. Women prefer metformin to insulin. Longer term outcomes for the offspring need to be established.
Expected future outcomes:
With funded long-term follow-up studies, we expect to be able to establish whether there is any benefit , such
as a reduction in the rate of childhood obesity and the degree of resistance to insulin, for the offspring of
mothers with gestational diabetes, who have been exposed to metformin in utero, given the potential of
metformin to affect fetal insulin action.
Name of contact:
Dr Bill Hague
Email/Phone no. of contact:
bill.hague@adelaide.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 250453
CIA Name: A/Pr Karen Jones
Admin Inst: University of Adelaide
Main RFCD: Gastroenterology and Hepatology
Total funding: $435,500
Start Year: 2003
End Year: 2007
Grant Type: Career Development Fellowships
Title of research award:
Gastroduodenal motility and glycaemic control in diabetes mellitusGastroduodenal motility and glycaemic
control in diabetes mellitus
Lay Description (from application):
Media Summary not available
Research achievements (from final report):
A/Prof Jones' research, which is now recognised internationally, relates to the application of nuclear medicine
and ultrasound techniques to the study of gastrointestinal motor function in humans and the pathophysiological
importance of gastric and small intestinal function in postprandial hypotension. The award has been used solely
to fund the salary of A/Prof Jones' salary as a clinical based researcher and not her research per se. The broad
aims of the CDA were to: (i) increase experience in peer review and ability to attract external research funds,
(ii) increase clinical research skills, (iii) Increase involvement with industry and (iv) increase skills in
supervision.In each of these areas A/Prof Jones has expanded her skills significantly. In the last decade A/Prof
Jones has been the recipient of a total of $6,677,536.00 in research funds from peer-reviewed sources (~90% in
the last 5 years). A/Prof Jones' research skills have been developed by optimising existing collaborations with
scientists within the Discipline of Medicine, University of Adelaide and other University of Adelaide/Royal
Adelaide Hospital Departments. In the past 5 years A/Prof Jones has been responsible for the conduct of a
number of investigator-driven pharmaceutical trials, the majority of which relate to diabetic gastroparesis. Her
supervisory skills have increased substantially; she has supervised a total of 7 PhD students, 3 have completed
and her 4 current students are all making satisfactory progress. One of her former students now holds an NHF
postdoctoral fellowship. A/Prof Jones' success in research is attested to by the number and quality of her
publications (total of 37 peer-reviewed papers in the past 5 years). At least 11 papers have been cited more than
50 times and she currently hs an 'h-index' of 25.
Expected future outcomes:
The NHMRC/Diabetes Australia CDA has made a huge impact on A/Prof Jones' career and places her in an
excellent position to receive ongoing support for her salary. A/Prof Jones has submitted applications for an
NHMRC Senior Research Fellowship, NHMRC Senior CDA, NHF Career Development Fellowship and has
submitted two applications for NHMRC project grants to continue her research.
Name of contact:
A/Professor Karen Jones
Email/Phone no. of contact:
karen.jones@adelaide.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 250483
CIA Name: Prof Antonio Ferrante
Admin Inst: University of Adelaide
Main RFCD: Medical Biotechnology
Total funding: $150,000
Start Year: 2003
End Year: 2004
Grant Type: NHMRC Development Grants
Title of research award:
Targeting protein kinase C in diabetes management using novel polyunsaturated fatty acidsTargeting protein
kinase C in diabetes management using novel polyunsaturated fatty acids
Lay Description (from application):
PKC regulates a diverse range of cellular processes in an isozyme-specific manner. There is strong recent
evidence to implicate PKC, especially PKC _, in mediating the actions of glucose in diabetes. This includes the
action of glucose in renal glomeruli, retina, aorta and heart of diabetic animals and in cultured cells from these
organs. More importantly, inhibition of PKC_ with the PKC_-specific inhibitor, LY333531, blocks the actions
of glucose. Recently, our research group designed and synthesised a family of novel polyunsaturated fatty
acids. One of these, MP5 (_-oxa- 21:3n-3), inhibited high glucose-induced activation of PKCβ in cultured
mesangial cells as well as in glomeruli of diabetic rats in a relatively selective manner. The overall aim of this
proposal is to evaluate the potential for a chemically engineered novel polyunsaturated fatty acid, MP5 (_-oxa21:3n-3), to treat pathogenesis associated with diabetes by targeting the PKC system. The specific aims are to:
1. Characterise the effects of MP5 on glucose- or advanced glycosylation end product-stimulated activation of
protein kinase C (PKC). 2. Determine whether esterification of MP5 into diacylglycerol is essential for the
action of MP5 3. Investigate whether MP5 is efficacious at preventing the actions of glucose in vitro e.g.
glucose stimulated TGF_ production in mesangial cells, and in vivo in streptozotocin-diabetic r
Research achievements (from final report):
Our group has generated a family of designer fats based on fish oils and one of these has demonstrated great
potential as an agent to fight against the development of complications caused by diabetes, such as kidney
failure. Funds provided by the NH&MRC have enabled our group to discover that this designer fat, called
MP5, is able to suppress the ability of high glucose concentrations to bring about biochemical changes which
damage the kidneys. In studies with animal models of experimental diabetes, our results have demonstrated
that MP5 made the diabetic animals less thirsty, reduced the amount of urine produced and greatly reduced the
severity of kidney damage. Important features of this fat are that the effects on thirst and urine output were seen
within 72 hours after the commencement of treatment and lasted for around two weeks after the treatments had
ended. These results demonstrate that MP5 and similar designer fats have the hallmarks of novel drugs to fight
against the development of diabetic complications.
Expected future outcomes:
This technology is now signed over to Peplin Biotech, an Australian company. It is currently under product
stability and toxicology studies. It expected that within the next 6 months, a commercial package will be
precipitated for licensing to a large international pharmaceutical company to produce a successful drug for
managing diabetes.
Name of contact:
Prof Antonio Ferrante
Email/Phone no. of contact:
antonio.ferrante@adelaide.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 264573
CIA Name: Prof Hamish Scott
Admin Inst: University of Adelaide
Main RFCD: Autoimmunity
Total funding: $1,045,422
Start Year: 2004
End Year: 2008
Grant Type: International Collaborations
Title of research award:
Novel Approaches to pathogenesis, diagnosis &treatment of autoimmune diseases based on new insights into
thymus-dependenNovel Approaches to pathogenesis, diagnosis &treatment of autoimmune diseases based on
new insights into thymus-dependen
Lay Description (from application):
An individual relies upon their immune system to protect against invasion by hostile organisms. The system
usually works well. Invading agents (the 'non-self') are detected and attacked by the immune system's
patrolling killer T cells. These normally beneficial cells are called T cells because they were formed and
educated in an organ called the thymus, which kick-starts our immune system in childhood, but falls into
inactivity by adolescence. Sometimes the education system in the thymus goes wrong and it releases T cells
that mistakenly attack 'self' instead of 'non-self'. This causes autoimmune diseases, such as type1 diabetes,
multiple sclerosis and rheumatoid arthritis. The Euro-Thymaide project aims to determine why and how selfattacking T cells are mistakenly released from the thymus into the body. Usually such errant T cells are
detected and destroyed within the thymus, before they have the opportunity to escape and cause autoimmune
diseases. The ultimate objective is to learn about the thymus recognition process and help the immune system
detect and destroy faulty T cells that patrol the body, thereby preventing the onset of autoimmune diseases.
Research achievements (from final report):
We have significantly explored the role of the thymus, the university of the immune system, in human disease.
WE have described how it develops, when and how it starts to function, and what happens if it misfunctions
and wears out. Studies on three organ-specific autoimmune diseases - Type 1 diabetes mellitus, Myasthenia
gravis and Graves'Autoimmune Thyroiditis - uncovered common pathophysiological mechanisms, which led to
a new paradigm determining susceptibility to disease. We have developed novel diagnostic tools for
hypoparatyroidism, and potential diagnostic tools for other autoimmune diseases.Our achievements have
furthered our basic knowledge on central tolerance in general, and pGE in particular, and provided exciting
inroads into a novel knowledge of the thymus-dependent mechanisms underlying human autoimmune diseases.
They provide a solid base for future investigations aiming at more specific and successful treatment of major
autoimmune diseases like T1D.
Expected future outcomes:
Additional publications. Potential novel therapies.
Name of contact:
Professor Hamish S. Scott
Email/Phone no. of contact:
hamish.scott@health.sa.gov.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: 349443
Start Year: 2005
CIA Name: A/Pr Mark Nottle
End Year: 2010
Admin Inst: University of Adelaide
Grant Type: Established Career Fellowships
Main RFCD: Biotechnology not elsewhere classified
Total funding: $721,601
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
I am a reproductive physiologist who collaborates with a number of leading Hospital, University and Institute
Research Groups nationally and internationally examining the potential of genetically modified pigs as organ,
tissue and cell donors for humans.
Research achievements (from final report):
The aim of the fellowship request was to isolate porcine embryonic stem cells (ESCs) to facilitate the
production of transgenic pigs expressing multiple transgenes for pig to human transplantation research. As a
result of this research we developed a new method for isolating stem cells and used this to have isolate several
porcine ESC lines. These have have been extensively characterised to confirm their ability to giv rise to all the
cell type sinth ebody incluidng th eprodcution of chimaeric pigs We have also used this method to isolate
porcine ESCs from cloned embryos and also demonstrated that our method can be used to isolate ESCs from
several strains of mice as well as cattle.
Expected future outcomes:
Future work will examine capacity of these cells to undergo multiple rounds of gnentic modifcation to produce
animals expressing multiple transgenses in the space of one generation for xenotransplantation research.
Something which cannot be done using current technology. We will also use these cells to develop the pig as a
large animal model for human stem cell research.
Name of contact:
Mark Nottle
Email/Phone no. of contact:
mark.nottle@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: 399123
CIA Name: A/Pr Simon Barry
Admin Inst: University of Adelaide
Main RFCD: Cellular Immunology
Total funding: $483,273
Start Year: 2006
End Year: 2008
Grant Type: NHMRC Project Grants
Title of research award:
The molecular identification of FoxP3 +ve regulatory T cellsThe molecular identification of FoxP3 +ve
regulatory T cells
Lay Description (from application):
The immune system has a series of checks and balances in place to distinguish foreign bodies from normal, or
self-antigens. In healthy individuals this prevents the immune system from attacking the cells and tissues of the
body, food proteins, and the beneficial bacteria of the gut. However in autoimmune disease the system
becomes imbalanced, allowing reactions to benign antigens, causing diseases such as diabetes, asthma and
rheumatoid arthritis. One of the key players in the maintenance of a healthy immune system is a specialized set
of T cells known as T Regulatory cells. These cells are rare, at 1-4% of all T cells, yet are potent modulators of
other T cells, and can prevent the activation of a T cell if it is reacting to a self-antigen. If they can control the
cause of autoimmune disease, and patient Treg cells can be manipulated, it may be possible to use them
therapeutically. Recently the switch that is required to generate regulatory cells was identified from patients
with a rare autoimmune disease called Immunodysregulation, polyendocrynopathy, enteropathy, X-linked
syndrome or IPEX. A mouse disease, Scurfy, with similar symptoms, is caused by the same mutations. The
mutated gene encodes a protein, FoxP3, and this protein is able to bind to other genes in T cells and regulate
their function. Without this protein, there are no T regulatory cells, resulting in autoimmune disorders. At this
time there is very little known about how the FoxP3 gene is able to make a T cell become a regulatory T cell,
and nothing is known about the genes that are turned off and on to facilitate this. If we can understand better
the role of this protein, FoxP3, in the generation and maintenance of T cells with regulatory function, we may
better be able to diagnose and treat autoimmune diseases, and this knowledge will have broad application to
many autoimmune disorders.
Research achievements (from final report):
The major aims of the grant have been achieved as we have now performed 4 chromatin immunoprecipitationarrays (chIP-chip) from biological replicate nTreg cells with our foxp3 immunoprecipitation protocol. We have
performed duplicate promoter arrays and duplicate whole genome arrays, and find over 90% agreement
between the promoter arrays and the whole genome arrays. We are among the first in Australia to perform
human chip-chip for a transcription factor and currently there are no published data for the targets of human
FoxP3, giving us a world first human foxP3 target gene set. The final goal of this grant was confirming by
quantitative-PCR that the ChIP material is enriched for these key target genes, and validation of the regulation
of these genes at the mRNA level. This is now complete, and in preparation for publication. We are now in the
process of testing these genes to define their role in Treg function using lentiviral overexpression or shRNAi.
Expected future outcomes:
We have developed a world first profile of the genes regulated by human foxp3, have discovered a novel Treg
biomarker, and have started to analyse Treg genes in fuctional assays. This may lead to novel therapeutic
targets, and modulation of Treg function will be applicable in autoimmune diseases and transplant tolerisation.
Name of contact:
Dr Simon C Aarry
Email/Phone no. of contact:
simon.barry@adelaide.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 399131
CIA Name: A/Pr David Kennaway
Admin Inst: University of Adelaide
Main RFCD: Endocrinology
Total funding: $631,782
Start Year: 2006
End Year: 2008
Grant Type: NHMRC Project Grants
Title of research award:
How does disruption of circadian rhythms induce diabetes?How does disruption of circadian rhythms induce
diabetes?
Lay Description (from application):
Increasing evidence suggests that disturbed circadian rhythms initiate and amplify metabolic and
cardiovascular disease. The increasing and already high proportion of workers engaged in shiftwork, and
increased frequency of disruption of these rhythms in the population more generally, implicate this body
system as contributing to the growing epidemic of obesity and diabetes and related disorders in our community
and world-wide. While we are now beginning to understand how our rhythms are synchronised to night and
day, how this rhythmicity is linked to our organs in the normal and common disease states such as diabetes is
poorly understood. The discovery of a special set of genes, called clock genes that function in all of the cells
in our bodies and strongly influence the function of our organs such as the liver, pancreas and heart has been
particularly important. We hypothesise that both environmentally (exogenous) and genetically (endogenous)
induced disruption of circadian rhythms causes metabolic dysfunction. This is due to altered central and
peripheral clock gene expression rhythms, which in turn alter metabolic rhythms and impair glucose
homeostasis. This project aims to determine the impact of disrupted rhythmicity on metabolism with a
particular emphasis on the possibility that the disrupted rhythmicity may be a predisposing factor for the
development of diabetes.
Research achievements (from final report):
We have established a new animal model that mimics a shiftwork schedule. We have shown that exposure of
mice and rats to repeated changes of the light/dark cycle altered sleep/wake behaviour. Thus the animals were
active in the dark phase and inactive in the light phase from the commencement of the schedule, validating its
use as a true shiftwork simulation. After 4 weeks of shiftwork simulation, liver function was enhanced when
the mice were preparing for rest instead of active. The consequences were elevated plasma insulin levels, a risk
factor for diabetes, in mice subjected to shiftwork simulation, which was exacerbated by a high fat diet. When
rats were subjected to shiftwork simulation, insulin secretion and insulin sensitivity were both impaired and
glucose tolerance reduced, all signs of prediabetes and this persisted for up to a week or more post shiftwork. ,
Mice with mutations in genes responsible for generating biological rhythms in cells also had impaired insulin
secretion, but compensated with increased production of hormones that protected against the insulin sensitivity.
When these mice were fed a high fat diet they also appeared to be protected from the deleterious impact of the
diet despite increased body fat., In summary we have confirmed and further delineated the major role of
cellular rhythms in metabolic homeostasis and provided compelling and direct evidence that disruption of
circadian rhythmicity alters the adipo-insulin axis and impairs glucoe tolerance, acting in a tissue specific
fashion. Understanding how disruption to cellular rhythms leads to diabetes, but can also enhance the
metabolic state of adipocytes with the potential to preserve metabolic homeostasis, may lead to novel ways to
improve the health of shiftworkers.
Expected future outcomes:
This research has provided important new information on how daily rhythms impact on metabolic health.
Using this knowledge we expect to design and test strategies for minimising the negative impact of shiftwork
on health.
Name of contact:
Assoc. Prof. David Kennaway
Email/Phone no. of contact:
NHMRC Research Achievements - SUMMARY
david.kennaway@adelaide.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 406700
CIA Name: Prof Hamish Scott
Admin Inst: University of Adelaide
Main RFCD: Autoimmunity
Total funding: $300,492
Start Year: 2007
End Year: 2008
Grant Type: International Collaborations
Title of research award:
Autoimmune polyendocrine syndrome type IAutoimmune polyendocrine syndrome type I
Lay Description (from application):
Our work package looks at Control of pathogenic autoimmunity through regulation by the autoimmune
regulator gene (AIRE) in thymic epithelial cells” and has a major influence on work package no 1). –“ Design
of specific tolerogenic peptide therapies based on the identification of tissue-restricted self-antigen epitopes
escaping tolerance”, but interacts either directly or indirectly with all other packages
Research achievements (from final report):
This project was conceived as an important initiative to bring together the leading scientists working on the
best available biological model for autoimmunity, Autoimmune Polyendocrine Syndrome Type I (APS I). The
groundbreaking research on this rare disease has provided new insights into mechanisms of tolerance induction
as well as providing tools for improved diagnostic tests and better care of patients. The results of this research
provide an example of an integrated effort to characterize the molecular details of autoimmunity creating the
basis for novel treatment and intervention strategies for autoimmune diseases. Equally important, the effort will
provide well structured information of the details of the clinical course, accessible on the internet by clinicians
worldwide and providing the basis for the improvement in patient care..
Expected future outcomes:
Additional publications. Better patient care. Potential novel therapies.
Name of contact:
Professor Hamish S. Scott
Email/Phone no. of contact:
hamish.scott@health.sa.gov.au
NHMRC Research Achievements - SUMMARY
Grant ID: 453464
CIA Name: Prof Antonio Ferrante
Admin Inst: University of Adelaide
Main RFCD: Endocrinology
Total funding: $418,447
Start Year: 2007
End Year: 2009
Grant Type: NHMRC Project Grants
Title of research award:
Omega 3 polyunsaturated fatty acid analogues in the treatment of diabetic complicationsOmega 3
polyunsaturated fatty acid analogues in the treatment of diabetic complications
Lay Description (from application):
Treatment of diabetes has become an even greater challenge to our community today. The ill health from
diabetes arises from the high blood sugar levels. Treatment of diabetic complications such as kidney damage
has now become a major goal. This research addresses this problem by trying to find out if a group of novel
polyunsaturated fatty acids can target the process initiated by high blood sugar responsible for kidney damage.
Research achievements (from final report):
Our attempts to establish the protective effects of novel polyunsaturated fatty acids in an experimental rat
model of diabetes against the development of diabetic nephropathy and associated complications have been
completed and objectives achieved, including the gaining of an understanding of the basis of their protective
effects. Taking into consideration all our other knowledge available on these novel fats and the classical omega
3 polyunsaturated fatty acids, it is evident that the limitations experienced in using omega3 fatty acid
supplementation to treat chronic diseases such as diabetes could be overcome by using the novel fats. The
advantages of the novel fats are with respect to an increase in potency, tissue stability and target selectivity. We
have been able to show that these have the ability to selectively target cellular enzymes stimulated by high
blood glucose which give rise to complications such as kidney damage. The work suggests that fats of this type
prevent or reduce the activation of these enzymes by high glucose. Animals treated with the novel fats showed
also protection against damage experienced by other organs such as the liver.
Expected future outcomes:
Further research on the novel fats would yield important information to make decisions on the therapeutic
potential of these fats over the natural omega3 fats and other diabetic medications. Studies should extend proof
to other diabetic models and gaining a better understanding of the structure responsible for the protection.
Name of contact:
Professor Tony Ferrante
Email/Phone no. of contact:
antonio.ferrante@health.sa.gov.au
NHMRC Research Achievements - SUMMARY
Grant ID: 453557
CIA Name: Prof Michael Horowitz
Admin Inst: University of Adelaide
Excellence
Main RFCD: Nutrition and Dietetics
Total funding: $2,007,200
Start Year: 2007
End Year: 2012
Grant Type: Centre of Clinical Research
Title of research award:
Centre of clinical research excellence in nutritional physiology, interventions, and outcomesCentre of clinical
research excellence in nutritional physiology, interventions, and outcomes
Lay Description (from application):
Over 20% of Australian adults either have diabetes, or are at imminent risk, while 60% are overweight or
obese. Conversely, some 40% of the elderly receiving domiciliary support are at risk of malnutrition. Poor
nutrition underpins numerous chronic diseases. We seek to capitalise on the expertise and multidisciplinary
collaborations of several groups, all leaders in their fields, and whose collective track record in clinical
nutrition research cannot be matched in Australia, to form a Centre of Excellence that encompasses the
physiology of nutrition, dietary intervention strategies, and evaluation of outcomes, in diabetic, overweight,
elderly, and critically unwell populations.
Research achievements (from final report):
The Centre of Clinical Research Excellence in Nutritional Physiology has made a number of substantial
achievements in the field of nutritional physiology, particularly in the areas of diabetes and glycaemic control,
obesity, nutrition in the elderly and nutrition in the critically ill. Examples are provided below:(i) Diabetes and
glycaemic controlWe have now refined the 'preload' concept with work confirming major, acute improvements
in postprandial glycaemic after a whey protein preload in patients with type 2 diabetes. This concept is now
ready to be taken forward in larger, and more prolonged, clinical trials, which have been initiated.We are
continuing to define the nature and regulation of sweet taste receptors in the huma small intestine, specifically
how their reguatlion differs between diabetes and health, and with acute changes in glycaemia.(ii)
ObesityRecent studies have focussed on evaluation the changes in both oral and small intestinal sensitivity to
ingested nutrients, including receptor mechanisms, in obesity when compared to health, as well as in response
to dietary restriction. Major differences, which are likely to be of pathogenetic relevance, have been
demonstrated. Our work in the are of high protein weight-loss diets and renal disease has demonstrated weight
loss of 12-15% without untoward effects.(iii) Nutrition in the elderlyOur group has established that the
provision of 'Meals-on-Wheels' to under-nourished older people is beneficial, and this has led to changes in the
nutritional value of the meals that are provided.(iv) Nutrition and critical illnessWe now have a unique
understanding of the gastrointestinal pathophysiology underlying the impaired provision of nutrition and
disordered blood glucose control in the critically ill. This has led to fundamental changes in the management
and feeding techniques, both nationally and internationally.
Expected future outcomes:
We will design a short course on 'disorders related to nutrition for the busy clinician' with the primary aim of
informing the primary care workforce (via General Practice, and Medicare Locals) to empower clinicians with
key knowledge and referral resources. We will also develope guidelines to assist generalist and specialist
clinicians in the implemenation of evidence-based nutritional practice.
Name of contact:
Dr Tim Murphy
Email/Phone no. of contact:
tim.murphy@adelaide.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 453640
Start Year: 2007
CIA Name: Prof Julie Owens
End Year: 2009
Admin Inst: University of Adelaide
Grant Type: NHMRC Project Grants
Main RFCD: Foetal Development and Medicine
Total funding: $545,183
Title of research award:
Functional and epigenetic consequences of maternal folate deficiency, supplementation and fetal growth
restrictionFunctional and epigenetic consequences of maternal folate deficiency, supplementation and fetal
growth restriction
Lay Description (from application):
Growing slowly before birth or being born early and premature are very common. Both conditions greatly
increase the risk of illness or death around birth and of the infant developing major conditions such as diabetes
and cardiovascular disease in later life. Despite their importance, we understand little of what causes fetal
growth failure or prematurity or why they influence an individual's health throughout life. Recent findings
suggest that low levels of folate in the mother, due to either dietary or genetic factors, may be involved in their
origins and their long-term outcomes. Folate is a nutrient required regularly in small amounts for growth and
maintenance of health. Folate supplementation in women is currently recommended before and in early
pregnancy, but may have a role throughout the whole of pregnancy in promoting growth and health of the
infant. Using experimental models, this project will determine if too little or too much maternal folate modifies
the genetic code of the infant (called epigenetic changes), which leads to later metabolic disease and high blood
pressure. These epigenetic changes are mild and subtle chemical modifications of DNA that persist in the cells
of the infant altering their function. The efficacy of maternal folate supplementation in improving these
outcomes for the small baby will also be tested in the models. Finally, the effect of folate status in the normal
and small human infant on the epigenetic state of their placenta, cord blood white blood cells and mucous cells
of the mouth will be tested. These outcomes will enable the design and testing of interventions with folate and
related nutrients in the mother to improve the health of their babies before birth and subsequently throughout
their lives. Because these pregnancy complications of being born small or early are common and account for
much of the diabetes that occurs in later life, the health benefits from development of effective interventions
may be large.
Research achievements (from final report):
The outcomes of this project include the demonstration that maternal methyl nutrient deficiency or excess
causes altered insulin action and glucose control in offspring. In addition, the mechanistic pathways were
shown to include epigenetic modifications to both functional and regulatory genes affecting growth and
glucose and lipid metabolism in key effector and regulatory tissues. Novel non-coding RNAs, microRNAs
were shown to be major targets of maternal methyl nutrient modulation in affecting the metabolic phenotype of
offspring. Another key finding was that maternal folic acid supplementation from before and throughout
pregnancy, at a level mimicking that recommended for pregnant women, adversely affects insulin control of
metabolism in offspring. This highlights the need for further investigation of the long term consequences of
maternal folic acid supplementation in humans, particularly since the introduction of food fortification in
Australia and elsewhere.
Expected future outcomes:
The findings of these studies will inform the design and conduct of future studies to assess the impact of
increased folic acid intake during pregnancy on health of offspring.
Name of contact:
Julie Owens
Email/Phone no. of contact:
julie.owens@adelaide.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 453647
CIA Name: Prof Michael Horowitz
Admin Inst: University of Adelaide
Main RFCD: Gastroenterology
Total funding: $543,302
Start Year: 2007
End Year: 2009
Grant Type: NHMRC Project Grants
Title of research award:
Upper gastrointestinal motility and glycaemic control in diabetes mellitusUpper gastrointestinal motility and
glycaemic control in diabetes mellitus
Lay Description (from application):
The application of novel techniques to evaluate gastrointestinal motor function has established that the rate at
which the stomach empties is abnormally slow in ~50% of people who have insulin-dependent (type 1) or noninsulin dependent (type 2) diabetes. Delayed stomach emptying, which was thought to be an infrequent
complication of diabetes, may contribute to a number of problems including symptoms such as nausea and
bloating, and poor control of blood glucose concentrations. The blood glucose level itself also has a reversible
effect on both stomach contractions and symptoms; when the blood glucose is abnormally high, the rate at
which the stomach empties is slower, and symptoms, such as fullness, are greater. The rate of stomach
emptying and the absorption of sugar from the intestine have a major influence on the rise in the blood glucose
level after a meal. This is important because in people with diabetes it is desirable to maintain blood glucose
levels as close as possible to normal to minimise the risk of complications such as eye and nerve damage.
Specific modifications in diet and recently developed drugs which have actions similar to that of the hormone,
glucagon-like peptide-1, may improve blood glucose control in type 2 diabetes by slowing the rate of gastric
emptying. People with cystic fibrosis frequently develop diabetes which is often difficult to manage; this may
result from abnormally rapid gastric emptying and impaired release of hormones. If so, pancreatic enzyme
replacement, in the form of tablets, should prove effective. Our group has conducted research in this area for
about 24 years and have performed the most comprehensive studies to date resulting in international
recognition. The studies proposed in the current application represent a logical development from our previous
work and have important implications for the management of diabetes.
Research achievements (from final report):
This research has highlighted the central role of the gut in diabetes management. Stomach and intestinal
function is frequently abnormal in people with diabetes, while conversely, gut function is a key determinant of
blood glucose control after meals. The work has employed novel research tools to gain insights into
physiological mechanisms that can be translated into effective dietary and pharmacological strategies for better
control of blood glucose.
Expected future outcomes:
A better understanding of the long term prognosis of disordered gut function in diabetes will emerge with
ongoing study, and more specific therapies will be developed. Dietary interventions that aim to stimulate gut
peptide release for the treatment of type 2 diabetes will be evaluated on a broader scale.
Name of contact:
A/Prof Chris Rayner
Email/Phone no. of contact:
chris.rayner@adelaide.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 453655
Start Year: 2007
CIA Name: Dr Vivienne Moore
End Year: 2009
Admin Inst: University of Adelaide
Grant Type: NHMRC Project Grants
Main RFCD: Foetal Development and Medicine
Total funding: $255,753
Title of research award:
Does women's nutrition during pregnancy influence metabolic health of their children?Does women's nutrition
during pregnancy influence metabolic health of their children?
Lay Description (from application):
The occurrence of type 2 diabetes is increasing around the world, with the rising incidence among children and
adolescents especially worrying. Widespread obesity has clearly contributed to this "epidemic", but does not
fully explain it. Diabetes develops over many years and obesity appears to exacerbate a pre-existing
susceptibility. Our work focuses on understanding and preventing this initial susceptibility. Metabolic changes
in the way the body produces and disposes of insulin, and responds to glucose, are seen much earlier in
individuals who become diabetic. These metabolic defects are thought to be due, in part, to sub-optimal
growth and development before birth (affecting the way the pancreas and liver function, for example). Poor
nutrition before birth may be an important underlying cause. Animal studies reliably demonstrate that a poor
quality diet of the pregnant mother can result in offspring that have impaired glucose tolerance and related
metabolic problems. We now need to determine whether this occurs in humans. A limited amount of
community-based research suggests this is possible. The balance between carbohydrate and protein in the
mother's diet may be a key factor, and possibly the type of carbohydrate (high or low glycaemic). Weight
before and during pregnancy could also be influential. We have been following a cohort of 500 children from
before birth, through childhood. We collected detailed information on the mothers' diets during pregnancy. In
this project, we plan to assess the glucose-insulin metabolism of the children at 8 years of age. We will then
investigate whether diet of the mothers during pregnancy affects the metabolism of the children later on.
Improving nutrition of pregnant women could lead to life-long improvement in metabolic health of the
children. This study will contribute to the evidence-base about whether maternal diet is important, and give
specific details about what kinds of changes are needed.
Research achievements (from final report):
In this project, we followed up a cohort of children whose mothers had joined a research study when they were
pregnant. We investigated relationships between maternal diet, body size and weight gain during pregnancy,
and insulin resistance (IR) in offspring at 9 years. Preliminary results of this project do not support arguments
that maternal diet, in isolation, has important consequences for child's metabolism. Rather, the important
predictive factor is high body weight of the mother before pregnancy. Overweight and obesity in women needs
to be addressed through public health intiatives, whether or not the effects we have identified are a direct
consequence of the intrauterine environment or reflect a common family/social environment.
Expected future outcomes:
Additional research hypotheses developed while the project was being undertaken concern a role for maternal
impaired glucose tolerance during pregnancy. These findings, and those of linked research about the family
environment and child obesity, will be completed in 2011.
Name of contact:
Vivienne Moore
Email/Phone no. of contact:
vivienne.moore@adelaide.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 453671
CIA Name: Dr Rebecca Robker
Admin Inst: University of Adelaide
Main RFCD: Reproduction
Total funding: $533,510
Start Year: 2007
End Year: 2009
Grant Type: NHMRC Project Grants
Title of research award:
Obesity and Infertility: Effects of diet-induced insulin resistance on oocyte quality.Obesity and Infertility:
Effects of diet-induced insulin resistance on oocyte quality.
Lay Description (from application):
The health of an embryo (and subsequently child) is largely determined by the health of the mother. It is well
documented that women who have poor pre-pregnancy health due to obesity are more likely to have difficulty
conceiving due to irregular ovulations and early embryo loss. My research using obese mice has found that
these fertility problems are partly due to alterations in the oocytes (eggs) within the ovary. Its surrounding
cells and fluid provide the oocyte with all of its required nutrients. I hypothesize that this follicular
environment is altered in females that are obese leading to inappropriate nutritional signals and suboptimal
development of the oocyte. The goals of my research are to use obese mice to 1) pinpoint exactly which
metabolic alterations lead to decreased oocyte development; 2) determine how these metabolic alterations
change the oocyte and the cells surrounding it; 3) use the information gained to analyse ovarian cells of women
and see if these same alterations occur in women who are obese. The findings will be highly significant
because they will 1) provide a greater understanding of how the maternal environment communicates
nutritional information to the oocyte, which ultimately forms the developing embryo.2) expand our knowledge
of the optimal nutritional conditions for oocyte and early embryo development. 3) identify biological
mechanisms that are altered during obesity and lead to decreased female fertility. 4) aid in the development of
improved agents for use at fertility clinics, for instance the development of solutions most closely mimicking
the critical components of the normal ovarian environment, for use in the culture of oocytes and embryos. 5)
provide a strong public health message to women of reproductive age: to achieve and maintain a healthy body
weight prior to becoming pregnant.
Research achievements (from final report):
The health of an embryo (and subsequently child) is largely determined by the health of the mother. It is well
documented that women who have poor pre-pregnancy health due to obesity are more likely to have difficulty
conceiving due to irregular ovulations and early embryo loss. The research supported by this award has found
that these fertility problems are due to alterations within the ovary. Using a mouse model of diet-induced
obesity, we have shown that insulin resistance is associated with impaired oocyte developmental competence
and altered blastocyst formation. These studies show, for the first time, that the detrimental effects of obesity
on female reproduction and embryo development commence with dramatic alterations in oocyte quality. We
have since found that oocytes of obese mice contain high levels of lipid which is associated with cellular stress.
Ovaries of obese women also contain increased lipid, increased inflammation and signs of cellular stress. ,
These findings are significant because they:, 1. provide greater understanding of how the maternal environment
communicates nutritional informtion to the oocyte, which ultimately forms the developing embryo., 2. identify
biological mechanisms that are altered during obesity and lead to decreased female fertility., 3. provide a strong
public health message to women of reproductive age: to achieve and maintain a healthy body weight prior to
becoming pregnant.
Expected future outcomes:
This research 1) expands our knowledge of the optimal nutritional conditions needed for oocytes and early
embryos. 2) aids in the development of improved agents for use at fertility clinics. 3) informs strategies for the
treatment of infertility in obese women and women with PCOS.
Name of contact:
Rebecca Robker
NHMRC Research Achievements - SUMMARY
Email/Phone no. of contact:
rebecca.robker@adelaide.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 481354
CIA Name: A/Pr Leonie Heilbronn
Admin Inst: University of Adelaide
Main RFCD: Endocrinology
Total funding: $380,559
Start Year: 2008
End Year: 2011
Grant Type: Career Development Fellowships
Title of research award:
Short term effects of overfeeding on metabolic risk in humansShort term effects of overfeeding on metabolic
risk in humans
Lay Description (from application):
Obesity is associated with increased risk of diabetes, heart disease and cancer. Obesity prevalence is rapidly
increasing and consitutes one of the greatest threats to human health. The aim of this study is to determine
mechanism/s underlying the close relationship between obesity and insulin resistance by inducing experimental
weight gain in humans with and without a genetic predisposition to diabetes. This project will help identify
new candidates for anti-diabetes drugs.
Research achievements (from final report):
The overall goal of my research during my CDA was to examine the physiological and molecular basis of over
and under nutrition in obesity, with a focus on identifying early mechanisms of insulin resistance. During my
CDA, we performed studies investigating effects of overfeeding on various outcomes in humans, including on
macrophage accumulation in adipose tissue and mitochondrial function in skeletal muscle. We also iniated
studies examining the effects of hyperbaric oxygen therapy on insulin sensitivity in type 2 diabetes, and begun
studies to phenotype individuals and mice born following IVF for diabetes and cardiovascular risk factors. This
CDA award enabled me to focus solely on research during this time. During my CDA, I completed my first
NHMRC project grant as CIA to examine the effects of high fat overfeeding and insulin resistance in sex and
BMI matched individuals with and without a family history of type 2 diabetes where I was directly responsible
for the budget, 2 staff members and a PhD candidate and had excellent research productivity with 27
publications. In Jan 2010, I transferred my research from Garvan Institute to the University of Adelaide where I
was appointed at Level D. The beginning of 2010 was spent setting up my research program and applying for
grants, of which I was succesful in obtaining a 2011 Royal Adelaide Hospital award, a 2012 NHMRC project
grant as CIA, as well as a 2012 DART and 2012 Channel 7 award.
Expected future outcomes:
My next NHMRC project award is due to start in October 2012. This study will compare the effects of periodic
fasting with and without energy restriction with continous energy restriction in humans, and am continuing my
work in hyperbaric oxygen therapy and characterising IVF born individuals.
Name of contact:
Leonie Heilbronn
Email/Phone no. of contact:
leonie.heilbronn@adelaide.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 490975
CIA Name: Dr Lisa Moran
Admin Inst: University of Adelaide
Main RFCD: Endocrinology
Total funding: $304,047
Start Year: 2008
End Year: 2012
Grant Type: Early Career Fellowships (Australia)
Title of research award:
The assessment and treatment of cardiovascular risk factors,diabetes and insulin resistance in Polycystic Ovary
SyndromeThe assessment and treatment of cardiovascular risk factors,diabetes and insulin resistance in
Polycystic Ovary Syndrome
Lay Description (from application):
Cardiovascular disease (CVD) and Type II Diabetes Mellitus (T2DM) are major health burdens in Australia.
T2DM is increased and CVD may be increased in polycystic ovary syndrome (PCOS), a condition present in
10% of women and 30% of obese reproductive aged women. We aim to explore risk factors for CVD and
T2DM in women with PCOS and to assess the effect of treatment strategies on metabolic and reproductive
features in PCOS. This is crucial for reducing disease risk in this common condition.
Research achievements (from final report):
The aim of this fellowship was the assessment and treatment of risk factors for cardiovascular disease (CVD)
and diabetes (DM2) in polycystic ovary syndrome (PCOS). PCOS is a very common condition affecting up to
1 in 5 women of reproductive age in Australia. It is associated with infertility, obesity, an increased risk of
DM2 and CVD and worsened psychological health. During my fellowship, I reported elevated levels in a
variety of novel markers for CVD in PCOS, namely asymmetric dimethylarginine (ADMA) and plasminogen
activator inhibitor-1 (PAI-1). I also reported that women with a newer 'milder' diagnosis of PCOS still present
with worsened blood vessel health, DM2 risk and anxiety. I additionally examined the effect of different
treatments on CVD and DM2 risk in PCOS. I reported that weight loss improved inflammation and blood
vessel function. Insulin sensitising drugs (such as metformin) or the oral contraceptive pill both improved CVD
and DM2 risk factors including PAI-1 and ADMA. However, the oral contraceptive pill was associated with
some deleterious effects on DM2 and CVD risk factors including worsened insulin resistance, inflammation
and glucose tolerance. I conducted evidence-based medicine including the first systematic literature review
examining the effectiveness of lifestyle treatments including diet and exercise on PCOS. This found lifestyle
treatment improved weight, reproductive hormones, excess hair growth and DM2 and CVD risk factors. I led
the development of NHMRC-approved evidence-based guidelines for the treatment of PCOS which reported
the importance of lifestyle treatment in conjunction with pharmacological and medical therapy for PCOS.
Expected future outcomes:
This research will contribute to the development of optimal screening and treatment strategies for DM2, CVD
and psychological dysfunction in PCOS. This research has already been incorporated in national NHMRCapproved evidence-based guidelines and will guide clinical practice.
Name of contact:
Lisa Moran
Email/Phone no. of contact:
lisa.moran@adelaide.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 519115
CIA Name: A/Pr Grigori Rychkov
Admin Inst: University of Adelaide
Main RFCD: Cell Physiology
Total funding: $516,553
Start Year: 2008
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
STIM1 and Orai1 proteins in store-operated calcium entry in liverSTIM1 and Orai1 proteins in store-operated
calcium entry in liver
Lay Description (from application):
The liver plays a central role in controlling vital functions of the body. Changes in calcium level in the liver
cells regulate most their functions, including fat and carbohydrate metabolism. There is ample evidence that
suggests that diseases such as fatty liver and cholestasis affect the control of calcium in the liver. This research
will investigate the mechanisms of calcium homeostasis in the liver and provide information for development
of new approaches for treating liver disease.
Research achievements (from final report):
Many cellular processes directly or indirectly depend on intracellular Ca2+ concentration and Ca2+-binding
enzymes. Specific responses to the rise in cytoplasmic Ca2+ depend on the amplitude of the rise in Ca2+, as
well as its duration, frequency, location and proximity of Ca2+ binding proteins. Sustained increases of
cytoplasmic Ca2+ beyond certain level are often toxic, as they initiate apoptosis or necrosis of the affected cell.
Consequently, Ca2+ must be tightly controlled through a range of Ca2+ channels, pumps, exchangers and
binding proteins. Our research investigates the mechanisms regulating the activity of a specific type of Ca2+
channels, CRAC channels, and their molecular components, Orai1, and STIM1 proteins, which are
ubiquitously expressed in animal cells. In the liver, activity of CRAC channels is essential for normal hepatic
responses to glucagon, insulin, and other hormones. In this project we identified novel mechanisms that
determine the amount of Ca2+ entering the cell through CRAC channels. These include regulation of CRAC
currents by intracellular and extracellular pH, specific amino residues in Orai1 and STIM1 proteins, and the
relative expression ratios of STIM1 and Orai1.
Expected future outcomes:
Results of the present research provide knowledge of the fundamental mechanisms of regulation of Ca2+
homeostasis, which is essential not only for its contribution to basic science but also for future control and
management of a range of diseases, and provide a foundation for identification of novel therapeutic targets in
abnormal Ca2+ signalling.
Name of contact:
Grigori Rychkov
Email/Phone no. of contact:
grigori.rychkov@adelaide.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 519245
CIA Name: Prof Jennifer Couper
Admin Inst: University of Adelaide
Main RFCD: Endocrinology
Total funding: $368,062
Start Year: 2008
End Year: 2011
Grant Type: NHMRC Project Grants
Title of research award:
Defining vascular health and modifiable risk factors over time in childhood.Defining vascular health and
modifiable risk factors over time in childhood.
Lay Description (from application):
Adult heart disease and strokes have their origin in childhood. We will follow healthy children and children
with diabetes or obesity over 2 years during puberty when blood vessel disease is detectable. We will define
which are the most sensitive markers of blood vessel disease and the continuum of risk factors. This is essential
knowledge to best define children at risk and to test clinical and public health interventions.
Research achievements (from final report):
Not Available
Expected future outcomes:
N/A
Name of contact:
Professor Jennifer Couper
Email/Phone no. of contact:
jennifer.couper@adelaide.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 565319
CIA Name: Dr Elizabeth Beckett
Admin Inst: University of Adelaide
Main RFCD: Gastroenterology
Total funding: $386,104
Start Year: 2009
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
Involvement of interstitial cells of Cajal in the pathogenesis of diabetic gastroparesisInvolvement of interstitial
cells of Cajal in the pathogenesis of diabetic gastroparesis
Lay Description (from application):
Diabetics commonly suffer from gastrointestinal symptoms such as bloating and nausea. We have preliminary
evidence that interstitial cells of Cajal (ICC), which are essential for normal gut motility, are particularly
vunerable to damage in diabetes. The goal of this study is to determine how the loss of ICC in diabetes leads to
delayed gastric emptying. Our overall aim is to identify potential therapeutic targets for improved treatment of
diabetes-related gastrointestinal motility disorders.
Research achievements (from final report):
This research award from the NHMRC has enabled a thorough and detailed investigation into the
pathophysiological basis for the disordered gastrointestinal function that commonly accompanies longstanding
diabetes mellitus. A murine model exhibiting obesity and chronically elevated blood sugar levels was utilised
to determine which regions of the gastrointestinal tract are most severely affected by this condition, and the
nature of the deficits present. Our experiments examined differences between non-diabetic and normal control
animals at the level of the whole animal, isolated gastrintestinal tissues, through to a detailed examination of
changes at the cellular and molecular level. In contrast to previously published findings from other research
groups using similar strains of mice, the deficits in pacemaking activity, motor neurotransmission and cellular
deficits were found to be subtle and the variability between animals in the diabetic population considerable,
with some animals exhibited irratic motility patterns and disrupted neural and ICC populations, whilst the
agstrointestinal tracts of others were not significantly altered by the diabetic condition.
Expected future outcomes:
These studies have been presented at international conferences and are currently being prepared for publication
as journal articles. Information attained from these studies will add to the body of knowledge in this field and
likely assist with the development of new targeted therapies for the gastrointestinal motility disorders that
commonly accompany longstanding diabetes mellitus.
Name of contact:
Elizabeth Beckett
Email/Phone no. of contact:
elizabeth.beckett@adelaide.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 570109
CIA Name: Prof Maria Makrides
Admin Inst: University of Adelaide
Main RFCD: Nutrition and Dietetics
Total funding: $1,462,626
Start Year: 2009
End Year: 2013
Grant Type: NHMRC Project Grants
Title of research award:
Effect of prenatal n-3 long chain polyunsaturated fatty acids on body mass in early childhoodEffect of prenatal
n-3 long chain polyunsaturated fatty acids on body mass in early childhood
Lay Description (from application):
In Australia more than 1 in 5 four year-olds are now classified as overweight. There is good evidence that
omega-3 fats inhibit the early development of fat cells and thereby reduce the later accumulation of excess
body fat. This will be the first human trial to examine whether an increased supply of low cost omega 3 fats in
pregnancy can reduce fatness and the likelihood of developing type II diabetes in childhood.
Research achievements (from final report):
The rising prevalence of overweight and obesity is a major public health concern for Australia now and for the
future. Up to 30% of Australian children and adolescents are overweight and in the last 10 years, the
prevalence of childhood overweight/obesity has increased 2-3 fold. Importantly, there is a clear tracking of
obesity risk and associated diseases across the life course, and increased accumulation of body fat in infancy
and early childhood is a major risk factor for obesity in adult life. It is therefore clear and widely recognised
that strategies which reduce the deposition of adipose tissue in early life are essential in order curb the rising
incidence of obesity. Despite this recognised need, there have been virtually no studies which have attempted
to investigate and validate such strategies. This is the largest study to date to investigate the hypothesis that
maternal n-3 Long Chain Polyunsaturated Fatty Acids (LCPUFA) supplementaion during pregnancy can
reduce the accumulation of body fat and lower the risk of dibaetes in their child. This study has the potential to
be the first to identify an effective and feasible intervention which can be applied during pregnancy in order to
reduce obesity risk and improve metabolic health in children at a population level.
Expected future outcomes:
This study has the potential to be the first to identify an effective and feasible intervention which can be
applied during pregnancy in order to reduce obesity risk and improve metabolic health in children at a
population level.
Name of contact:
Beverly Muhlhausler
Email/Phone no. of contact:
beverly.muhlhausler@adelaide.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 626977
CIA Name: A/Pr Nam Nguyen
Admin Inst: University of Adelaide
Main RFCD: Nutritional Physiology
Total funding: $444,087
Start Year: 2010
End Year: 2013
Grant Type: NHMRC Project Grants
Title of research award:
Effects of gastric bypass and banding for obesity on gastrointestinal function, body weight, glycaemia and
symptomsEffects of gastric bypass and banding for obesity on gastrointestinal function, body weight,
glycaemia and symptoms
Lay Description (from application):
The increasing incidence of obesity poses a significant impact on the health care system. Bariatric surgery not
only achieves sustained weight loss but also reverses the associated complications. This proposal aims to
examine the mechanisms that mediate weight loss, improvement in blood glucose control and symptoms after
bariatric surgery. The results will provide insights into future development of minimally invasive interventions
for the management of obesity and diabetes.
Research achievements (from final report):
Our studies indicate that Roux-en-Y gastric bypass induces substantially greater weight loss and resolution of
comorbidities than that of gastric banding at intermediate and long-term follow-up, in keeping with the data
from US and Europe, and confirming that RYGB is a more effective bariatric procedure for morbid obesity.
Since these data were presented at local and international meetings, the number of gastric banding performed in
Adelaide has been reduced, with more younger bariatric surgeons are willing to learn and perform RYGB in
Adelaide. We have also demonstrated for the first time that rapid transit of nutrients to the distal intestine after
RYGB is the major determinant for the post-prandial exaggerated GLP-1 responses, improvement in glycemia
and weight loss. , Furthermore, we have identified that posture, but not meal volume, has a major impact on the
rate of gastrointestinal transit of meal after RYGB, which in turn, lead to changes to blood glucose, blood
pressure, heart rate and meal related symptoms. Thus, in RYGB patients who have significant dumping
syndrome, consuming meal at supine or semi-supine position may minimize the symptoms and improve quality
of life, a relationhsip which was found to be closely related in our survey. In contrast to healthy and diabetic
subjects, consuming whey protein 30 minutes prior to main meal in RYGB subjects did not reduce postprandial blood glucose, haemodynamics or meal related symptoms.
Expected future outcomes:
The superior outcomes of RYGB over LAGB for weight reduction and co-morbidities resolution suggest that
RYGB should be the procedure of choice, and it is expected that these results will change the pattern of choice
for bariatric surgery in Australia over the next few years.
Name of contact:
A/Prof Nam Nguyen
Email/Phone no. of contact:
quoc.nguyen@health.sa.gov.au
NHMRC Research Achievements - SUMMARY
Grant ID: 627123
Start Year: 2010
CIA Name: Dr Kathryn Gatford
End Year: 2012
Admin Inst: University of Adelaide
Grant Type: NHMRC Project Grants
Main RFCD: Foetal Development and Medicine
Total funding: $760,612
Title of research award:
Preventing impaired beta-cell plasticity, insulin secretion and diabetes after IUGRPreventing impaired beta-cell
plasticity, insulin secretion and diabetes after IUGR
Lay Description (from application):
Babies who are born small are at increased risk of later diabetes, partly because restricting growth before birth
also impairs development of insulin-secreting cells in the pancreas, impairing later insulin secretion and
contributing to diabetes. We will define the mechanisms underlying impaired insulin secretion in a wellestablished animal model of fetal growth restriction. Importantly, we will also test interventions to improve
insulin secretion after intrauterine growth restriction.
Research achievements (from final report):
In our first aim, we have tested whether, and how, poor gowth before birth reduces the capacity of the insulinsecreting beta-cells to make more insulin when challenged. Analyses so far suggest that those who grew poorly
before birth are less able to maintain control of glucose when challenged, despite making MORE insulin,
suggesting that reduced insulin sensitivity places greater demands on the pancreas in these individuals. We
have also conducted novel studies of effects of restricted growth before birth on postnatal immune function,
cardiovascular function and learning in these animals, with the aim of validating an animal model to allow
many effects of different treatments for the growth-restricted individual to be measured, in addition to effects
on insulin action and glucose tolerance. In the second aim of this project, we have also evaluated two
interventions, one in pregnancy and one in early life, designed to improve adult metabolic health and prevent
diabetes in those who grew poorly before birth. Treating growth-restricted newborns for 16 days with the drug
exendin-4, used in diabetics to increase insulin secretion, reduced the excess fat deposition that normally
occurs shortly after birth in these individuals. We have now generated a cohort of animals including
unrestricted control, untreated growth-restricted animals, growth-restricted exendin-4-treated animals and
growth-restricted animals whose mothers were fed methyl donors in late pregnancy. Adult studies are being
completed in parallel with animals in NHMRC project 1011767, and analyses of glucose tolerance, insulin
secretion and insulin sensitivity will be complete by the end of 2013.
Expected future outcomes:
These studies will improve our understanding of how poor growth before birth increases the risk of diabetes in
later life, especially why adaptation of the pancreas to make more insulin appears to be impaired. We will also
have tested two different intervention approaches to improve long-term health in these individuals.
Name of contact:
Dr Kathryn Gatford
Email/Phone no. of contact:
kathy.gatford@adelaide.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 627127
CIA Name: Dr Richard Young
Admin Inst: University of Adelaide
Main RFCD: Nutritional Physiology
Total funding: $425,133
Start Year: 2010
End Year: 2013
Grant Type: NHMRC Project Grants
Title of research award:
Glucose detection pathways in the gutGlucose detection pathways in the gut
Lay Description (from application):
Glucose is a critical fuel for living organisms and its presence in the gut triggers nerves that slow stomach
emptying. However, little is known of how glucose is actually detected in the gut. We have established that
sweet taste molecules of the tongue are also present in the gut, where they may detect glucose. This research
will measure the expression and function of these molecules in the gut of humans and mice, and reveal key
information on their potential as targets in health and disease.
Research achievements (from final report):
This research has shown that a novel glucose sensor in the human intestine, the sweet taste receptor (STR), is
tightly controlled according to blood glucose and dietary glucose in human health. In contrast, intestinal STRs
were abnormally controlled in type 2 diabetic patients in association with enhanced glucose absorption - a
defect that may worsen blood glucose control and progress diabetic disease. , My work also showed that
dietary exposure to an artificial sweetener increased the levels of an intestinal glucose transporter (SGLT-1)
and glucose absorption in mice, an effect that was absent in mice lacking STRs. These data suggest that intake
of artificial sweeteners, while beneficial in reducing energy intake, may worsen overall blood glucose control
in individuals. , I showed that defects in intestinal STRs and glucose transporters were evident both in critically
ill patients and in a mouse model of critical illness - both in association with glucose malabsorption. This was
the first study to examine the molecular mechanisms of disordered nutrient absorption during critical illness, a
key determinant of clinical outcome., I also provided new information on how the intestine sends information
on dietary nutrients to the central nervous system via specific nerve pathways, and on the cell types that
express STRs in the human intestine. This work was presented as awarded oral presentations at national and
international meetings, in media and published in lead journals.
Expected future outcomes:
This work is leading to new understanding of the role of intestinal STRs in human health and disease. It will
also provide inputs into new therapies to optimise blood glucose control and nutrient delivery in patients with
type 2 diabetes and critical illness.
Name of contact:
Dr Richard L Young
Email/Phone no. of contact:
richard.young@adelaide.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 627139
CIA Name: A/Pr Christopher Rayner
Admin Inst: University of Adelaide
Main RFCD: Gastroenterology and Hepatology
Total funding: $780,873
Start Year: 2010
End Year: 2013
Grant Type: NHMRC Project Grants
Title of research award:
Upper gastrointestinal function and glycaemic control in diabetes mellitusUpper gastrointestinal function and
glycaemic control in diabetes mellitus
Lay Description (from application):
There is now increasing recognition that the stomach and intestines, by regulating the absorption of nutrients
into the body and by releasing hormones that enhance insulin secretion, play a central role in the control of
blood glucose in diabetes mellitus. We seek to understand the nature and causes of disturbed gut function in
diabetes, so that we can optimise dietary and drug strategies to prevent and treat this condition.
Research achievements (from final report):
Key insights derived from this Project Grant are that:(i) The rate at which meals empty from the stomach varies
considerably between individuals with diabetes, but remarkably little within individuals when followed over a
period of ~25 years. Stomach emptying is an important determinant not just of blood glucose control after
meals, but of how well different diabetes drugs work. (ii) The rate of emptying of carbohydrates from the
stomach into the small intestine is of critical importance on determining the release of the 'incretin' hormones
that control insulin release and blood glucose levels after meals.(iii) 'Sweet taste receptors' in the small intestine
play an important role in triggering hormone release that controls blood glucose after a meal in humans, but
stimulating these receptors with artificial sweeteners is not sufficient to release these hormones in humans.(iv)
Dietary approaches to lower blood glucose responses after meals may be a useful adjunct to the use of drugs
called 'DPP-4 inhibitors' in managing diabetes.(v) Bile, secreted into the small intestine in response to meals,
not only aids digestion but potentially plays a key signalling role in blood glucose control.
Expected future outcomes:
(i) Gut function will increasingly be seen as being a fundamental determinant of blood glucose control and of
the response to treatments for diabetes, and (ii) manipulation of gut function by dietary approaches, alone or in
combination with drugs, should be further developed as a novel approach to diabetes.
Name of contact:
A/Prof Chris Rayner
Email/Phone no. of contact:
chris.rayner@adelaide.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 627227
Start Year: 2010
CIA Name: Prof Gary Wittert
End Year: 2012
Admin Inst: University of Adelaide
Grant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $1,817,271
Title of research award:
Effect of sex steroids, inflammation, environmental and biopsychosocial factors on cardiometabolic disease
risk in menEffect of sex steroids, inflammation, environmental and biopsychosocial factors on cardiometabolic
disease risk in men
Lay Description (from application):
Heart disease is more frequent and occurs at an earlier age in men than women. The reason is unknown. Apart
from obesity and associated disturbances of metabolism, changes in sex hormones such as testosterone,
together with the effects of inflammation may be important, and may in turn be affected by environment,
lifestyle behaviours, and stress. To untangle these relationships, we will use cutting edge technology, in a large
sample of men, in partnership with other international scientists.
Research achievements (from final report):
1.A decreased levels of the male hormone testosterone with increasing age is not due to ageing as such but
rather reflects the burden of disease, particularly obesity. When fat mass decreases testosterone levels increase.
Significance: A low testosterone level should not be attributed to age and reflexively treated with testosterone.
Rather detect and treat obesity and associated chronic disease with a lifestyle modification program., 2. Sex
hormone binding globulin (SHBG), a protein, made in the liver, carries testosterone in the blood. A low level is
associated with obesity and insulin resistance but it is not a risk factor for type 2 diabetes whereas low
testosterone is an independent risk factor. Significance: NHMRC funded clinical trial to determine in men aged
50+ with prediabetes, whether testosterone together with a lifestyle program prevents the progression to
diabetes over and above lifestyle program alone., 3. Lower urinary tract symptoms (LUTS) (waking to pass
urine, frequency, and urgency) are common but not an inevitable part of ageing. They share risk factors with
diabetes and cardiovascular disease in particular obesity, obstructive sleep apnoea, high blood pressure,
depression and lack of physical activity. These symptoms improve or even resolve with correction of risk
factors. Significance: when LUTS are present don't just assume it is due to ageing or the prostate; think beyond
the prostate., 4. Obstructive sleep apnoea is common affecting 52% of men aged 40+ and is moderately severe
or severe in 25%. The associated comorbidities occur independent of the presence of sleepiness.
Expected future outcomes:
1. Relative contributions of sleep disorders, stress, obesity, lifestyle, low testosterone and inflammation to
incident diabetes and cardiovascular disease , 2. Sleep disorders: (i) relationship to sex hormones, disease risk;
(ii) improved clinical algorithms for screening, 3. Relationships between urinary BPA and or phthalate levels,
endocrine status and disease risk.
Name of contact:
Prof Gary Wittert
Email/Phone no. of contact:
gary.wittert@adelaide.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1009002
CIA Name: Prof Shaun McColl
Admin Inst: University of Adelaide
Main RFCD: Cellular Immunology
Total funding: $514,041
Start Year: 2011
End Year: 2013
Grant Type: NHMRC Project Grants
Title of research award:
The role of CCR6 in IL-17-producing CD8+ T lymphocyte activation and traffickingThe role of CCR6 in IL17-producing CD8+ T lymphocyte activation and trafficking
Lay Description (from application):
T lymphocytes play an important role in the control of infection, but can also contribute to diseases such as
autoimmune disease and cancer. This research will identify the function of a new subtype of T lymphocyte and
determine whether inhibiting its function prevents disease.
Research achievements (from final report):
The research conducted in this project has resulted in several discoveries relating to the basic function of the
immune system. We have identified a new subset of CD8+ T cells that secrete high levels of the proinflammatory cytokine IL-17. We believe that they function in a helper capacity, by providing large quantities
of IL-17 to drive inflammation during immune responses against intracellular infectious agents. In addition, we
are investigating the biological function of CCR6 on these IL-17-producing, CD8+ T cells, particularly on the
role of CCR6 in their homing to sites of antigen deposition. , We have discovered a novel regulatory function
of CD8+ T cells during immune priming. Under priming conditions in which the level of IFN? is low, CD8+ T
cells drive expression of high levels of CCR6 expression on CD4+ T cells via surface expression of TGF?. This
observation not only sheds light on the functional regulation of CCR6 on T cells during immune priming, it
demonstrates novel CD4 and CD8+ T cell collaboration during priming and identifies a novel regulatory
function of CD8+ T cells with respect to programming CD4+ T cell migratory capacity. , We have discovered
a novel role for CCR6 in the regulation of the germinal centre reaction. Deletion of CCR6 results in accelerated
formation of germinal centres, increased levels of antibody, but antibodies of lower affinity than WT mice.
Expected future outcomes:
The research into these areas is ongoing. We have identified a number of novel lymphpcyte subsets based on
their expression of specific chemokine recptors. In the future, we believe this will allow us to more speifically
control the immune response which will be of enormous benefit for the treatment of a wide range of immunerelated pathologies.
Name of contact:
Shaun Mccoll
Email/Phone no. of contact:
shaun.mccoll@adelaide.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1011767
Start Year: 2011
CIA Name: Prof Julie Owens
End Year: 2013
Admin Inst: University of Adelaide
Grant Type: NHMRC Project Grants
Main RFCD: Foetal Development and Medicine
Total funding: $923,511
Title of research award:
Preventing insulin resistance and obesity following fetal growth restrictionPreventing insulin resistance and
obesity following fetal growth restriction
Lay Description (from application):
Babies who are born small are at increased risk of diabetes and obesity in later life, partly because restricting
growth before birth decreases the insulin sensitivity of muscle and diverts nutrients to fat deposition. We will
define the mechanisms underlying impaired insulin sensitivity in fetal growth restriction. Importantly, we will
also test interventions to improve insulin sensitivity after intrauterine growth restriction.
Research achievements (from final report):
Insulin resistance and related disorders, including obesity and Type 2 diabetes mellitus (T2DM), are epidemic
in Australia and internationally. Low birth weight is one of the largest risk factors, accounting for at least 18%
of the prevalence of T2DM, with its associated catch-up growth adding further to susceptibility, by inducing
obesity. These disorders are now appearing at earlier ages and in children; prevention or early intervention is
therefore essential. Intrauterine growth restriction (IUGR) is also associated with impaired neurological
development and cognition, but in contrast with metabolic outcomes, infant catch-up growth predicts
improvements in these. Optimally, interventions should prevent the adverse consequences of IUGR and catchup growth for insulin resistance and obesity, whilst preserving beneficial cognitive outcomes of catch-up
growth. We have developed a novel approach to assessment of plasticity of insulin action, identified muscle as
the initial site of insulin resistance following IUGR and the molecular changes responsible and shown directly
that experimental IUGR and catch-up growth affect behaviour and learning. Importantly, pharmacological
intervention with a GLP-1 analogue in the IUGR neonate limits catch-up growth, onset of obesity and increases
production of insulin. Because inflammation may be a common feature of these altered outcomes following
IUGR, we examined immune function and found that IUGR may suppress inflammatory responses in skin,
without impairing other aspects of function.
Expected future outcomes:
Future outcomes will include delineating the impact of maternal or neonatal methyl nutrient supplementation or
other treatments in IUGR on glucose control, insulin action, obesity and cognitive function and behaviour in
later life.
Name of contact:
Julie Anne Owens
Email/Phone no. of contact:
julie.owens@adelaide.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 145670
Start Year: 2001
CIA Name: Prof Stephen Davis
End Year: 2002
Admin Inst: University of Melbourne
Grant Type: NHMRC Project Grants
Main RFCD: Neurology and Neuromuscular Diseases
Total funding: $278,418
Title of research award:
The Adverse Effects of Diabetes on Stroke: An Echoplanar MRI StudyThe Adverse Effects of Diabetes on
Stroke: An Echoplanar MRI Study
Lay Description (from application):
Stroke is the most common, major brain disease in Australia. It is the third most common cause of death and
the most common cause of adult disability. There is a close link between diabetes and stroke. Firstly, diabetes
is an important risk factor for the development of stroke. Secondly, about one third of stroke patients have
diabetes. In general, their outcome is much worse than other patients. In fact little is known about the cause of
this adverse effect in stroke patients and there is uncertainty whether intensive control of blood sugar in acute
stroke improves outcome. Our pilot work suggests that raised brain lactate, together with larger stroke size,
might together be responsible for the worse outcome in diabetic patients. We can now measure brain lactate
and stroke size with new MRI techniques called echoplanar MRI, which can allow measurements of brain
chemistry, blood flow, potentially viable and dead tissue. A new monitoring device allows non-invasive
measurement of blood sugar every 5 minutes. Using these strategies, we are planning a comprehensive study
of the causes of the worse stroke outcome with diabetes. In addition, we are incorporating a study to determine
whether intensive control of blood sugar in the first 3 days after stroke, compared with standard treatment,
reduces brain lactate and growth of the actual stroke. An understanding of these effects will have important
implications for the acute treatment of stroke patients. If we can show that rigorous control of blood sugar
reduces brain lactate and stroke growth, our study will lay the ground work for a large clinical trial. This could
have important implications, both in Australia, and overseas.
Research achievements (from final report):
This body of work has demonstrated that acute hyperglycemia in stroke is an independent predictor of adverse
outcome, has shed new light on the mechanisms and duration of hyperglycemia and indicated the importance
of a specific cerebral location in its pathogenesis. We have shown that the duration of post-stroke
hyperglycemia is independently associated with infarct expansion and worse clinical outcome. Major original
contributions include the demonstration that frequent measures of tissue glucose, every 5 minutes, over the first
72 hours after onset provide more robust correlations with infarct volume changes, final infarct size and
clinical outcome. These serial changes are superior to single glucose estimations. This is the first report of
continuous glucose monitoring after stroke. In a separate study we have been the first to show that a specific
cerebral location, namely the insular cortex, is an important and independent determinant of acute post-stroke
"stress hyperglycemia". We have postulated that insular ischemia produces neuroendocrine dysregulation as
part of a more generalised acute stress response. This has important implications for future studies of poststroke hyperglycemia. Our research has helped to elucidate the mechanism of the adverse effect of
hyperglycemia on clinical outcome, by increasing brain lactate production and factilitating conversion of
critically-hypoperfused at-risk brain tissue, in the ischemic penumbra, into frank infarction. We have also
shown the important contributions and interactions of both elevated hematocrit and elevated glucose in stroke
prognosis. Further research has been performed, analysing the prothrombotic state in the acutely ischemic
brain, incorporating measures of PAI-1 and other hematological determinants. Taken as a whole, the work on
hyperglycemia and acute stroke has been widely cited and we are acknowledged as one of the leading
international centres in this field.
Expected future outcomes:
This work indicates the importance of continuous glucose monitoring in acute stroke patients and supports the
hypothesis of normalisation of post-stroke hyperglycemia using intravenous insulin infusions. Positive results
of an on-going trial, testing whether intensive glucose normalisation modifies lactate generation and infarct
expansion, will help change clinical practice.
NHMRC Research Achievements - SUMMARY
Name of contact:
Professor Stephen Davis
Email/Phone no. of contact:
stephen.davis@mh.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 145769
CIA Name: Dr Sofianos Andrikopoulos
Admin Inst: University of Melbourne
Main RFCD: Endocrinology
Total funding: $212,485
Start Year: 2002
End Year: 2003
Grant Type: NHMRC Project Grants
Title of research award:
The role fructose-1,6-bisphosphatase on the regulation of hepatic gluconeogenesisThe role fructose-1,6bisphosphatase on the regulation of hepatic gluconeogenesis
Lay Description (from application):
Type 2 or adult onset diabetes is a disease characterised by high blood sugar that causes damage to the kidneys,
eyes and to the circulation and many patients die from heart attack or stroke. There is an increase in the
prevalence of diabetes in Australia and a substantial portion of the health budget is utilised by caring for people
with diabetes. Determining what exactly causes the increase in blood sugar levels is critical in the treatment of
the disease. It is known that the sugar produced and released by the liver is an important contributor to the high
blood sugar levels found in patients with diabetes. The main biochemical pathway responsible for this is called
gluconeogenesis, a complex arrangement of enzymes, which convert amino acids and fat into sugar. Although
it is known that this pathway is overactive in patients with diabetes, the exact reason for this is not clearly
understood. The aim of this proposal is to produce a transgenic mouse that has an increase in liver sugar
production as a result of an increase in gluconeogenesis, and to study its effects on blood sugar levels.
Furthermore, studies will be performed to understand the regulation of this pathway by infusing the transgenic
mice with insulin, the hormone that inhibits gluconeogenesis. The mechanism of action of insulin will be
determined by the measurement of key enzymes that regulate gluconeogenesis. The significance of this grant
is to identify possible sites for the development of new drugs or gene therapy that will lead to a decrease in the
production of sugar by the liver. This will lead to better control of blood sugar levels and slow down or even
prevent the onset of diabetes complications.
Research achievements (from final report):
Type 2 diabetes is characterised by an increase in blood sugar levels which over time has detrimental effects on
the health of the patients compromising kidney and eye function and contributing to an increase in the risk of
heart disease and stroke. Thus understanding the reason that blood sugar levels are increased in Type 2 diabetes
is crucial in the management of this disease. Research has shown that a biochemical pathway in the liver called
gluconeogenesis, which produces sugar, is overactive and contributes to the high sugar levels in patients with
diabetes. Furthermore our group has shown that an enzyme in gluconeogenesis called FBPase is increased in
animal models of Type diabetes and that this may be the reason for increased sugar production. The of this
project was to generate a transgenic mouse that overexpressed the human form of FBPase in the liver, to
determine whether this genetic alteration will lead to increased gluconeogenesis and eventually diabetes.
During the course of this project we cloned the human FBPase gene, inserted it into a vector and generated
liver FBPase transgenic mice. Over the last 10 months we have been studying the physiological outcomes of an
increase in liver FBPase, with the suggestion that it results in an increase in sugar production. If this transgenic
mouse develops increased sugar production it will identify FBPase as a potential therapeutic target for the
development of drug therapy for patients with Type 2 diabetes.
Expected future outcomes:
Interventions decreasing blood sugar levels are very important in reducing the risk of death from heart attacks
and stroke in Type 2 diabetes. This project has the potential of showing whether an enzyme, called FBPase,
involved in sugar production can be a potential therapeutic target for the development of drug compounds
which would be beneficial in patients with Type 2 diabetes.
Name of contact:
Sofianos Andrikopoulos
Email/Phone no. of contact:
NHMRC Research Achievements - SUMMARY
sof@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 156703
CIA Name: Prof Frank Alford
Admin Inst: University of Melbourne
Main RFCD: Endocrinology
Total funding: $347,037
Start Year: 2001
End Year: 2003
Grant Type: NHMRC Project Grants
Title of research award:
Comparison between AICAR and exercise-induced stimulation of skeletal muscle AMP-K on fat/glucose
metabolism in diabetesComparison between AICAR and exercise-induced stimulation of skeletal muscle
AMP-K on fat/glucose metabolism in diabetes
Lay Description (from application):
Background and Rationale: Exercise is important in the life of the diabetic. In well controlled diabetes, the
rates of whole body sugar usage and energy production in skeletal muscle (SkM) in response to acute exercise
are similar to non-diabetics. However in diabetics, little information is available as to how SkM processes
sugar and produces energy during exercise. Insulin controls SkM sugar and energy processing in sedentary
subjects. During exercise, these processes are controlled by non-insulin factors. The chemical catalyst AMP
activated protein kinase (AMP-K), which has been investigated only in normal exercising rats, is an important
alternative regulator of acute sugar processing and energy supply for exercising SkM. No studies of AMP-K
activity are available in diabetes. Our studies will focus on i) how important is the stimulation of SkM AMP-K
in diabetes to efficient SkM sugar processing and energy production; ii) if the benefits of exercise can be
simulated by pharmacological stimulation of AMP-K in sedentary diabetic subjects. We aim to i) compare the
metabolic effects of exercise vs pharmacological stimulation of AMP-K in normal and diabetic subjects; ii)
define the molecular mechanisms which trigger the AMP-K metabolic responses; iii) determine if the
circulating levels of insulin, blood sugar and/or blood fat influence the AMP-K metabolic responses. Likely
Outcomes: pharmacological stimulation of AMP-K will improve SkM sugar metabolism, but less so in
diabetes. The associated AMP-K stimulation of SkM fat metabolism may blunt the beneficial SkM sugar
responses, particularly in diabetes. This information will be used in future drug developments for diabetics
which aim to simulate the beneficial AMP-K metabolic effects of exercise.
Research achievements (from final report):
Exercise favourably impacts on glucose and fat metabolism, promoting oxidation or burning of glucose and fat
via activation of a specialised muscle enzyme or catalyst, AMP-activated protein kinase (AMPK). This may
lead to a reduction of the patients' medications required to achieve good control of diabetes, or even prevent
emergence of the disease. However effective long term exercise programs are difficult to maintain in a
community. Our research examined whether administration of a chemical agent (AICAR), which substitutes
for the "natural" activator of AMPK, could mimic the metabolic benefits of exercise-induced activation of
AMPK. In normal subjects: AICAR administration increased AMPK-stimulated utilisation of glucose (sugar)
and fat by muscle, but glucose was metabolised (burnt) predominantly via the non-oxidative low energy output
pathway and tissue fat oxidation (burning) was sourced from the bloodstream. The increased muscle utilisation
of glucose was matched by an increase in liver glucose output. When tissue fat oxidation was blocked prior to
AICAR, muscle glucose utilisation was further increased, again via the non-oxidative low energy output
pathway. These metabolic responses are different from those seen when the same subject is exercised, glucose
being burnt in muscle only via the high energy oxidative pathway and the increased fat oxidation being derived
from the body's fat stores. In contrast, in poorly controlled diabetes, fasting muscle AMPK activity status is
increased and fails to rise further with exercise. Also AICAR alone and AICAR + fat oxidation blockade in the
diabetic caused a significant fall in blood glucose levels, not via improved muscle glucose or fat burning, but
via a reduced output of glucose from the liver. Thus, these metabolic responses in muscle to AICAR did not
mimic the positive metabolic health responses of exercise and were different in the diabetic state compared to
normals.
Expected future outcomes:
AICAR or other chemical agents that appear to mimic the exercise-induced activation of the key physiological
regulator (AMPK) of the exercise metabolic responses are unlikely to be effective substitutes for exercise,
NHMRC Research Achievements - SUMMARY
especially in diabetics. Clearly exercise provides multiple beneficial effects on glucose and fat metabolism,
other than those produced by activation of the AMPK pathway alone.
Name of contact:
Prof Frank Alford
Email/Phone no. of contact:
frank.alford@svhm.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 188826
CIA Name: Dr Adamandia Kriketos
Admin Inst: University of Melbourne
Main RFCD: Endocrinology
Total funding: $425,000
Start Year: 2002
End Year: 2009
Grant Type: Career Development Fellowships
Title of research award:
Understanding the molecular mechanisms of the development of the Insulin Resistance Syndrome - from the
laboratory to thUnderstanding the molecular mechanisms of the development of the Insulin Resistance
Syndrome - from the laboratory to th
Lay Description (from application):
Not Available
Research achievements (from final report):
This Career Development Award was beneficial to the postdoctoral career of Dr Adamandia Kriketos. She was
able to conduct clinical research in the area of type 2 diabetes. In particular, her work investigated the role of
family history on the development of insulin resistance and the risk of developing type 2 diabetes. Following a
relocation to Melbourne, Dr Kriketos was able to conduct clinical research in the area of obesity (weight loss
and weight regain) using the clinical research skills she had acquired in the earlier stages of the CDA at the
Garvan Institute in Sydney.
Expected future outcomes:
Findings from this research are currently being further investigated in a NHMRC Project Grant examining the
roles of cytokines and hormones in weight regain following weight loss.
Name of contact:
Dr Adamandia Kriketos
Email/Phone no. of contact:
a.kriketos@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 208940
CIA Name: Prof Mark Cooper
Admin Inst: University of Melbourne
Main RFCD: Endocrinology
Total funding: $210,990
Start Year: 2002
End Year: 2004
Grant Type: NHMRC Project Grants
Title of research award:
Characterisation of Novel AGE Binding Proteins: Implications for Diabetic Vascular
Complications.Characterisation of Novel AGE Binding Proteins: Implications for Diabetic Vascular
Complications.
Lay Description (from application):
This project will explore a process known as advanced glycation and in particular how this may lead to organ
injury in diabetes. Diabetes is characterised by sustained elevation of blood glucose levels which interact with
proteins to generate products known as advanced glycation end-products (AGEs). These AGEs bind to other
proteins some of which have been isolated and are considered receptors. Our own group has identified a new
family of proteins known as ERM proteins which bind to AGEs. This is a highly novel finding which now
needs to be examined in more detail. The ERM proteins which include ezrin, radixin and moiesin are found at
many sites of diabetic complications including the kidney, retina and blood vessel wall. They have a number
of functions including effects on cell adhesion and cell structure. This is important in diabetes where changes
in cells including altered structure have been observed. This grant will characterise the interactions between
AGEs and ERM proteins at the molecular and cellular level. It will define how AGEs influence cells via
interactions with ERM proteins. These studies have the potential to lead to treatments that may modulate the
AGE/ERM interactions, thereby retarding or preventing diabetic vascular complications. These complications
are of important clinical significance since they are the major cause of morbidity and mortality in the diabetic
population. Furthermore, diabetes is a major cause of premature atherosclerosis in our community, diabetic
kidney disease is the leading cause of end-stage renal failure in the Western world and diabetic retinopathy
(eye disease) is the main cause of blindness in the working age population.
Research achievements (from final report):
We have identified a novel interaction between proteins which have been chronically modified by glucose and
specific proteins known as the ERM proteins. Studies have demonstrated that these ERM proteins may be
excellent targets for developing drugs that reduce diabetic complications. The experiments provide further
evidence for this possibility and strengthen the rationale for the strategy being developed as part of this project.
Expected future outcomes:
Generation of novel inhibitors of the glycated protein/ERM interaction can now be developed since the
molecular basis for this interaction has been further clarified in these experimental studies.
Name of contact:
Leon Bach
Email/Phone no. of contact:
leon.bach@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 208945
CIA Name: Dr Sofianos Andrikopoulos
Admin Inst: University of Melbourne
Main RFCD: Endocrinology
Total funding: $406,980
Start Year: 2002
End Year: 2004
Grant Type: NHMRC Project Grants
Title of research award:
Investigation of the genetic basis of insulin hypersecretion in a mouse model of pancreatic islet
failureInvestigation of the genetic basis of insulin hypersecretion in a mouse model of pancreatic islet failure
Lay Description (from application):
Type 2 diabetes is a chronic disease that is associated with blindness, kidney failure, heart attacks and stroke
and these are secondary to high blood sugar levels. Thus, determining the cause of high blood sugar levels in
type 2 diabetes will lead to better management of the disease and ease the financial burden on the public health
system. High blood sugar in type 2 diabetes results from the inability of the body to secrete enough insulin.
Insulin is the main hormone that lowers blood sugar levels and is produced by the pancreas. The reason for
reduced insulin secretion in type 2 diabetes is not known. Paradoxically, it has been shown that some people
who are at an increased risk of developing diabetes (eg people with obesity or a family history of diabetes)
secrete more insulin than normal. It is not clear why this is, but a few studies have suggested that reducing
insulin secretion in these circumstances can protect the pancreas and preserve its ability to secrete the
appropriate amount of insulin. The DBA/2 is a mouse strain that like humans with type 2 diabetes, its pancreas
can also fail to secrete the appropriate amount of insulin and under these circumstances becomes diabetic.
Furthermore our laboratory has generated evidence that shows that like people who are at risk of diabetes,
DBA/2 mice in fact secrete more insulin prior to becoming diabetic. Whether the cause of this increased
insulin secretion is linked to the eventual reduction of secretion is not known. The aim of this study is to
identify the gene that causes increased insulin secretion in the DBA/2 mouse. Furthermore, genetically
manipulated animals will be produced that contain only this gene to determine its effect on insulin secretion.
Should the identification of this gene be related to the eventual failure of the pancreas to secrete enough
insulin, then it would provide a target for drug therapy to correct insulin levels and therefore reduce blood
sugar levels.
Research achievements (from final report):
Reduced secretion of the hormone insulin from the pancreas is the cause of high blood sugar levels in patients
with Type 2 diabetes. Paradoxically there is enough evidence to suggest that too much insulin secretion is
present in at least some patients who are at risk of developing with Type 2 diabetes and that it may contribute
to the eventual demise of the pancreas. The DBA/2 mouse is a model of reduced insulin secretion when
exposed to obesity/insulin resistance which, interestingly, secretes more insulin in the normal "non-stressed"
state. Furthermore we believe that this insulin hypersecretion is genetically determined in DBA/2 mice. With
support from this grant we have identified a gene , we have called Hip1, that is associated with insulin
hypersecretion, and that this gene is upregulated 5-fold in DBA/2 islets., , The significance of this work is that
Hip1 may provide a diagnostic tool for identifying subjects at risk of developing diabetes and also has the
potential of providing a target for the development of therapeutic agents for the prevention of diabetes in the
subsection of diabetes-prone subjects that hypersecrete insulin.
Expected future outcomes:
It is anticipated that future outcomes will be to determine the reason that Hip1 is induced in DBA/2 islets and
to determine whether subjects who are at risk of developing Type 2 diabetes also have increased Hip1
expression.
Name of contact:
Sofianos Andrikopoulos
Email/Phone no. of contact:
sof@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 208950
CIA Name: Dr Erica Fletcher
Admin Inst: University of Melbourne
Main RFCD: Sensory Systems
Total funding: $211,320
Start Year: 2002
End Year: 2004
Grant Type: NHMRC Project Grants
Title of research award:
TRAFFICKING OF METABOLITES BETWEEN M LLER CELLS AND NEURONS IN DIABETIC
RETINOPATHY.TRAFFICKING OF METABOLITES BETWEEN M LLER CELLS AND NEURONS IN
DIABETIC RETINOPATHY.
Lay Description (from application):
Diabetes is the leading cause of blindness in the working population. In some diabetics, blood vessels within
the retina proliferate, haemorrhage or cause retinal detachment. The underlying changes within the retina that
lead to the proliferation of blood vessels are not well understood. One of the factors that leads to changes in
retinal blood vessels is an incease in growth factors from cells in the retina called Muller cells. Muller cells
are vital for the normal function of the retina, and are known to be abnromal late in diabetes. They may also be
dysfunctional early in diabetes and could play a significant role in the early chnages seen in diabetes. Therefore
a good understanding of how Muller cells change and the time at which they change is vitally important to gain
a better undetrstanding of the defects that are associated with diabetes. Furthermore, an understanding of the
basic underlying cellular changes that occur in diabetes will aid the development of more specific therapeutic
agents in the future.
Research achievements (from final report):
The aim of this study was to characterize the role that supporting cells within the retina, called Muller cells,
play in diabetic retinopathy. We examined the changes in retinal function, turnover of neurotransmitter within
Muller cells and their metabolic coupling in an animal model of Type I diabetes. We found that the neurons
within the retina become abnormal before the first sign of vascular change and that the turnover of the
neurotransmitter, glutamate, by Muller cells is abnormal. Abnormalities in metabolic coupling, tested by
examining the trafficking of lactate between Muller cells and neurons was not seen. These findings are
important because they suggest that there are changes within the retina well b efore the onset of vascular
disease. If these are explored further, this may lead to better ways of detecting those at risk of developing
diabetic retinopathy.
Expected future outcomes:
We are continuing to explore the role of Muller cells in animal models of Type I diabetes. In particular we will
continue to explore why neurons and Muller cells are abnormal before the first vascular abnormalities develop.
Name of contact:
Erica Fletcher
Email/Phone no. of contact:
elf@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 209001
CIA Name: Prof Joseph Proietto
Admin Inst: University of Melbourne
Main RFCD: Endocrinology
Total funding: $412,200
Start Year: 2002
End Year: 2004
Grant Type: NHMRC Project Grants
Title of research award:
Investigation of transgenic mouse models of Type 2 diabetesInvestigation of transgenic mouse models of Type
2 diabetes
Lay Description (from application):
Type 2 diabetes is a common condition characterised by high blood glucose, that afflicts 700,000 Australians.
It causes blindness, kidney failure and an increased risk of heart attack and stroke. despite intensive study over
many years, the reasons for the elevated blood glucose in this condition are not fully understood. Several
abnormalities can contribute to the high glucose and different researchers have proposed different defects as
the initial cause. It has proven difficult to unravel the sequence of events in the evolution of the syndrome
because high glucose can cause insulin resistance and a defect in insulin secretion, both of which can lead to
high blood glucose. One approach to study the consequences of specific defects is to genetically engineer them.
The aims of this project are to: 1. make a mouse with reduced ability to store glucose in muscle. 2. test the
metabolic consequences of a defect in the manufacture of glycogen (starch) in muscle. 3. study the effects of
combining a defect in glucose storage with one that results in an oversupply of glucose. 4. study the effects on
a mouse with a genetic predisposition for failure of beta cells (insulin making cells) of a defect in muscle
glucose storage and over production of glucose. A successful completion of this grant will greatly enhance
our understanding of how blood glucose is increased in Type 2 diabetes.
Research achievements (from final report):
The aim of this project is to investigate the impact of a defect in the action of muscle glycogen synthase, ( the
enzyme that manufactures glycogen in muscle) on glucose metabolism. It is known that patients with type 2
diabetes have a defect in glucose storage in muscle. To achieve this aim we will delete the glycogen synthase
gene in the muscules of mice using a technique that can selectively delete genes in specific tissues. This is a
complex technique that requires the production of two lines of transgenic mice, one in which the wildtype
(normal) glycogen synthase gene has been replaced by a modified gene in which extra pieces of DNA have
been added to allow deletion of parts of it, and a second mouse line in which there is expressed a deleting gene
that is only active in muscle. Breeding the two mice together will make a third mouse line in which the target
gene and the cutting gene are both present. We have made the deleting mouse and the target mouse is being
made now. A second aim of this project is to determine the impact of other known abnormalities present in
diabetes such as increased glucose production and impaired insulin secretion when added to this defect. This
will be achieved by mating the glycogen synthase knockout mouse with mice that have the other two defects.
The major benefit of this study is that it may point to which defects are more important in the development of
type 2 diabetes and thus which make the best targets for therapy.
Expected future outcomes:
We will determine if the glycogen synthase defect included in adult mice will result in insulin resistance in
muscle. These mice will have little or no glycogen in muscle and the effect of this on exercise tolerence can
also be studied. The glycogen synthase target mice can also be used to delete glycogen synthase in other tissue
such as brain and fat cells.
Name of contact:
Joseph Proietto
Email/Phone no. of contact:
j.proiteeo@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 209026
CIA Name: Prof Mark Cooper
Admin Inst: University of Melbourne
Main RFCD: Nephrology and Urology
Total funding: $361,650
Start Year: 2002
End Year: 2004
Grant Type: NHMRC Project Grants
Title of research award:
Role of vasoactive hormones and cytokines in diabetic nephropathyRole of vasoactive hormones and cytokines
in diabetic nephropathy
Lay Description (from application):
Kidney disease is a major cause of disability and premature death in the Australian population. In diabetic
kidney disease a major factor which accelerates the progression of this disorder is the presence of hypertension.
Indeed international and national organisations now recommend aggressive blood pressure treatment in the
diabetic patient. This proposal aims to optimise blood pressure treatment in diabetes and evaluate novel more
potent blood pressure lowering agents which block within the kidney important hormonal pathways implicated
in diabetic kidney disease. This approach will assist in determining key factors which mediate the damage to
the kidney induced by elevated blood pressure. It is anticipated that these studies will lead to more rational,
targeted and powerful antihypertensive agents which will retard or prevent the development of diabetic
nephropathy.
Research achievements (from final report):
This study has identified new strategies to reduce diabetic complications, specifically renal disease. We used
various combination drugs which influence multiple hormone systems within the kidney and showed that these
newre agents were more effective than conventional treatments which block only one hormone pathway.
Furthermore, we identified new hormone pathways which appeared to be altered in the diabetic kidney and
provide new targets for better treatments to prevent, reverse and rertard diabetic kidney disease which is now
the leading cause of kidney failure in the Western world.
Expected future outcomes:
These new treatments will be tested in the clinic. Furthermore, the new targets identified such as ACE2 will be
further explored and potentially this could lead to new drugs for diabetic kidney disease.
Name of contact:
Prof Mark Cooper
Email/Phone no. of contact:
mark.cooper@baker.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 219170
CIA Name: Prof Richard Gilbert
Admin Inst: University of Melbourne
Main RFCD: Cellular Immunology
Total funding: $4,715,000
Start Year: 2002
End Year: 2006
Grant Type: International Collaborations
Title of research award:
Novel strategies for the early identification provention and treatment of the microvascular complications of
diabetesNovel strategies for the early identification provention and treatment of the microvascular
complications of diabetes
Lay Description (from application):
Despite recent advances, approximately one third of subjects with type 1 diabetes develop kidney disease and
similar proportion develop vision-threatening eye disease. Indeed, in many instances eye and kidney disease
occur in the same individual. The central aim of this proposed Special Program is the exploration of
mechanisms that lead to the development and progression of these devastating complications of type 1 diabetes
with a particular focus on novel strategies, directly applicable to man, for their prevention and treatment.
Participants in Special Program include both established diabetes researchers and investigators from other areas
of academia (blood vessel biology and applied genetics). Strong interrelationships between the various
investigators and their departments already exist and will be further consolidated with continued collaboration,
sharing a combination of models, novel interventions and complex genetic techniques that would not be
possible outside of a large collaborative framework. In addition to academic collaboration, interactions with
industry-based drug discovery programs is also an important component in developing new treatment strategies
for diabetic kidney and eye disease. The Special Program will thus consist of a range of studies of direct
relevance to diabetic kidney and diabetic eye disease in humans. It is expected that these studies will lead to
new strategies for the prevention, treatment and even the reversal of long term complications of diabetes.
Research achievements (from final report):
We have been exploring new approaches to the treatment of the longterm complications of diabetes. To do this
we needed an animal model that closely resembles humans with regard to the development of diabetes
complications. Having established such a model, then set about developing new therapies for their treatment.
During the period of this grant we have had some major successes with new drug and stem cell-based
treatments that we have shown reduce the development and progression of the complications of diabetes. A
small human trial exploring the effects of stem cell treatment has been completed and we are well undreway to
test our new drug treatments also.
Expected future outcomes:
We have continued to develop our discoveries and anticipate having a new therapy ready to be tested for the
treatment of diabetic kidney disease in humans sometime in the next 2-3 years.
Name of contact:
Prof. Richard Gilbert
Email/Phone no. of contact:
richard.gilbert@utoronto.ca
NHMRC Research Achievements - SUMMARY
Grant ID: 237033
CIA Name: Dr Amanda Edgley
Admin Inst: University of Melbourne
Main RFCD: Systems Physiology
Total funding: $552,051
Start Year: 2003
End Year: 2008
Grant Type: Early Career Fellowships (Australia)
Title of research award:
Targeting Obesity: manipulating metabolism using genetically modified miceTargeting Obesity: manipulating
metabolism using genetically modified mice
Lay Description (from application):
Not Available
Research achievements (from final report):
The industry component of the fellowship was undertaken at AstraZeneca Pharmaceuticals, Sweden, in the
Dept. of Integrative Pharmacology. During this period Dr Edgley entered into an entirely new area of research,
gaining experience in characterising metabolic disturbances in animal models of Type 2 diabetes, and
examining the properties of novel agents for correction of these metabolic disturbances. Specifically, she
developed techniques assessing fat and sugar use by the tissues in living mice. These techniques are restricted
to few groups around the world. In January 2006, Dr Edgley returned to the Dept. of Physiology at Monash
University to continue the academic portion of the fellowship. AstraZeneca continued to support Dr Edgleys
new research program by donating a equipment to facilitate studies of heart function in living mice. In January
2007, Dr Edgley moved to the Department of Medicine, St. Vincent's Hospital, joining the Diabetic
Complications group headed by Assoc. Prof. Darren Kelly. The Diabetic Complications group is actively
studying cardiac complications of diabetes at clinical and basic science levels, including in vivo studies of
cardiac function in diabetic patients and animal models, focussing on pre-clinical and early phase clinical drug
development. Since returning to Australia Dr Edgley has imported and bred a special colony of mice, that
spontaneously develop type 2 diabetes (the only colony of such mice in Australia), and developed techniques to
measure heart function in these mice and has successfully characterised reduced heart function in these mice,
similar to what is seen in human patients with diabetes.
Expected future outcomes:
We now have a well characterised model of obesity and type 2 diabetes with reduced heart function in our
mouse model, and are commencing studies to investigate the effect of novel agents in preventing the metabolic
changes and attenuating the reduced heart function
Name of contact:
Amanda Edgley
Email/Phone no. of contact:
aedgley@medstv.unimelb.edu.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: 251746
CIA Name: Dr Sofianos Andrikopoulos
Admin Inst: University of Melbourne
Main RFCD: Endocrinology
Total funding: $435,500
Start Year: 2003
End Year: 2007
Grant Type: Career Development Fellowships
Title of research award:
Investigating Insulin Secretory Dysfunction in Type 2 DiabetesInvestigating Insulin Secretory Dysfunction in
Type 2 Diabetes
Lay Description (from application):
Not Available
Research achievements (from final report):
Type 2 diabetes is a disease characterised by high sugar levels associated with a reduced in the levels of the
hormone insulin. The aim of this study was to determine the mechanism for this reduced production and
secretion of insulin in Type 2 diabetes. Using appropriate models with susceptibility to developing diabetes it
was found that one of the mechanisms for reduced insulin secretion was an increase in the detrimental
compounds called reactive oxygen species or ROS. These compounds are produced as a result of the normal
function of cells, however in diabetes there is an increase in ROS such that they reduce the amount of insulin
being produced and secreted. We showed that strategies that reduced the levels of ROS were associated with
better insulin release. Furthermore, we identified a gene associated with altered insulin secretion, called
nicotinamide nucleotide transhydrogenase (Nnt), which is involved in the production of ROS. We found that in
models that are susceptible to diabetes the levels of Nnt were increased leading to higher insulin secretion. This
increase in the ability to secrete more insulin and therefore produce was ROS may eventually lead to diabetes
by reducing the ability to secrete insulin. Our results suggest that therapies that stimulate secretion of insulin in
diabetes should be avoided.
Expected future outcomes:
It is expected that further insights into the mechanism by which an increased ability to secrete insulin may
contribute to diabetes will be made in the future. This has inplications for the treatment of patients with
diabetes as drugs that stimulate insulin secretion should be avoided in diabetes.
Name of contact:
Sof Andrikopoulos
Email/Phone no. of contact:
sof@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 299800
CIA Name: A/Pr Ulrike Grunert
Admin Inst: University of Melbourne
Main RFCD: Sensory Systems
Total funding: $367,500
Start Year: 2004
End Year: 2006
Grant Type: NHMRC Project Grants
Title of research award:
Synaptic connectivity of colour pathways in primate retinaSynaptic connectivity of colour pathways in primate
retina
Lay Description (from application):
The first step in the visual process occurs when light enters the eye and activates specialised nerve cells called
photoreceptors. The photoreceptors for daytime vision (called cones for their cone-like shape) comprise three
types, which are sensitive to the long- ("red"), medium- ("green") or short-wavelength ("blue") regions of the
visible spectrum. Although the properties of the cones are well known, the way in which they are functionally
connected to nerve pathways for vision is not clearly understood. Clinical research has shown that reduced
sensitivity to blue light is a feature of the early stages of certain visual diseases (for example, glaucoma), so it
is important to know how the short-wavelength ("blue") cones contribute to visual functions such as form,
motion and colour perception. Such knowledge can help to design better tests for diagnosis of visual disorders,
and will improve our understanding of the normal function of the visual system in the human brain. In this
project the connections of neurones in the primate retina (the nerve cells which line the back of the eye) will be
analysed. The blue cones and other nerve cells will be identified using contemporary anatomical methods
(double- and triple-label immunocytochemistry) combined with a new method for high-resolution light
microscopy, called deconvolution microscopy. Immunocytochemistry is a method borrowed from the field of
immunology, where specific antibodies are raised which bind selectively to "label" specific populations of
neurones. Deconvolution microscopy allows rapid and simultaneous visualisation of multiple labelled cell
classes, at a resolution close to the limit of the light microscope. Together, these techniques allow the "wiring
diagram" of the blue cones within the retina to be analysed to a higher level of accuracy than previously
achieved. The results will improve our understanding of the role of blue-cone circuits in normal vision and
visual disorders.
Research achievements (from final report):
We used high-resolution microscopy and new labelling methods to reveal the connection patterns of nerve
pathways for red-green and blue-yellow colour vision in the primate eye., These findings have helped us to
understand the basis of colour vision and the causes of colour blindness.
Expected future outcomes:
N/A
Name of contact:
Ulrike Grunert
Email/Phone no. of contact:
uhg@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 299862
CIA Name: A/Pr Barbara Coulson
Admin Inst: University of Melbourne
Main RFCD: Medical Virology
Total funding: $348,875
Start Year: 2004
End Year: 2006
Grant Type: NHMRC Project Grants
Title of research award:
Analysis of the role of rotavirus infection in development of type 1 diabetesAnalysis of the role of rotavirus
infection in development of type 1 diabetes
Lay Description (from application):
Our earlier studies in children with a family history of type 1 diabetes have shown that infection with a
common virus, rotavirus, may be one factor contributing to their progression to diabetes. Rotavirus is the most
common cause of diarrhoea, vomiting and dehydration in young children, and it was thought that rotavirus
infection is usually confined to the intestine. To understand how rotavirus infection might promote diabetes,
my group has developed a mouse model. Using mice for these studies allows us to control infection and
completely analyse the results of infection, which we cannot do in humans. A type of mouse that is very likely
to develop type 1 diabetes in its first 6 months of life is infected by mouth with rotavirus. We have shown that
these mice develop diabetes 7 weeks faster than the same type of mice that are not given virus. In this project,
we will determine the effects of mouse age, virus strain, the number of times infection occurs, and levels of
virus growth in the intestine or pancreas on virus-induced diabetes acceleration. The ability of treatments for
rotavirus infection, and vaccination against rotavirus, to block this accelerated diabetes also will be tested. We
expect that rotavirus will be found growing in the pancreas, that virus growth is necessary for diabetes
acceleration, and that prevention of rotavirus infection will also prevent the rapid diabetes onset. This model
could prove to be suitable for testing the effectiveness and safety of new drugs and vaccines against both
rotavirus and type 1 diabetes. Our studies will be crucial in determining the importance of rotavirus infection in
the development of type 1 diabetes.
Research achievements (from final report):
Rotaviruses are the main case of severe diarrhoea in infants and young children. Live rotavirus vaccines have
been introduced into Australia in 2007. This research award led to the discovery that rotavirus infection
modulates type 1 diabetes in mice. These mice are the best available models for human disease. Rotavirus
infection of infant or young adult mice was protective against diabetes development. However, infection of
older adult mice with pre-existing pancreatic damage produced diabetes acceleration. This latter result is in line
with previous studies in genetically at-risk children. These mouse studies suggest that any effect of rotavirus
infection on diabetes development in at-risk children might depend on the timing of the infection.
Expected future outcomes:
Further use of the mouse models developed using this research award will facilitate elucidation of the
mechanisms behind rotavirus modulation of type 1 diabetes. The ability of human rotaviruses and vaccine
viruses to modulate diabetes also can now be tested.
Name of contact:
Barbara Coulson
Email/Phone no. of contact:
barbarac@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 300004
CIA Name: Prof Judy Savige
Admin Inst: University of Melbourne
Main RFCD: Nephrology and Urology
Total funding: $253,500
Start Year: 2004
End Year: 2006
Grant Type: NHMRC Project Grants
Title of research award:
The risks of Thin basement membrane nephropathy (TBMN)The risks of Thin basement membrane
nephropathy (TBMN)
Lay Description (from application):
Our aims are to save the $10 million spent on inappropriate investigations in TBMN each year by the
Australian community; to identify and treat individuals with TBMN at risk of renal impairment in order to
delay the onset of kidney failure; to understand the underlying disease mechanisms in order to develop specific
treatments; and to contribute to the development of a diagnostic assay for TBMN that flags mutations
associated with renal impairment and includes a screening test for modifying genes. The proposed project will:
1. change the practice of clinicians by providing evidence for our clinical definition of TBMN and reduce the
need for renal biopsies and other investigations thus saving the Australian community up to $10 million
annually; 2. demonstrate that a peripheral retinopathy distinguishes between TBMN and X-linked Alport
syndrome. This will be a major advance in the diagnosis of Alport syndrome too determine how often
individuals with persistent haematuria who have proteinuria >500 mg/day or renal impairment actually have
TBMN. Identify the genetic risk factors for renal impairment in TBMN in both the genes directly responsible
for TBMN as well as in the modifying genes. 3. determine the mechanisms by which genetic mutations and
modifying genes in TBMN cause disease and predispose to renal impairment. Understanding these mechanisms
is the first step in the development of specific treatments.
Research achievements (from final report):
At least 1% of the population has persistent haematuria, and this is due to Thin basement membrane
nephropathy (TBMN) and less often to X-linked Alport syndrome. TBMN is usually a benign condition but 7%
hospital-based patients go on to develop renal failure. These studies investigated why some patients develop
renal impairment. They helped develop a novel diagnostic assay for TBMN (and for X-linked Alport
syndrome), confirmed a simple eye test distinguished between these conditions, demonstrated further novel
causative mutations in TBMN, identified an independent genetic mutation that contributed to renal impairment,
and described a novel canine model for TBMN.
Expected future outcomes:
We will make our diagnostic assays for TBMN and Alport syndrome generally available, and will examine
how the underlying mutations result in disease at the molecular level. Understading how mutations cause
disease is the first step in developing specific treatments.
Name of contact:
Prof Judy Savige
Email/Phone no. of contact:
jasavige@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 350229
Start Year: 2005
CIA Name: A/Pr Geoffrey Howlett
End Year: 2007
Admin Inst: University of Melbourne
Grant Type: NHMRC Project Grants
Main RFCD: Medical Biochemistry: Proteins and Peptides
Total funding: $439,500
Title of research award:
Apolipoproteins and Amyloid Formation in AtheromaApolipoproteins and Amyloid Formation in Atheroma
Lay Description (from application):
We propose to study the poorly understood, disease-associated process of amyloid formation, using a sensitive
and reproducible model developed in our laboratory. Amyloid deposits are a feature of several
neurodegenerative and metabolic disorders such as Alzheimer's and Parkinson's disease and are also common
in atherosclerotic plaque or atheroma. They are composed of tangled networks of fibrillar proteins together
with several non-fibrillar proteins and proteoglycans. Atherosclerotic plaques typically consist of fibrous
proteins, lipids and foam cells derived from macrophages via receptor-mediated uptake of oxidized low density
lipoproteins. Our model system is based on the formation of amyloid fibrils from apolipoprotein (apo) C-II
which accumulates in atherosclerotic plaques where it co-localizes with serum amyloid P component, a marker
of amyloid fibrils. ApoC-II is a component of plasma lipoproteins and an important activator of the enzyme
lipoprotein lipase, which functions in the transport and distribution of triacylglycerols to tissues. We have
shown that apoC-II (79 amino acids) readily forms amyloid fibrils under lipid-free conditions, adopting a crossbeta sheet structure that reacts with the amyloid stains thioflavin T and Congo Red. The formation and
properties of apoC-II amyloid fibrils and the amyloid-like properties of oxidized lipoproteins are the subject of
the present proposal. We will characterize the effects of lipids and oxidation on the rate of formation and the
properties of apoC-II amyloid fibrils. We will also study the effects of oxidation on the amyloid-like properties
of lipoproteins and their interactions with serum amyloid P component and cell surface receptors.
Research achievements (from final report):
Protein aggregation and amyloid formation accompanies numerous medical conditions, notably Alzheimer
disease and Parkinson's disease. These diseases involve a variety of normally non-fibrillar proteins with at least
20 human proteins identified as components of different types of amyloid. The prevalence of apolipoproteins in
atherosclerotic plaques suggests a general propensity for human apolipoproteins to form pathogenic amyloid
fibrils. In this project we identified several factors that affect amyloid fibril formation by lipid-free human
apolipoprotein C-II (apoC-II). We discovered a new apoC-II fibril morphology promoted by lipid bilayers and
developed a reversible kinetic scheme to describe apoC-II fibril formation. We also demonstated the
accumulation of fibrillar deposits of apolipoproteins in atherosclerotic plaques and the ability of amyloid fibrils
to activate scavenger cells, an early event in the development of atherosclerosis and heart disease. Our studies
provide new insight into the structure and mechanism of formation of amyloid fibrils and the role of in vivo
factors such as oxidation and the binding of amyloid specific proteins in regulating amyloid growth.
Expected future outcomes:
Our observations highlight the potential importance of amyloid deposits in atherosclerosis. Our structural and
mechanistic studies suggest new strategies for reversing amyloid fibril formation and for the development of
inhibitors for the treatment of atherosclerosis and other amyloid related diseases.
Name of contact:
Geoffrey Howlett
Email/Phone no. of contact:
ghowlett@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 350253
Start Year: 2005
CIA Name: A/Pr Barbara Coulson
End Year: 2009
Admin Inst: University of Melbourne
Grant Type: Established Career Fellowships
Main RFCD: Medical Microbiology not elsewhere classified
Total funding: $538,250
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
I am a physiologist with expertise in endocrinology determining the roles of particular regulatory peptides in
the normal functions of the gastrointestinal tract and in the development of gastrointestinal, renal and prostate
cancers.
Research achievements (from final report):
My research program has encompassed discoveries of rotavirus cell receptor specificities and entry
mechanisms; structural determinations of rotavirus-receptor complexes; understanding how rotavirus
modulates cell signalling , interferes with transcription and evades antiviral responses; identification of immune
cells invaded by rotavirus; determining the extent and mechanisms of rotavirus modulation of type 1 diabetes;
and development of inhibitors of rotavirus-cell entry. This research will continue to help build Australia's
future capacity and intellectual rigor in virological research through training of Post-Doctoral Fellows and
students. Development of diagnostic reagents and techniques to detect novel emerging rotavirus strains,
adaption of vaccine implementation to local conditions, monitoring vaccine effects, developing drugs to treat
the children not protected by vaccination and an understanding of how these vaccines intersect with other
conditions such as type 1 diabetes all will require this expertise. The rigor, depth and extent of rotavirus
research training I provide is not available from any other Australasian, South-East Asian or Western Pacific
laboratory.
Expected future outcomes:
This fellowship has enabled subtantial progress in understanding rotavirus disease and pathogenesis, which will
assist in development of advanced treatments and vaccines.
Name of contact:
Barbara Coulson
Email/Phone no. of contact:
barbarac@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 350424
Start Year: 2005
CIA Name: Dr Suzanne Rogers
End Year: 2007
Admin Inst: University of Melbourne
Grant Type: NHMRC Project Grants
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $499,000
Title of research award:
Cellular Mechanisms and Physiological Roles of GLUT12 Mediated Glucose Transport in Glucose
HomeostasisCellular Mechanisms and Physiological Roles of GLUT12 Mediated Glucose Transport in
Glucose Homeostasis
Lay Description (from application):
Diabetes affects almost one million Australians, although only 50% are aware they have the disease. Type 2
diabetes accounts for about 90% of diabetes and usually occurs after the age of 40. As a leading cause of death,
adult blindness, lower limb amputation, kidney failure, stroke and heart attack, diabetes has huge economic and
social consequences and has been designated an Australian National Health priority. A clinical feature of Type
2 diabetes is high blood glucose levels. This occurs because insulin does not effectively stimulate the transfer
of glucose from the blood into muscle and fat. The reasons for this are not fully understood. Insulin normally
works to move glucose transporter (GLUT) proteins to the surface of muscle and fat cells. One GLUT that has
been studied extensively in muscle and fat is GLUT4. GLUT4 moves to the cell surface in response to insulin
and this response is one of the defects that is known to occur in Type 2 diabetes. Glucose then accumulates in
the blood, leading to many of the complications of diabetes. We have discovered a novel glucose transporter,
GLUT12, that is also present in muscle and fat. We have shown that GLUT12, like GLUT4, responds to
insulin. GLUT12 could therefore be a critical backup for GLUT4. We have also found that GLUT12 responds
to glucose itself, suggesting a unique role in controlling blood glucose levels. We will explore how GLUT12
acts in muscle and fat cells to find whether GLUT12 can act as a backup for GLUT4. We will also study
GLUT12 in tissue from normal animals and in animals with features of Type 2 diabetes. To determine the role
of GLUT12 in maintaining normal blood glucose levels, we will produce mice with an inactive GLUT12 gene.
Our research could identify novel ways of increasing GLUT12 activity. The eventual goal will be to find a
pharmaceutical compound that can improve glucose transport into muscle, reduce high blood glucose levels
and thus the complications of Type 2 diabetes.
Research achievements (from final report):
Diet related obesity is prevalent in modern society and is linked to increased incidence of Type 2 diabetes.
More than one million Australians have diabetes with economic and social burden. A feature of the disease is
high blood glucose levels. We have discovered a novel protein that may provide the missing link between
nutrient overload, high blood glucose and development of Type 2 diabetes. Understanding this link may
provide novel strategies for prevention and treatment of diabetes.
Expected future outcomes:
Future investigations will aim to delineate a mechanism for insulin resistance that may be a novel target for
diabetic therapy .
Name of contact:
Suzanne Rogers
Email/Phone no. of contact:
s.rogers@medicine.unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 350434
CIA Name: Dr Erica Fletcher
Admin Inst: University of Melbourne
Main RFCD: Sensory Systems
Total funding: $258,000
Start Year: 2005
End Year: 2007
Grant Type: NHMRC Project Grants
Title of research award:
Muller cell reactivity during diabetic retinopathyMuller cell reactivity during diabetic retinopathy
Lay Description (from application):
Diabetes is the leading cause of blindness in the working population. In some patients with diabetes, blood
vessels within the retina proliferate, haemorrhage or cause retinal detachment. The underlying changes within
the retina that lead to the proliferation of blood vessels are not well understood. One of the factors that leads to
changes in retinal blood vessels is an increase in growth factors from cells within the retina called Muller cells.
Muller cells are vital for the normal function of the retina and are known to be abnormal late in diabetes. They
may also be dysfunctional early in diabetes and could play a significant role in causing the early changes seen
in diabetes. Therefore a good understanding of how Muller cells change and the time at which they change is
vitally important to gain a better understanding of the defects that are associated with diabetes. Furthermore, an
understanding of the basic underlying cellular changes that occur in dibaetes will aid the development of more
specific therapeutic agents in the future.
Research achievements (from final report):
The central aim of this study was to evaluate the role of the supporting cells play in causing blood vessel
changes at the back of the eye during diabetes. This study showed that diabetes doesn't just cause changes in
blood vessels at the back of the eye as previously thought. Rather, there are other supporting cells at the back of
the eye that are altered before the blood vessels change. Moreover, the cells at the back of the eye that allow us
to see, are altered from a very early stage of diabetes. We examined the mechanism by which diabetes induced
changes in the supporting cells and identified that a new class of receptors called purines play an important
role. The results of this project are importand for two reasons. First, the information on cell changes will enable
us to develop predictive tools that determine which patients might be at risk of progression of diabetic
retinopathy. Secondly, by examining the novel class of receptors in more detail we may be in a position in the
future to develop a new class of drugs that prevents the development of diabetic complications..
Expected future outcomes:
we will continue to understand the mechanisms by which glia and neurons change during diabetic retinopathy
Name of contact:
Erica Fletcher
Email/Phone no. of contact:
elf@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 350448
CIA Name: Prof Tien Wong
Admin Inst: University of Melbourne
Main RFCD: Endocrinology
Total funding: $212,500
Start Year: 2005
End Year: 2007
Grant Type: NHMRC Project Grants
Title of research award:
Early Retinal Vessel Changes In Diabetes and the Metabolic SyndromeEarly Retinal Vessel Changes In
Diabetes and the Metabolic Syndrome
Lay Description (from application):
Diabetes mellitus affects a large proportion of adult Australians. Furthermore, many non-diabetic Australians
are at high risk of developing diabetes (e.g., people with lesser glucose abnormalities, and those who are obese,
have high blood pressure, or have high lipid levels). It has been suggested that diseases affecting small blood
vessels (microvascular disease) in the body is closely related to the development of both diabetes and the "prediabetes" state. The current study will examine the relationship of microvascular disease in the retina (at the
back of the eye) to diabetes, pre-diabetes status and diabetes complications. We will use a computer-imaging
technique to measure the diameters of retinal blood vessel from digital photographs taken in 2,177 participants
of the 1999-2000 Australian Diabetes, Obesity and Lifestyle (AusDiab) Study, a community-based survey of
people aged 25 years and older examining risk factors and complications of diabetes. In the proposed study,
we aim to answer the following questions: 1) Are changes in the retinal blood vessel diameter (e.g., narrowed
or dilated vessels) associated with diabetes and pre-diabetes? 2) Are these retinal vessel changes related to
obesity, high blood pressure and high lipid levels? 3) Are retinal vessel changes related to diabetes
complications, such as heart disease, kidney disease, nerve problems and foot ulcers? 4) Do retinal vessel
diameter changes predict people who will subsequently develop diabetes, irrespective of their risk factor
profile? Using this well-characterized population, and existing digital retinal photographs, the proposed study
will offer a unique and cost-effective opportunity to address important gaps in our understanding of how
diabetes and "pre-diabetes" develop, and whether they are related to microvascular diseases. This may
ultimately lead to new treatment and preventive approaches targeted at the small blood vessels in the body.
Research achievements (from final report):
We have shown that retinal arterioles are wider in those persons with diabetes than those without, while retinal
venules are wider in those persons with diabetes and retinopathy than those with diabetes but without
retinopathy. Persons with diabetes who have wider retinal arterioles also have a higher risk of developing
diabetic retinopathy, suggesting retinal arteriolar dilation is a specific sign of diabetic microvascular
dysfunction and may be a preclinical marker of diabetic retinopathy. Persons who do not have diabetes, but
have narrower retinal arterioles have a higher risk of diabetes, providing further evidence that microvascular
changes may contribute to the pathogenesis of diabetes.
Expected future outcomes:
Retinal vascular imaging may be used to stratify a persons risk for diabetes (in those without diabetes), and
diabetic complications, in particular diabetic retinopathy, in those with diabetes.
Name of contact:
Tien Wong
Email/Phone no. of contact:
twong@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 350483
CIA Name: Dr Glenn McConell
Admin Inst: University of Melbourne
Main RFCD: Exercise Physiology
Total funding: $340,750
Start Year: 2005
End Year: 2007
Grant Type: NHMRC Project Grants
Title of research award:
IS NITRIC OXIDE A CENTRAL REGULATOR OF EXERCISE-INDUCED SKELETAL MUSCLE
MITOCHONDRIAL BIOGENESIS?IS NITRIC OXIDE A CENTRAL REGULATOR OF EXERCISEINDUCED SKELETAL MUSCLE MITOCHONDRIAL BIOGENESIS?
Lay Description (from application):
Mitochondria are the energy producing parts of the cell and are the major controllers of metabolism. There is
now good evidence that reduced muscle mitochondrial size contributes to diabetes. Exercise is good for
diabetics due partly to increasing muscle mitochondrial production (mitochondrial biogenesis). Unfortunately,
little is known about the mechanisms involved in increased muscle mitochondrial biogenesis following
exercise. It has been shown recently that nitric oxide (NO), a gas made by muscle during exercise, plays a role
in mitochondrial biogenesis in fat cells. This project will determine whether NO is a central regulator of
exercise-induced mitochondrial biogenesis in skeletal muscle. If we find that NO increases mitochondrial
biogenesis in muscle, drugs designed to mimic these exercise effects may prevent or improve diabetes. We
will firstly establish if specific drug treatments that alter NO levels in muscle cells grown in culture alter
mitochondrial biogenesis. These results will help us to clarify the role of NO in mitochondrial biogenesis.
However, it is difficult to directly examine the effects of exercise in cultured cells. Therefore, further studies
will then use real life models such as rodents that have been exercised to examine the role of NO and exercise
on mitochondrial biogenesis. We will feed a drug to decrease NO levels in normal rats; and use mice,
genetically altered to be lacking in NO to determine if these treatments decrease mitochondrial biogenesis that
is normally seen following endurance exercise. Furthermore, since defects in mitochondrial biogenesis have
such an important impact on diabetic humans, we will use humans to examine if differences in NO levels in
skeletal muscle among type 2 diabetics or endurance-trained athletes correlate with mitochondrial biogenesis.
Finally, we will infuse a drug into type 2 diabetics that increases NO in muscle to determine if it also increases
mitochondrial biogenesis.
Research achievements (from final report):
Mitochondria are the energy procing oragns of the cell. Defective small skeletal muscle mitochondria are now
recognised as a major component of the metabolic abnormalities of diabetes. Exercise increases mitochondrial
volume and improves mitochondrial function (mitochondrial biogenesis). Many research groups are attempting
to determine how exercise increases mitochondrial biogenesis and thereby prevents or improves diabetes.
There are large gaps in our current knowledge. Prior to commencing our grant funding a paper presented
convincing evidence that nitric oxide (NO) regulates mitochondrial biogenesis in fat cells. As skeletal muscle
NO production increases during exercise, NO could provide an important link between exercise and its
beneficial effects on diabetes. In this project we examined whether NO plays an important role in the increase
in mitochondrial biogenesis in response to exercise. We provided clear evidence that NO plays an important
role in resting (basal) skeletal muscle mitochondrial biogenesis but not the increase in skeletal muscle
mitochondrial biogenesis in response to acute exercise or exercise training. Based on this we have begun
investigations into other potential regulators of skeletal muscle mitochondrial biogenesis in response to
exercise.
Expected future outcomes:
We have begun investigations into other potential regulators of skeletal muscle mitochondrial biogenesis in
response to exercise, in particular free radicals. We have also obtained NHMRC funding to examine whether
exercise training can correct deficits in skeletal muscle mitochondrial biogenesis in adulthood when one is born
small.
Name of contact:
NHMRC Research Achievements - SUMMARY
Dr Glenn Mcconell
Email/Phone no. of contact:
mcconell@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 350485
CIA Name: Prof George Jerums
Admin Inst: University of Melbourne
Main RFCD: Endocrinology
Total funding: $465,000
Start Year: 2005
End Year: 2007
Grant Type: NHMRC Project Grants
Title of research award:
Role of circulating advanced glycation end products (AGEs) in diabetic nephropathy: Effect of benfotiamine
interventionRole of circulating advanced glycation end products (AGEs) in diabetic nephropathy: Effect of
benfotiamine intervention
Lay Description (from application):
Advanced glycation products (AGEs) are compounds formed by the addition of sugars to amino acids (the
building blocks of proteins). The addition of sugars to proteins induces biological changes that have been
implicated in the development of diabetic complications, especially diabetic kidney disease. AGEs are a
diverse group of compounds and to date the exact role that specific AGEs play in the causation of diabetic
kidney disease is still unclear. However, new methods are now available that allow the comprehensive
quantification of individual AGE levels in blood. Our study involves the comparison of AGE blood levels, as a
group or as specific AGEs with markers of diabetic kidney disease such as albumin (protein) excretion in the
urine and the rate that the kidney filters the blood to form urine (glomerular filtration rate). Benfotiamine is a
thiamine (vitamin B1) derivative that has been shown to decrease the formation of AGEs and to prevent kidney
disease in diabetic animals. The present clinical study will assess whether benfotiamine has similar effects on
AGEs and kidney disease in patients with type 2 diabetes. If successful, this study has the potential to provide
a new treatment strategy for diabetic kidney disease in humans.
Research achievements (from final report):
The main focus of the grant was to examine the effects of a lipid soluble derivative of thiamine (benfotiamine)
on kidney function in people with type 2 diabetes and early kidney disease. This was a multicentre study
involving Austin Health, Royal Prince Alfred Hospital and Royal North Shore Hospital. The study involved 86
participants who were studied for 7 months. Due to slow recruitment, the study has just been completed and the
results are being analysed.
Expected future outcomes:
This is the first randomised, prospective, placebo controlled trial of the effects of benfotiamine on early renal
disease in patients with type 2 diabetes. It is expected that effects of benfotiamine on albuminuria and
glomerular filtration rate, as well as on circulating markers of protein damage will be ready for publication in
2009.
Name of contact:
Professor G Jerums
Email/Phone no. of contact:
ah-endo@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 359374
CIA Name: Prof Doris Young
Admin Inst: University of Melbourne
Main RFCD: Primary Health Care
Total funding: $499,263
Start Year: 2006
End Year: 2008
Grant Type: NHMRC Strategic Awards
Title of research award:
PEACH study- Patient Engagement and Coaching for Health: an intensive treatment intervention for patients
with type 2 diPEACH study- Patient Engagement and Coaching for Health: an intensive treatment intervention
for patients with type 2 di
Lay Description (from application):
This study uses practice nurses integrated in existing general practice structures to implement telephone
coaching for patients with type 2 diabetes (T2D) in a disadvantaged community. This is an evidence based
patient empowerment strategy designed to increase patient self-management and engagement with the health
care system to improve health outcomes.
Research achievements (from final report):
This project has enabled us to train 30 practice nurses working in general practice to use telephone coaching to
engage with patients with poorly controlled diabetes care using best practice guidelines. We have enabled the
practice nurses in both intervention and control practices to learn to recruit patients using practice databases,
collect clinical information, administer questionnaires and engage in primary care research. Some Practice
nurses have learnt to use telephone coaching methodology and web based instruments. Others are aware of the
rigour needed to conduct proper clinical trials in a busy general practice.We have also estimated the costs of
this additional role by practice nurses working in general practice and the barriers and facilitators to achieve
this. If this intensive telephone coaching of diabetes patients by practice nurses were shown to provide better
diabetes, blood pressure and cholesterol control and uptake of healthier lifestyles, then we can implement this
as the new role for practice nurses in the management of chronic diseases in the GP primary care setting.This
has future workforce implications for practice nurses working in primary care.
Expected future outcomes:
We expect that the patients with type 2 diabetes who have received telephone coaching from practice nurses
about their diabetes management have better blood sugar, blood pressure and cholesterol control than those
who have not over an 18 month period and that this is achieved by appropriate medications and adopting
healthier lifestyles
Name of contact:
Professor Doris Young
Email/Phone no. of contact:
d.young@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 365313
CIA Name: Prof Mauro Sandrin
Admin Inst: University of Melbourne
Main RFCD: Transplantation Immunology
Total funding: $580,390
Start Year: 2007
End Year: 2008
Grant Type: NHMRC Project Grants
Title of research award:
Tolerance Induction to Porcine Islet XenograftsTolerance Induction to Porcine Islet Xenografts
Lay Description (from application):
The current treatment for diabetes involves diet, drugs and insulin treatment. While these are satisfactory for
some adult onset diabetes, it is clear that in juvenile diabetes, the disease can progress in the presence of careful
insulin dosage. It is apparent that the whole islet as a functional unit is likely to give the best control of
diabetes, as when patients are transplanted with whole or segments of pancreas from human donors, as not only
is there an improvement in their diabetic status, the vessel lesions improve. Transplantation therefore offers a
new therapy to diabetic patients for reversal of their disease and improvement in the serious side affects found
in the eye, kidney and blood vessels. However, transplantation introduces a problem in that there is simply not
sufficient human islets available for organ or islet transplantation, and in this light, animals are being examined
as a possible source of islets. This is called xenografting or xenotransplantation. Of all the animal species, the
pig is the most suitable donor for a variety of reasons, for example similar control of blood sugar to humans.
The ultimate aims of the study are to examine possible genetic modifications that would allow the production
of transgenic pig islets for transplantation to humans for the treatment of diabetes. The focus of the proposed
studies is to elucidate the optimal combinations using mouse models. Importantly this study will establish the
proof of principle and provide information on the genes that will be useful to finally genetically modify pigs for
clinical use.
Research achievements (from final report):
The critical shortage of donor organs represents an enormous health burden to Australia. Thus, there is an
urgent need for alternative treatments. Xenotransplantation represents the most promising solution to this
problem. Xenotransplantation, the transplantation of organs from species other than humans, is now seen as a
viable solution to the world wide problem of lack of supply of suitable human donors. However, the first
immunological barrier to both xenotransplantation and mismatched ABO blood group transplantation is
rejection due to natural antibodies circulating in the serum of the recipient. These antibodies recognise antigens
on the donor tissue that are absent in the recipient., The production of pigs, with a disruption in the gene that
encodes the enzyme that makes the antigen that antibodies recognise represented a critical step towards the
clinical reality of xenotransplantation. We have now been focusing on the development protocols and
therapeutic approaches to the cellular (T cell) phase of the xenograft response. Our hypothesis is that the
expression of key immunomodulatory molecules in modified grafts will lead to prolonged, if not indefinite,
xenograft survival. We evaluated nine candidate molecules, expressed locally as transgenes, for their ability to
extend survival of porcine cellular xenografts in mice. From these, three key immunomodulatory molecules
were identified (CTLA4Ig, ICOSIg and Indoleamine 2,3-dioxygenase (IDO)) that lead to significantly
prolonged, but not indefinite survival of xenografts.,
Expected future outcomes:
This information will form the basis of therapeutic principles that will be applied to our preclinical large
diabetic animal model. This information will be essential for potential clinical pig-to-human
xenotransplantation and should identify both the molecular and cellular mechanisms involved in xenograft
prolongation.
Name of contact:
Mauro Sandrin
Email/Phone no. of contact:
m.sandrin@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 400004
Start Year: 2006
CIA Name: A/Pr Mary Wlodek
End Year: 2008
Admin Inst: University of Melbourne
Grant Type: NHMRC Project Grants
Main RFCD: Foetal Development and Medicine
Total funding: $438,521
Title of research award:
Perinatal and intergenerational influences on adult diabetesPerinatal and intergenerational influences on adult
diabetes
Lay Description (from application):
The aim of this project is to determine the effects of restriction of nutrient supply before and after birth on
growth and the development of adult onset diabetes. Being born small and its associated neonatal catch-up
growth independently predict adult diabetes. Placental restriction is a major cause of reduced nutrition and
growth before birth and is implicated in this "programming" of disease. Our novel findings suggest that
placental compromise increases appetite but also impairs milk quality and supply which limits overfeeding and
catch-up growth initially, but on weaning, may independently lead to diabetes. We will determine if this is a
direct result of poor nutrition and made worse by overfeeding in response to restored nutrition. We hypothesize
that placental compromise permanently reduces an individual's metabolic capacity and that the extent of
availability of nutrition after birth determines the consequences for insulin action and increased body fat.
Manipulations of postnatal nutrition (by cross-fostering) and fat oxidation will be performed, which are pivotal
to understanding the roles of catch-up growth and increased food intake in disease onset. We have found that
cross-fostering small rat pups at birth onto mothers with normal lactation improves growth during lactation.
The proposed studies will establish the cross-fostering effect on the development of diabetes and identify a
developmental stage during which nutritional or other manipulations may have beneficial consequences for the
health of the breastfeeding small infant. We propose to determine whether adult females, exposed to placental
restriction as a fetus, produce offspring that develop diabetes, and establish whether this effect is caused by
programming before conception and/or an altered fetal environment. Identification of critical periods after
birth, rather than before, would offer a greater likelihood that practical public health interventions can be
developed to improve adult health.
Research achievements (from final report):
We have demonstrated that being born small programs gender specific metabolic dysfunction. Male rats are
more adversely affected. We have characterised the response to a glucose tolerance test, measured muscle
mitochondiral biogenesis and pancreatic Bcell mass and deficits in bone bending strength. Importantly we have
demonstrated that improved postnatal nutrition can prevent these programmed deficits ameloriating disease
outcomes.
Expected future outcomes:
We aim to characterise the effects of metabolic dysfunction in females on their adaptation to pregnancy and the
impact on intergenerational metabolic disease transmission.
Name of contact:
Assoc Prof Mary Wlodek
Email/Phone no. of contact:
m.wlodek@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 400011
Start Year: 2006
CIA Name: Dr Odilia Wijburg
End Year: 2008
Admin Inst: University of Melbourne
Grant Type: NHMRC Project Grants
Main RFCD: Immunology not elsewhere classified
Total funding: $314,773
Title of research award:
The role of secretory antibodies in mucosal homeostasisThe role of secretory antibodies in mucosal
homeostasis
Lay Description (from application):
This proposal will address the role of the antibodies that are present in all secretions from the gut, the lungs, the
eye and mouth in maintaining the health of the mucosal (ie mucous covered) tissues from which they originate.
It has long been presumed that these antibodies stop bacteria and other pathogens adhering to the surface of
mucosal tissues. Our preliminary findings suggest that they have another very important role in removing
excess inflammatory material from beneath the lining of the mucosal tissues, to prevent recognition of this
material by the immune system. Such recognition could result in serious consequences both locally (ie. in the
gut) and more distally eg. in the pnacreas leading to diabetes. As a consequence, we believe that these
antibodies are fundamental to health. The research could have important ramifications for diseases resulting
from immune responses against host tissues, so-called autoimmune diseases like diabetes.
Research achievements (from final report):
The secretory immune system is exemplified by the production of large amounts of dimeric IgA and
pentameric IgM. These antibodies are secreted across the epithelium of the mucosal surfaces by the polymeric
immunoglobulin receptor (pIgR). In this project, we use the B6.pIgR-/- mouse as a model for deficiency of the
secretory immune system. We demonstrated that in B6.pIgR-/- mice 1) access of luminal antigens to the
systemic immune system is increased, 2) B cell populations are dysregulated, 3) populations of regulatory-type
CD4+ T cells in the mucosal tissues are increased and 4) production of inflammatory mediators is increased.
These observations confirm our hypothesis that secretory antibodies help prevent unwanted inflammatory
responses at mucosal surfaces., We next investigated whether increased exposure to luminal antigens results in
enhanced inflammatory and/or autoimmune responses using the diabetes-prone Non-Obese Diabetes mouse.
The pIgR mutation was backcrossed onto NOD mice and we observed a reduced incidence of diabetes in
NOD.pIgR-/- mice. Further analysis of NOD.pIgR-/- mice demonstrated that this reduced incidence in diabetes
was not due to altered kinetics of CD8+ T cell responses against relevant autoantigens, but, as a result of
increased exposure to luminal antigens in the absence of secretory antibodies, the number of autoantigen
specific T cells is possibly diluted in draining lymph nodes, resulting in reduced incidence of diabetes.,
Benefits: Understanding the impact of the secretory immune system on regulation of inflammatory responses to
self and/or luminal antigens is of significant importance for our understanding of autoimmunity. The impact of
mucosal vaccination strategies on the regulatory functions of the secretory immune system should be
considered. ,
Expected future outcomes:
Detailed understanding of the regulatory functions of secretory antibodies at mucosal surfaces and its
significance for the development of inflammatory and/or autoimmune responses.
Name of contact:
Odilia Wijburg
Email/Phone no. of contact:
odilia@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 400143
Start Year: 2006
CIA Name: Dr David Stapleton
End Year: 2008
Admin Inst: University of Melbourne
Grant Type: NHMRC Project Grants
Main RFCD: Protein Targeting and Signal Transduction
Total funding: $538,765
Title of research award:
Structure and function of the AMPK glycogen-binding domainStructure and function of the AMPK glycogenbinding domain
Lay Description (from application):
The AMP-activated protein kinase (AMPK) is an enzyme responsible for coordinating metabolism in response
to energy supply (diet) and energy demand (exercise). Research into this kinase can increase our
understanding of how diet and exercise are so important for maintaining health. The kinase acts either by
"sensing" when cellular energy levels become too low for normal functioning or when the body tells it by
sending a chemical messenger (hormone) that overall energy levels are low. This results in activation of
energy-producing pathways and inhibition of energy-consuming pathways, allowing cells to match supply with
demand to ensure their survival. The AMPK comprises of three proteins that together form a functional
enzyme. I have previously found that AMPK localizes to a source of cellular energy called glycogen (sugar
stores) via one part that I have called the glycogen-binding domain. In this application I aim to obtain a
thorough understanding of the molecular basis of how the glycogen-binding domain affects AMPK function in
muscle and heart following exercise. In addition this research may lead to the identification of new molecules,
similar to glycogen, that are important for AMPK regulation and may lead to the development of a new class of
drugs for Type 2 Diabetes. Research into AMPK promises to dramatically increase our knowledge of how to
reduce the risk of cardiovascular and neurodegenerative diseases, diabetes and obesity and provide an
understanding of the reasons these diseases develop.
Research achievements (from final report):
The AMP-activated protein kinase (AMPK) is an enzyme responsible for coordinating metabolism in response
to energy supply (diet) and energy demand (exercise). The AMPK acts either by "sensing" when cellular
energy levels become too low for normal functioning. This results in activation of energy-producing pathways
and inhibition of energy-consuming pathways, allowing cells to match supply with demand to ensure their
survival. The AMPK comprises of three proteins that together form a functional enzyme. I have previously
found that AMPK localizes to a source of cellular energy called glycogen (sugar stores) via one part that I have
called a carbohydrate-binding module. During this project I have discovered that the carbohydrate-binding
module from one of the three proteins called the beta subunit, associates with a part of glycogen that is only
found when glycogen is being used. This suggests that AMPK binds to glycogen when energy is being created
and we think leads to inhibition of AMPK because this enzyme is only activated when energy is low. In
addition, this research grant has allowed for the development of new methodology to isolate glycogen
molecules from any cell type. This has resulted in the discovery of a new protein that binds to glycogen and
new insights into how proteins important for glycogen synthesis and breakdown actually bind to glycogen and
how diet and exercise alter this association. These findings may lead to new approaches for treating Type 2
diabetes where energy metabolism is disrupted.
Expected future outcomes:
The long-term goal of this research is to understand the regulation of skeletal muscle AMP-activated protein
kinase by glycogen that will lead to novel strategies for the treatment of Type 2 diabetes.
Name of contact:
David Stapleton
Email/Phone no. of contact:
dis@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 400219
CIA Name: Prof Paul Gleeson
Admin Inst: University of Melbourne
Main RFCD: Autoimmunity
Total funding: $579,764
Start Year: 2006
End Year: 2008
Grant Type: NHMRC Project Grants
Title of research award:
Organ-specific autoimmunity: The role of the thymus and periphery in shaping the gastric-specific T cell
repertoireOrgan-specific autoimmunity: The role of the thymus and periphery in shaping the gastric-specific T
cell repertoire
Lay Description (from application):
The immune system normally protects against invasion by pathogens such as harmful viruses and bacteria. In
autoimmune diseases the same mechanisms that are used to protect us are erroneously targeted to our own
tissues. White blood cells, called T lymphocytes are responsible for attacking our own tissues in autoimmune
diseases. Our studies will employ a range of molecular, genetic and imaging technologies to track the rare and
potential harmful white blood cells. Our studies should reveal the mechanisms by which these self destructive
T lymphocytes are silenced in healthy individuals on the one hand, and on the other hand escape to cause
destruction in individuals with autoimmune diseases. This fundamental information will allow the
development of therapeutic strategies to selectively "turn-off" these destructive T lymphoctyes in individuals
with autoimmune disease and thereby remove the damaging immune response and cure the disease.
Research achievements (from final report):
The immune system normally protects against invasion by pathogens such as harmful viruses and bacteria. In
autoimmune diseases the same mechanisms that are used to protect us are erroneously targeted to our own
tissues. Our studies have employed a range of molecular, genetic and imaging technologies to track the rare
and potential harmful T lymphocytes in an organ-specific autoimmune disease known as autoimmune gastritis.
Autoimmune gastritis is due to a CD4+ T cell response to the gastric H/K ATPase α and β subunits (H/Kα and
H/Kβ). Our studies have revealed the mechanisms by which these self destructive CD4+ lymphocytes are
silenced in healthy individuals. A set of experiments showed that prevention of autoimmune gastritis requires
the extra-thymic deletion of highly autoaggressive H/K ATPase-specific T cells to produce a T cell repertoire
that is susceptible to the suppressive activity of regulatory T cells. These studies have identified three elements
of CD4+ T cell tolerance to gastric self-antigens (1) peripheral T cell deletion, (2) functional ignorance of
gastric-specific T cells and (3) suppression of potentially pathogenic T cells by Foxp3+ Tregs This
fundamental information will allow the development of therapeutic strategies to selectively "turn-off" these
destructive T lymphoctyes in individuals with autoimmune disease and thereby remove the damaging immune
response and cure the disease.
Expected future outcomes:
Our work has identified the mechanisms of CD4+ T cell tolerance to gastric self-antigens. Given these
findings, and defined H/K ATPase-specific T cell populations it will now be possible to document the effects
of inflammatory mediators on loss of self-tolerance and the development of organ-specific autoimmunity.
Name of contact:
Paul Gleeson
Email/Phone no. of contact:
pgleeson@unimelb.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 400238
CIA Name: Dr Kenneth Knight
Admin Inst: University of Melbourne
Main RFCD: Surgery
Total funding: $451,651
Start Year: 2006
End Year: 2008
Grant Type: NHMRC Project Grants
Title of research award:
Optimising islet transplantation with vascularized tissue engineering chambersOptimising islet transplantation
with vascularized tissue engineering chambers
Lay Description (from application):
Diabetics have high blood sugar levels because cells in the pancreas known as "islets" produce too little of the
hormone insulin. Most diabetics need daily insulin injections to maintain normal blood sugar levels.
Transplanting islets is the most promising way to treat type 1 diabetes, but, apart from the obvious difficulty of
rejection of "foreign" islets, several major problems remain: (1) there are insufficient pancreata (and therefore
islets) for transplantation; and (2) the efficiency of delivery of surviving islet transplants is too low. In pilot
studies we have grown a new living "pancreatic organ" in mice by inserting islets from genetically-related mice
together with a structural protein matrix, growth factors and blood vessels inside a plastic chamber. The blood
vessels maintain nutrition to the islet cells and simultaneously allow insulin to be released into the bloodstream,
thus normalising the high blood sugar in diabetics. In Aim 1 of these experiments we will find the optimal way
to grow mature islets in blood vessel-containing chambers in diabetic mice, focusing on (a) the best time to add
islets to the chamber - 0, 1 or 2 weeks after establishment, (b) the minimum number of islets to effectively
normalise blood sugar and (c) how long we can keep islets alive and functional in chambers, examining periods
up to 12 months. In Aim 2 we will test the ability of islet "stem cells" (provided by our co-investigators at
Walter & Eliza Hall Institute, Melbourne) to survive in the chambers and to produce sufficient insulin to
effectively lower blood sugar levels to normal in diabetic mice. In Aim 3 we will grow human islets in
chambers in special diabetic mice that do not reject "foreign" tissue, in order to confirm similar behaviour of
human islets in this controlled environment. Using this data, we hope to create a research model of functioning
islets, that is accessible, retrievable and manipulable, for the further study of diabetes and transplantation.
Research achievements (from final report):
Our research has led to the development of potentially new methods for islet transplantation for the control of
diabetes: , 1. We have shown that a 21 day period of blood vessel growth in our chamber model prior to the
transplantation of islets results in an improved islet graft survival and function in diabetic mice for up to 9
months. , 2. We have also shown by using a modified version of the chamber model that is based on the
femoral artery and vein, that transplanted islets seeded into a gelatin sponge and supplemented with nerve
growth factor have improved survival and function., 3. Our chamber model can be used to differentiate putative
pancreatic adult precursor cells into cells secreting insulin, glucagon and somatostatin., Our models allow for
futher study into pancreatic islet/adult precursor cell transplantation, to characterise the effect of treatments and
to futher optimise these methods as potential methods of islet transplantation in the clinic.
Expected future outcomes:
We have developed a model that can be used to further study diabetes and islet or pancreatic stem cell
transplantation. In particular this islet/stem cell model can be retrieved to further characterize the impact of
treatments.
Name of contact:
Ass. Prof. Anthony Penington
Email/Phone no. of contact:
a.penington@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 400269
CIA Name: Dr Sofianos Andrikopoulos
Admin Inst: University of Melbourne
Main RFCD: Endocrinology
Total funding: $430,321
Start Year: 2006
End Year: 2008
Grant Type: NHMRC Project Grants
Title of research award:
Identification and characterisation of a gene causing insulin hypersecretion in a mouse model of diabetes
susceptibilityIdentification and characterisation of a gene causing insulin hypersecretion in a mouse model of
diabetes susceptibility
Lay Description (from application):
Diabetes is a disorder primarily characterised by the inability to produce and secrete the pancreatic hormone
insulin, which regulates plasma sugar levels. This results in increased sugar levels which cause diabetic
complications such as retinopathy and nephropathy. The inability to produce and secrete insulin is due to both
defects in function as well as a reduction in pancreatic beta cells. Paradoxically it has been shown that some
patients who are at risk of develping diabetes actually secrete more insulin than normal. Furthermore it has
been suggested that this increase in insulin secretion actually may be associated with the decreased production
and secretion of insulin characteristic of diabetes. The DBA/2 mouse is a model of reduced insulin production
and secretion when exposed to high sugar levels or diabetes. However we have shown that in the normal nonstressed state DBA/2 mice actually secrete more insulin than normal and that this occurs from a very early age,
suggesting that this trait is inherited. We have subsequently performed genetic studies and have identified a
segment of DNA containing 10 genes associated with increased insulin secretion in DBA/2 mice. The level of
one of these genes we have called Hip1 is increased 5-fold in DBA/2 mice, providing a candidate gene for
increased insulin secretion in this model of diabetes susceptibility. However, whether Hip1 is also responsible
for reduced insulin production and secretion in the DBA/2 mouse is not known. Therefore the overall
hypothesis of this project is that th