Identifying Novel Targets To Treat And Prevent Diabetic Complications
Funder
National Health and Medical Research Council
Funding Amount
$697,209.00
Summary
Diabetes is the leading cause for kidney failure requiring dialysis or transplantation. Diabetic patients also have a higher risk to suffer from heart attacks, stroke and amputations in particular once kidney damage occurs. Current strategies fail to completely protect patients from complications. My research will uncover knowledge gaps in our understanding of diabetes complications, identify new targets ultimately leading to urgently needed more effective treatments and prevention strategies to ....Diabetes is the leading cause for kidney failure requiring dialysis or transplantation. Diabetic patients also have a higher risk to suffer from heart attacks, stroke and amputations in particular once kidney damage occurs. Current strategies fail to completely protect patients from complications. My research will uncover knowledge gaps in our understanding of diabetes complications, identify new targets ultimately leading to urgently needed more effective treatments and prevention strategies to reduce the burden of disease in diabetes.Read moreRead less
An obesity epidemic is evident in first world countries including Australia. Twenty seven percent of men aged 55-64 in this country are obese. Obesity results in increased mortality and morbidity from type 2 diabetes, cardiovascular disease, renal disease and endometrial cancer, among others. Given our flaccid lifestyles, it is imperative that the metabolic processes underlying obesity be fully understood, to allow development of suitable treatment modalities. This proposal seeks to establish an ....An obesity epidemic is evident in first world countries including Australia. Twenty seven percent of men aged 55-64 in this country are obese. Obesity results in increased mortality and morbidity from type 2 diabetes, cardiovascular disease, renal disease and endometrial cancer, among others. Given our flaccid lifestyles, it is imperative that the metabolic processes underlying obesity be fully understood, to allow development of suitable treatment modalities. This proposal seeks to establish an important new element in our understanding of the development of obesity, the transcription factor STAT5. With previous NHMRC support, we developed sophisticated genetically modified mice which lack defined signalling processes initiated by growth hormone, an anti-obesity agent. These studies showed a strong correlation between ability to activate STAT5 and resistance to obesity. There is fragmentary literature evidence to support our hypothesis, which could also explain some of leptins anti-obesity actions. Using mice which lack STAT5, we shall establish a role for STAT5 as an antiobesity agent. The actions of STAT5 are normally blocked by feedback inhibitors referred to as SOCS, discovered by Australians. We shall define which SOCS is the feedback regulator for obesity control, allowing us to develop specific anti-SOCS agents which will act as novel anti-obesity agents.Read moreRead less
ADVANCE-ON: A Post-trial Observational Study Of ADVANCE
Funder
National Health and Medical Research Council
Funding Amount
$775,867.00
Summary
The ADVANCE (Action in Diabetes and Vascular Disease) study demonstrasted that intensive control of blood glucose only reduced kidney disease but that control of blood pressure reduced both cardiovascular and kidney disease. This 10-year post-trial follow up study will determine whether intensive control of blood glucose exerts cardiovascular benefits that emerge in the long term in patients with type 2 diabetes.
A Novel Role For Alzheimer Tau Protein In Insulin Secretion And Type 2 Diabetes
Funder
National Health and Medical Research Council
Funding Amount
$1,023,712.00
Summary
There is a strong association between type 2 diabetes and Alzheimer's disease, however the reason for this is not known. In Azheimer's disease a protein called tau does not function normally and contributes to the declining cognitive function. We have shown that when tau is absent, this lowers blood glucose and reduces the hallmark defects that contribute to type 2 diabetes. By understanding how tau works we may be able to provide better therapeutic agents to treat type 2 diabetes.
Type 2 diabetes is caused by multiple genetic defects, resulting in high blood sugar levels. These high sugar levels are primarily due to a decrease in the concentration of insulin, a hormone produced by the pancreas. A number of recent studies have aimed to identify which genes are regulated under conditions that mimic diabetes. One gene shown to have altered expression levels under these conditions is an enzyme called fructose-1,6-bisphosphatase (or FBPase). This enzyme is involved in the meta ....Type 2 diabetes is caused by multiple genetic defects, resulting in high blood sugar levels. These high sugar levels are primarily due to a decrease in the concentration of insulin, a hormone produced by the pancreas. A number of recent studies have aimed to identify which genes are regulated under conditions that mimic diabetes. One gene shown to have altered expression levels under these conditions is an enzyme called fructose-1,6-bisphosphatase (or FBPase). This enzyme is involved in the metabolism of sugar and is usually expressed at undetectable levels in the pancreas, but when blood sugar levels are high, the amount of FBPase in the pancreas increases considerably. We hypothesise that this increase in FBPase may contribute to the decrease in insulin secretion by the pancreas, seen in the diabetic state. The aim of this proposal therefore is to study mice that we have modified to express increased FBPase specifically in the pancreas, in order to determine whether this will lead to a decrease in insulin release and to diabetes. If this is the case, then FBPase could be targeted for the development of drugs that would improve the control of blood sugar levels in diabetes.Read moreRead less
Validating A New Model For Growth Hormone Receptor Activation
Funder
National Health and Medical Research Council
Funding Amount
$472,500.00
Summary
Growth hormone is an important hormone therapeutic for treating dwarfism. Recently, many new therapeutic applications for growth hormone have been discovered, particularly in relation to its anabolic actions. These include post surgery recovery, enhanced bone fracture healing, Crohns disease, dilated cardiomyopathy, infertility and ageing. The hormone exerts these actions through its receptor, which is a class1 cytokine receptor, similar to many receptors important in regulating immunity, inflam ....Growth hormone is an important hormone therapeutic for treating dwarfism. Recently, many new therapeutic applications for growth hormone have been discovered, particularly in relation to its anabolic actions. These include post surgery recovery, enhanced bone fracture healing, Crohns disease, dilated cardiomyopathy, infertility and ageing. The hormone exerts these actions through its receptor, which is a class1 cytokine receptor, similar to many receptors important in regulating immunity, inflammation, metabolism and cancers. In principle, if we can find out how the GH receptor works, this information would help in designing drugs to treat many immune and inflammatory disorders. With current NHMRC support we have developed a model which describes how GH activates the receptor at a molecular level. The model involves two pre-associated receptors at the cell surface binding to the hormone, with the result that the receptors are rotated relative to each other, and this brings the two JAK2 signalling units attached tothe receptor inside the cell into alignment, so they can activate each other. We can activate the receptor without hormone by artificially rotating it. This model is a prediction based on several techniques, but lacks proof of rotation. There are also a number of issues relating to the need for rigidity in the receptors, so the torque can be transmitted into the cell, since many believe there is no rigidity just above the membrane. We predict there is , but need to prove this. This information is vital for designing small orally active mimics of growth hormone, and for developing GH antagonists, likely to be useful for breast and colon cancer. Finally, we have evidence that the specificity of receptor signalling can be changed by mutating the outer part of the receptor (novel). We believe this can be used to change the activity spectrum of GH, hence decrease side effects, by developing analogs which activate one pathway or the other.Read moreRead less
The Regulation Of Aromatase In The Context Of Obesity And Postmenopausal Breast Cancer.
Funder
National Health and Medical Research Council
Funding Amount
$436,601.00
Summary
Current hormone therapy for breast cancer using inhibitors of oestrogen formation results in serious side-effects including bone loss, joint pain and possibly cognitive issues. Our current work is aimed at understanding how oestrogen formation is regulated with the goal of developing breast-specific inhibitors of oestrogen formation to obviate these problems. In addition, this work is aimed at devising therapeutic intervention to break the linkage between obesity and breast cancer.
A Multi-ethnic Cohort And Intervention Trial To Identify Early Biomarkers For Type 2 Diabetes And Customise Individualized Environments For Disease Prevention
Funder
National Health and Medical Research Council
Funding Amount
$597,376.00
Summary
Diabetes is often called a lifestyle disease, however, large clinical studies have shown that diabetes cannot always be prevented through lifestyle modification. This collaborative study between Shanghai Institutes of Biological Science and Sydney University will identify biomarkers that predict the development of type 2 diabetes. Using this knowledge, the best interventions (including diet, exercise and medications) to improve an individual’s risk profile for type 2 diabetes will be identified.
Investigating The Novel Role Of SEPS1 In The Prevention Of Islet Beta Cell Failure And Diabetes
Funder
National Health and Medical Research Council
Funding Amount
$535,804.00
Summary
SEPS1 is an important glucose-regulated protein whose function is to protect tissues from oxidative stress. Inhibition of SEPS1 by hyperglycaemia, is a mechanism for progression of Type 1 and Type 2 diabetes once hyperglycaemia supervenes. The overall aim of the project is to investigate the function of the novel SEPS1, using transgenic and knockout approaches.
Testosterone Intervention For The Prevention Of Diabetes Mellitus In High Risk Men: A Randomised Trial
Funder
National Health and Medical Research Council
Funding Amount
$5,054,654.00
Summary
Type 2 diabetes (T2DM) is increasingly common, costly and deadly. Some men at risk of T2DM have low testosterone (T) levels. Our preliminary data suggests that T treatment may prevent the development of T2DM, and improve cardiovascular and sexual function, body composition and bone density, and mood. This remains to be fully tested in a randomized placebo-controlled trial, and this project will do so in a 2-year study of T treatment compared to placebo in men at risk of T2DM participating in a l ....Type 2 diabetes (T2DM) is increasingly common, costly and deadly. Some men at risk of T2DM have low testosterone (T) levels. Our preliminary data suggests that T treatment may prevent the development of T2DM, and improve cardiovascular and sexual function, body composition and bone density, and mood. This remains to be fully tested in a randomized placebo-controlled trial, and this project will do so in a 2-year study of T treatment compared to placebo in men at risk of T2DM participating in a lifestyle program.Read moreRead less