Development Of A Specific Activin Antagonist For Therapeutic Applications
Funder
National Health and Medical Research Council
Funding Amount
$504,287.00
Summary
Activin is a key regulator of homeostasis in several organs and tissues, including ovaries, testes, liver and skin, and alterations in activin�s activity can result in fibrosis, cachexia and cancer. In this grant we propose to develop a specific activin antagonist by modifying the activin A propeptide. This novel reagent could be used to promote liver growth in severe hepatic disease and prevent fibrosis in numerous tissues.
Activin Type II Receptor Antagonists: Mechanism Of Action And Biological Applications
Funder
National Health and Medical Research Council
Funding Amount
$507,270.00
Summary
Activin is a member of the TGF- family of growth and differentiation factors. Over-expression in mice leads to muscle and liver wasting, scarring during wound healing, disturbances to the reproductive system and various endocrine disorders. Activin's biological activity is promoted by its binding in series to two receptors termed Type I and II. Previous studies by this investigator have shown that selective modification of activin's protein structure can result in activin forms (in this instance ....Activin is a member of the TGF- family of growth and differentiation factors. Over-expression in mice leads to muscle and liver wasting, scarring during wound healing, disturbances to the reproductive system and various endocrine disorders. Activin's biological activity is promoted by its binding in series to two receptors termed Type I and II. Previous studies by this investigator have shown that selective modification of activin's protein structure can result in activin forms (in this instance called activin-M108A) which bind to Type II receptors but fail to promote binding to the Type I receptor. This has led to the hypothesis that activin-M108A may compete for native activin binding to Type II receptors and thus prevent activin's recruitment of the Type I receptor with the consequence that activin's biological activity is inhibited. It is proposed to test this hypothesis by producing sufficient amounts of activin-M108A and testing its inhibitory effects in several mouse models of liver damage, muscular degeneration and ovarian and testicular disease. If activin-M108A, or related modified forms of activin, decrease the morbidity and mortality associated with these murine diseases, then we envisage that these activin type II receptor antagonists will also be beneficial for the treatment of related human conditions.Read moreRead less
Intervening In The Natural History Of Type 1 Diabetes: An Integrated Approach
Funder
National Health and Medical Research Council
Funding Amount
$9,466,000.00
Summary
This Program brings together four of Australia’s top type 1 diabetes clinical and lab-based research teams. The program has three intersecting themes. The first theme, pathogenesis, focuses on early life and understanding why type 1 diabetes develops. The second theme, prevention, seeks to identifying new drugs to stop the disease from occurring. The third theme, treatment, aims to improve therapies to replace the cells that are destroyed during the disease process.
Diabetic cardiomyopathy (DiabCM) is common in people with diabetes. It predisposes to heat failure. Its cause remains unclear and there is no specific treatment for DiabCM. Inflammation is a fundamental tissue response to a metabolic insult and it occur in DiabCM. The central hypothesis in this work is that inflammation through myocardial macrophage cells contributes to DiabCM. This hypothesis will be tested in animal models and also in cell culutre studies.
Investigation Of Pancreatic Insulin-secreting Cell Function And Survival
Funder
National Health and Medical Research Council
Funding Amount
$375,750.00
Summary
Diabetes remains a major health problem in Australia. Both type 1 and type 2 diabetes is eventually due to pancreatic insulin-producing beta-cell destruction, which is caused mainly by the cell death, so called 'apoptosis' or programmed suicide of the cells. Thus, attempting to protect beta-cells against death and rescue their insulin secretory function is emerging as a strategy for the treatment of diabetes. However, how the beta-cells undergo death and how to protect the cell death are still n ....Diabetes remains a major health problem in Australia. Both type 1 and type 2 diabetes is eventually due to pancreatic insulin-producing beta-cell destruction, which is caused mainly by the cell death, so called 'apoptosis' or programmed suicide of the cells. Thus, attempting to protect beta-cells against death and rescue their insulin secretory function is emerging as a strategy for the treatment of diabetes. However, how the beta-cells undergo death and how to protect the cell death are still not completely understood. We have recently discovered a new protein, named sphingosine kinase, that is a strong protector against cell death. We also found that this enzyme is involved in process of insulin secretion. Thus, this application seeks to establish a dual role of this enzyme in protecting beta-cells from death and promoting insulin secretion by the cells. This will ultimately allow us to create new therapeutic strategy to target this protein for the management of diabetes.Read moreRead less
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 ....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.Read moreRead less