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
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.
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
Role And Mechanism Of Connective Tissue Growth Factor In Diabetic Cardiomyopathy
Funder
National Health and Medical Research Council
Funding Amount
$382,820.00
Summary
Diabetic cardiomyopathy is a condition where the heart muscle is directly damaged by diabetes. It is being recognised as a prominent cause of both acute and chronic heart failure in diabetes. It is common and occurs in up to 60% of diabetic patients . At present however, no treatments are available to directly treat the cardiomyopathy. This condition can also occur in people with diabetes who have high blood pressure and-or coronary artery disease and may combine with these problems to worsen pa ....Diabetic cardiomyopathy is a condition where the heart muscle is directly damaged by diabetes. It is being recognised as a prominent cause of both acute and chronic heart failure in diabetes. It is common and occurs in up to 60% of diabetic patients . At present however, no treatments are available to directly treat the cardiomyopathy. This condition can also occur in people with diabetes who have high blood pressure and-or coronary artery disease and may combine with these problems to worsen patient outcomes. We have generated data in experimental diabetes in rodents that strongly implicates a heart growth factor in causing diabetic cardiomyopathy. This protein, called connective tissue growth factor (CTGF), is increased in diabetic cardiomyopathy, and is elevated by high glucose and other factors in diabetes. We have published data showing that CTGF causes tissue scarring like that which occurs in cardiomyopathy, by affecting signals in cells called fibroblasts. It increases the laying down of extracellular matrix (ECM) and also inhibits the degradation of ECM by the proteins that break down matrix, known as the MMPand PAI systems. Such accumulation of ECM is thought to be a major factor leading to abnormal muscle function in cardiomyopathy. We now plan to block CTGF in this diabetic heart model to determine if we can prevent diabetic cardiomyopathy. We have generated two methods to inhibit CTGF in the animal model. Echocardiography (a heart ultrasound test), and molecular analysis of the heart tissue will determine if we can prevent the otherwise adverse functional and structural changes of diabetes in the heart. We will also study our baboon model of diabetes to determine if diabetic cardiomyopathy with increased heart CTGF is present in the primates. Cell culture studies from rat heart fibroblasts and myocytes will determine how CTGF has the effect on cells to cause cardiomyopathy and how we might further prevent this condition developing in diabetes.Read moreRead less
Non-alcoholic steato-hepatitis (NASH) is a common disease of liver inflammation and scarring, which may progress to cirrhosis or liver cancer. While type 2 diabetes causes a higher rate of NASH and more rapid NASH progression the reasons for this are not clear. We have developed a novel animal model of NASH with diabetes added to dietary induced obesity. We show that a growth factor is elevated in the affected livers. We plan to block the growth factor to see if we can prevent NASH worsening.