Does Enhanced Vitamin D Activity In Bone Heal The Skeleton In Disorders Of FGF23 Excess?
Funder
National Health and Medical Research Council
Funding Amount
$855,925.00
Summary
X-linked hypophosphatemia (XLH) is a genetic disorder which results in phosphate wasting and rickets. This severe disorder has no effective treatment. We have compelling new evidence that the rickets in XLH is not primarily a disorder of low blood phosphate, but rather specific issue of low cellular levels and activity of vitamin D (1,25D) within bone. This proposal is designed to specifically demonstrate this new concept and outline a new paradigm for a new XLH treatment.
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.
Obesity is becoming more common in Australian adults and children, and is a major contributor to a number of diseases including type 2 diabetes, cardiovascular disease and some cancers. Current weight loss strategies using either lifestyle modification (diet and exercise) or drugs are relatively ineffective in the majority of obese individuals. This is partly due to the fact that we have an incomplete knowledge of the factors that regulate weight in humans. In laboratory studies we have shown th ....Obesity is becoming more common in Australian adults and children, and is a major contributor to a number of diseases including type 2 diabetes, cardiovascular disease and some cancers. Current weight loss strategies using either lifestyle modification (diet and exercise) or drugs are relatively ineffective in the majority of obese individuals. This is partly due to the fact that we have an incomplete knowledge of the factors that regulate weight in humans. In laboratory studies we have shown that human fat cell development can be dramatically accelerated by fibroblast growth factor-1 (FGF-1). This growth factor is produced by human endothelial cells, which are cells that line the blood vessels in fat tissue. When human fat cell precursors (preadipocytes) are cultured in the presence of FGF-1 the preadipocytes divide much more rapidly than normal and, additionally, then develop into mature fat cells much more rapidly than normal. These processes involved in development of new fat cells form the basis of fat tissue expansion in the body. The effect of FGF-1 on human fat cell development is far greater in magnitude than that of other known factors that promote fat cell growth. The aim of this project is to determine the actual biochemical pathways that mediate the effect of FGF-1 in promoting fat cell growth and development. Results obtained will provide insight into the cellular and molecular mechanisms regulating expansion of fat tissue mass in humans. Research aimed at identifying these underlying mechanisms, or at potentially contributing or exacerbating factors, is critically important in development of novel and more effective approaches to prevention and treatment of obesity.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.
Insulin-like Growth Factor Binding Protein-2 Is A Crucial Activator Of Aggressive Behaviour In Cancer Cells
Funder
National Health and Medical Research Council
Funding Amount
$612,885.00
Summary
The insulin-like growth factor (IGF) system, required for normal development and adult life, is often altered in many diseases including cancer. Key regulators of the IGF system are the IGF binding protein (IGFBP) of which IGFBP-2 is the 2nd most abundant. IGFBP-2 may enhance or inhibit the IGFs, but the mechanisms are not clear. This proposal aims to dissect IGFBP-2 action with the ultimate goal to provide knowledge for the development of targeted therapeutic modulators of IGFBP-2 activity.
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.