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.
ATR-X Syndrome: Role Of ATRX In Testicular Growth And Spermatogenesis
Funder
National Health and Medical Research Council
Funding Amount
$650,881.00
Summary
Infertility is surprisingly common and affects 1 in 20 Australian men. Testosterone and its receptor, the androgen receptor, are well known to be essential for spermatogenesis and fertility. We have identified an important regulator protein (ATRX) of androgen receptor activity and show that loss of function of ATRX in testes of mice leads to spermatogenesis defects. Identifying the molecular action of ATRX will lead to a better understanding of the underlying causes of infertility in men.
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
Effects Of Replacement And Withdrawal Of Testosterone In Human Males On Muscle, Bone And Fat
Funder
National Health and Medical Research Council
Funding Amount
$156,682.00
Summary
Male sex hormone or androgen deficiency (AD) is a common, but under-diagnosed condition. AD decreases well being and contributes to muscle weakness, bone fragility and weight gain. Cutting edge technology will be used to help explain how AD may relate to these negative effects, particularly on muscle function. Given the importance of aging, frailty, osteoporosis and obesity, understanding the role of hormones in these conditions may have major implications for prevention and treatment.
Role Of UBL-5 In Mitochondrial Function And Glucose Metabolism
Funder
National Health and Medical Research Council
Funding Amount
$647,539.00
Summary
Type 2 diabetes is caused by insulin resistance, a condition that is characterised by the inability of insulin to elicit its normal function to lower blood sugar levels. The cause of insulin resistance is not known. In this study we will determine the role of a novel gene called UBL-5 to elicit insulin resistance in muscle and fat by generating genetically-induced models in which this gene has been deleted. By understanding the role of UBL-5 in insulin resistance, better therapeutic strategies c ....Type 2 diabetes is caused by insulin resistance, a condition that is characterised by the inability of insulin to elicit its normal function to lower blood sugar levels. The cause of insulin resistance is not known. In this study we will determine the role of a novel gene called UBL-5 to elicit insulin resistance in muscle and fat by generating genetically-induced models in which this gene has been deleted. By understanding the role of UBL-5 in insulin resistance, better therapeutic strategies can be developed to treat Type 2 diabetes.Read moreRead less
Targeting Nicotinamide Adenine Dinucleotide Biosynthesis To Improve Metabolism
Funder
National Health and Medical Research Council
Funding Amount
$844,596.00
Summary
Nicotinamide adenine dinucleotide (NAD) is a cellular metabolite that regulates many biological processes. NAD levels decline with age and also in obesity and interventions that increase NAD levels produce favourable metabolic effects. In this proposal we will utilise a range of novel experimental models to define the molecular pathways that mediate the beneficial effects of NAD.