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.
Targeting Ceramide Metabolism To Improve Lipid-induced Insulin Resistance
Funder
National Health and Medical Research Council
Funding Amount
$604,327.00
Summary
We have shown that the buildup of ceramide in muscle plays a key role in the inhibition of normal insulin action when the body is exposed to excessive amounts of fat, which leads to poor control of blood sugar levels and Type 2 diabetes. Using mass spectrometry we will now measure different ceramide types, to investigate which contribute to defects in insulin action. We will also examine whether enzymes involved in ceramide formation or degradation can be targeted to improve insulin responses.
Fragility Fractures: The Neglected Role Of Cortical Porosity
Funder
National Health and Medical Research Council
Funding Amount
$865,474.00
Summary
We just discovered that bone lost with age occurs mostly from pores within the cortex (outer shell) of the bone; These pores become larger (porosity) making bones fragile. This process is poorly detected by bone density (currently used tool) so that most people with weak bones are missed. To address this issue, we have for the first time, develop a technology to accurately quantify porosity in living peoples. With teams around the world, we aim here to fill this gap in the diagnosis.
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
NR4A Orphan Nuclear Receptor Signalling In Skeletal Muscle: Evidence For Crosstalk With The Beta-adrenergic Pathway.
Funder
National Health and Medical Research Council
Funding Amount
$323,749.00
Summary
The NR4A subgroup of are 'orphan' members of the nuclear hormone receptor (NR) superfamily (that are all implicated in human disease). NRs are hormone-dependent DNA binding proteins that translate nutritional and pathophysiological signals into gene regulation. The importance of this 'drugable' gene family in the context of promoting and maintaining human health is underscored by the diversity of medicinals associated with dysfunctional hormone signalling, in the context of inflammation, diabete ....The NR4A subgroup of are 'orphan' members of the nuclear hormone receptor (NR) superfamily (that are all implicated in human disease). NRs are hormone-dependent DNA binding proteins that translate nutritional and pathophysiological signals into gene regulation. The importance of this 'drugable' gene family in the context of promoting and maintaining human health is underscored by the diversity of medicinals associated with dysfunctional hormone signalling, in the context of inflammation, diabetes, dyslipidemia, and endocrine disorders (e.g ~15% of the top selling therapeutic compounds target NRs). The NR4A subgroup are stress response genes which are induced by a wide range of physiological stimuli and have been implicated in the response to energy excess (over-eating) and diet induced obesity. The NR4A subgroup are expressed in skeletal muscle, a major mass peripheral tissue that accounts for ~40% of the body mass and energy expenditure. This lean tissue is a major site of fat oxidation, insulin-stimulated glucose utilization and cholesterol metabolism. Therefore this tissue plays a notable role in insulin sensitivity, the blood lipid profile, and energy balance. Accordingly, muscle has a significant role in the progression of dyslipidemia, diabetes and obesity. Surprisingly, the function of the NR4A subgroup in skeletal muscle metabolism has not been examined. Nevertheless, given the data on NR4A mediated gene regulation, and the potential therapeutic utility for the treatment of metabolic disease, the contribution of skeletal muscle to NR4A action must be defined. Correspondingly, the objective of this proposal is to examine the role of the NR4A subgroup and is relevant to understanding the basis of dyslipidemia and obesity.Read moreRead less
Sex Steroids Modulate The Neuronal Control Of Bone Formation
Funder
National Health and Medical Research Council
Funding Amount
$620,647.00
Summary
It is well recognised that changes in sex hormones are pivotal to the development of osteoporosis in both men and women. Our group has been instrumental in identifying a novel and powerful system regualting bone mass and strength by neural activity. Recent findings indicate critical interactions between these two pathways in the control of bone formation. Greater understanding of these interactions could lead to therapies capable of controlling this extremely common disease.
Novel Metabolic Actions Of HDL With Therapeutic Potential For Type 2 Diabetes
Funder
National Health and Medical Research Council
Funding Amount
$559,471.00
Summary
Our proposal investigates a novel approach to treat type 2 (late onset) diabetes. We have identified an important link between HDL (good) cholesterol and glucose metabolism. The current proposal is to conduct studies in humans to determine whether therapies which increase HDL result in sustained reduction of blood glucose. Given the escalating global prevalence of obesity and type 2 diabetes, this work is potentially of great significance.