The Pathogenesis Of Motor Neuron Degeneration Caused By A Triplet Repeat Expansion In The Androgen Receptor Gene.
Funder
National Health and Medical Research Council
Funding Amount
$284,748.00
Summary
Male sex hormones, or androgens, work by binding to a specific receptor, known as the androgen receptor. Androgens have an important and yet poorly understood role in nerve function. Our research is investigating how a genetic mutation in the androgen receptor causes Kennedy?s disease. This is a rare disease, affecting adult males, which causes nerves to die. The nerves which are affected are those supplying our muscles, called motor neurons. This leads to muscle wasting in the face and body. Ot ....Male sex hormones, or androgens, work by binding to a specific receptor, known as the androgen receptor. Androgens have an important and yet poorly understood role in nerve function. Our research is investigating how a genetic mutation in the androgen receptor causes Kennedy?s disease. This is a rare disease, affecting adult males, which causes nerves to die. The nerves which are affected are those supplying our muscles, called motor neurons. This leads to muscle wasting in the face and body. Other symptoms include testicular wasting, reduced fertility and breast tissue enlargement. It is currently not known what causes motor nerves to degenerate in Kennedy?s disease. We are endeavouring to investigate the cause of Kennedy?s disease via the generation of a transgenic mouse carrying this mutation. It is only through a studying transgenic mouse affected by this disease can we begin to understand what is happening to nerves to cause them to die, and importantly, how can we prevent them from dying. These studies will also provide crucial information on the effects of sex hormones on nerves. As there is currently no treatment for Kennedy?s disease, an aim of this project is to investigate how we can treat this disease. This will be the first time that we can systemically test potential treatments and work toward preventing the degeneration of these nerves. Kennedy?s disease is related to a number of other neurodegenerative diseases including Huntington?s disease, which are caused by similar genetic mutations. All of these diseases are caused by degeneration of specific nerve cells. Evidence suggests that there may be similar mechanisms involved in all of these diseases. The results of this study will therefore help us to understand a range of diseases and may eventually lead to the development of therapeutic strategies to prevent their debilitating effects.Read moreRead less
Role Of Impaired Insulin Signalling In Fatty Acid-induced Muscle Insulin Resistance In Vivo
Funder
National Health and Medical Research Council
Funding Amount
$481,500.00
Summary
Type 2 diabetes represents an escalating global health problem. In Australia 7.5% of the population has diabetes and another 16% insulin resistance (impaired action of insulin in tissues). As well as diabetes, insulin resistance is closely associated with obesity, dyslipidaemia, hypertension and cardiovascular diseases (Syndrome X). While genetic factors play a role, a high caloric intake (particularly with a high fat content) and a sedentary lifestyle are extremely important environmental contr ....Type 2 diabetes represents an escalating global health problem. In Australia 7.5% of the population has diabetes and another 16% insulin resistance (impaired action of insulin in tissues). As well as diabetes, insulin resistance is closely associated with obesity, dyslipidaemia, hypertension and cardiovascular diseases (Syndrome X). While genetic factors play a role, a high caloric intake (particularly with a high fat content) and a sedentary lifestyle are extremely important environmental contributors to Syndrome X and diabetes. From evidence that we and others have obtained over the last few years it is now evident that an important mediator of insulin resistance is the quantity of fat molecules which accumulate in muscle and liver. This project examines mechanisms whereby this fat accumulation can disrupt the signalling mechanism normally causing increased glucose metabolism in response to insulin. While basic experiments in cell systems have identified some candidates, a need exists to demonstrate whether they actually cause the insulin resistance in the whole animal or human, or are merely associated with it. We will combine metabolic-physiological studies with a novel technique we have recently established in our laboratory for introducing DNA into skeletal muscle of laboratory animal models. We now aim to exploit this approach to obtain more definitive data about the importance of insulin signalling changes to insulin resistance. Two major steps in insulin signalling will be investigated, involving the insulin receptor substrate proteins and the kinase Akt-PKB, both strongly implicated in lipid-induced insulin resistance. This knowledge will be invaluable in improving strategies to lessen or prevent lipid-associated insulin resistance, a major contributor to the metabolic derangement in Type 2 diabetes and Syndrome X.Read moreRead less
Hormonal Predictors Of Cardiovascular Outcomes And Mortality In Ageing Men: The Role Of Androgens And The IGF System.
Funder
National Health and Medical Research Council
Funding Amount
$125,035.00
Summary
As men age levels of testosterone and growth hormone fall while ill health increases. We do not know if low hormone levels directly cause heart disease. We will measure testosterone and IGF1, which reflects growth hormone, in 4,200 older men, and relate hormone levels to the future risk of ill health especially heart disease, stroke and large artery blockages. This will clarify whether low hormone levels increase risk of ill health, and the value of studies to test hormone therapy in older men.
Osteoblast Control Of Mesenchymal Progenitor Cell Differentiation: The Role Of Glucocorticoids And Wnt Signalling.
Funder
National Health and Medical Research Council
Funding Amount
$443,131.00
Summary
Osteoporosis is an important and growing health issue. Reduced ability to make new bone is an important cause of osteoporosis. In this project we will study how the immature cells which eventually make bone are recruited and controlled. In particular, we will study how genes coding for important growth factors are regulated so that the proper signals are sent to young cells to induce them to become bone-making rather than fat-making cells.
Glycaemia And Cardiovascular Disease Outcomes In Patients With Diabetes And CKD: Methodology, Relationship And
Funder
National Health and Medical Research Council
Funding Amount
$143,661.00
Summary
Diabetes is increasing and now the primary cause of chronic kidney disease (CKD). At present the care of people with diabetes and CKD aims to achieve normal blood glucose levels in the safest possible way in order to prevent acute and chronic complications and improve outcomes and quality of life. In this project we will examine the best means by which to measure, monitor and treat blood glucose levels in such people and explore the effect of intensive blood glucose control.
I am an academic clinician who has a principal interest in all aspects of diabetes, especially treatment and complications, and who is also involved in studies of antimalarial pharmacology.
Mechanisms Of Pro-atherogenic Effects Of Androgens In Human Vascular Cells
Funder
National Health and Medical Research Council
Funding Amount
$211,320.00
Summary
Atherosclerosis is the most important cardiovascular disease and is now the leading cause of death in Western societies. A major clue to the causality of the disease is the striking gender gap in its prevalence and severity. The gender gap in atherosclerotic cardiovascular disease may be due to genetic, lifestyle or hormonal differences between males and females. Of these, hormonal differences are the most amenable to therapeutic intervention. Accordingly, there has been a lot of interest in the ....Atherosclerosis is the most important cardiovascular disease and is now the leading cause of death in Western societies. A major clue to the causality of the disease is the striking gender gap in its prevalence and severity. The gender gap in atherosclerotic cardiovascular disease may be due to genetic, lifestyle or hormonal differences between males and females. Of these, hormonal differences are the most amenable to therapeutic intervention. Accordingly, there has been a lot of interest in the potential protective effects of estrogens but few have studied the role of androgens with sophisticated approaches to androgen physiology and pharmacology. Clues from epidemiological and our recent studies suggest that androgenic influences on atherosclerosis may involve positive and negative effects on atherogenesis but the mechanisms are not understood. We now propose a comprehensive approach to studying androgenic effects on vascular biology both to enhance knowledge as well as potentially opening new therapeutic options in selective androgen receptor modulation.Read moreRead less
The Physiological Relevance Of Calcitonin In Osteoclast Function
Funder
National Health and Medical Research Council
Funding Amount
$437,640.00
Summary
Throughout adult life, bone tissue is continuously remodelled. The two main processes involved in bone remodelling, are bone formation and bone breakdown. Bone formation is controlled by cells known as osteoblasts and bone breakdown is controlled by cells known as osteoclasts. Under normal circumstances these two processes are tightly coupled. Excessive breakdown of bone, causes these two processes to become unbalanced and results in bone loss. This is the basis of many bone diseases such as ost ....Throughout adult life, bone tissue is continuously remodelled. The two main processes involved in bone remodelling, are bone formation and bone breakdown. Bone formation is controlled by cells known as osteoblasts and bone breakdown is controlled by cells known as osteoclasts. Under normal circumstances these two processes are tightly coupled. Excessive breakdown of bone, causes these two processes to become unbalanced and results in bone loss. This is the basis of many bone diseases such as osteoporosis, a condition in which the bones become fragile and therefore more susceptible to fracture. 1 in 2 women and 1 in 5 men aged 70 years and older suffer from osteoporosis in Australia. Despite this, the mechanisms which control osteoclast breakdown of bone are not well understood. Our laboratory is interested in how hormones affect osteoclast action. We plan to examine the role of the hormone calcitonin, thought to be important inhibitor of osteoclastic bone breakdown. This will be achieved by studying transgenic mice in which the receptor for calcitonin is specifically removed from osteoclasts. This will allow us to precisely determine the role of calcitonin in osteoclast function. Current treatment for osteoporosis involves the administration of drugs which inhibit bone breakdown. This project will increase our understanding of how calcitonin acts to regulate the function of osteoclasts. We believe that this research is of great importance as osteoporosis is becoming more prevalent as the population ages.Read moreRead less