The Physiological Role Of Calcitonin And Its Receptor In Bone Cell Metabolism.
Funder
National Health and Medical Research Council
Funding Amount
$496,446.00
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 3 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, an important inhibitor of osteoclastic bone breakdown. This will be achieved by studying transgenic mice in which the receptor, or target, for calcitonin is specifically removed from osteoclasts. This will allow us to precisely determine the role of calcitonin in osteoclast function. Data generated by our research group indicates that calcitonin is also involved in controlling bone formation, however, the way in which calcitonin acts on osteoblasts remains poorly understood. Therefore, studying our transgenic mice will also help clarify the role calcitonin plays in bone formation. 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 bone breakdown and bone formation and may assist in the design of new therapies for osteoporosis. We believe that this research is of great importance as osteoporosis is becoming more prevalent as the population ages.Read moreRead less
How Does Disruption Of Circadian Rhythms Induce Diabetes?
Funder
National Health and Medical Research Council
Funding Amount
$631,782.00
Summary
Increasing evidence suggests that disturbed circadian rhythms initiate and amplify metabolic and cardiovascular disease. The increasing and already high proportion of workers engaged in shiftwork, and increased frequency of disruption of these rhythms in the population more generally, implicate this body system as contributing to the growing epidemic of obesity and diabetes and related disorders in our community and world-wide. While we are now beginning to understand how our rhythms are synchro ....Increasing evidence suggests that disturbed circadian rhythms initiate and amplify metabolic and cardiovascular disease. The increasing and already high proportion of workers engaged in shiftwork, and increased frequency of disruption of these rhythms in the population more generally, implicate this body system as contributing to the growing epidemic of obesity and diabetes and related disorders in our community and world-wide. While we are now beginning to understand how our rhythms are synchronised to night and day, how this rhythmicity is linked to our organs in the normal and common disease states such as diabetes is poorly understood. The discovery of a special set of genes, called clock genes that function in all of the cells in our bodies and strongly influence the function of our organs such as the liver, pancreas and heart has been particularly important. We hypothesise that both environmentally (exogenous) and genetically (endogenous) induced disruption of circadian rhythms causes metabolic dysfunction. This is due to altered central and peripheral clock gene expression rhythms, which in turn alter metabolic rhythms and impair glucose homeostasis. This project aims to determine the impact of disrupted rhythmicity on metabolism with a particular emphasis on the possibility that the disrupted rhythmicity may be a predisposing factor for the development of diabetes.Read moreRead less
An obesity epidemic is evident in first world countries including Australia. Twenty seven percent of men aged 55-64 in this country are obese. Obesity results in increased mortality and morbidity from type 2 diabetes, cardiovascular disease, renal disease and endometrial cancer, among others. Given our flaccid lifestyles, it is imperative that the metabolic processes underlying obesity be fully understood, to allow development of suitable treatment modalities. This proposal seeks to establish an ....An obesity epidemic is evident in first world countries including Australia. Twenty seven percent of men aged 55-64 in this country are obese. Obesity results in increased mortality and morbidity from type 2 diabetes, cardiovascular disease, renal disease and endometrial cancer, among others. Given our flaccid lifestyles, it is imperative that the metabolic processes underlying obesity be fully understood, to allow development of suitable treatment modalities. This proposal seeks to establish an important new element in our understanding of the development of obesity, the transcription factor STAT5. With previous NHMRC support, we developed sophisticated genetically modified mice which lack defined signalling processes initiated by growth hormone, an anti-obesity agent. These studies showed a strong correlation between ability to activate STAT5 and resistance to obesity. There is fragmentary literature evidence to support our hypothesis, which could also explain some of leptins anti-obesity actions. Using mice which lack STAT5, we shall establish a role for STAT5 as an antiobesity agent. The actions of STAT5 are normally blocked by feedback inhibitors referred to as SOCS, discovered by Australians. We shall define which SOCS is the feedback regulator for obesity control, allowing us to develop specific anti-SOCS agents which will act as novel anti-obesity agents.Read moreRead less
Genomic And Non-genomic Actions Of Androgens In Regulation Of Fat Mass And Metabolism
Funder
National Health and Medical Research Council
Funding Amount
$395,421.00
Summary
Men have lower amounts of body fat than women, but are more likely to deposit fat around the stomach and abdominal region than women. This increased abdominal fat in men significantly increases the risk of developing type 2 diabetes and heart disease. The differences between men and women suggest that there is hormonal control of fat development; however, little is known regarding how male sex hormones, androgens, control these processes. We will investigate how androgens control fat formation, ....Men have lower amounts of body fat than women, but are more likely to deposit fat around the stomach and abdominal region than women. This increased abdominal fat in men significantly increases the risk of developing type 2 diabetes and heart disease. The differences between men and women suggest that there is hormonal control of fat development; however, little is known regarding how male sex hormones, androgens, control these processes. We will investigate how androgens control fat formation, and the response of fat and muscle tissue to glucose and insulin, using mutant mouse strains. These mouse strains have a mutation in the androgen receptor, a protein which acts as a key-lock mechanism to allow tissues to respond to androgens. This mutation stops the androgen receptor from functioning, so these mice can be used to determine the function of androgens acting through the androgen receptor. We will study three strains of mutant mice: (i) in which the androgen receptor is non-functional in all tissues of the body; (ii) in which the androgen receptor is non-functional only in fat tissue, but normal in all other tissues; and (iii) in which the androgen receptor is non-functional only in skeletal muscle, but is normal in all other tissues. The aim of our research is to determine the effect of the mutations in these three different mouse lines on paramateres including the amount of fat formed, the site of fat deposition, the levels of lipids and insulin in the blood and their response to glucose. The androgen receptor is a master switch that turns on or off other genes. Therefore, we also aim to identify which genes are controlled by the androgen receptor in fat and muscle. This research will identify how androgens control fat development and function, and will identify genes that mediate these actions in fat and muscle. This will provide potential molecules that could be used therapeutically to treat obesity and prevent type 2 diabetes and heart disease.Read moreRead less