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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
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.
The Nuclear Growth Hormone Receptor- Its Actions And Mechanism Of Nuclear Translocation
Funder
National Health and Medical Research Council
Funding Amount
$531,696.00
Summary
We and others have found that cell surface receptors for growth factors such as EGF, FGF and growth hormone can be found in the nucleus of proliferating cells. We have shown that many cancers have elevated nuclear GH receptor including leukemia, breast and colon cancer. If we artificially target the GH receptor to the nucleus, the resulting cells are tumorigenic when injected into immunocompromised mice, rapidly form ing metastasising tumours. To create more effective inhibitors of this tumourog ....We and others have found that cell surface receptors for growth factors such as EGF, FGF and growth hormone can be found in the nucleus of proliferating cells. We have shown that many cancers have elevated nuclear GH receptor including leukemia, breast and colon cancer. If we artificially target the GH receptor to the nucleus, the resulting cells are tumorigenic when injected into immunocompromised mice, rapidly form ing metastasising tumours. To create more effective inhibitors of this tumourogenesis, and to define the physiological roles of nuclear GH receptor, we will define the transport process which carries the receptor to the nucleus and block it. We will also seek to define how the receptor in the nucleus interacts directly with DNA to inhibit programmed cell death. To carry out these projects we will use sophisticated proteomics -mass spectrometry to identify the proteins interacting with the receptor in the transport and gene activation processes. The role of candidates will be tested by preventing their expression or by direct inhibition of their action using drugs or dominant negative versions. These approaches will provide leads to new anti-cancer therapeutics, and therapies for blocking diabetic blindness and kidney failure.Read moreRead less