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.
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
Factors Regulating The Temporal And Spatial Assembly Of G-protein Coupled Receptor-mediated Arrestin Complexes
Funder
National Health and Medical Research Council
Funding Amount
$472,770.00
Summary
G-protein coupled receptors are proteins that are present at the surface of most cells in the human body. They recognise and bind to specific molecules, such as hormones, the act of which results in a specific signal being transmitted into the cell. This signal alters the function of the cell and so it is critical that it is appropriate, both in type and duration. G-protein coupled receptors and the molecules that activate them provide an essential function within the human body for communicatin ....G-protein coupled receptors are proteins that are present at the surface of most cells in the human body. They recognise and bind to specific molecules, such as hormones, the act of which results in a specific signal being transmitted into the cell. This signal alters the function of the cell and so it is critical that it is appropriate, both in type and duration. G-protein coupled receptors and the molecules that activate them provide an essential function within the human body for communicating between cells, and consequently between organs. They are a major mechanism by which nerve signals are transmitted and hormones regulate bodily functions. They are therefore an important target for pharmaceuticals, with up to 50% of ethical drugs and many drugs of abuse acting upon them. It is critical to understand how these receptors alter cellular function once they receive an appropriate signal, but it is also essential to know how such responses are switched off. Arrestins are proteins within cells that interact with G-protein coupled receptors to 'arrest' their signalling. They desensitise the cell to continuous stimulation, but also act to resensitise the cell to respond to future, separate signals. Recently, they have also been shown to provide alternative mechanisms of altering cellular activity by interacting with other cellular proteins. These interactions greatly increase the potential ways in which a cell can respond once a G-protein coupled receptor is activated. Understanding the resulting complexity is essential if we are to fully exploit the vast therapeutic potential of this important receptor family.Read moreRead less