Role Of Betaglycan In Gonadal And Adrenal Tumourigenesis
Funder
National Health and Medical Research Council
Funding Amount
$487,500.00
Summary
TGF-beta and inhibin are related multifunctional growth factors which regulate a number of important cellular functions, including proliferation, differentiation, and survival. Betaglycan is a cell-surface protein that binds both inhibin and TGF-beta. Betaglycan appears to regulate the binding and availability of the TGF-betas and inhibins to their signaling receptors, and its presence on the cell surface increases the efficiency of TGF-beta and inhibin function. Deletion of the inhibin gene in ....TGF-beta and inhibin are related multifunctional growth factors which regulate a number of important cellular functions, including proliferation, differentiation, and survival. Betaglycan is a cell-surface protein that binds both inhibin and TGF-beta. Betaglycan appears to regulate the binding and availability of the TGF-betas and inhibins to their signaling receptors, and its presence on the cell surface increases the efficiency of TGF-beta and inhibin function. Deletion of the inhibin gene in mice produces tumours in the ovary, testis, and adrenal gland in 100% of the mice. In this current proposal, we will delete the betaglycan gene in the primary target tissues for inhibin (the anterior pituitary and gonads). The hypothesis we are testing is that the loss of a co-receptor for inhibin (i.e. betaglycan) results in a loss of cellular sensitivity to inhibin, thus resulting in altered growth characteristics which predispose the gonads and adrenals to cancer. We will examine these cells in culture and in living animals to determine whether our hypotheses are correct. We will also conduct a series of histological, biochemical, and biological experiments in order determine the underlying causes of any observed growth dysregulation. This work is expected to yield information relevant to the role of betaglycan in inhibin-TGFb-regulated processes in normal and cancerous growth, which may allow future design of therapies for cancer.Read moreRead less
I am a Molecular Biologist who has built up a large set of transgenic animal models based around the NPY system to use them in an integrated physiology approach to investigate important regulatory mechanisms in the interaction of the brain with peripheral
Epilepsy is a devastating disease with many patients poorly treated. We have identified a novel ion channel target in the brain that reduces seizure susceptibility. The aim of this proposal is to fully explore this target in a number of epilepsy mouse models using both pharmacology and molecular techniques.
The Role Of The NPY System In The Regulation Of Appetite And Satiety
Funder
National Health and Medical Research Council
Funding Amount
$1,088,384.00
Summary
Eating disorders that have a causative role in the development of obesity and anorexia present massive health care problems for which current preventive methods and therapies are unsatisfactory. The studies proposed here combine sophisticated molecular techniques with state-of-the-art biochemical and physiological analyses. By utilising a panel of unique mouse models (many of which are only available to us), missing or overproducing key factors in the regulation of appetite and satiety this rese ....Eating disorders that have a causative role in the development of obesity and anorexia present massive health care problems for which current preventive methods and therapies are unsatisfactory. The studies proposed here combine sophisticated molecular techniques with state-of-the-art biochemical and physiological analyses. By utilising a panel of unique mouse models (many of which are only available to us), missing or overproducing key factors in the regulation of appetite and satiety this research will make highly original and internationally competitive contributions to the understanding of these disorders. The results will have a significant impact on the development of novel diagnostics and potential treatments for obesity and anorexia. In addition, funding provided through this grant would not only help to find answers to these important questions but will also provide the basis for the generation of several novel mouse models. These animal models will also be beneficial tools for the wider scientific community here in Australia and worldwide. We have a proven record in the generation and comprehensive analysis of transgenic and knockout mice models making this proposal not only feasible but also highly likely to succeed and provide great new insight into extremely important health problems.Read moreRead less
Identifying Brain Pathways Responsible For Stress Induced Obesity
Funder
National Health and Medical Research Council
Funding Amount
$895,663.00
Summary
Obesity-associated diseases are leading causes of death and are expected to increase as the obesity epidemic worsens. New evidence also shows that stress, an ever-increasing factor of life, can when combined with high caloric food lead and accelerate the development of obesity. The results from this study will help to identify new agents that may help reduce body weight and fat mass particular under conditions of increased stress.
Identification Of Cancer Initiating Cells In Small-cell Lung Cancer
Funder
National Health and Medical Research Council
Funding Amount
$364,420.00
Summary
Lung cancer is the leading cause of cancer deaths worldwide. Recently a unique mouse model of small-cell lung cancer (SCLC) has been generated that closely mimics the human disease. We will use this model to identify the cells that give rise to SCLC upon genetic alteration. Results obtained will assist in designing more effective intervention strategies aimed at overcoming initial and acquired resistance of these tumours against cytotoxic and targeted drugs.
The Role Of Crim-1 In Lens Development And Eye Disease.
Funder
National Health and Medical Research Council
Funding Amount
$196,527.00
Summary
We have recently isolated a novel gene (Crim1) and shown it to be strongly expressed during eye development. Its protein structure indicates that it may act to regulate the activities of two growth factor families, the TGF superfamily and the insulin-IGFs. These growth factors effect the behaviour of many cell types that influence events in normal and pathological development. For example in the eye lens, TGF 1 can induce cataractous changes in epithelial cells and early differentiating fibres; ....We have recently isolated a novel gene (Crim1) and shown it to be strongly expressed during eye development. Its protein structure indicates that it may act to regulate the activities of two growth factor families, the TGF superfamily and the insulin-IGFs. These growth factors effect the behaviour of many cell types that influence events in normal and pathological development. For example in the eye lens, TGF 1 can induce cataractous changes in epithelial cells and early differentiating fibres; however, TGF signalling appears to be required for events in late stages of fibre cell maturation. Cataract is the leading cause of blindness and arises when lens cell architecture is disrupted and-or proteins aggregate abnormally. In humans, following ocular trauma, eye surgery, or in association with other diseases, cataracts can develop. These cataracts feature the development of subcapsular fibrotic plaques which obscure vision. We have shown that lenses cultured in the presence of TGF can mimic production of these plaques suggesting that these cataracts result from inappropriate activation of TGF . TGF is expressed in the lens and is abundant in the ocular media that bathes the lens. Thus, it appears that complex regulation of TGF bioavailability is required; epithelial cells and young fibre cells need to be protected from its cataractogenic effects, whereas older fibres require TGF signalling for maturation and-or survival. The expression pattern of Crim1 in the lens is consistent with it having a key role in inhibiting TGF in the lens. Thus, we hypothesise that Crim1 plays important roles in the lens, possibly via the modulation of members of the TGF superfamily and insulin-IGFs. We predict that Crim1 acts to maintain the lens epithelial phenotype and facilitate events in early fibre differentiation. If so, this may have implications for devising molecular strategies for preventing or slowing diseases, such as the various forms of human cataract.Read moreRead less