Molecular Determinants Of Advanced Disease In Ovarian Granulosa Cell Tumours
Funder
National Health and Medical Research Council
Funding Amount
$612,244.00
Summary
Granulosa cell tumours of the ovary (GCT) represent 5-10% of malignant ovarian cancers. They are distinct from the more common epithelial tumours and although considered to have a much better prognosis, they have a propensity to late recurrence. Recurrent or aggressive GCT have a poor prognosis. These studies will investigate the molecular basis of recurrence and aggressive behaviour in GCT. This will provide both prognostic information and also potential therapeutic targets.
Androgen Receptor Signalling In Development And Progression Of Prostate Cancer
Funder
National Health and Medical Research Council
Funding Amount
$753,420.00
Summary
Prostate cancer is a major health problem in Australia, being the second leading cause of cancer deaths in men. Although there have been improvements in the diagnosis and treatment of prostate cancer, there are no effective treatments for advanced (metastatic) disease that has spread to other parts of the body. Currently, the only therapy for advanced disease involves the reduction in circulating androgens such as testosterone by surgical or medical castration, i.e. androgen ablation. Because pr ....Prostate cancer is a major health problem in Australia, being the second leading cause of cancer deaths in men. Although there have been improvements in the diagnosis and treatment of prostate cancer, there are no effective treatments for advanced (metastatic) disease that has spread to other parts of the body. Currently, the only therapy for advanced disease involves the reduction in circulating androgens such as testosterone by surgical or medical castration, i.e. androgen ablation. Because prostate cells are dependent on testicular androgens for their growth and survival, surgical or medical castration results in an initial tumour regression. However, tumours inevitably develop resistance to androgen ablation therapy and regrow. In this study we aim to provide the most comprehensive analysis to date of the role of androgen signalling in the initiation and progression of prostate cancer. This will enable us to identify the most effective means of eliminating androgen-dependent prostate tumours and identify tumours with high metastatic potential. Our studies will indicate whether treatments targeting androgen signalling are a more effective strategy to inhibit prostate cancer growth while minimising undesirable side effects.Read moreRead less
Type 2 diabetes represents an escalating global health problem. In Australia 7.2% of the population has diabetes but an additional 16% have difficulty handling glucose, a problem which frequently precedes the development of diabetes. Resistance of tissues to the action of insulin is an essential pre-requisite for type 2 diabetes but is also closely associated with the syndrome of obesity, dyslipidaemia, hypertension and cardiovascular diseases (Syndrome X). Genetic factors combined with a high c ....Type 2 diabetes represents an escalating global health problem. In Australia 7.2% of the population has diabetes but an additional 16% have difficulty handling glucose, a problem which frequently precedes the development of diabetes. Resistance of tissues to the action of insulin is an essential pre-requisite for type 2 diabetes but is also closely associated with the syndrome of obesity, dyslipidaemia, hypertension and cardiovascular diseases (Syndrome X). Genetic factors combined with a high caloric intake and a sedentary lifestyle are together responsible for the development of insulin resistance. From evidence that we and others have obtained in recent years it is evident that an important mediator of insulin resistance is the amount of fat which accumulates in muscle and liver. One way in which this abnormality seems to cause insulin resistance is through interference with the normal signalling mechanism which causes increased glucose metabolism in response to insulin. While experiments in cell systems have identified some candidate molecules that may be involved, a need exists to demonstrate whether their dysregulation actually causes the insulin resistance in the whole animal or human, or are merely associated with it. We will use novel techniques to manipulate the levels of one of these candidate genes, protein kinase B-Akt, and its regulators in the muscle of rodents. We will then examine the effects of these manipulations on insulin resistance using a combination of metabolic and molecular tests. Building upon earlier work we will also determine how important different subtypes of this molecule are for both normal and abnormal insulin-glucose metabolism, and whether these molecules or others in the pathway are more important in insulin resistance. This knowledge will be invaluable in tailoring specific novel treatment strategies or drugs for prevention or treatment of insulin resistance, and thus reducing the burden of type 2 diabetes and Syndrome X.Read moreRead less
Roles Of The Nuclear Growth Hormone Receptor In Cell Proliferation And Survival
Funder
National Health and Medical Research Council
Funding Amount
$429,387.00
Summary
We have discovered that the cell surface receptor for growth hormone travels to the cell nucleus in dividing cells, including cancer cells. Given the role of growth hormone in promoting growth postnatally, we seek to uncover how the nuclear receptor promotes proliferation directly, and by gene splicing. We have identified strong candidates for its direct actions through proteomics, and a DNA binding site for the receptor. Here we will investigate its role in proliferation, gene splicing and DNA ....We have discovered that the cell surface receptor for growth hormone travels to the cell nucleus in dividing cells, including cancer cells. Given the role of growth hormone in promoting growth postnatally, we seek to uncover how the nuclear receptor promotes proliferation directly, and by gene splicing. We have identified strong candidates for its direct actions through proteomics, and a DNA binding site for the receptor. Here we will investigate its role in proliferation, gene splicing and DNA strand break repair after cell irradiation.Read moreRead less
Adiponectin - Multimerization, Secretion And Action
Funder
National Health and Medical Research Council
Funding Amount
$478,844.00
Summary
Adiponectin is a hormone produced by fat tissue. It functions to control blood glucose levels and acts to prevent damage to blood vessels associated with heart disease and stroke. Adiponectin levels in the blood are low in subjects with obesity, diabetes and heart disease, and in animals with these conditions, additional adiponectin is of benefit. It has recently been recognised that adiponectin is produced in different forms - a low weight form made up of a small number of adiponectin molecules ....Adiponectin is a hormone produced by fat tissue. It functions to control blood glucose levels and acts to prevent damage to blood vessels associated with heart disease and stroke. Adiponectin levels in the blood are low in subjects with obesity, diabetes and heart disease, and in animals with these conditions, additional adiponectin is of benefit. It has recently been recognised that adiponectin is produced in different forms - a low weight form made up of a small number of adiponectin molecules and a higher weight form (HMW adiponectin) made up of large numbers of adiponectin molecules complexed together. We and others have shown that the HMW adiponectin is particularly beneficial. This projects aims to understand the processes regulating the production of differing types of adiponectin by fat cells. It will also examine how the different types of adiponectin have their effects in different tissues such as liver and muscle. The information gained will increase our understanding of how illnesses such as diabetes are associated with obesity. It may also lead to the development of treatments aimed at increasing adiponectin levels - particulalry HMW adiponectin - which may be of benefit in patients with diabetes and cardiovascular disease.Read moreRead less
Validating A New Model For Growth Hormone Receptor Activation
Funder
National Health and Medical Research Council
Funding Amount
$472,500.00
Summary
Growth hormone is an important hormone therapeutic for treating dwarfism. Recently, many new therapeutic applications for growth hormone have been discovered, particularly in relation to its anabolic actions. These include post surgery recovery, enhanced bone fracture healing, Crohns disease, dilated cardiomyopathy, infertility and ageing. The hormone exerts these actions through its receptor, which is a class1 cytokine receptor, similar to many receptors important in regulating immunity, inflam ....Growth hormone is an important hormone therapeutic for treating dwarfism. Recently, many new therapeutic applications for growth hormone have been discovered, particularly in relation to its anabolic actions. These include post surgery recovery, enhanced bone fracture healing, Crohns disease, dilated cardiomyopathy, infertility and ageing. The hormone exerts these actions through its receptor, which is a class1 cytokine receptor, similar to many receptors important in regulating immunity, inflammation, metabolism and cancers. In principle, if we can find out how the GH receptor works, this information would help in designing drugs to treat many immune and inflammatory disorders. With current NHMRC support we have developed a model which describes how GH activates the receptor at a molecular level. The model involves two pre-associated receptors at the cell surface binding to the hormone, with the result that the receptors are rotated relative to each other, and this brings the two JAK2 signalling units attached tothe receptor inside the cell into alignment, so they can activate each other. We can activate the receptor without hormone by artificially rotating it. This model is a prediction based on several techniques, but lacks proof of rotation. There are also a number of issues relating to the need for rigidity in the receptors, so the torque can be transmitted into the cell, since many believe there is no rigidity just above the membrane. We predict there is , but need to prove this. This information is vital for designing small orally active mimics of growth hormone, and for developing GH antagonists, likely to be useful for breast and colon cancer. Finally, we have evidence that the specificity of receptor signalling can be changed by mutating the outer part of the receptor (novel). We believe this can be used to change the activity spectrum of GH, hence decrease side effects, by developing analogs which activate one pathway or the other.Read moreRead less
Insulin-like Growth Factor Binding Protein-2 Is A Crucial Activator Of Aggressive Behaviour In Cancer Cells
Funder
National Health and Medical Research Council
Funding Amount
$612,885.00
Summary
The insulin-like growth factor (IGF) system, required for normal development and adult life, is often altered in many diseases including cancer. Key regulators of the IGF system are the IGF binding protein (IGFBP) of which IGFBP-2 is the 2nd most abundant. IGFBP-2 may enhance or inhibit the IGFs, but the mechanisms are not clear. This proposal aims to dissect IGFBP-2 action with the ultimate goal to provide knowledge for the development of targeted therapeutic modulators of IGFBP-2 activity.