Research Trial:
Prince Henry's Institute is seeking non-smoking, healthy but overweight men aged 40-70 years for a study of testosterone treatment on body fat and cardiovascular disease.
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Research Projects

Molecular pathogenesis of granulosa cell tumours of the ovary

Supervisor: Professor Peter Fuller
Telephone: 03 9594 4379
Email: peter.fuller@princehenrys.org

Granulosa cell tumours of the ovary represent 10% of ovarian tumours. These tumours arise as their name implies, from the granulosa cells of the ovarian follicle. They both respond to endocrine signals and also synthesise hormones. The group at PHIMR has over the last decade been involved in their clinical characterisation, particularly the development of the use of inhibin as a tumour marker, and also in early studies to define the molecular pathogenesis. In particular, we wish to establish the events, (i.e. mutations) that give rise to these endocrine tumours. The approach involves the use of a panel of tumours obtained from women with the disease and also the use of two established cell lines. Our current focus is on the analysis of the status of signalling pathways known to be important in the regulation of growth and differentiation in granulosa cells in both the tumours and cell lines. The project would involve the use of molecular techniques for mutagenesis detection to seek to identify abnormalities in signalling pathways, particularly known oncogenes in these tumours. Where abnormalities are found, their significance would then be analysed in the cell lines. The cell lines and the tumours also express the novel oestrogen receptor, ERb . Little is known, at least in granulosa cells, of the genes regulated by this molecule and the cell lines place us in a unique position to determine the genes that are regulated by ERb . This will be identified using the microarray facility recently established in the institute. The analysis and characterisation of these genes is likely to be of significance in reproductive function.

Understanding the molecular mechanisms of action of aldosterone and the mineralocorticoid receptor

Supervisor: Professor Peter Fuller
Phone:03 9594 4379
Email: peter.fuller@princehenrys.org

The adrenal steroid aldosterone is a key regulator of blood pressure. Excessive aldosterone levels cause hypertension and contribute to the pathogenesis of cardiac disease. Our laboratory has a program of work focused on various aspects of aldosterone action and the diseases that may arise from this action. This project examines the receptor protein for aldosterone, the mineralocorticoid receptor (MR), which acts as a transcription factor to regulate gene expression. We are offering the following Honours projects:

1. Regulation of target genes by the MR: This project would involve the analysis of the regulatory regions of an aldosterone-induced gene (channel-inducing factor) in the colon using molecular biology, cell culture systems, transfection and reporter assays.

2. Interdomain interactions: The MR consists of a number of functional domains that interact with one another. The student will examine the effect of this "cross-talk" on receptor function in vitro and in cultured mammalian cells, using techniques to measure ligand binding, receptor activity and the ability of the receptor to interact with other proteins involved in transcription.

3. Interacting proteins: Using a yeast screening method, we have identified a number of novel proteins that interact with the MR, and that may be important for the ability of the receptor to regulate gene expression. The student will examine the ability of these proteins to interact with and regulate MR function in vitro and in cultured mammalian cells, using techniques to measure MR ligand and DNA binding, and receptor activity.

Adrenal Steroid Hormones and Cardiac Fibrosis.

Supervisor: Dr Morag Young
Phone: 03 9594 4286
Email: morag.young@princehenrys.org

Congestive cardiac failure (CCF) is a major cause of morbidity and mortality. CCF affects 1% of 50 year olds and up to 25% of eighty year olds. CCF is the most common cause of emergency hospital admissions in adult medicine and in those admitted to hospital has one-year mortality of up to 60%. The underlying pathogenetic process in many cases is myocardial fibrosis. Understanding the mechanisms involved in the development of myocardial fibrosis will allow the development of new therapeutic modalities with which to address this major health problem. We and others have identified aldosterone as a key mechanism in the development of myocardial fibrosis and CCF. Understanding how too much aldosterone, or over activation of its receptor, combined with an increase in salt retention produces fibrosis will enable development of therapies for preventing the progression of fibrosis and thus the development of heart failure.

This project involves the pathophysiological actions of aldosterone in the heart and blood vessels. We have shown previously that aldosterone and salt administration to rats causes fibrosis of the tissue, compromising cardiac function. This data is supported by clinical observations. However, the mechanisms involved are largely unknown. We do know that an inflammatory response occurs in the early stages of the response. The pathways that regulate this will be determined. Results from this study will clarify the role of the adrenal hormone aldosterone in the normal physiology and pathology of the heart, and in the pathology of heart disease, heart failure and vessel disease. A better understanding of aldosterone effects and targets in the heart will provide a further basis for future pharmacological interventions and treatments for heart disease, especially in the area of heart failure and cardiac fibrosis.

Specific projects will investigate the role of mineralocorticoid hormones and their receptors in normal heart function and in fibrotic heart disease that results in heart failure. They will investigate the mechanisms by which blood levels of mineralocorticoid hormones, inappropriate for the salt intake of an individual (such as those frequently observed in humans with heart failure) induce excessive collagen deposition in the heart. Techniques used will include small animal surgery and animal handling, histology, immunohistochemistry, molecular biology and cell culture.