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Projects available: Ovarian cancer1. Identification of plasma protein markers suitable for the early detection of ovarian cancer Supervisors: Associate Professor David Robertson, Dr. Peter Stanton (Male Reprodutive Endocrinology and Metabolism Group) Detection of ovarian cancer at its earliest stages provides a good prognosis for full recovery; however survival diminishes greatly when the cancer spreads beyond the ovary. Early detection of ovarian cancer is difficult owing to ill defined and vague symptomology and current ovarian cancer markers lack the accuracy needed to provide a suitable early detection test. There is thus the need to develop appropriate tests, however, our knowledge related to the events that cause ovarian cancer is very limited. We propose to use a new proteomic approach using a series of novel fractionation procedures to identify a number of candidate blood protein markers produced by ovarian cancers which may be suitable as early cancer markers. The study will consist of two parts. Part I will be directed to establish the appropriate methodologies to fractionate the proteins in plasma, reducing its complexity, and subsequently to identify potential candidate proteins that are present in plasma from women with ovarian cancers but not present in healthy women. In order to identify cancer-specific proteins, plasma from healthy women will be compared with plasma and ascites fluid (which surrounds the tumour), and the ovarian tumour cells within this fluid, from women with ovarian cancer. Part II will consist of the assessment of these candidate proteins as suitable early cancer markers. This project will be facilitated by recent methodological advances in the area of proteomics which will enable the detection of >1000 proteins in plasma. The identification of cancer-specific markers in plasma which can be detected in the early stages of ovarian cancer will provide the basis for the development of a screening test for its early detection and consequently a better prognosis for women with this disease. Women would thus be able to undergo regular screens for ovarian health in the same way as is currently possible with the breast and cervix.
2. Discriminating the roles of inhibin A and B in reproductive systems Supervisor: Dr. Craig Harrison Inhibins, heterodimers of related α-and β-subunits, antagonise the actions of TGF b ligands that utilize activin type II receptors as part of their signalling complex. Inhibin A and B negatively regulate the production and secretion of follicle stimulating hormone (FSH) from the anterior pituitary, control intragonadal events including ovarian follicle development and steroidogenesis, and act as tumor suppressors in the gonads and adrenal cortex. The expression patterns of the inhibin isoforms are sexually, spatially and temporally dimorphic suggesting that inhibin A and B may be functionally/mechanistically distinct. The implications for reproductive physiology and pathophysiology of a distinct inhibin B mechanism of action are significant. It would identify potential molecular targets for the development of therapeutic means for modulating fertility. In addition, an understanding of the mechanisms involved in inhibin A and B actions will enhance the management/ monitoring of reproductive disorders and possibly identify biomarkers with improved sensitivity and specificity.
3. Inhibin and premature ovarian failure Supervisor: Associate Professor David Robertson A number of modified inhibin forms have now been identified in a subgroup of women with premature ovarian failure. We hypothesise that these modified inhibin forms will have reduced bioactivity leading to a faster decline in the ovarian follicle supply and thus premature loss of follicles however their biological activities are unknown. We are proposing to produce this modified inhibin form by recombinant methodologies and test its biological activity in a variety of systems in order to substantiate this hypothesis.
4. Activin type II receptor antagonists: mechanism of action and biological applications Supervisor: Dr. Craig Harrison Activins, members of the TGF- b superfamily, are important pleiotropic regulators of diverse cellular functions, differentiation and proliferation that, of necessity, are precisely constrained by multiple mechanisms. Despite these constraints a deregulated activin signalling pathway has been implicated in a variety of disorders, including fibrosis, cachexia and cancer. These observations highlight a growing need for the development and therapeutic use of exogenous antagonists that can block activin signalling. We have recently developed the first activin type II receptor antagonist (activin-M108A) and have shown that it is capable of blocking signalling in vitro by activin and the related ligand, myostatin. Wehypothesise that activin-M108A and related antagonists will inhibit the in vitro and in vivo responses of all TGF-β superfamily members that signal via activin type II receptors. We are currently assessing the effects of the activin receptor antagonist in three murine disease models: (1) Mouse cirrhosis model; (2) Inhibin-deficient mouse model; and (3) mdx mouse model of muscular dystrophy. If the blockade of the activin signalling pathway by activin-M108A decreases the morbidity and mortality associated with these murine diseases, then we envisage that activin type II receptor antagonists will also be beneficial in a number of human disease settings. |
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