Research Trial:
Researchers at Monash Medical Centre, Clayton in collaboration with the World Health Organisation are trialing a new male contraceptive method. We need healthy couples living in a stable relationship and not planning pregnancy for two years.
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1. Apo2L/TRAIL as a regulator of cell death in transformed cells

Supervisors: Dr Steve Bouralexis and A/Prof Matthew Gillespie

Contact: steve.bouralexis@princehenrys.org;matthew.gillespie@princehenrys.org

Disturbances in mechanisms that direct abnormal cells to undergo cell death frequently and critically contribute to tumorigenesis, yielding a logical target for potential therapeutic intervention. There is currently heightened interest in the extrinsic apoptosis pathway, with several pro-apoptotic receptor agonists (PARAs) in development. One of these PARAs include the recombinant ligand Apo2L/TRAIL.Gene array studies comparing cancer cells that respond to Apo2L/TRAIL compared to those that do not respond have identified several genes that may be involved in determining cell fate. This project examines the role of these genes with a particular emphasis on overcoming Apo2L/TRAIL resistance.

Skills: The student will learn commonly used molecular biology techniques, such as: gene knock-down (Si-RNA), gene over-expression in cell lines, semi-quantitative and real time PCR, western blotting, tissue culture, FACS, Immunofluorescence and assays critical for determining cell viability and apoptosis.

2. Inhibition of osteoclasts to block cancer and inflammation induced bone loss.

Supervisors: Dr Julian Quinn and A/Prof Matthew Gillespie

Contact: julian.quinn@princehenrys.org

Many common diseases cause loss of bone, either locally in focal lesions, or more generally throughout the skeleton. Bone destruction is a common feature of cancers that invade bone (e.g. breast cancer) but is also seen in inflammatory diseases both chronic (e.g. rheumatoid arthritis) and in acute bacterial infections. Central to all bone destruction in health and disease is the osteoclast cell, which is related to macrophages but is specialized to resorb (destroy) bone. Both in inflammation and in cancer, the number of osteoclasts increases greatly, resulting in bone loss. It is critical to block this bone destruction, and to do so in a way that does not impair bone formation as many current anti-osteoclastic therapies do.

Our research has focused upon the identification of novel factors that influence osteoclast formation and activity as well as understanding the processes that control how osteoclasts form and activate. We have identified a number of new molecules that can inhibit osteoclast differentiation from haematopoietic progenitors (e.g. IL-4, IL-12, IL-18, sFRP-1 and OCIL) and also identified a number of therapies (anti-cancer and anti-diabetic) that unfortunately stimulate osteoclast numbers. We need determine the mechanism by which these inhibitors and stimulators work, specifically whether they alter osteoclast progenitor commitment, and how cells of the immune system may exacerbate osteoclast formation.

You will gain experience in tissue culture assays, protein and mRNA analysis and methods of cell marker expression analysis.

3. Factors affecting osteoblast differentiation

Supervisors: Dr Vicky Kartsogiannis and A/Prof Matthew Gillespie

Contact: vicky.kartsogiannis@princehenrys.org

We have performed gene array studies using an osteoblast-like stromal cell line to identify PTH-responsive genes in mature osteoblasts. Arrays were performed using RNA extracted at 1, 6 and 24 hrs to identify immediate early, early and late genes. This project seeks to determine the role of these PTH target genes in osteoblast differentiation and in normal bone physiology. We are particularly focusing our attention on the role of the immediate early genes determining their effects upon osteoblast, adipocyte and osteoclast differentiation, using a variety of in vitro models (overexpression, siRNA, and retroviral delivery) and animal models where appropriate. Techniques will include: cell culture, molecular biology (RNA isolation, RT- PCR, Southern / Northern hybridisation), immunohistochemical techniques.