Dunedin School of Medicine

Current research projects

Genetic Pathways of Melanoma, Cell Survival and Invasion

In this project we are investigating PAX3 and Mitf as important factors required for the survival or invasion of melanoma cells. If true then PAX3 and Mitf could be excellent strategic targets for melanoma therapy. Malignant melanomas are notoriously aggressive malignant neoplasm of melanocytes, and show expression of markers of early development. The incidence of melanoma is particully high in New Zealand and Australia, indeed the highest in the world. Reliable incidence and mortality figures from the United States, Australia, New Zealand, and Scotland indicate that the incidence and mortality of malignant melanoma is increasing worldwide. Read more...

The Role of PAX2 and PAX8 in Cancers of the Urogenital Tract

Enhanced cell survival and/or proliferation leads to cancer, and other hyperproliferative diseases. Changes in gene expression play central roles in these diseases, affecting outcomes such as cell survival, attachment, cell-cell contact, differentiation status, metastasis, and many other changes. Changes in gene expression act alongside gene mutations to change the cell's internal milieu, and clearly play an important role in cancer. The present challenge is to identify changes in gene expression that are associated with the cause of cancer, rather than being a consequence of cancer onset.

Rearrangements of PAX3, PAX5 and PAX8 have been implicated in cancers, such as alveolar rhabdomyosarcoma, lymphoma, acute lymphocytic leukaemia, and thyroid carcinoma. The PAX3 gene, for example, is fused to the FKHR gene in translocations involving chromosomes 2 and 13; t(2;13)(q35;q14) found in alveolar rhabdomyosarcoma. We are presently studying the role of PAX2 and PAX8 in renal cell carcinomas and other urogenital cancer types. A principle methodology that we are using is siRNA knockdowns in culture cells. We are also begining to develop lentiviral systems for gene knockdown and are addressing mechanisms of PAX function. Read more...

Role of PAX2 in Renal-Coloboma Syndrome/ the Role of PAX Genes in Eye, Urogenital Tract, and Central Nervous System Development

Congenital abnormalities of the kidney and urinary tract are common in the human population, occurring at a frequency of 1-2 per hundred live births. It is thought that a high proportion of these congenital abnormalities occur as the result of a breakdown in the mechanisms regulating development. In 1995 we showed that PAX2 mutations cause renal-coloboma syndrome, and since then we have characterized a number of PAX2 mutations and analyzed the role of PAX2 in mammalian kidney development. Abnormal regulation of cell growth and survival underlies many human diseases, including cancer, developmental abnormalities, and degenerative diseases. Therefore the major aim of this project is to uncover the cellular pathways regulated by PAX genes that dictate the growth or survival of cells during development and disease.

In humans and mice, PAX2 mutations cause kidney, eye, and central nervous system abnormalities. It appears that the PAX2 protein coordinates normal developmental pathways by regulating the expression of downstream genes. Aberrant PAX2 expression consequently disrupts normal gene expression resulting in abnormal development. Read more...

Polycystic Kidney Disease

Autosomal dominant polycystic kidney disease (ADPKD) is the most common, potentially lethal, monogenic disease in humans. The incidence is about 1:500, affecting approximately 4-7,000 individuals in New Zealand and 10 million worldwide. In most families, ADPKD is caused by heritable mutations of either the PKD1 (85%) or PKD2 (10-15%) genes. 95% of ADPKD carriers experience renal failure by age 70, and there is no effective treatment. In the present project we are investigating the role of PAX2 in polycystic kidney disease. Read more...

Gene-targeted Therapies for Cancer and Polycystic Kidney Disease/Gene Delivery Systems

The delivery of oligonucleotides, including siRNAs across lipid bilayers of cells presents great challenges because of their membrane impermeance. SiRNAs are polyanions and unassisted permeation across lipid bilayers is negligable. Double stranded RNA can be delivered to C.elegans by feeding or soaking, but effective delivery of siRNAs and other oligonucleotides to mammalian cells is still under intense investigation. Typically oligonucleotides are introduced into mammalian cells in conjunction with cationic liposomes that mask their negative charge and "smuggle" them into the cytoplasm.

The longer term aim of this project is to develop novel oligonucleotide delivery systems that could be used in vivo, hopefully in future for the treatment of human diseases such as cancer and polycystic kidney disease. Read more...