My research group is primarily involved in the genetic, biochemical and cellular analysis of polycystic kidney disease (PKD). The PKDs are a group of inherited disorders that result in cyst development in the kidney (and often elsewhere) ultimately resulting in renal failure. We have used positional cloning approaches to identify genes causing the two major forms of PKD: autosomal dominant (ADPKD) and autosomal recessive (ARPKD). ADPKD is a common (frequency of 1/400-1000), late-onset disorder that accounts for ~5% of patients requiring kidney transplant or dialysis at an annual cost of >$750 million in the US. ARPKD is usually an infantile disease that is associated with a high level of neonatal death and childhood renal failure.

A major focus of the laboratory now is to characterize mutations that lead to these disorders and correlate the types of changes to the disease presentation and progression. Using genomic approaches, genes encoding related proteins have also been identified and characterized. Other approaches that we are taking to study these disorders are to develop animal models that either have a disrupted copy of the endogenous gene or which over-express a transgene. These systems allow the normal function of the proteins in renal (and other organs) development to be assessed and to analyze the mutational mechanism. We are also exploring the cellular and subcellular localization of the PKD proteins and have shown, in common with other PKD proteins, that an important site of expression is on the primary cilia of epithelial cells. The overall aim of these studies is to understand the normal function of the PKD proteins and define the pathobiology associated with mutations so that rational therapies can be developed for these disorders.