Novel Therapeutic Strategies for PKD

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Polycystic kidney diseases (PKD) affect greater than or equal too 500,000 patients in the US and > 6 million worldwide, but the only form of "therapy" is renal replacement by dialysis or transplantation. The most common and important renal malformations are genetic in origin. Autosomal dominant (AD)PKD has an incidence of greater than or equal too1:500 and accounts for greater than or equal too 7% of all patients on dialysis, while autosomal recessive (AR)PKD) has an incidence of greater than or equal too 1: 20,000 with a mortality of greater than or equal too50% in the newborn period and accounts for >5% cases of endstage renal failure in children. The overall goal of this program project is to establish a multidisciplinary team to develop and apply the expanding new understanding of the molecular cellular and physiological basis of polycystic kidney diseases to the development of novel, rational therapeutic approaches. The ultimate goal is to develop preventive and/or therapeutic treatments to slow disease progression and thus offer treatment that is at present lacking. Medical scientists from the Departments of Medicine, Pediatrics, Urology, Gene Therapy Institute and Cancer Center have established a critical mass with a multifaceted approach to study renal morphogenesis and malformations ranging from molecular, cellular, physiological, genetic and clinical approaches, thus constituting a combined basic and translational program. The five projects and two cores will be highly interactive and are scientifically integrated in a scheme that focuses on the regulation of the function of the PKD 1 gene product, polycystin by phosphorylation, Project 1; the role of polycystin- 1 in the control of renal morphogenesis, Project 2; the role of the WTl-target protein "sprouty" in cystic kidney devlopment, Project 3; the analysis of sodium and potassium transport in ARPKD, project 4; and the functional consequences of apical EGF receptor signalling in ARPKD, Project 5. The Core will provide and develop viral vectors, renal cell lines and organ cultures as well as transgenic, knock-out and other mouse models In addition, this Core will centralize services and functional assays including adhesion, migration, 3D gel tubulogenesis, embryonic mouse kidney organ culture and microinjections. These integrated studies will increase our understanding of the underlying biology of polycystic kidney diseases sufficiently to lead to testing of therapeutic approaches in human cells in vitro and mice in organ culture and in vivo by small molecule and/or gene therapy strategies.