Molecular pathophysiology of Pkd2 mutations

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DESCRIPTION (provided by applicant): Our long-term objective is ,to understand the pathophysiology of autosomal dominant polycystic kidney disease (ADPKD) as a basis for therapy. Autosomal dominant polycystic kidney disease (ADPKD) is the most common lethal monogenic genetic diseases of man, affecting approximately 1 in 1,000 individuals. ADPKD leads to cystic replacement of renal tissue and progressive renal failure, requiring renal replacement therapy in half of the cases by age 50. It is a systemic disease involving the kidney, liver, pancreas, arteries and the heart. Mutations in PKD1 and PKD2 cause almost all cases of ADPKD. PKD1 and PKD2 encode polycystin-1and-2 (PC1 and PC2), respectively. We have recently shown that PC1 acts as a G-protein coupled receptor and PC2 functions as a Ca2+permeable cation channel. PC1 and PC2 receptor channel complex play a critical role in mechanosensation of fluid flow shear stress. We have shown that native PC2 functions as a Ca2+ permeable cation selective ion channel in renal epithelial cells. Mostly recently, we have shown that PC2 channel, in concert with PC1, regulates cell cycle progression by serving as a membrane anchor and directly regulates the cytosol/nuclear translocation of Id2, a transcription regulator. The major object of this renewal proposal is to continue our studies on PC2 to understand the signaling pathways mediated by polycystins and the molecular mechanisms leading to cyst formation. We will focus on 5 lines of investigation: 1) we will characterize a germline Pkd2 knockout mice we recently generated; 2) we will generate adult PC2 knockout mouse models by disrupting the pore region of PC2; 3) we will determine the physiological significance of PC2-ld2 interaction; 4) we will develop kidney epithelial cell lines from Pkd2 mutants and their wild type littermates; 5) we will study the effect of PC2 mutation on PC2 mediated signaling pathway in cells and in vivo. These studies are likely to lead to new developments of therapies that may palliate or cure ADPKD.