CELL BIOLOGY OF POLYCYSTIC KIDNEY DISEASE PROTEINS

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The polycystic kidney diseases ('PKD') comprise a range of genetically diverse disorders characterized by the development of multiple fluid-filled kidney cysts and progression to renal failure. Our long-term goal is to understand the molecular mechanisms underlying cyst formation and to develop rational therapies for PKD patients. While the autosomal dominant forms of the disease affect mostly adults, the autosomal recessive form typically affects children and has an incidence of 1 in 20,000 newborns. Recent Identification of PKHD1, the gene mutated in autosomal recessive PKD, has made the study of its gene product - 'fibrocystin' or 'polyductin' ('FPC') - possible for the first time. The Principal Investigator has previously worked extensively on the dominant forms of PKD and has shown that the products of the genes mutated in this form (polycystins -1 (PC1) and -2 (PC2)) are localized in the primary cilia of renal epithelial cells and function as mechanosensors. Preliminary data from the Principal Investigator's group reveal that FPC is localized to the cilium of canine kidney epithelial cells with concentration in the basal body/centrosome area and appears to mediate mechanosensation through interactions with polycystin protein complex. In this proposal, the Principal Investigator plans to define the FPC/polycystin protein complex and validate the hypothesis that FPC contributes to mechanosensation in renal epithelia. By using a combination of specific cellular assays, she also proposes to study the role of FPC in cell cycle, and to determine the subcellular locations of FPC function. The studies will likely reveal the functional relationship between the autosomal recessive PKD protein and the autosomal dominant PKD proteins, and will provide new insights into disease mechanisms which will likely lead to new strategies for therapy.