Genetic Mechanisms of Polycystic Kidney Disease

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DESCRIPTION (provided by applicant): Our research program centers on understanding the molecular mechanism of autosomal dominant polycystic kidney disease (ADPKD). ADPKD is a heterogeneous disease. Mutations in two causal genes, PKD1 and PKD2, which have been mapped to chromosomes 16p 13.3 and 4q21-23, respectively, result in similar clinical manifestations. Although considerable progress toward understanding the disease mechanisms and some functions of its causal gone products, polycystin-1 and -2 has been made, the cellular events resulting from PKD1 or PKD2 mutations that cause cystogenesis and the functional relationship between the polycystins remain poorly defined. To further dissect and characterize the biological functions of the polycystins, we have begun to generate mouse models with a 'conditional' targeted mutation in Pkd2 that can be induced temporally and spatially by CreloxP and Flpe-FRT-mediated systems. In parallel, we have also proposed to create a mouse model with an allele (Pkd2flox stop) in which the expression of Pkd2 can be conditionally restored using the Cre-loxP system. Together with our other Pkd mutant models, such as the null-Pkdl and/or -Pkd2, the conditionally 'turn-on' and 'turn-off' models will provide the incomparable tools we need to address several unclear questions. These include whether or not the restoration of polycystin-2 mediated by the Cre-loxP system in mice bearing the Pkd2 restorable allele is able to rescue cystic phenotypes or arrest the progression of ADPKD in the disease model (e.g., Pkd2WS25/-), how fast is the progressional rate of cystic disease in ADPKD, and what are the extrarenal functional roles of polycystin-2, and how does the cystogenesis depend on loss of heterozygosity. Moreover, the mice with a genetically combinatorial allelic series will enable us to determine if polycysin-1 and -2 have a completely overlapping functions during mouse embryogenesis and development, and if the mice with trans-homozygous Pkdl and Pkd2 leads to severer developmental defects than those seen in either alone. By studying these mice and the cell lines derived from them, we will gain further insights into the role of polycystin-2 in the initiation and progression of cyst formation and the regulation of renal epithelial cell physiology. We will also learn more about the relationship between polycystin-1 and -2 during the cystogenesis of ADPKD, and will hopefully be able to establish a therapeutic basis for this disease.