Characterization of the Murine pcy Mutation

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Polycystic kidney diseases (PKD) are among the leading causes of progressive renal failure in children and adults. Currently, there is no known therapy that can inhibit or retard the progression to renal failure in PKD patients. Despite the recent molecular identification of PKD1 and PKD2, the two genes most commonly mutated in human PKD, the genetics and pathogenesis of renal failure in PKD remains poorly understood. Homozygous pcy/pcy mice develop a slowly progressive form PKD that has many characteristics resembling human PKD. Understanding the molecular lesion in pcy mice will provide important additional insights into the genetics and pathogenic pathways involved in the development of renal failure in PKD. This proposal aim to elucidate the molecular defect in the pcy mouse and to improve our understanding of modifier genes that determine the severity of the renal cystic disease phenotype. Towards the identification and characterization of the pcy mutation at the molecular level, we will (1) isolate the minimal pcy interval in BACs contigs using the RPCI-23 mouse genomic library for sequencing by the NIH mouse genome sequencing project and (2) identify the pcy gene by systematically characterize; candidate genes located within our pcy interval. Towards improving our understanding of modifier genes that regulates the severity of the polycystic kidney disease phenotype, we will (1) isolate the two mapped modifier loci into separate congenic strains using marker assisted selective breeding approaches and (2) use gene expression profiling to catalog the set of genes that are differentially expressed in the kidneys of congenic mice with the mild PKD and in the kidneys of age matched congenic mice with the severe PKD.