Pathogenesis of wpk-induced Renal and Cerebral Disease

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DESCRIPTION (provided by applicant): Inherited renal cystic diseases, including the various forms of polycystic kidney disease (PKD) are prevalent conditions that usually affect multiple organs. There are numerous human genes, which when mutated, lead to a variety of cystic phenotypes with variable extrarenal manifestations. There are several rodent models, some with mutations in known human PKD genes. Others models represent rodent PKD genes, but could also function as modifier genes for other rodent models and human PKD. However, all of these models have made important contributions to our knowledge of PKD. The present proposal will isolate the rat wpk gene which causes renal changes similar to human autosomal recessive PKD. Additionally, affected rats have a cerebral defect (hydrocephalus with agenesis or hypoplasia of the corpus callosum) similar to that seen in human oro-facial-digital, genitopatellar and cerebro-renal-digital syndromes. Currently we localized the wpk gene to an 8cM region of rat Chromosme 5, a location known to harbor a rodent PKD modifier locus. The long term goal of our research is to identify genes and pathways involved in renal cystogenesis in order to develop therapeutic interventions. We hypothesize that the wpk gene represents a human PKD gene and/or a modifier locus. Our Specific Aim is to: 1) Identify, clone and characterize the wpk gene by crossing the Wistar-wpk rat with inbred Brown Norway rats and using chromosomal markers to localize the gene. Aside from the positional approach, we will identify candidate genes from with the 8cM regions to test and screening rat ESTs from that region. Microarrays will be evaluated for misexpressed mRNAs derived from genes within this 8cM target region. The identification of the wpk gene and its protein product will allow insight into cystogenesis as well as important information on shared pathways in kidney and brain development. This model and the wpk gene are important for 2 major reasons: a) they have cystic disease and unique cerebral pathology similar to a few human conditions and b) the wpk lies in a chromosomal region known to modify other rodent forms of PKD and may be an important modifier locus for PKD (rodent and human).