Mouse models of human disorders have provided essential insights into disease pathogenesis, are an important resource to test potential therapeutic approaches, and in the case of polycystic kidney disease, they have made major contributions to the discovery that cysts can arise from dysfunction of renal cilia. However, for many investigators, using mouse models for their studies has major limitations associated with the expense and expertise required to generate and characterize the phenotype of a new mouse mutant or they have difficulty in obtaining an existing mutant necessary for their study. Therefore, one of the major goals of the Engineered Mouse Core (Core B) is to foster the use and availability of the mouse as a model system to study PKD related pathologies. We will accomplish this by providing RPKDCC investigators with a unique opportunity to generate hypomorphic or an allelic series of mutations in genes or regions of genes of interest and by establishing transgenic lines that express inducible forms of Cre recombinase within specific ductal epithelium of interest to PKD researchers. The generation of allelic series of mutations will facilitate structure-function studies and analysis of phenotype-genotype correlations. As a demonstration of the feasibility of our approach, the Core will focus in the initial year on identifying multiple mutations in mouse Pkhd1. These data will nicely complement ongoing studies with human ARPKD patients in the Clinical and Genetic Resource Core. The inducible Cre recombinase lines will permit disruption or activation of genes in specific cells of interest to the RPKDCC investigator in the context of a "normal" adult mouse. This important modification will allow the mutant mice to bypass lethality and the severe developmental abnormalities that have plagued many of the gene knockouts or early conditional mutations generated in the cystogenes. With these reagents, investigators can now analyze gene function in vivo in the context of a mature ductal epithelium of the adult. Furthermore, the mouse resources generated from this Core will be used for the isolation of constitutive or inducible mutant cell lines by the Cell Physiology Core for subsequent in vitro studies. Overall, the intention of the core is to provide unique resources that will help overcome barriers for RPKDCC investigators, so that they can utilize the mouse for in vivo studies or cell lines derived from them to understand the function of cystogenes in ductal epithelial cell physiology.