This application describes a comprehensive training program designed to transition Dr. Ryan from a mentored scientist into an independent investigator in the area of Pediatric Gl and Hepatology studying the role of the Notch signaling pathway in liver and bile duct development. Dedicated sponsors and a carefully chosen research advisory committee will assist and guide Dr. Ryan in this process. The Children's Hospital of Philadelphia and nearby University of Pennsylvania campus provide a fertile learning environment with many investigators on campus studying liver disease and Notch signaling. The environment lends itself to frequent interactions and collaborations. Dr. Ryan's training program will include seminars and conferences as well as a research program designed to allow Dr. Ryan to develop the skills and experience necessary to transition to independence as a physician scientist. Cholestatic liver disease is a significant cause of morbidity and death, yet little is known regarding the molecular regulation of bile duct growth and remodeling. Mouse models and cell culture systems provide excellent means with which to study the mechanisms that control liver and bile duct growth and remodeling. We have discovered a unique phenotype of bile duct proliferation in mice heterozygous for mutations in the Notch pathway ligand, Jag1, and modifier genes, Lunatic fringe (Lfng), Radical fringe (Rfng), and Manic fringe (Mfng). The proposed aims are designed to delineate the time course over which the phenotype develops, analyze Notch receptor-ligand interactions and elucidate the mechanisms underlying the bile duct proliferation. To achieve these aims, we will utilize in vivo mouse models as well as derive primary cholangiocyte cell lines from the double heterozygous mice. Relevance: The data gained from the proposed experiments will contribute to the understanding of bile duct growth and remodeling. This knowledge will potentially lead to directed therapies for cholestatic liver disease in adults and children and insight into the pathogenesis of these disorders.
