Project Summary/Abstract This proposal comprises a five year research and career development program for Dr. Vikas Gupta to achieve independence as an investigator in hepatobiliary diseases. Dr. Gupta is a physician-scientist who completed his training in an NIH-sponsored Medical Scientist Training Program. The proposed research and career development activities will occur at Weill Medical College of Cornell University within the Tri-Institutional region encompassing Memorial Sloan Kettering Cancer Center and Rockefeller University. To facilitate his goal of leading his own independent research group, Dr. Gupta will engage in a number of career development activities spanning the acquisition of new technical skills, didactic coursework, grant writing, workshops, mentoring, conference presentations, and support from a dedicated mentoring committee. He has laid out a clear timeline for these activities in addition to timing of subsequent publications and acquisition of funding. The combination of research and career development plans described in this proposal will allow the candidate to mature into a successful and independent physician-scientist. The research focus of the proposal is upon understanding the role of peribiliary mesenchymal derived Wnts in controlling columnar cholangiocyte proliferation and cellular identity/differentiation during homeostasis and disease, which builds upon previously published research by Dr. Gupta. Diseases of the large bile ducts such as primary sclerosing cholangitis and cholangiocarcinoma have had little therapeutic options outside of liver transplantation. The lack of advance is underscored by gaps in our understanding of large bile duct pathophysiology. An epithelium of columnar cholangiocytes lines the lumen of large bile ducts, which in turn are surrounded by a population of peribiliary mesenchymal cells (PMCs) which are Gli1+. How these two cell populations communicate with one another is crucial to understanding how fibrosing and cancerous diseases of the biliary tree arise. The main hypothesis of this study is that PMCs form a Wnt secreting niche that regulates the proliferation and cellular identify of cholangiocytes through paracrine effects and regulates their own cellular identity through autocrine effects. The first aim of this research proposal is to define how Wnts from PMCs and columnar cholangiocytes change with injury. The second aim is to understand the mechanism through which PMC derived Wnts controls proliferation and cellular identity during homeostasis. The third aim is dissect the role of PMC derived Wnts for proliferation and fibrosis after biliary injury. The experiments that are presented in this proposal will provide a new mechanistic understanding of the role of Wnt signaling in biliary pathophysiology. This work will have broad implications for how we understand biliary homeostasis and how to dissect fibrosing and cancerous diseases of the biliary tree.