Overall Project Summary/Abstract (Center for Gene Therapy of Cystic Fibrosis) For the past 21 years, this P30 Center for Gene Therapy of Cystic Fibrosis has focused on developing effective treatments for cystic fibrosis (CF) through an increased understanding of disease pathogenesis, the identification of relevant cellular targets for gene manipulation, and the development of technologies capable of effectively delivering or editing the CFTR gene in vivo. The creation of multiple types of CF pig and ferret models had led to an expansion of CF research over the past 5-year funding period. While during previous funding cycles CF lung research has been one focus area and within the scope of these P30 CF Centers, we have also greatly expanded research in other areas directly within the NIDDK mission. These areas of research will be further expanded in this application through the Center's Research Cores and the focus of faculty research areas. These areas include research on CF pancreatic disease and its similarities and differences to other forms of juvenile pancreatitis, cystic fibrosis-related diabetes (CFRD) research, CF gallbladder disease, and CF intestinal disease. Many of these areas were already strengths during the previous funding period. Furthermore, the creation of the tools required to interrogate CF disease processes in organs like the pancreas have been enabled by new genetic engineering approaches in ferrets through the Center's Animal Models Core. The Center has productively fostered CF research through the following mechanisms. 1) The Center's Pilot and Feasibility Program, which has sponsored 66 pilots over the previous 21 years of funding, has brought numerous new Members and expertise into the Center, and has fostered the maturation of talented junior Associate Members to independent tenure-track faculty. 2) The establishment or expansion of several core facilities (Vector Core, Cell and Tissue Core, Comparative Pathology Core, Animal Models Core, and Clinical Core) devoted to CF research has provided Center investigators with specialized vectors, CF model systems (human, pig, ferret and mouse), and approaches that are testing important hypotheses about CF pathogenesis and developing effective therapies. These resources have also enabled the Center to serve as a resource for the distribution of viral vectors and CF pig and ferret resources to numerous outside institutions. 3) Expansion of the number of CF ferret and pig models that develop lung, pancreatic, gallbladder and intestinal abnormalities like those observed in CF patients has greatly facilitated research by Center Members. 4) The Center's Enrichment Programs have fostered interdisciplinary interactions and training. 5) Establishment of formal internal and external mechanisms for review of the Center, the Cores, and the Pilot and Feasibility projects has ensured a high level of excellence and the most appropriate utilization of the Center's resources. In summary, the Ce...