PROJECT SUMMARY (GENETICALLY MODIFIED MOUSE CORE) The significant incidence of digestive, liver and pancreatic diseases in the American population demands continued exploration of a broad array of corresponding mechanistic pathways, pathophysiologic sequelae, and potential therapeutic approaches. In many cases these investigations can only be accomplished, or can be accomplished most efficiently and relevantly, using model systems established in intact animals. The use of mouse models in these pursuits is now well established for their power, feasibility, flexibility, and enormous potential. Creation of such models, by targeted alterations of the mouse genome, is an essential component of an overall research effort in understanding normal functions and pathologic perturbations in the digestive tract, liver, and pancreas. The Genetically Modified Mouse Core (GMMC) provides investigators of the University of Pennsylvania Center for the Molecular Study of Digestive and Liver Diseases (CMSDLD) with the ability to carry out these technologically-demanding studies in a cost effective and efficient manner and enhance the rigor and relevance of these approaches. The GMMC has a dedicated and highly skilled staff that applies state-of-the-art equipment and techniques, and the facility consists of a microinjection suite, an adjacent dedicated cage room, and an off-site and highly secure cryopreservation storage facility. Major services available to CMSDLD investigators include the generation of transgenic mice by DNA pronuclear injection, creation of chimeric mice by ES cell injection into blastocysts, and direct genome mutation, editing, and modification via the use of targeted endonuclease (TALEN and Crispr-CAS technologies); these are complemented by the genotyping of founder mice, assisted (in vitro) fertilization, cryopreservation, long-term cryostorage, and shipping of frozen embryos or sperm to/from other facilities. To provide these services, the GMMC utilizes multiple microinjection platforms, laser-assisted technologies, state-of-the-art cryopreservation approaches, and highly efficient line re-derivation pipelines. All functions, from ordering services, to following workflow, to storing and sending out lines, are on-line and can be monitored in real-time. These efforts by the GMMC contribute substantially to the overall productivity of CMSDLD investigators and enhance the rigor and relevance of their studies to the mechanisms of digestive, liver, and pancreatic diseases in physiologically- intact mammalian systems. Moreover, the GMMC enhances interactions and collaborations for CMSDLD investigators and lowers the technical and financial barriers that would otherwise impede the application of these approaches for individual investigators. Thus the Genetically Modified Mouse Core contributes greatly to the research efforts of the CMSDLD.