PROJECT SUMMARY (GMMC) The Genetically Modified Mouse Core (GMMC) has been an integral part of the CMSDLD at the Perelman School of Medicine, University of Pennsylvania since 1997. The GMMC is directed by Dr. Douglas Epstein, PhD, Professor and Vice Chair, Department of Genetics. Dr. Epstein is an experienced investigator with considerable expertise in technologies and experimental approaches that center on mouse models of disease, developmental genetics, and genome editing. An experienced technical team, led by Dr. Jean Richa, provides expertise in a full range of transgenic technologies, enabling the GMMC to regularly introduce new and improved services. GMMC services include the generation of genetically altered mice by direct genome editing (CRISPR/Cas9), DNA microinjection into fertilized oocytes to create transgenic lines, generation of chimeric mice via embryonic stem cell injection into blastocysts. The GMMC also carries out embryo re-derivation, embryo and sperm cryopreservation, in vitro fertilization (IVF), and centralized cryopreservation storage. The GMMC uses state-of- the-art laser conditioning of the zona to facilitate IVF and has intracytoplasmic sperm injection capability on-line to complement IVF services. Newly developed services during the current funding period include the major expansion of cryopreservation services with corresponding expansion of the cryopreservation facility, integration of CRISPR/Cas9 direct genome modifications with a newly established Perelman School of Medicine CRISPR core, and electroporation of DNA and RNA into embryos to increase throughput and decrease wait time for GMMC services. In the past 5 years, 32 CMSDLD investigators used GMMC services to generate 167 independent mouse lines (primarily by CRISPR/Cas9 editing) and to store 64 mouse lines (by cryopreservation). Usage is expected to stay the same, or increase over the next five years. Additional Institutional (non-CMSDLD) support is provided for equipment maintenance and facility infrastructure upgrades and maintenance. An extensive network of collaborations exists within the CMSDLD focusing on the use of genetically modified mouse models of digestive and liver diseases. These joint projects among CMSDLD members highlight the role of the GMMC not only as an essential technical resource but also as a key hub for collaborative research among CMSDLD investigators, as exemplified by the numerous joint publications and successful grant applications arising from mice generated, stored, and/or re-derived by the GMMC.