PROJECT SUMMARY DISEASE MODELING UNIT The advent of high-throughput sequencing has allowed rapid discovery of the genetic causes of disease. However, our ability to translate these discoveries into therapeutics has not kept pace due, at least in part, to a lack of precise, predictive animal models which still serve as a critical step toward translating potential new treatments for use in the clinic. The mouse remains a near indispensable tool on the road to clinical application. Genetically accurate mouse models can be designed to recapitulate most human disease pathology and therefore allow for detailed studies and preclinical testing of novel therapeutics. JAX has a long history of developing and studying mouse models of human disease and the institutional commitment, scale, and expertise to build The Jackson Laboratory (JAX) Center for Precision Genetics (JCPG). Indeed, JAX is currently funded as one of three Pilot Centers for Precision Genetics, (U54 OD020351). The next iteration of the JCPG will build on the groundwork laid by this effort that was able to successfully move, within one grant cycle, from disease model development through completion of the preclinical work to now move toward clinical trials. The JCPG infrastructure now proposed refines, focuses and expands on the infrastructure and services that were essential to the successes of the previous pilot. The next JCPG will serve our existing diverse set of clinical collaborators even better and broaden access for an even larger portion of the biomedical community. The JCPG Disease Modeling Unit (DMU) is key to launching development of a new disease model. Working closely first with the Bioinformatics Core to establish an optimal genetic/genomic design the DMU will then guide each model through phenotypic characterization working in consultation with preclinical and clinical partners (JCPG Pre/CoClinical Core) to validate and establish the model before passing the new model to the Resource and Services Core for colony maintenance, preservation and worldwide distribution. The overall goal of the Disease Modeling Unit (DMU) is to refine the operation of the JCPG Cores into a single integrated, flexible, and cohesive disease modeling pipeline that can support the growing and diverse needs of the biomedical community. Many key components are already in place so the DMU will focus on building the program and project management infrastructure to integrate innovative new tools and analysis platforms. To accomplish this the DMU will: 1) build a comprehensive precision model development and characterization pipeline that has the scale, management infrastructure, and bioinformatics tools to support external nominations from the community, 2) leverage ongoing JCPG projects to “seed” the pipeline with “shovel-ready” high-impact projects that will allow refinement of pipeline structure and processes and, 3) develop and execute three Demonstration Projects to extend JCPG technical and scientific capabilities to support a wider array of disease modeling needs.