The Jackson Laboratory Knockout Mouse Production and Phenotyping Project (JAX KOMP2)

PROJECT SUMMARYIn response to "NOT-RM-20-015", we propose an urgent competitive revision to The Jackson LaboratoryKnockout Mouse Phenotyping Project (KOMP2) to develop the next generation of precision mouse models formechanistic discovery of SARS-CoV2 infection and therapeutic discovery of COVID-19 disease treatments.The worldwide response to the COVID-19 pandemic has triggered a surge in demand for animal models tounderstand the underlying biology and pathology of SARS-CoV-2 infection and for the preclinical developmentof novel therapeutic strategies. Several mouse models have recently been reported that respond with varyingdegrees to SARS-CoV-2 infection. However, given the diversity of patient outcomes, any one mouse model ona standard inbred genetic background does not reflect the impact of host genetic context on SARS-CoV-2infection and response to treatment. We therefore propose to create a second-generation mouse modelplatform incorporating diverse genetic backgrounds, to characterize the variation in SARS-CoV-2 infectiondynamics and the development of clinically-relevant disease. The proposed project will rapidly provide theresearch community with an urgently needed resource for linking the variability in COVID-19 disease outcomewith underlying host genetic features, and for developing precision therapies tailored to treat the individualpatient. Our Specific Aims are: 1) To create a panel of genetically diverse transgenic models for SARS-CoV-2infection; 2) To characterize infectivity, phenotypic response, disease outcome, and transcriptomeheterogeneity of these models; and 3) To distribute these models and our outcome data to the scientificcommunity.