In response to ?NOT-RM-20-015?, we propose an urgent competitive revision to The Jackson Laboratory Knockout Mouse Phenotyping Project (KOMP2) to develop the next generation of precision mouse models for mechanistic 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 to understand the underlying biology and pathology of SARS-CoV-2 infection and for the preclinical development of novel therapeutic strategies. Several mouse models have recently been reported that respond with varying degrees to SARS-CoV-2 infection. However, given the diversity of patient outcomes, any one mouse model on a standard inbred genetic background does not reflect the impact of host genetic context on SARS-CoV-2 infection and response to treatment. We therefore propose to create a second-generation mouse model platform incorporating diverse genetic backgrounds, to characterize the variation in SARS-CoV-2 infection dynamics and the development of clinically-relevant disease. The proposed project will rapidly provide the research community with an urgently needed resource for linking the variability in COVID-19 disease outcome with underlying host genetic features, and for developing precision therapies tailored to treat the individual patient.
Our Specific Aims are: 1) To create a panel of genetically diverse transgenic models for SARS-CoV-2 infection; 2) To characterize infectivity, phenotypic response, disease outcome, and transcriptome heterogeneity of these models; and 3) To distribute these models and our outcome data to the scientific community.
The Knockout Mouse Phenotyping Program (KOMP2) seeks to create an encyclopedia of gene function for the ~20,000 genes in the mouse and to ultimately create a resource for understanding gene function in humans. The Jackson Laboratory (JAX) will contribute to this goal by efficiently generating knockout lines and sharing functional data for 1,500 mouse genes. The JAX team will enhance the value of these data by linking them with current genetic and biological knowledge, enabling the scientific community to discover the roles of these genes in human health and disease.
|Rozman, Jan; Rathkolb, Birgit; Oestereicher, Manuela A et al. (2018) Identification of genetic elements in metabolism by high-throughput mouse phenotyping. Nat Commun 9:288|
|Meehan, Terrence F; Conte, Nathalie; West, David B et al. (2017) Disease model discovery from 3,328 gene knockouts by The International Mouse Phenotyping Consortium. Nat Genet 49:1231-1238|
|Karp, Natasha A; Mason, Jeremy; Beaudet, Arthur L et al. (2017) Prevalence of sexual dimorphism in mammalian phenotypic traits. Nat Commun 8:15475|
|Samuelov, Liat; Li, Qiaoli; Bochner, Ron et al. (2017) SVEP1 plays a crucial role in epidermal differentiation. Exp Dermatol 26:423-430|
|Bowl, Michael R; Simon, Michelle M; Ingham, Neil J et al. (2017) A large scale hearing loss screen reveals an extensive unexplored genetic landscape for auditory dysfunction. Nat Commun 8:886|
|Sundberg, John P; Dadras, Soheil S; Silva, Kathleen A et al. (2017) Systematic screening for skin, hair, and nail abnormalities in a large-scale knockout mouse program. PLoS One 12:e0180682|
|Snyder, Elizabeth M; McCarty, Christopher; Mehalow, Adrienne et al. (2017) APOBEC1 complementation factor (A1CF) is dispensable for C-to-U RNA editing in vivo. RNA 23:457-465|
|Peterson, Kevin A; Beane, Glen L; Goodwin, Leslie O et al. (2017) CRISPRtools: a flexible computational platform for performing CRISPR/Cas9 experiments in the mouse. Mamm Genome 28:283-290|
|Teboul, Lydia; Murray, Stephen A; Nolan, Patrick M (2017) Phenotyping first-generation genome editing mutants: a new standard? Mamm Genome 28:377-382|
|Brophy, Patrick D; Rasmussen, Maria; Parida, Mrutyunjaya et al. (2017) A Gene Implicated in Activation of Retinoic Acid Receptor Targets Is a Novel Renal Agenesis Gene in Humans. Genetics 207:215-228|
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