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

项目摘要 作为对“NOT-RM-20-015”的回应，我们对杰克逊实验室提出了一项紧急竞争性修订 敲除小鼠表型分析项目（KOMP 2），开发下一代精确小鼠模型， SARS-CoV 2感染的机制发现和COVID-19疾病治疗的治疗发现。 全球对COVID-19大流行的反应引发了对动物模型的需求激增， 了解SARS-CoV-2感染的基础生物学和病理学，并进行临床前开发 新的治疗策略。最近报道了几种小鼠模型，其响应于不同的 感染SARS-CoV-2。然而，考虑到患者结局的多样性，任何一种小鼠模型， 标准的近交遗传背景不能反映宿主遗传背景对SARS-CoV-2的影响 感染和治疗反应。因此，我们建议建立第二代小鼠模型 整合不同遗传背景的平台，以表征SARS-CoV-2感染的变异 动态和临床相关疾病的发展。该项目将迅速提供 研究界迫切需要将COVID-19疾病结果的可变性联系起来的资源 与潜在的宿主遗传特征，并开发精确的治疗方法， 病人我们的具体目标是：1）建立一组遗传多样性的SARS-CoV-2转基因动物模型 感染; 2）表征感染性、表型应答、疾病结果和转录组 这些模型的异质性;以及3）将这些模型和我们的结果数据分发给科学家， 社区

PROJECT SUMMARY 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.