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

项目总结 作为对“NOT-RM-20-015”的回应，我们建议对杰克逊实验室进行紧急竞争性修订 基因敲除老鼠表型项目(KOMP2)，以开发下一代精密鼠标模型 SARS-CoV2感染的机制发现和新冠肺炎疾病治疗方法的发现。 全球对新冠肺炎大流行的反应引发了对以下动物模型的需求激增 了解SARS-CoV-2感染的基本生物学和病理学以及临床前的发展 新的治疗策略。最近有报道称，几种小鼠模型对不同的 SARS-CoV-2感染的程度。然而，考虑到患者结果的多样性，任何一只小鼠模型 标准近交系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，我们建议创建第二代小鼠模型 整合不同遗传背景的平台，用于表征SARS-CoV-2感染的变异 临床相关疾病的动态和发展。拟议中的项目将迅速提供 拥有迫切需要的资源来将新冠肺炎疾病结局的可变性联系起来的研究社区 具有潜在的宿主遗传特征，并用于开发针对个体治疗的精确疗法 有耐心的。我们的具体目标是：1)创建一组针对SARS-CoV-2的遗传多样性转基因模型 感染性；2)表征感染性、表型反应、疾病转归和转录组 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 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.