Generating Novel Humanized Mouse Models for in vivo COVID19 Mechanism Studies and Therapeutics Tests

项目总结 COVID19大流行以前所未有的速度在全球蔓延， 毁灭。随着美国感染人数超过140万人，这一数字令人眼花缭乱 关于SARS-CoV-2感染哪些组织以及如何感染的信息量令人困惑 引发灾难性的免疫反应和组织破坏。此外，随着快速的 候选疗法的数量不断增加，迫切需要能够 忠实地概括了人类疾病，并可扩展，为临床前测试提供动力。 我们将利用我们在老鼠遗传学方面的广泛专业知识来产生两种新的老鼠模型 在选定的细胞类型/组织中表达人类病毒受体ACE2(HACE2) 或在小鼠内源性ACE2表达模式中。HACE2基因的表达将 允许有效的SARS-CoV-2感染。我们将使用受感染的人源化小鼠来解剖 柯萨奇病毒19从最初感染宿主细胞到抗病毒和促炎的进展 使用单细胞方法对急性呼吸窘迫综合征的发展作出反应 例如单细胞RNAseq。同时，我们还将使用受感染的人源化小鼠来测试 FDA批准的候选药物在阻止COVID19方面的有效性。我们 预计这些人性化的鼠标模型将成为大量 COVID的研究方向在PAR-20-177中被列为高度优先领域。

PROJECT SUMMARY The COVID19 pandemic has spread across the globe with unprecedented speed and devastation. With infected individuals rising past 1.4 million in the US, there is a dizzying amount of information causing confusion around which tissues SARS-CoV-2 infects and how it triggers catastrophic immune response and tissue destruction. Furthermore, with the rapidly increasing number of candidate therapies, there is an urgent need for animal models that faithfully recapitulate the human disease and is scalable to provide power for preclinical testing. We will use our extensive expertise in mouse genetics to generate two novel mouse models that express human viral receptor ACE2 (hACE2) in either selected cell types/tissues of interest or in the endogenous pattern of ACE2 expression in mice. Expression of the hACE2 gene will allow efficient SARS-CoV-2 infection. We will use infected humanized mice to dissect the progression of COVID19 from initial infection of host cells, to antiviral and pro-inflammatory responses, to development of acute respiratory distress syndrome, using single cell approaches such as single cell RNAseq. In parallel, we will also use infected humanized mice to test the effectiveness of candidate FDA approved drugs for their effectiveness in halting COVID19. We expect that these humanized mouse models will be valuable platforms for a large number of COVID research directions listed as Areas of High Priority in PAR-20-177.