Triple humanized ACE2-TMPRSS-FcGRT mouse models for COVID research in the C57BU6 and BALBIc backgrounds.

第I/II阶段摘要 Synbal和拉霍亚免疫学研究所（LJI）正在共同努力， 为COVID-19研究提供突破性的新工具，以加强研究和药物开发 COVID-19疾病。我们的目标是创造一套最先进的人源化小鼠品系 通过在小鼠基因座精确敲入人类迷你基因， 在三个位点中的每一个。COVID-19的临床特征很难被现有的单一 转基因小鼠模型;这些品系得的疾病较轻。在这SBIR快速通道阶段I/II 格兰特，该小组将人源化ACE 2病毒受体，其共感染蛋白TMRPSS 2， 主要抗体清除受体FCGRT，以产生双重和三重人源化菌株， C57 BL/6 J和BALB/c背景。这两种背景是Th 1应答者和Th 2应答者。 响应者，分别，并将允许建模的极端变化的人类病理学 在被感染的患者中观察到。多重人源化小鼠品系将上级单一- 基因转基因模型;因此，将允许更好的基础研究和药物 发展为了验证菌株，我们计划彻底表征SAR-CoV的影响， 2感染的临床，病毒学，组织病理学和免疫学水平，并发表 调查结果。在该项目中产生的产物菌株，三重人源化C57 B6 L/6 J- ACE 2/TMPRSS 2/FCGRT小鼠和双重人源化BALB/c-hACE 2/hTMPRSS 2和 C57 BL/6 J-ACE 2/TMPRSS 2小鼠将随时可用于学术研究， 通过我们的动物供应商合作伙伴杰克逊实验室或 Taconic Biosciences.

Abstract Phase I/II Synbal and the La Jolla Institute for Immunology (LJI) are combining efforts to create breakthrough new tools for COVID-19 research to enhance research and drug development for COVID-19 disease. We aim to create a state-of-the-art set of humanized mouse strains susceptible to SARS-CoV-2, via the precision knock-in of a human mini gene at the mouse locus in each of three loci. The clinical features of COVID-19 are poorly mimicked by the existing single transgenic mouse models; those strains get a milder disease. In this SBIR Fast track PHASE I/II grant, the team will humanize the ACE2 viral receptor, its co-infection protein TMRPSS2, and the main antibody clearance receptor FCGRT to create double and triple humanized strains in C57BL/6J and BALB/c backgrounds. These two backgrounds are Th1 responders and Th2 responders, respectively, and will allow modeling of the extreme variability of human pathology observed in infected patients. The multiply humanized mice strains will be superior to the single- gene transgenic models available to date; and, thus, will allow for better basic research and drug development. To validate the strains, we plan to thoroughly characterize the effects of SAR-CoV- 2 infection at the clinical, virologic, histopathologic, and immunologic levels, and publish the findings. The product strains created in this project, the triple humanized C57B6L/6J- ACE2/TMPRSS2/FCGRT mice and the double humanized BALB/c-hACE2/hTMPRSS2 and C57BL/6J-ACE2/TMPRSS2 mice will be made readily available for the academic and pharmaceutical research communities through our animal vendor partner Jackson Labs or Taconic Biosciences.