A novel model to study COVID-19 and Hypertension

研究 COVID-19 和高血压的新模型

• 批准号: 10287008
• 负责人: BINA JOE
• 金额: $ 23.18万
• 依托单位: UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-14 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10287008
• 关键词: 2019-nCoV; ACE2; Address; Animal Model; Animals; Antihypertensive Agents; Blood Pressure; COVID-19; COVID-19 pandemic; COVID-19 pathogenesis; COVID-19 severity; COVID-19 therapeutics; COVID-19 vaccine; COVID-19 vaccine evaluation; CRISPR/Cas technology; Communities; Contracts; Dahl Hypertensive Rats; Data; Development; Diet; Dietary Sodium; Etiology; Experimental Models; Felis catus; Ferrets; Gene Expression; Genes; Germ-Free; Hamsters; Hand; Human; Hypertension; Individual; Intake; K-18 conjugate; Knock-in; Knock-out; Knowledge; Light; Medical; Modeling; Mus; Names; Organ; Pathogenesis; Pathology; Patients; Play; Predisposition; Publishing; Rattus; Reporting; Research; Risk; Role; SARS-CoV-2 infection; SARS-CoV-2 transmission; Sodium Chloride; Sodium-Restricted Diet; Study models; Symbiosis; Testing; Therapeutic; Time; Transgenic Mice; Vaccines; Virus; Virus Shedding; Work; animal data; base; design; dietary salt; dysbiosis; effectiveness evaluation; fecal transplantation; gut microbiota; high risk; high salt diet; host microbiota; in vivo; interest; microbial; microbiota; nonhuman primate; novel; novel coronavirus; protein expression; receptor; salt sensitive; salt sensitive hypertension; sex

7. Project Summary/Abstract Animal models fare indispensable for understanding the pathology of COVID-19 as well as for developing vaccines. They are also important to discern the etiology of COVID-19 in specific groups at risk, such as individuals with pre-existing hypertension. While there are hamsters, ferrets, cats, nonhuman primates and K18- hACE2 transgenic mice as possible models for studying COVID-19, none serves the purpose of studying the relationship between hypertension and susceptibility to COVID-19 because (1) wild-type research models do not get infected with the human SARS-CoV-2 and/or (2) they are not genetically prone to hypertension. To fill this unmet need, we propose to develop in vivo experimental platform for studying COVID-19 in the setting of hypertension. In preliminary data, we present evidence for the development of a novel knock-in rat model of the hypertensive Dahl Salt-sensitive (S) rat edited using the CRISPR/Cas9 technology to express the human ACE2 gene (hACE2), which is the receptor for SARS-CoV-2. The gene hACE2 is inserted to replace the rat Ace2 locus. The required rat Ace2 knockout as the control strain (rAce2-KO) has also been generated. By comparing these 2 strains, in Aim 1 we will examine the suitability of this rat model for studying COVID-19. Further, based on our recent published work using germ-free rats indicating that introduction of microbiota to germ-free rats upregulated colonic Ace2 expression and blood pressure combined with the existing knowledge of a strong relationship between salt-sensitive hypertension and the gut microbiota; in Aim 2, we will test the hypothesis that the loss of normal symbiosis between the host and gut microbiota during a hypertensive state is responsible for the lower ACE2 expression in multiple organs.

7.项目总结/摘要 动物模型对于理解COVID-19的病理学以及开发 疫苗。它们对于在特定风险群体中识别COVID-19的病因也很重要，例如 有高血压病史的人。虽然有仓鼠，雪貂，猫，非人类灵长类动物和K18- hACE 2转基因小鼠作为研究COVID-19的可能模型，没有一个能达到研究COVID-19的目的。 高血压与COVID-19易感性之间的关系，因为（1）野生型研究模型 感染了人类SARS-CoV-2和/或（2）他们在遗传上不容易患高血压。填补这一 为了满足未满足的需求，我们建议开发体内实验平台，用于在以下环境中研究COVID-19： 高血压在初步的数据中，我们提出了一种新的敲入大鼠模型的发展证据， 使用CRISPR/Cas9技术编辑的高血压Dahl盐敏感（S）大鼠，以表达人ACE 2 基因（hACE 2），其是SARS-CoV-2的受体。插入基因hACE 2以替换大鼠Ace 2基因座。 还产生了作为对照品系（rAce 2-KO）的所需大鼠Ace 2敲除。通过比较这些 2株，在目标1中，我们将检查该大鼠模型用于研究COVID-19的适用性。此外，根据我们的 最近发表的使用无菌大鼠的工作表明，将微生物群引入无菌大鼠 结肠Ace 2表达上调和血压升高结合现有的知识， 盐敏感性高血压与肠道微生物群之间的关系;在目标2中，我们将检验以下假设： 在高血压状态期间，宿主和肠道微生物群之间正常共生关系的丧失是导致 ACE 2在多个器官中表达降低。