A novel model to study COVID-19 and Hypertension

研究 COVID-19 和高血压的新模型

基本信息

批准号：
10428648
负责人：
BINA JOE
金额：
$ 19.31万
依托单位：
UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
依托单位国家：
美国
项目类别：
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/10428648
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 Virus Virus Shedding Work animal data base design dietary salt dysbiosis effectiveness evaluation fecal transplantation gut microbiota high risk high salt diet host microbiota hypertensive hypertensives in vivo interest microbial microbiota nonhuman primate novel novel coronavirus protein expression receptor salt sensitive salt sensitive hypertension sex vaccine development

项目摘要

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 的病理学以及开发不可或缺的疫苗。它们对于识别特定高危人群中的 COVID-19 病因也很重要，例如患有高血压的人。虽然有仓鼠、雪貂、猫、非人类灵长类动物和 K18- hACE2 转基因小鼠作为研究 COVID-19 的可能模型，但没有一个能够用于研究高血压与 COVID-19 易感性之间的关系，因为 (1) 野生型研究模型不感染人类 SARS-CoV-2 和/或 (2) 他们在遗传上没有患高血压的倾向。为了填补这个未满足的需求，我们建议开发体内实验平台来研究 COVID-19 高血压。在初步数据中，我们提供了开发新型基因敲入大鼠模型的证据使用 CRISPR/Cas9 技术编辑高血压 Dahl 盐敏感 (S) 大鼠以表达人类 ACE2 基因（hACE2），它是 SARS-CoV-2 的受体。插入基因 hACE2 以取代大鼠 Ace2 基因座。所需的大鼠 Ace2 敲除作为对照菌株 (rAce2-KO) 也已生成。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研究表明将微生物群引入无菌大鼠结肠 Ace2 表达和血压的上调与现有知识相结合盐敏感性高血压与肠道菌群的关系；在目标 2 中，我们将检验以下假设：高血压状态下宿主和肠道微生物群之间正常共生的丧失是导致多个器官中 ACE2 表达较低。