ACE2 SARS-CoV2-mediated valve disease in a microphysiological tissue-chip model

项目总结 最近的报道发现血管紧张素转换酶2(ACE2)作为血管紧张素转换酶受体的作用。 介导SARS冠状病毒2(SARS-CoV-2)进入宿主细胞。主动脉瓣 是心血管系统中一种强烈表达ACE2和其他肾素的特殊组织- 血管紧张素系统(RAS)介体。然而，目前还没有研究测试ACE2或RAS在卵巢癌组织中的表达 主动脉瓣增加了其强烈感染SARS-CoV-2的倾向。我们也不知道SARS冠状病毒- 2患者存在瓣膜病变时，感染机率增加。我们假设这一点改变了 钙化性主动脉瓣病变进展过程中ACE2的表达和RAS信号转导 增加对SARS-CoV-2感染的易感性，从而进一步发展瓣膜病理。这 假设将通过以下三个具体目标进行检验：目标1侧重于研究表达谱 ACE2和RAS信号分子在瓣膜疾病的不同阶段在人体体外瓣膜切片中的表达。目标 2试图设计并验证一种可以模拟正常的三维人体主动脉瓣组织芯片 (健康的)和患病的主动脉瓣小叶。目的3将测试ACE2介导的SARS-CoV-2感染的作用 在这些瓣膜芯片模型上，以了解瓣膜病理负荷是否使瓣膜更严重 SARS-CoV-2感染。我们还将测试ACE2阻断作为一种潜在的治疗策略的有效性。如果 建议的试验是成功的，这笔R15拨款将为未来更大规模的临床前试验奠定基础 应用我们的瓣膜芯片研究SARS-CoV-2感染对心血管和心脏的病理影响 阀门系统。拟议的研究还与强大的研究暴露计划交织在一起，以提供 为本科生提供有益的研究经验，通过我们的 临床合作者Vallurupalli博士。我们将从多种多样的本科生中选择 阿肯色大学，教育部指定的为少数族裔服务的机构，包括 学生在生物医学研究劳动力中的代表性不足。

PROJECT SUMMARY Recent reports have uncovered the role of angiotensin-converting enzyme 2 (ACE2) as the receptor for mediating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry into host cells. The aortic valve is one specific tissue within the cardiovascular system that has robust expression of ACE2 and other renin- angiotensin system (RAS) mediators. However, there are no studies that test if ACE2 or RAS expression in the aortic valve increases the propensity for its robust infection by SARS-CoV-2. We also do not know if SARS-CoV- 2 infection probability increases if there is existing valve pathology in the patient. We hypothesize that altered ACE2 expression and RAS signaling during calcific aortic valve disease (CAVD) progression potentiates increased susceptibility to SARS-CoV-2 infection, and thereby further progression of valve pathology. This hypothesis will be tested via the following three specific aims: Aim 1 focuses on studying the expression profile of ACE2 and RAS signaling molecules at various stages of valve disease in human ex vivo valve sections. Aim 2 seeks to engineer and validate a three-dimensional human aortic valve tissue-chip that can mimic normal (healthy) and diseased aortic valve leaflets. Aim 3 will test the ACE2-mediated effects of SARS-CoV-2 infection on these valve-chip models to understand if valve pathological burden predisposes the valve to more severe SARS-CoV-2 infection. We will also test the efficacy of ACE2 blockade as a potential therapeutic strategy. If the proposed experiments are successful, this R15 grant will set the stage for future larger-scale preclinical testing studies using our valve-chip to study the pathological effects of SARS-CoV-2 infection on the cardiovascular and valve systems. The proposed studies are also intertwined with a robust research exposure plan for providing meritorious research experiences to undergraduate students, with exposure to clinical perspectives via our clinical collaborator Dr. Vallurupalli. We will draw from the diverse pool of undergraduates available at the University of Arkansas, a minority-serving institution as designated by the Department of Education, including students underrepresented in the biomedical research workforce.