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

微生理组织芯片模型中的 ACE2 SARS-CoV2 介导的瓣膜疾病

基本信息

批准号：
10438067
负责人：
Kartik Balachandran
金额：
$ 43.66万
依托单位：
UNIVERSITY OF ARKANSAS AT FAYETTEVILLE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10438067
关键词：
2019-nCoV 3-Dimensional ACE2 Amino Acids Arkansas Arrhythmia Biomedical Research COVID-19 COVID-19 patient Cardiac Myocytes Cardiovascular system Cell Survival Cells Clinical Collagen Development Disease Disease Progression Education Endothelial Cells Engineering Ensure Environment Enzymes Exposure to Extracellular Matrix Family suidae Fibroblasts Future Glycosaminoglycans Grant HIV Histology Human Human Resources Hydrogels Immunohistochemistry In Situ Hybridization In Vitro Infection Inflammation Inflammatory Institution Laboratories Mass Spectrum Analysis Mechanics Mediating Mediator of activation protein Minority-Serving Institution Modeling Myocarditis Pathologic Pathology Patients Phenotype Physiological Physiology Population Preclinical Testing Predisposition Probability Proteomics Renin-Angiotensin System Reporting Research Respiratory Failure Role SARS coronavirus SARS-CoV-2 infection SARS-CoV-2 spike protein Sampling Sclerosis Severities Signal Transduction Signaling Molecule Structure Student recruitment Students System Techniques Testing Therapeutic Tissue Banks Tissue Microarray Tissues Training Programs Underrepresented Students Universities Validation Viral Load result Work aortic valve aortic valve disorder base calcification career comorbidity cytokine cytokine release syndrome design efficacy testing experience experimental study hemodynamics histological stains human disease innovation interstitial cell mortality novel prototype receptor severe COVID-19 success undergraduate research undergraduate student viron

项目摘要

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.

项目概要最近的报告揭示了血管紧张素转换酶 2 (ACE2) 作为受体的作用介导严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 进入宿主细胞。主动脉瓣是心血管系统内的一种特定组织，具有 ACE2 和其他肾素的强烈表达血管紧张素系统（RAS）介质。然而，尚无研究测试 ACE2 或 RAS 是否在细胞中表达。主动脉瓣增加了 SARS-CoV-2 强烈感染的可能性。我们也不知道 SARS-CoV- 2 如果患者存在瓣膜病变，则感染概率会增加。我们假设改变了钙化性主动脉瓣疾病 (CAVD) 进展期间 ACE2 表达和 RAS 信号传导增强对 SARS-CoV-2 感染的易感性增加，从而导致瓣膜病理学进一步进展。这假设将通过以下三个具体目标进行检验：目标 1 侧重于研究表达谱人体离体瓣膜切片中瓣膜疾病各个阶段的 ACE2 和 RAS 信号分子。目的 2 寻求设计和验证可以模仿正常人主动脉瓣的三维人体主动脉瓣组织芯片（健康）和患病的主动脉瓣叶。目标 3 将测试 ACE2 介导的 SARS-CoV-2 感染效应在这些瓣膜芯片模型上了解瓣膜病理负担是否会使瓣膜变得更严重 SARS-CoV-2 感染。我们还将测试 ACE2 阻断作为潜在治疗策略的功效。如果拟议的实验是成功的，这笔 R15 资助将为未来更大规模的临床前测试奠定基础研究使用我们的瓣膜芯片来研究 SARS-CoV-2 感染对心血管和心血管的病理影响阀门系统。拟议的研究还与强大的研究接触计划交织在一起，以提供为本科生提供有价值的研究经验，并通过我们的课程接触临床观点临床合作者 Vallurupalli 博士。我们将从多样化的本科生中选拔阿肯色大学，教育部指定的少数族裔服务机构，包括学生在生物医学研究队伍中的代表性不足。