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.

项目摘要最近的报道发现了血管紧张素转换酶2（ACE2）作为受体的作用介导严重的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中的一种特定组织，具有ACE2和其他肾素 - 血管紧张素系统（RAS）介质。但是，尚无研究测试ACE2或RAS在主动脉瓣增加了SARS-COV-2的稳健感染倾向。我们也不知道SARS-COV是否是 2如果患者存在现有瓣膜病理，感染概率会增加。我们假设发生了变化钙化主动脉瓣疾病（CAVD）进展增强期间的ACE2表达和RAS信号传导增加对SARS-COV-2感染的敏感性，从而进一步发展瓣膜病理学。这假设将通过以下三个特定目的进行检验：AIM 1专注于研究表达曲线人体离体瓣膜各个瓣膜疾病的各个阶段的ACE2和RAS信号分子的。目的 2试图设计和验证一个可以模拟正常的三维人主动脉瓣组织芯片（健康）和患病的主动脉瓣膜。 AIM 3将测试SARS-COV-2感染的ACE2介导的作用在这些阀芯片模型上，以了解瓣膜病理负担是否使瓣膜更为严重 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。如果是提议的实验成功了，此R15赠款将为将来的大规模临床前测试奠定基础使用我们的瓣膜芯片研究SARS-COV-2感染对心血管和心血管和阀系统。拟议的研究还与强大的研究暴露计划交织在一起对本科生的功绩研究经验，并通过我们的临床观点接触临床合作者Vallurupalli博士。我们将从可在阿肯色大学，教育部指定的少数派服务机构，包括在生物医学研究人员中，学生人数不足。