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

• 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
• 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

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 最近的报道已经揭示了血管紧张素转换酶2（ACE 2）作为血管紧张素受体的作用。 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异性组织，其具有ACE 2和其他肾素-血管紧张素转换酶的稳健表达。 血管紧张素系统（RAS）介质。然而，还没有研究检测ACE 2或RAS表达是否在血管内皮细胞中， 主动脉瓣增加了其被SARS-CoV-2强烈感染的倾向。我们也不知道SARS-CoV- 如果患者存在瓣膜病变，则感染概率增加。我们假设 钙化性主动脉瓣疾病（CAVD）进展过程中ACE 2表达和RAS信号增强 增加对SARS-CoV-2感染的易感性，从而进一步发展瓣膜病理学。这 假设将通过以下三个具体目标进行测试：目标1侧重于研究表达谱 ACE 2和RAS信号分子在人离体瓣膜切片中瓣膜疾病不同阶段的表达。目的 2旨在设计和验证一种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检测ACE 2介导的SARS-CoV-2感染的效应 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ACE 2阻断作为潜在治疗策略的有效性。如果 建议的实验是成功的，这个R15赠款将为未来更大规模的临床前试验奠定基础 使用我们的瓣膜芯片研究SARS-CoV-2感染对心血管和 阀门系统拟议的研究还与一个强大的研究暴露计划交织在一起， 值得研究的经验，本科生，与接触的临床观点，通过我们的 临床合作者Vandalupalli博士。我们将从不同的本科生池中抽取， 阿肯色州大学，教育部指定的少数民族服务机构，包括 学生在生物医学研究队伍中的代表性不足。