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

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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.