Pre-exposure Immunologic Health and Linkages to SARS-COV2 Serologic Responses, Endothelial Cell Resilience, and Cardiovascular Complications: Defining the mechanistic basis of high risk endotypes.

暴露前免疫健康及其与 SARS-COV2 血清学反应、内皮细胞弹性和心血管并发症的联系：定义高风险内型的机制基础。

基本信息

批准号：
10855043
负责人：
Timothy An-thy Chan
金额：
$ 80.69万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-30 至 2024-11-30
项目状态：
已结题

项目摘要

Abstract The objective of this proposal is to understand the immunologic foundations of heart disease which can occur as a result of COVID19. Cardiac impairment, when it develops is often fatal, and our hypothesis is that the maintenance of endothelial function is critical to surviving the protracted nature of COVID19 pneumonia, especially in those with reduced or delayed antibody responses. Our first aim will be to analyze those differences in immune function which pre-date infection but appear to impact the risk of fatal COVID. This will be done by enrolling those at high risk for developing COVID19 (frontline healthcare workers), and performing serially assessments of their immunologic function if they develop COVID. We will specifically investigate the mechanisms that link pre-infection inflammatory pathways to protective serologic responses and symptom severity and recovery. Our second aim will be to perform in vitro experiments to assess the requirements for endothelial cell dysfunction and infectivity. We will compare various inflammatory and cardiovascular stimuli which seem to play a role in promoting COVID19-related cardiovascular complications. Our third aim is to characterize immune cells, endothelial cells, and cardiomyocytes in heart tissue from those with COVID19-induced left ventricular dysfunction. Using single cell sequencing techniques, we will determine cellular and molecular signatures that characterize the microenvironment of the COVID19-affected heart, compared to appropriate controls. Our conceptual model is that pre-existing immune dysfunction 1) reduces the efficiency of neutralizing antibody responses, and 2) in conjunction with cardiovascular disease risk factors, induces endothelial downregulation/depletion of nodal regulators which protect against inflammatory insults. This renders endothelial cells unable to withstand COVID-specific stimuli. Once completed, this study will provide the necessary information to improve the identification of those at risk for COVID-related heart disease and develop rationale approaches to improve the improve survival in the setting of COVID.

抽象的该提议的目的是了解可能发生的心脏病的免疫学基础由于COVID19。心脏障碍，当它发育时通常是致命的，我们的假设是维持内皮功能对于幸存Covid19肺炎的长期性质至关重要，特别是在抗体反应减少或延迟的人中。我们的第一个目的是分析预先感染的免疫功能的差异，但似乎影响致命的共同风险。这将通过注册那些有高风险的Covid19来完成（前线医疗保健工人），并对其免疫功能进行连续评估冠状病毒。我们将特别研究将感染前炎症途径联系起来的机制保护性血清学反应以及症状严重程度和恢复。我们的第二个目标是进行体外实验以评估内皮细胞的要求功能障碍和感染力。我们将比较似乎发挥作用的各种炎症和心血管刺激在促进共vid19相关的心血管并发症中的作用。我们的第三个目的是表征来自心脏组织中的免疫细胞，内皮细胞和心肌细胞患有共vid19诱导的左心室功能障碍的人。使用单细胞测序技术，我们将确定表征由CoVID19影响的微环境的细胞和分子特征与适当的对照相比，心脏。我们的概念模型是预先存在免疫功能障碍1）降低中和的效率抗体反应和2）与心血管疾病风险因素结合使用，诱导内皮防止炎症性损伤的淋巴结调节剂的下调/耗竭。这渲染内皮细胞无法承受共证的特异性刺激。完成后，本研究将提供必要的信息，以改善与共同相关心脏病风险的人的识别并发展基本原理方法是提高共同环境中的生存率。