Viral subversion of intercellular coupling during myocarditis

心肌炎期间细胞间耦合的病毒颠覆

基本信息

批准号：
10656515
负责人：
James William Smyth
金额：
$ 53.84万
依托单位：
VIRGINIA POLYTECHNIC INST AND ST UNIV
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：
2022-07-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10656515
关键词：
Action Potentials Acute Adenovirus Infections Adenoviruses Adhesions Affect Antiviral Agents Arrhythmia Biochemical Biological Models Biology Cardiac Cardiac Myocytes Cardiovascular Diseases Cause of Death Cell Line Clinical Research Complement Confocal Microscopy Connexin 43 Connexins Coupling Dangerousness Data Electrons Electrophysiology (science)Etiology Gap Junctions Gene Expression Generations Genetic Transcription Goals Heart Heart Diseases Heart failure Human Immune response Infection Inflammation Inflammatory Intercalated disc Intercellular Junctions Ion Channel Knowledge Mechanics Modeling Molecular Molecular Probes Mus Mutation Myocarditis Myocardium PIK3CG gene Pathogenesis Pathologic Phosphoric Monoester Hydrolases Phosphotransferases Potassium Proteins Proteomics Regulation Research Role Serotyping Signal Transduction Species Specificity Structure Sudden Death System Testing Therapeutic Intervention Time Transgenic Animals United States Ventricular Viral Viral Proteins Virus Diseases Virus Replication Work beta catenin clinical efficacy in vivo Model induced pluripotent stem cell derived cardiomyocytes innovation insight intercellular communication model development novel protein expression protein function research study sudden cardiac death therapeutic target transcription factor ultra high resolution viral myocarditis voltage young adult

项目摘要

SUMMARY Cardiovascular disease remains the principal cause of death in the United States, with myocarditis contributing to 42% of all sudden deaths in young adults. Human adenovirus type 5 is a leading etiological agent of viral myocarditis, yet research is lacking due to host species specificity limiting the development of model systems for cardiac infection. The effect of active adenoviral infection on cardiomyocyte function and arrhythmogenesis that precedes immune responses and progression to heart failure is unknown. Gap junctions, predominantly comprising the protein connexin43 (Cx43) in the ventricular intercalated disc, facilitate action potential propagation during each heartbeat. An intimate association and interplay between gap junctions, other ID resident ion channels, and components of mechanical junctions is now well accepted. Alterations in ID mechanical and electrical coupling cause arrhythmias, and while it has been demonstrated that adenovirus directly targets adhesion late in infection, the relationship between adenoviral myocarditis and Cx43 gap junction, or other ion channel, function and regulation remains unexplored. Indeed, treatment for viral myocarditis is largely supportive, with no therapeutic interventions or antivirals demonstrating significant clinical efficacy to date. Through study of adenoviral infection of cardiac muscle at the molecular level, we will address significant gaps in the knowledge regarding mechanisms underlying the impact of infection on cardiomyocyte intercellular coupling and electrophysiology while identifying therapeutic targets to limit viral spread and/or rescue electrical coupling in diseased hearts. Our long term goal is to elucidate the pathological mechanisms of viral myocarditis and resulting arrhythmogenic subversion of cardiac ion channels and junctional structures. The objective of this R01 proposal is to determine how electrical and mechanical intercellular coupling is affected during acute adenoviral cardiac infection to precipitate an arrhythmogenic substrate. Our central hypothesis is that adenovirus hijacks junction protein expression and function leading to an arrhythmogenic substrate prior to gross pathological remodeling and the appreciable host immune responses. We will test this hypothesis with the following two Specific Aims: Aim 1: Determine the role of early adenoviral proteins in generation of an arrhythmogenic cellular landscape. The working hypothesis for this aim is that early adenoviral proteins activate a PI3K/β-catenin signaling axis targeting Cx43 and cardiac ion channel function, contributing to arrhythmogenesis. Aim 2: Determine the role of connexins and gap junction intercellular communication in adenoviral pathogenesis. The working hypothesis for this aim is that adenovirus stabilizes cellular junctions to facilitate viral spread while limiting intercellular communication to enhance viral replication.

概括心血管疾病仍然是美国主要的死亡原因，其中心肌炎是导致死亡的主要原因 5 型人类腺病毒是病毒的主要病原，占所有年轻人猝死的 42%。心肌炎，但由于宿主物种特异性限制了模型系统的发展，因此缺乏研究活性腺病毒感染对心肌细胞功能和心律失常发生的影响。主要是在免疫反应和进展为心力衰竭之前的间隙连接。包含心室闰盘中的蛋白质 connexin43 (Cx43)，促进动作电位每次心跳期间的传播。间隙连接和其他 ID 之间的密切关联和相互作用。驻留离子通道和机械连接部件现在已被广泛接受。机械和电气耦合会导致心律失常，虽然已证明腺病毒感染后期直接靶向粘连，腺病毒心肌炎与Cx43间隙的关系事实上，病毒的治疗尚未探索。心肌炎在很大程度上是支持性的，没有治疗干预或抗病毒药物显示出显着的临床意义通过在分子水平上研究腺病毒感染心肌，我们将解决迄今为止的疗效。关于感染对心肌细胞影响的机制的知识存在重大差距细胞间耦合和电生理学，同时确定治疗靶点以限制病毒传播和/或我们的长期目标是阐明病变心脏的电耦合。病毒性心肌炎以及由此导致的心脏离子通道和连接结构的心律失常性破坏。该 R01 提案的目标是确定细胞间的电气和机械耦合是如何进行的在急性腺病毒心脏感染期间受到影响，沉淀出致心律失常的底物。假设是腺病毒劫持连接蛋白的表达和功能，导致心律失常我们将测试这一点。该假设具有以下两个具体目标：目标 1：确定早期腺病毒蛋白在该目标的工作假设是早期产生致心律失常的细胞景观。腺病毒蛋白激活针对 Cx43 的 PI3K/β-连环蛋白信号轴和心脏离子通道功能，目标 2：确定连接蛋白和细胞间间隙连接的作用。腺病毒发病机制中的通讯。实现这一目标的工作假设是腺病毒。稳定细胞连接以促进病毒传播，同时限制细胞间通讯以增强病毒复制。