Viral subversion of intercellular coupling during myocarditis

心肌炎期间细胞间耦合的病毒颠覆

• 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
• 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

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死亡的主要原因，心肌炎导致 年轻人的所有突然死亡的42％。人类腺病毒5型是病毒的领先病因 心肌炎，但由于宿主的规格特异性限制了模型系统的发展，因此缺乏研究 用于心脏感染。活性腺病毒感染对心肌细胞功能和心律失常的影响 在免疫反应和进展到心力衰竭之前，尚不清楚。间隙连接，主要是 在心室插入式椎间盘中完成蛋白质连接蛋白43（CX43），促进了动作电位 每个心跳期间的传播。间隙连接之间的亲密关联和相互作用，其他ID 驻留离子通道和机械连接的组件现在已被广泛接受。 ID的更改 机械和电气耦合会引起心律不齐，虽然已证明腺病毒病毒 直接靶向感染后期依从性，腺病毒心肌炎与CX43间隙之间的关系 交界处或其他离子通道，功能和调节仍然出乎意料。确实，病毒治疗 心肌炎在很大程度上受支持，没有治疗干预措施或抗病毒药均表现出明显的临床 迄今为止的功效。通过研究分子水平心脏肌肉的腺病毒感染，我们将解决 关于感染对心肌细胞影响的机制知识的显着差距 细胞间耦合和电生理学，同时识别治疗靶标，以限制病毒扩散和/或 在解散的心脏中拯救电耦合。我们的长期目标是阐明病理机制 病毒性心肌炎以及心脏离子通道和连接结构的心律失常颠覆。 该R01提案的目的是确定电气和机械的细胞间耦合 在急性腺病毒心脏感染期间受到影响，导致心律不齐的底物。我们的中心 假设是腺病毒劫持了连接蛋白表达和功能导致心律失常 底物进行总体病理重塑和可欣赏的宿主免疫反应。我们将测试这个 假设以下两个具体目标：目标1：确定早期腺病毒蛋白在 心律失常细胞景观的产生。这个目标的工作假设是 腺病毒蛋白激活靶向CX43和心脏离子通道功能的PI3K/β-catenin信号轴， 有助于心律失常。 AIM 2：确定连接素和间隙连接的作用 腺病毒发病机理中的通讯。这个目的的工作假设是腺病毒 稳定细胞连接以促进病毒传播，同时限制细胞间通信以增强病毒 复制。