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主要的死亡原因，其中心肌炎是导致死亡的主要原因 占年轻人猝死总数的 42%。 5 型人类腺病毒是病毒的主要病原体 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 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 在免疫反应和进展为心力衰竭之前的情况尚不清楚。间隙连接，主要是 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。 ID变更 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 连接或其他离子通道的功能和调节仍有待探索。事实上，病毒治疗 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 迄今为止的功效。通过在分子水平上研究心肌的腺病毒感染，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 拯救患病心脏中的电耦合。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，沉淀致心律失常底物。我们的中央 假设是腺病毒劫持连接蛋白的表达和功能，导致心律失常 在总体病理重塑和明显的宿主免疫反应之前的底物。我们将测试这个 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 致心律失常细胞景观的产生。该目标的工作假设是早期 腺病毒蛋白激活针对 Cx43 和心脏离子通道功能的 PI3K/β-连环蛋白信号轴， 有助于心律失常的发生。目标 2：确定连接蛋白和间隙连接细胞间的作用 腺病毒发病机制中的通讯。该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。