Arrhythmogenic mechanisms of acute viral myocarditis

急性病毒性心肌炎的致心律失常机制

• 批准号: 10385778
• 负责人: Rachel L. Padget
• 金额: $ 0.43万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-10 至 2022-05-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10385778
• 关键词: Acute; Address; Adenovirus Infections; Adenoviruses; Adult; Affect; Animal Disease Models; Animal Model; Arrhythmia; Biological Models; Cardiac; Cardiac Myocytes; Cardiac health; Cardiovascular Diseases; Cause of Death; Cell physiology; Cells; Chronic Disease; Clinic; Complement; Confocal Microscopy; Connexin 43; Connexins; Coupling; DNA; Data; Development; Dilated Cardiomyopathy; Disease; Etiology; Functional disorder; Gap Junctions; Gene Expression; Generations; Genes; Genetic Translation; Goals; Heart; Heart Diseases; Human; Immune response; Impairment; In Vitro; Infection; Injections; Intercellular Junctions; Knowledge; Laboratories; Lead; Mediating; Messenger RNA; Modeling; Mus; Mutation; Myocarditis; Optics; Patients; Phosphorylation; Predisposition; Process; Progressive Disease; Protein Biosynthesis; Protein Isoforms; Proteome; Regulation; Research; Role; Species Specificity; Stress; Technology; Testing; Time; Tissues; Translating; Translation Initiation; Translations; United States; Viral; Viral Proteins; Western Blotting; Work; acute infection; adenoviral-mediated; in vivo; induced pluripotent stem cell; insight; interest; mammary; mouse model; novel; polysome profiling; ribosome profiling; sudden cardiac death; viral myocarditis; young adult; Acute; Address; Adenovirus Infections; Adenoviruses; Adult; Affect; Animal Disease Models; Animal Model; Arrhythmia; Biological Models; Cardiac; Cardiac Myocytes; Cardiac health; Cardiovascular Diseases; Cause of Death; Cell physiology; Cells; Chronic Disease; Clinic; Complement; Confocal Microscopy; Connexin 43; Connexins; Coupling; DNA; Data; Development; Dilated Cardiomyopathy; Disease; Etiology; Functional disorder; Gap Junctions; Gene Expression; Generations; Genes; Genetic Translation; Goals; Heart; Heart Diseases; Human; Immune response; Impairment; In Vitro; Infection; Injections; Intercellular Junctions; Knowledge; Laboratories; Lead; Mediating; Messenger RNA; Modeling; Mus; Mutation; Myocarditis; Optics; Patients; Phosphorylation; Predisposition; Process; Progressive Disease; Protein Biosynthesis; Protein Isoforms; Proteome; Regulation; Research; Role; Species Specificity; Stress; Technology; Testing; Time; Tissues; Translating; Translation Initiation; Translations; United States; Viral; Viral Proteins; Western Blotting; Work; acute infection; adenoviral-mediated; in vivo; induced pluripotent stem cell; insight; interest; mammary; mouse model; novel; polysome profiling; ribosome profiling; sudden cardiac death; viral myocarditis; young adult

PROJECT SUMMARY Cardiovascular disease remains the leading cause of death in the United States with up to 42% of sudden cardiac death in young adults caused by myocarditis. Adenovirus is now recognized as a leading etiological agent of viral myocarditis, yet our understanding of adenoviral infection in the heart is lacking due to viral host species specificity and historical difficulty in developing model systems of cardiac infection. In all forms of heart disease, subcellular remodeling of the cardiomyocyte occurs with disruptions in gap junction-mediated electrical coupling known to lead to fatal arrhythmias. The primary cardiac gap junction protein, connexin43 (Cx43), is now known to have internally translated isoforms that can modulate gap junction formation and cardiac health. Adenovirus hijacks host cell translational machinery to affect alternative translation initiation of viral and host mRNA, and such changes would rapidly affect the cardiomyocyte proteome and therefore electrical status of the heart. My proposed research will address gaps in the knowledge regarding mechanisms of arrhythmogenesis during acute viral myocarditis and the contribution of alterations in translation initiation to this process. Aim 1: Investigate arrhythmogenic mechanisms in an acute adenoviral myocarditis mouse model. Administering MAdv3 using a retro-orbital injection in C57/B6 mice, MAdv3 DNA is found preferentially in cardiac tissue. A mouse model will be defined for acute adenoviral myocarditis and their susceptibility to arrhythmogenesis. Aim 2: Determine the role of altered translation initiation in adenoviral-mediated cell junction remodeling. Many cellular junctional genes, such as Connexin 43 (Cx43), undergo alternate translation initiation to function properly. This alternate translation initiation is impaired in disease. Adenovirus modulates the host's translational machinery to favor alternate translation mechanisms for viral protein synthesis by maintaining levels of host cell’s eIF2α activity. The proposed research will broaden the understanding of how adenovirus infects the heart and causes sudden cardiac death during acute infection. Successful completion of the work proposed will provide a new model for acute viral myocarditis and provide insight into mechanisms of arrhythmogenesis. This proposal is significant because it will elucidate how adenovirus infects the working heart in an adult mouse model, how the infected cell's' translational landscape can lead to arrhythmogenesis, and it will test the potential of restoring of that landscape after infection in protection against sudden cardiac death.

项目摘要 心血管疾病仍然是美国死亡的主要原因，突然的42％ 由心肌炎引起的年轻人心脏死亡。腺病毒现在被认为是领先的病因 病毒心肌炎的药物，但是由于病毒宿主，我们缺乏对心脏腺病毒感染的理解 物种特异性和历史难度在开发心脏感染模型系统方面。在各种形式的心中 疾病，心肌细胞的亚细胞重塑发生在间隙连接介导的中断 已知导致致命心律不齐的电耦合。主要心脏间隙连接蛋白，connexin43 （CX43），现在已知具有内部翻译的同工型，可以调节间隙连接组和 心脏健康。腺病毒劫持宿主细胞翻译机械，以影响 病毒和宿主mRNA，这种变化将迅速影响心肌细胞蛋白质组，因此 心脏的电状态。我提出的研究将解决有关机制知识的差距 急性病毒心肌炎期间心律失常的发生以及翻译启动改变的贡献 这个过程。 AIM 1：研究急性腺病毒心肌炎小鼠中心律失常机制 模型。优先发现使用C57/B6小鼠中的恢复轨道注射MADV3 DNA在C57/B6小鼠中使用MADV3进行管理 在心脏组织中。将为急性腺病毒心肌炎定义小鼠模型及其对 心律失常。目标2：确定改变翻译起始在腺病毒介导的细胞中的作用 连接重塑。许多细胞连接基因，例如连接蛋白43（CX43），都可以替代 翻译启动以正常运行。这种替代的翻译启动在疾病中受到损害。腺病毒 调节宿主的翻译机制，以偏爱病毒蛋白的替代翻译机制 通过维持宿主细胞的EIF2α活性的水平来合成。拟议的研究将扩大 了解腺病毒如何感染心脏并在急性感染过程中导致心脏猝死。 成功完成提议的工作将为急性病毒心肌炎提供新的模型，并提供 深入了解心律失常的机制。该提议很重要，因为它将阐明 腺病毒感染成人小鼠模型中的工作心脏，如何感染细胞的翻译景观 可能导致心律失常，它将测试在感染后恢复该景观的潜力 防止心脏突然死亡。