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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：
10522824
负责人：
James William Smyth
金额：
$ 54.68万
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/10522824
关键词：
Action Potentials Acute Address 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 Pathogenesis Pathologic Phosphoric Monoester Hydrolases Phosphotransferases Potassium Primary Infection Proteins Proteomics Regulation Research Resolution 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 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.

总结