Role of mitochondrial extracellular vesicles in CVB3 myocarditis by sex

线粒体细胞外囊泡在不同性别的 CVB3 心肌炎中的作用

• 批准号: 10852725
• 负责人: DeLisa Fairweather
• 金额: $ 2.44万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 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 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10852725
• 关键词: 2019-nCoV; Acute; Autophagosome; Biopsy; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cells; Coxsackie Viruses; Diagnosis; Dilated Cardiomyopathy; Disease; Disparate; Enterovirus; Goals; HIV; Heart; Heart Transplantation; Heart failure; Hepatitis C virus; Human poliovirus; Incidence; Infection; Inflammation; Influenza A virus; Lytic; MicroRNAs; Mitochondria; Mitochondrial Proteins; Myocardial; Myocarditis; Myocardium; Patients; Publishing; Risk; Role; Severities; Sex Differences; Sudden Death; Time; Travel; Tropism; Viral; Virus; Virus Diseases; Virus Replication; Wages; Woman; extracellular vesicles; heart damage; men; sex; undergraduate student

PROJECT SUMMARY An estimated 3.1 million cases of myocarditis/cardiomyopathy were diagnosed in 2017. Patients with myocarditis are at risk of sudden death from acute heart failure and progression to dilated cardiomyopathy, often necessitating a heart transplant. The incidence and severity of myocarditis is higher in men than women. Additionally, there are no disease-specific therapies to reduce myocarditis. Enteroviruses including coxsackievirus group B3 (CVB3) are a common cause of myocarditis in the US. Viruses are frequently found in endomyocardial biopsies from patients with myocarditis. There is currently no clear understanding of why an enterovirus like CVB3 would target the heart or the mechanism for how a relatively mild viral infection like CVB3 leads to heart failure. Previously it was hypothesized that an overwhelming lytic CVB3 infection damages the heart. It was recently published that the predominant mode of viral egress for CVB3 from cardiomyocytes is in extracellular vesicle-like mitochondrial autophagosomes, and that CVB3 requires mitochondrial fission for viral replication. Interestingly, other viruses that cause myocarditis have been found to use mitochondria to promote viral replication including influenza A, HIV, poliovirus, hepatitis C virus and SARS-CoV-2. The high energy demands of cardiac muscle and abundant mitochondria in the heart provide for the first time an explanation for why such disparate types of viruses, with no obvious cardiac tropism, replicate in the heart. The overall goal of this proposal is to determine whether the CVB3 replicative cycle through mitochondria in cardiomyocytes induces sex differences in cardiac inflammation during myocarditis and to determine whether microRNA and/or protein from mitochondrial-derived extracellular vesicles influence viral replication and inflammation in a sex-specific manner. The specific goal of this diversity supplement is to provide salary and travel for an undergraduate student.

项目摘要 估计在2017年诊断出310万例心肌炎/心肌病病例。心肌炎患者 受到急性心力衰竭和进展到扩张心肌病的突然死亡的风险，通常 需要心脏移植。男性的心肌炎的发病率和严重程度高于女性。 此外，没有疾病特异性疗法可减少心肌炎。肠病毒包括 Coxsackievivirus B3（CVB3）是美国心肌炎的常见原因。病毒经常在 来自心肌炎患者的心内膜活检。目前尚不清楚为什么 像CVB3这样的肠病毒将针对心脏或机制，以使相对温和的病毒感染像CVB3 导致心力衰竭。以前据推测，压倒性的裂解CVB3感染损害了 心。最近发表的是，心肌细胞中CVB3的病毒出口的主要模式是 细胞外囊泡状线粒体自噬体，CVB3需要线粒体裂变才能进行病毒 复制。有趣的是，已经发现其他引起心肌炎的病毒使用线粒体来促进 病毒复制，包括流感，HIV，脊髓灰质炎病毒，丙型肝炎病毒和SARS-COV-2。高能量 心脏心脏肌肉和大量线粒体的需求首次提供了解释 为什么这种不同类型的病毒（没有明显的心脏自然主义）在心脏中复制。总体目标 该建议是确定通过线粒体中的CVB3复制循环诱导的 心肌炎期间心脏炎症的性别差异，并确定microRNA和/或蛋白质是否 从线粒体衍生的细胞外囊泡中影响性别特异性的病毒复制和炎症 方式。这种多样性补充的具体目标是为本科提供薪水和旅行 学生。