Regulation of cardiomyocyte inflammation during viral infection

病毒感染过程中心肌细胞炎症的调节

基本信息

批准号：
10244888
负责人：
Ram Savan
金额：
$ 22.39万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-21 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10244888
关键词：
Acute Acute Myocarditis Address Antiviral Agents Antiviral Response Attenuated Biological CD8-Positive T-Lymphocytes Cardiac Cardiac Myocytes Cardiomyopathies Cessation of life Complex Containment Coxsackie B Viruses Cytomegalovirus Data Detection Development Dilated Cardiomyopathy Disease Progression Down-Regulation Environment Family Family Picornaviridae Gene Targeting Genes Genetic Transcription Goals Heart Heart Diseases Heart failure Hepatitis C Hepatocyte Human Human Parvovirus B19 IFNAR1 gene Immune Immune response Immunologic Surveillance Immunologics Impairment Infection Inflammation Inflammatory Inflammatory Response Injury Innate Immune Response Interferon Receptor Interferons MHC Class I Genes Mediating MicroRNAs Modeling Molecular Molecular Target Muscle Myoblasts Myocardial Myocardial tissue Myocarditis Myocardium Myosin ATPase Neurons Pathogenesis Pathogenicity Pathology Pathway interactions Patients Play Predisposition Prevention Proteins RNA Regulation Regulator Genes Resolution Role Severities Severity of illness Signal Transduction Simplexvirus Skeletal Muscle Stimulus Surface Testing Therapeutic Intervention Tissues Untranslated RNA Ventricular Ventricular Arrhythmia Viral Virus Virus Diseases base cardiogenesis cost crosslinking and immunoprecipitation sequencing cytokine fascinate heart function immunoregulation insight member molecular targeted therapies muscle regeneration myocardial damage novel premature prevent response tissue injury tissue repair tissue-repair responses transcriptome sequencing treatment strategy viral myocarditis virology

项目摘要

Project Summary / Abstract Myocarditis is an inflammatory pathology of the myocardium, driven by both infectious and non-infectious agents, that often precedes acute heart failure, ventricular arrhythmias, and dilated cardiomyopathies. Thus, understanding the mechanisms that regulate its onset and resolution is crucial for the prevention and treatment of myocardial disease. MicroRNAs are short non-coding RNAs that fine-tune inflammatory responses by post- transcriptionally regulating immune genes. Of these, miR-208b and miR-499-5p, members of a family of microRNAs specific to skeletal muscle and cardiac tissue (myomiRs) are aberrantly expressed in patients with acute myocardial inflammation and predict disease severity. However, the biological significance of these observations is poorly understood. We have previously shown that miR-208b and miR-499-5p, are aberrantly induced by viral infection and associated antiviral cytokines in hepatocytes, where they silence both type I and type III interferon (IFN) responses resulting in diminished viral clearance. In this study, we are proposing that cardiomyocytes have evolved a similar mechanism to block interferon-mediated inflammation, which cardiotropic viruses utilize to avoid immune detection and elimination. We propose that miR-208b and miR- 499-5p expression in the heart is elevated by proinflammatory injury and results in the loss of inflammatory control and the premature resolution of crucial antiviral responses that render cardiomyocytes susceptible to cellular death and could promote cardiac tissue damage. We propose to identify the distinct damage- associated stimuli that regulate myomiR expression and how these coordinate inflammatory responses. We will use unbiased approaches to identify the key molecular targets regulated by myomiRs. We will test if myomiRs antagonize antiviral responses that leads to persistence of viral infections associated with myocardial disease. Overall, our integrative approach will build a comprehensive gene regulatory network that encompasses the complex interactions between microRNAs, host immune responses, tissue repair and viral clearance in cardiac disease, from which we can discover novel molecular targets for therapeutic intervention.

项目摘要 /摘要心肌炎是心肌的炎症病理学，受感染和非感染的驱动通常在急性心力衰竭，心室心律不齐和扩张心肌病之前的药物。因此，了解调节其发作和解决方案的机制对于预防和治疗至关重要心肌疾病。 microRNA是简短的非编码RNA，可通过后通过转录调节免疫基因。其中，miR-208b和mir-499-5p，一个家庭成员特定于骨骼肌和心脏组织（肌瘤）的microRNA异常表达急性心肌炎症并预测疾病的严重程度。但是，这些的生物学意义观察很少了解。我们以前已经表明miR-208b和miR-499-5p异常是由病毒感染和肝细胞中相关抗病毒细胞因子诱导，它们都使I型和I型静音 III型干扰素（IFN）反应导致病毒清除率降低。在这项研究中，我们提出心肌细胞已经发展出类似的机制，以阻止干扰素介导的炎症，这心形病毒用于避免免疫检测和消除。我们建议miR-208b和mir- 心脏中499-5p的表达因促炎损伤而升高，并导致炎症丧失控制和过早解决关键抗病毒反应，使心肌细胞容易受到影响细胞死亡，并可能促进心脏组织损伤。我们建议确定明显的损害 - 相关的刺激，调节肌瘤表达以及这些协调炎症反应如何。我们将使用无偏的方法来识别由肌瘤调节的关键分子靶标。我们将测试是否肌瘤拮抗抗病毒反应，导致与心肌相关的病毒感染的持久性疾病。总体而言，我们的综合方法将建立一个全面的基因调节网络包括microRNA，宿主免疫反应，组织修复和病毒之间的复杂相互作用心脏病的清除率，我们可以从中发现用于治疗干预的新分子靶标。