Mechanistic characterization of a new master regulator of cardiac virus infections

心脏病毒感染新主调节因子的机制表征

基本信息

批准号：
10045127
负责人：
Federica Accornero
金额：
$ 58.14万
依托单位：
OHIO STATE UNIVERSITY
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：
2020-09-08 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10045127
关键词：
3&apos Untranslated Regions Address Affect Amino Acyl-tRNA Synthetases Antiviral Agents Antiviral Response Automobile Driving Biological Models Brain Cardiac Cardiac Myocytes Cardiology Cardiomyopathies Cause of Death Cells Complex Coupled Coxsackie B Viruses Custom Data Disease Elements Equilibrium Family Fibroblasts Fibrosis Gene Expression Genes Genetic Hand Heart Heart failure Immunity Impairment In Vitro Infection Infiltration Inflammation Inflammatory Inflammatory Response Influenza A virus Injury Interferon Type I Interferons Knockout Mice Lead Ligase Link Lymphocyte Measures Mediator of activation protein Messenger RNA Modeling Mus Myocarditis Myocardium Necrosis Nuclear Protein Outcome Pathogenicity Pathology Pathway interactions Pharmaceutical Preparations Phosphorylation Play Post-Transcriptional Regulation Prevention Production Proteins Proteomics Reporting RiboTag Ribonucleoproteins Ribosomes Role Signal Transduction Sterility Therapeutic Tissues Translations Viral Virus Virus Diseases Virus Replication biological adaptation to stress cardioprotection cytokine experimental study fighting glutamyl-prolyl-tRNA synthetase heart damage heart function in vivo mRNA Stability multidisciplinary overexpression pressure prevent programs recruit response therapeutic target tool transcriptome transcriptome sequencing viral myocarditis virology

项目摘要

Project Summary Cardiac viral infection is a common cause of heart failure for which therapeutics are lacking. Viruses primarily damage the heart by directly lysing host cells and causing widespread necrosis. The heart responds to infection by recruiting inflammatory cells to fight and prevent the spread of the virus. Inflammation is essential for a successful antiviral response, but excessive inflammation can cause a net harm to the myocardium during infection. The heart must carefully tune inflammation to prevent viral proliferation while avoiding the harm caused by excessive inflammation. Understanding the factors involved in tuning the heart's inflammatory response will be necessary to develop therapeutics for cardiac viral infection. We discovered that a protein called BEX1 (brain expressed X-linked 1) serves a pro-inflammatory role in the heart during sterile injury. We have also found that BEX1 acts in cardiomyocytes as part of a ribonucleoprotein complex regulating the level of pro-inflammatory mRNAs. Nevertheless, the direct mechanism by which BEX1 regulates cardiac inflammation has not been elucidated, and it is not known if BEX1 regulates the heart's response to virus infections. In this proposal we seek to understand BEX1's role in the response of the heart to viruses with the following aims: 1) To determine the effect of BEX1 on cardiotropic viral infection in vivo; 2) To determine the contribution of BEX1 to antiviral gene programs in the heart; and 3) To elucidate the mechanism by which BEX1 regulates antiviral responses. Preliminary data have led us to the hypothesis that BEX1 plays an antiviral role by regulating a protein called EPRS (glutamyl-prolyl-tRNA synthetase). Evaluating this hypothesis and elucidating the role of BEX1 in immunity and inflammation will be necessary to gain a better understanding of viral infection and inflammatory diseases, and could lead to the discovery of valuable therapeutic targets.

项目概要心脏病毒感染是心力衰竭的常见原因，目前尚缺乏治疗方法。主要是病毒通过直接裂解宿主细胞并导致广泛坏死来损害心脏。心脏会响应通过招募炎症细胞来对抗和防止病毒传播来抵抗感染。炎症是必不可少的成功的抗病毒反应，但过度炎症可能会对心肌造成净伤害感染。心脏必须仔细调节炎症，以防止病毒增殖，同时避免伤害过度炎症引起的。了解调节心脏炎症的因素响应对于开发心脏病毒感染的治疗方法是必要的。我们发现有一种蛋白质 BEX1（大脑表达的 X 连锁 1）在无菌性损伤期间在心脏中发挥促炎作用。我们还发现 BEX1 在心肌细胞中作为核糖核蛋白复合物的一部分发挥作用，调节心肌细胞的水平促炎症 mRNA。尽管如此，BEX1 调节心脏的直接机制炎症尚未阐明，也不知道 BEX1 是否调节心脏对病毒的反应感染。在本提案中，我们试图了解 BEX1 在心脏对病毒的反应中的作用以下目的： 1）确定BEX1对体内心肌病毒感染的作用； 2）确定 BEX1 对心脏抗病毒基因程序的贡献； 3）阐明其机制 BEX1 调节抗病毒反应。初步数据使我们假设 BEX1 具有抗病毒作用通过调节一种名为 EPRS（谷氨酰脯氨酰-tRNA 合成酶）的蛋白质来发挥作用。评估这个假设并为了更好地了解 BEX1 在免疫和炎症中的作用，有必要病毒感染和炎症性疾病，并可能导致有价值的治疗靶点的发现。