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

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

展开

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.

项目摘要心脏病毒感染是缺乏治疗剂的心力衰竭的常见原因。病毒主要是通过直接裂解宿主细胞并导致广泛坏死来损害心脏。心脏回应通过招募炎症细胞来抗击并防止病毒的传播。炎症是必不可少的对于成功的抗病毒反应，但过度炎症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，同时避免伤害由过度炎症引起。了解调整心脏炎症的因素为了开发心脏病毒感染的治疗剂是必要的。我们发现一种蛋白质在无菌损伤过程中，称为BEX1（脑表示X连锁1）在心脏中发挥了促炎作用。我们还发现BEX1在心肌细胞中起作用，作为调节水平的核糖核蛋白复合物的一部分促炎性mRNA。然而，BEX1调节心脏的直接机制炎症尚未阐明，尚不清楚BEX1是否调节心脏对病毒的反应感染。在此提案中，我们试图了解Bex1在心脏对病毒反应中的作用以下目的：1）确定BEX1对体内心脏病毒感染的影响； 2）确定 BEX1对心脏中抗病毒基因程序的贡献； 3）阐明了该机制 BEX1调节抗病毒反应。初步数据使我们提出了BEX1抗病毒的假设通过调节称为EPRS的蛋白质（谷氨酸 - 丙基-TRNA合成酶）的作用。评估这一假设和阐明BEX1在免疫和炎症中的作用以更好地了解病毒感染和炎症性疾病，可能导致发现有价值的治疗靶标。