Mechanistic characterization of a new master regulator of cardiac virus infections

项目摘要 心脏病毒感染是心力衰竭的常见原因，缺乏治疗方法。病毒主要 通过直接溶解宿主细胞并引起广泛坏死来损害心脏。心脏会对 通过募集炎性细胞来对抗和防止病毒的传播。炎症必不可少 对于成功的抗病毒反应，但过度的炎症可导致心肌的净损害， 感染心脏必须仔细调整炎症，以防止病毒增殖，同时避免伤害 是由过度炎症引起的了解调节心脏炎症的因素 对于开发用于心脏病毒感染的治疗剂将是必要的。我们发现一种蛋白质 称为BEX 1（大脑表达的X连锁1）在无菌损伤期间在心脏中起促炎作用。我们 他们还发现，BEX 1在心肌细胞中作为核糖核蛋白复合物的一部分， 促炎基因然而，BEX 1调节心脏的直接机制 炎症尚未阐明，也不知道BEX 1是否调节心脏对病毒的反应 感染.在这项提案中，我们试图了解BEX 1在心脏对病毒的反应中的作用， 以下目的：1）确定BEX 1在体内对亲心病毒感染的作用; 2）确定BEX 1在体内对亲心病毒感染的作用。 BEX 1对心脏中抗病毒基因程序的贡献;和3）阐明BEX 1对心脏中抗病毒基因程序的作用机制。 BEX 1调节抗病毒反应。初步数据使我们假设BEX 1在抗病毒中起作用， 通过调节一种叫做EPRS（谷氨酰-脯氨酰-tRNA合成酶）的蛋白质发挥作用。评估这一假设， 阐明BEX 1在免疫和炎症中的作用对于更好地理解 病毒感染和炎性疾病，并可能导致发现有价值的治疗靶点。

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.