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。病毒为主 通过直接裂解宿主细胞和引起广泛的坏死来损害心脏。心脏会对 通过招募炎性细胞来对抗和防止病毒的传播。炎症是必不可少的 对于成功的抗病毒反应，但过度炎症会在治疗期间对心肌造成净损害 感染。心脏必须仔细调节炎症反应，以防止病毒扩散，同时避免损害 由过度的炎症引起的。了解调节心脏炎症反应的相关因素 对于开发心脏病毒感染的治疗方法来说，应答将是必要的。我们发现一种蛋白质 被称为BEX1(脑表达X连锁1)的基因在无菌损伤期间在心脏中起到促炎作用。我们 还发现BEX1在心肌细胞中作为核糖核蛋白复合体的一部分，调节水平 促炎症的mRNAs然而，BEX1调节心脏功能的直接机制 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。在这项建议中，我们试图了解BEX1的S在心脏对病毒的反应中所扮演的角色 目的：1)确定BEX1在体内对嗜心性病毒感染的作用；2)确定BEX1对体内嗜心病毒感染的影响 BEX1对心脏抗病毒基因程序的贡献；3)阐明BEX1在心脏抗病毒基因程序中的作用机制 BEX1调节抗病毒反应。初步数据使我们假设BEX1发挥抗病毒作用 通过调节一种名为EPRS(谷氨酰-脯氨基-tRNA合成酶)的蛋白质来发挥作用。评估这一假说，并 阐明BEX1在免疫和炎症中的作用对于更好地理解 病毒感染和炎症性疾病，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.