Regulation of cardiomyocyte inflammation during viral infection

项目总结/摘要 心肌炎是心肌的炎症病理，由感染性和非感染性两种因素驱动。 急性心力衰竭、室性心律失常和扩张型心肌病的先兆。因此，在本发明中， 了解调节其发病和消退的机制对于预防和治疗至关重要 心肌病的症状microRNA是短的非编码RNA，通过后炎症反应来微调炎症反应。 转录调节免疫基因。其中，miR-208 b和miR-499- 5 p是miR-208家族的成员。 骨骼肌和心脏组织特异性microRNA（myomiRs）在患有心肌梗死的患者中异常表达。 急性心肌炎症和预测疾病严重程度。然而，这些的生物学意义 观察结果知之甚少。我们之前已经证明miR-208 b和miR-499- 5 p在细胞内是异常的， 由肝细胞中的病毒感染和相关的抗病毒细胞因子诱导，在肝细胞中它们沉默I型和 III型干扰素（IFN）应答导致病毒清除减少。在这项研究中，我们提出， 心肌细胞已经进化出类似的机制来阻断干扰素介导的炎症， 亲心病毒利用以避免免疫检测和消除。我们认为miR-208 b和miR-208 b可能与miR-208 b的表达有关。 499- 5 p在心脏中的表达因促炎性损伤而升高，并导致炎性细胞因子的丧失。 控制和过早解决关键的抗病毒反应，使心肌细胞易受 细胞死亡，并可能促进心脏组织损伤。我们建议鉴定明显的损伤- 相关刺激调节myomiR表达以及这些如何协调炎症反应。我们 将使用公正的方法来确定由myomiRs调控的关键分子靶点。我们将测试如果 myomiRs拮抗导致与心肌炎相关的病毒感染持续存在的抗病毒反应， 疾病总的来说，我们的综合方法将建立一个全面的基因调控网络， 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。 清除心脏疾病，从中我们可以发现新的分子靶点的治疗干预。

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.