Regulation of cardiomyocyte inflammation during viral infection

项目摘要/摘要 心肌炎是一种心肌炎性病理，由感染性和非感染性两种因素引起 药物，通常是急性心力衰竭、室性心律失常和扩张型心肌病的先兆。因此， 了解其发病和消退的调控机制对预防和治疗具有重要意义。 心肌疾病的风险。MicroRNAs是一种短小的非编码RNA，它通过后调节炎症反应 转录调控免疫基因。其中miR-208B和miR-499-5P属于 骨骼肌和心肌组织特异性microRNAs(MyomiRs)在慢性阻塞性肺疾病患者中异常表达 急性心肌炎和预测疾病严重程度。然而，这些生物的生物学意义 人们对观察结果知之甚少。我们之前已经证明miR-208B和miR-499-5P是异常的 由病毒感染和相关的抗病毒细胞因子在肝细胞中诱导，在那里它们抑制I型和 III型干扰素(干扰素)反应导致病毒清除减少。在这项研究中，我们建议 心肌细胞已经进化出一种类似的机制来阻止干扰素介导的炎症，这 嗜心病毒用来避免免疫检测和消除。我们建议miR-208B和miR- 499-5p在心脏中的表达因前炎症损伤而升高，并导致炎症的丧失 控制和过早分解使心肌细胞易感的关键抗病毒反应 细胞死亡，并可能促进心脏组织损伤。我们建议确定不同的损害- 调节myomiR表达的相关刺激以及这些刺激如何协调炎症反应。我们 将使用无偏见的方法来确定由myomiRs调控的关键分子靶点。我们将测试是否 MyomiRs拮抗导致与心肌相关的病毒感染持续存在的抗病毒反应 疾病。总体而言，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 心脏疾病的清除，从中我们可以发现治疗干预的新分子靶点。

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.