Role of Extracellular MicroRNAs in Myocardial Ischemia-Reperfusion Injury

项目摘要 包括缺血性心肌梗死(MI)在内的心脏病仍然是#年死亡的主要原因。 美国，而再灌注治疗，如经皮冠状动脉介入治疗，仍然是最有效的策略 为限制心肌梗死范围和保护心功能，再灌注本身可对心肌造成致命性损伤。在……里面 对缺血再灌注(I/R)的反应，心肌释放各种危险分子，这些分子被证明是 对心脏有害。我们最近发现，包括许多microRNAs(MiRNAs)在内的细胞RNA 在I/R期间从心脏释放，细胞外RNA有助于心肌炎症和损伤。 我们的初步研究表明，从心脏分离的RNA或单链miRNA模拟 (miR-34、-122、-133a、-142、146a、-208a)在心肌细胞、中性粒细胞和 巨噬细胞。利用基因缺失模型和药物抑制剂，我们证明了，在基于细胞的 分析表明，心脏RNAs或microRNA模拟物通过固有的 免疫Toll样受体7信号转导通路。这项提案的主要目标是确定 细胞外miRNAs在心肌I/R损伤中的作用及其分子机制探讨。 该提议基于以下三个假设：1)miRNAs是从受损的心肌中释放出来的 2)miRNAs通过TLR7信号途径发挥作用 在心肌细胞和中性粒细胞中，3)药物抑制miRNAs和TLR7信号后 缺血性损伤将对I/R损伤提供心脏保护。在具体目标1中，我们将确定 细胞外miRNAs在I/R期间心肌炎症和损伤中的作用 将测试TLR7信号在miRNA介导的I/R心肌炎症和损伤中的作用。 目的3，我们将探索miRNA-TLR7信号转导通路作为治疗骨肉瘤的潜在靶点。 心肌I/R损伤。拟议的研究解决了细胞外miRNAs在体内的一种独特和新的功能 心肌炎症和损伤在缺血性心脏病发病机制和治疗中的重要意义 心肌梗死。

Project Summary Heart diseases including ischemic myocardial infarction (MI) continue to be the leading cause of mortality in the U.S. While reperfusion therapy such as percutaneous coronary intervention remains the most effective strategy to limit infarct size and preserve cardiac function, reperfusion itself can cause lethal injury to myocardium. In response to ischemia-reperfusion (I/R), myocardium releases various danger molecules that are proven to be harmful to the heart. We have recently identified that cellular RNAs including many microRNAs (miRNAs) are released from the heart during I/R and that extracellular RNA contributes to myocardial inflammation and injury. Our preliminary investigations demonstrate that RNA isolated from the heart or single-stranded miRNA mimics (miR-34, -122, -133a, -142, 146a, -208a) induce a robust cytokine response in cardiomyocytes, neutrophils, and macrophages. Using genetic deletion models and pharmacological inhibitors, we demonstrate, in cell-based assays, that cardiac RNAs or microRNA mimics induce cytokine production specifically through the innate immune Toll-like receptor 7 (TLR7) signaling. The over goals of this proposal are to determine the role of extracellular miRNAs in myocardial I/R injury and explore the underlying molecular mechanisms. The proposal is based on the following three hypotheses: 1) that miRNAs are released from injured myocardium during I/R and play a role in myocardial inflammation and injury, 2) that miRNAs act through TLR7 signaling in cardiomyocytes and neutrophils, 3) that pharmacological inhibition of miRNAs and TLR7 signaling after ischemic insult will offer cardio-protection against I/R injury. In Specific Aim 1, we will determine the contribution of extracellular miRNAs to myocardial inflammation and injury during I/R. In Specific Aim 2, we will test the role of TLR7 signaling in miRNA-mediated myocardial inflammation and injury in I/R. In Specific Aim 3, we will explore the miRNA-TLR7 signaling as a potential therapeutic target for the treatment of myocardial I/R injury. The proposed studies address a unique and novel function of extracellular miRNAs in myocardial inflammation and injury, with significant implications in pathogenesis and treatment of ischemic myocardial infarction.