心肌缺血再灌注损伤是导致缺血性心脏病患者伤残甚至死亡的重要原因，固有免疫应答是其发生的重要机制。激活固有免疫应答的关键分子- - Toll样受体（TLRs）的发现，使心肌缺血再灌注损伤暴露了一个可能的干预靶点- - TLR4。microRNAs（miRNAs）通过结合靶基因的信使RNA调节基因的表达，参与调控固有免疫应答。我们的预实验发现miRNAs可能参与调控TLR4介导的心肌缺血再灌注损伤，但具体作用和机制不明。本项目将采用miRNAs的过表达和阻断技术，在体外心肌细胞和小鼠心肌缺血再灌注损伤模型中，探索miRNAs对TLR4介导的心肌缺血再灌注损伤的作用及机制，并通过敲除小鼠TLR4基因进一步阐明TLR4介导的心肌缺血再灌注损伤的免疫学机制，以及miRNAs与TLR4信号通路的关系与作用。本项目将重点解答miRNAs能否干预TLR4介导的心肌缺血再灌注损伤的关键问题，为临床防治提供理论指导。

Ischemic cardiomyopathy, resulting in high disability and motality, is mainly caused by myocardial ischemia reperfusion (I/R) injury. The innate immune response plays an important role in myocardial I/R injury. Discovery of Toll-like receptors (TLRs) - a key issue of innate immune response, exposes a possible target to prevent myocardial I/R injury, which is TLR4. MicroRNAs (miRNAs) regulate target gene expression by combining to its messenger RNA, thus regulating innate immune response. We have found that miRNAs may be involved in regulating TLR4-mediated myocardial I/R injury, but the functions and mechanisms are still unclear. In this project, we will explore the functions and mechanisms of miRNAs in TLR4-mediated myocardial I/R injury in vitro and in mouse myocardial I/R injury model, by over expressing or antagonizing miRNAs. Also we will knock out TLR4 in mouse to define the mechanisms by which TLR4 mediate myocardial I/R injury, and by which miRNAs regulate TLR4-mediated signaling pathway. These will provide important information for new approaches for the treatment of patients with ischemic cardiomyopathy.