Thrombin-PAR-1 Signaling in Cardiac I/R Injury

描述(由申请人提供)：心肌I/R损伤是一个重要的临床问题，在血管成形术、溶栓剂治疗和冠状动脉旁路手术后恢复血流后，心肌组织会丢失。这项建议的广泛、长期目标是了解凝血酶如何在心肌缺血-再灌注(I/R)损伤中促进炎症反应。我们的初步数据表明，I/R损伤导致内皮细胞损伤和凝血因子渗入心肌。心肌细胞组织因子启动凝血级联反应，产生凝血酶。我们假设凝血酶裂解内皮细胞上的PAR-1增加了促炎介质如KC和MCP-1的表达，并促进了PMN的募集。该提案包含三个具体目标。特异靶1将确定PAR-1在心肌I/R损伤中的作用。特异性靶蛋白2将确定Egr-L的表达模式及其在心肌L/再灌注损伤中的作用。特异性目标3将鉴定心肌I/R损伤中凝血酶-PAR-1依赖的炎症基因。我们的研究将增加对凝血酶-PAR-1信号通路在心肌I/R损伤中作用的基础知识，并可能导致开发新的治疗方法来保护缺血心肌。

DESCRIPTION (provided by applicant): Myocardial I/R injury is a significant clinical problem and contributes to loss of myocardial tissue after restoration of blood flow after angioplasty, after administration of thrombolytics and following coronary artery bypass surgery. The broad, long-term goal of this proposal is to understand how thrombin contributes to inflammation during myocardial ischemia-reperfusion (I/R) injury. Our preliminary data suggest that I/R injury induces endothelial cell damage and leakage of clotting factors into the myocardium. Cardiomyocyte tissue factor initiates the clotting cascade and generates the coagulation protease thrombin. We hypothesize that thrombin cleavage of PAR-1 on endothelial cells increases the expression of proinflammatory mediators, such as KC and MCP-1, and recruitment of PMNs. The proposal contains three specific aims. Specific Aim 1 will determine the role of PAR-1 in myocardial I/R injury. Specific Aim 2 will determine the expression pattern of Egr-l and its role in myocardial L/R injury. Specific Aim 3 will identify thrombin-PAR-1-dependent inflammatory genes in myocardial I/R injury. Our studies should increase the fundamental knowledge of the role of the thrombin-PAR-1 signaling pathway in myocardial I/R injury and may lead to the development of novel therapies to preserve ischemic myocardium.