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，是血管成形术后血流恢复、溶栓治疗和冠状动脉搭桥手术后心肌组织损失的原因。本研究的长远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。我们的初步数据表明，I/R损伤诱导内皮细胞损伤和凝血因子渗漏到心肌。心肌细胞组织因子启动凝血级联并产生凝血蛋白酶凝血酶。我们假设内皮细胞上PAR-1的凝血酶切割增加了促炎介质的表达，如KC和MCP-1，以及pmn的募集。该建议包含三个具体目标。特异性Aim 1将决定PAR-1在心肌I/R损伤中的作用。特异性Aim 2将确定egr - 1的表达模式及其在心肌L/R损伤中的作用。特异性Aim 3将鉴定心肌I/R损伤中凝血酶- par -1依赖性炎症基因。我们的研究应该增加对凝血酶- par -1信号通路在心肌I/R损伤中的作用的基本认识，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.