REGULATION OF FIBRINOLYSIS AT SITES OF ARTERIAL INJURY

血管损伤引起的纤维蛋白沉积是导致血管损伤的关键因素。 急性和慢性动脉疾病的发病机制。 纤溶 系统构成了对血管内纤维蛋白的关键反应机制 形成，并在决定结果中发挥着重要作用， 动脉损伤 此应用程序的总体目标是定义 调节环境中纤维蛋白溶解的机制 受伤的动脉 在初步研究中，我们设计了一种小鼠 派-1缺陷小鼠的颈动脉损伤模型，并证明， 这些动物表现出增强的富含血小板的动脉 血栓 我们还假设纤溶酶原与动脉血管的结合 血栓是其清除的主要决定因素， 和载脂蛋白（a）通过抑制动脉纤维蛋白溶解而延缓动脉纤维蛋白溶解 纤溶酶原向动脉损伤部位的募集。 测试这些 假设，我们将我们的颈动脉损伤模型应用于转基因小鼠 a）缺乏或过表达派- 1，B）表现出组织特异性表达 或表达抗失活的因子V突变体 通过活化蛋白C，或c）表达人载脂蛋白（a）。 这 项目有四个具体目标。 具体目标1是研究 可变的和组织特异性的派-1表达对 小鼠急性动脉血栓。 具体目标2是确定 载脂蛋白（a）抑制纤溶酶原向急性动脉粥样硬化的募集 血栓，并确定血小板因子V是否有助于 血小板对纤维蛋白溶解的抑制。 具体目标3是检查 新生内膜形成的时间过程和细胞特征 小鼠颈动脉后FeC 13损伤，并研究的影响， 载脂蛋白（a）对新生内膜形成的影响。 具体目标4： 产生人纤溶酶原的转基因小鼠，并使用这些小鼠， 动物探索机制，抑制外源性 纤溶酶原激活剂。 本报告中概述的初步数据 应用程序以及本程序项目的互动性 拨款申请强烈支持这些目标的可行性。 我们预计，从这些研究中获得的信息将 大大提高了我们对调节纤维蛋白的机制的理解， 动脉损伤部位的清除率，并更好地定义 纤溶系统在急慢性动脉粥样硬化发病中的作用 疾病

Fibrin deposition in response to vascular injury is a key factor in the pathogenesis of acute and chronic arterial diseases. The fibrinolytic system constitutes a critical response mechanism to intravascular fibrin formation and plays a major role in determining the out come of arterial injury. The overall goal of this application is to define mechanisms that regulate fibrinolysis within the environment of the injured artery. In preliminary studies, we have devised a murine carotid injury model to PAI-1-deficient mice and demonstrated that these animals exhibit enhanced clearance of platelet-rich arterial thrombi. We also hypothesize that binding of plasminogen to arterial thrombi is a major determinant of their clearance, and that factor V and apolipoprotein (a) retard arterial fibrinolysis by inhibiting plasminogen recruitment to sites of arterial injury. To test these hypotheses, we will apply our carotid injury model to transgenic mice that a) lack or overexpress PAI- 1, b) exhibit tissue-specific expression of factor V or express a factor V mutant that is resistant to inactivation by activated protein C, or c) express human apolipoprotein (a). This project has four Specific Aims. Specific Aim 1 is to study the effects of variable and tissue-specific PAI-1 expression on the clearance of acute arterial thrombi in mice. Specific Aim 2 is to determine if apolipoprotein (a) inhibits recruitment of plasminogen to acute arterial thrombi and to determine if platelet factor V contributes to the inhibition of fibrinolysis by platelets. SpecificAim 3 is to examine the time course and cellular characteristics of neointima formation in murine carotid arteries after FeC13 injury and to study the effects of apolipoprotein (a) on neointima formation. Specific Aim 4 is to generate mice transgenic for human plasminogen and to use these animals to probe mechanisms that inhibit the function of exogenous plasminogen activators. The preliminary data outlined in this application as well as the interactive nature of this program project Grant application strongly support the feasibility of these objective. We anticipate that the information gained from these studies will greatly enhance our understanding of mechanisms that regulate fibrin clearance at sites of arterial injury and better define the role of the fibrinolytic system in the pathogenesis of acute and chronic arterial disease.