GENETIC MODELS FOR THE STUDY OF PAI1 FUNCTION IN THE VASCULATURE

纤溶活性的降低被认为是为了加速 促进血栓形成和纤维蛋白的动脉粥样硬化形成过程 在发展中的动脉粥样硬化性病变内沉积。第I类 纤溶酶原激活物抑制物(PAI-1)是 组织型纤溶酶原激活物和尿激酶型 纤溶酶原激活物(UPA)，并被发现在一种 通常被定义为原生生物的临床状况的数量。在……里面 初步研究表明，PAI-1过表达 转基因小鼠与apoE缺陷(PAI-1 TG+：apoE)杂交 与消炎痛相比，小鼠表现出动脉粥样硬化加速 小鼠，而PAI-1基因缺失的小鼠似乎受到保护。在此基础上 研究表明，我们假设PAI-1在脑出血中起主要作用。 动脉粥样硬化的发病机制及其在血管损伤中的反应 通过其对纤溶酶原激活(PA)系统的调节 对纤维蛋白清除、单核/巨噬细胞的影响 募集、血管平滑肌细胞迁移和增殖 和细胞外基质合成。为了检验这些假设，我们 建议一，确认我们在试点研究中的初步发现，即PAI-1 TG+_：APOE基因缺失小鼠发生更多的动脉粥样硬化 与产仔对照相比，在较早的时间点， 并描述这些动脉粥样硬化病变的细胞特征； 第二，确定致动脉粥样硬化的PAI-1配体的来源，如 Vitronectin在动脉粥样硬化发展中的作用；第三，检查 PA系统的其他组成部分的贡献，如tPA 和uPA，对动脉粥样硬化病变的发展和 对血管损伤的反应。这笔赠款的目标是定义 纤溶酶原激活物-1调节血管内膜病变形成的机制 动脉粥样硬化的形成和血管损伤后。一种对 这些机制可能有助于深入了解病理生理学和 血管疾病的治疗。

Decreased fibrinolytic activity has been suggested to accelerate the process of arterial atherogenesis by facilitating thrombosis and fibrin deposition within developing atherosclerotic lesions. Type I plasminogen activator inhibitor (PAI-1) is the primary inhibitor of tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA) and has been found to be increased in a number of clinical conditions generally defined as prothombotic. In preliminary studies, we have demonstrated that PAI-1 overexpressing transgenic mice cross bred with apoE deficient (PAI-1 TG+:apoE null) mice exhibit accelerated atherosclerosis compared to littermate mice while PAI-1 null mice appear protected. On the basis of these studies, we hypothesize that PAI-1 plays a major role in the pathogenesis of atherosclerosis and in the response to vascular injury through its regulation of the plasminogen activation (PA) system with resulting effects on fibrin clearance, monocyte/macrophage recruitment, vascular smooth muscle cell migration and proliferation and extracellular matrix synthesis. To test these hypothesis, we propose to one, confirm our initial findings in pilot studies that PAI-1 TG+_:apoE null mice develop a larger number of atherosclerotic lesions and at earlier time points compared with littermate controls, and characterize the cellular features of these atherosclerotic lesions; two, determine the source of proatherogenic PAI-1 ligands, such as vitronectin, in the development of atherosclerosis; and three, examine the contributions of other components of the PA system, such as tPA and uPA, to the development of atherosclerotic lesions and the response to vascular injury. The goals of this grant are to define the mechanisms by which PAI-1 regulates intimal lesion formation during atherogenesis and following vascular injury. An understanding of these mechanisms may lend insight into the pathophysiology and treatment of vascular diseases.