GENETIC MODELS FOR THE STUDY OF PAI1 FUNCTION IN THE VASCULATURE

纤维蛋白溶解活性的降低被认为加速了 通过促进血栓形成和纤维蛋白形成动脉粥样硬化的过程 在发展中的动脉粥样硬化病变内沉积。 i型 纤溶酶原激活物抑制剂（PAI-1）是纤溶酶原激活物的主要抑制剂。 组织型纤溶酶原激活物（tPA）和尿激酶型 纤溶酶原激活物（uPA），并已发现增加， 许多临床状况通常被定义为原血栓性。 在 初步研究表明，PAI-1过表达 与apoE缺陷型（PAI-1 TG+：apoE）杂交的转基因小鼠 null）小鼠与同窝小鼠相比表现出加速的动脉粥样硬化 小鼠，而PAI-1缺失小鼠似乎受到保护。 根据这些 研究中，我们假设PAI-1在 动脉粥样硬化的发病机制和对血管损伤的反应 通过调节纤溶酶原激活（PA）系统， 对纤维蛋白清除、单核细胞/巨噬细胞产生影响 募集、血管平滑肌细胞迁移和增殖 和细胞外基质合成。 为了验证这些假设，我们 我建议，证实我们在试点研究中的初步发现，PAI-1 TG +_：apoE敲除小鼠发生大量动脉粥样硬化 病变和较早的时间点与同窝对照相比， 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 玻连蛋白，在动脉粥样硬化的发展;和三，检查 PA系统的其他组分的贡献，例如tPA 和uPA，动脉粥样硬化病变的发展和 对血管损伤的反应。 该补助金的目标是确定 PAI-1调节内膜损伤形成的机制 动脉粥样硬化形成和随后的血管损伤。 了解 这些机制可能有助于深入了解病理生理学， 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.