Regulation of vasoreactivity by urokinase

描述(申请人摘要)：尿激酶(UPA)是一种多功能药物 参与多种病理生理过程的蛋白质 如癌症、血管生成和炎症。除了它的纤溶作用 活性，我们最近观察到uPA及其主要片段调节 收缩大鼠离体主动脉环并调节血压。这个 UPA介导的血管反应性在纤溶或其他方面的作用 病理生理事件尚未被调查，这是这一事件的主题 格兰特。在具体目标1中，我们建议审查UPA的贡献 生长因子结构域和“连接肽”对血管松弛的作用 血管收缩的环及其由uPAR和PM-1调节。我们将 探讨低密度脂蛋白相关受体在细胞生成中的作用 尿激酶型纤溶酶原激活剂的生物活性片段及其可能参与的b整合素 信号转导-kringle结合蛋白。Upa-kringle中的元素 将对调节血管活动的物质进行检测。在具体目标2中，我们将研究 UPA调节血管反应性的机制。我们将研究一下 内源性uPA、uPAR和PAL-I在转基因小鼠血压调节中的作用 缺乏这些蛋白质。UPA介导的血管收缩性能将在 小鼠缺乏前列腺素途径中的PGI2受体和关键酶， 将COX-1和COX-2包括在特定目标3中，我们将考察其相对 尿激酶型纤溶酶原激活剂介导的血管反应性和蛋白水解性在动脉粥样硬化模型中的作用 我们实验室发展出的肺微栓子依赖于 UPA的行动。我们假设uPA调节血管的能力 Tone有助于其纤溶活性以及其他由uPA介导的 信号转导事件，如细胞黏附和迁移。鉴定 UPA及其受体中血管活性成分的研究将为深入了解 这些疾病的病理生理学和确定新的靶点 治疗性干预。

DESCRIPTION (Applicant's abstract): Urokinase (uPA) is a multifunctional protein that has been implicated in several pathophysiological processes such as cancer, angiogenesis, and inflammation. In addition to its fibrinolytic activity, we recently observed that uPA and its major fragments regulate the contraction of isolated aortic rings and modulate blood pressure in rats. The contribution of uPA-mediated vascular reactivity to fibrinolysis or these other pathophysiologic events has not been investigated and is the subject of this grant. In Specific Aim 1, we propose to examine the contribution of the uPA growth factor domain and "connecting peptide" to vasorelaxation and the role of the kringle in vasoconstriction and their regulation by uPAR and PM- 1. We will explore the role of the low-density lipoprotein related receptor in generating bioactive fragments from uPA and the involvement of b integrins as potential signal transducing-kringle binding proteins. The elements in the uPA-kringle that regulate vasoactivity will be examined. In Specific Aim 2, we will study the mechanism by which uPA modulates vasoreactivity. We will examine role of endogenous uPA, uPAR and PAl-I in regulating blood pressure in transgenic mice lacking these proteins. uPA-mediated vascular contractility will be examined in mice lack PGI2 receptors and critical enzymes in the prostaglandin pathway, including COX-1 and COX-2 In Specific Aim 3, we will examine the relative contribution of uPA-mediated vasoreactivity and proteolysis in a model of pulmonary microembolism developed in our laboratory that is dependent on the actions of uPA. We hypothesize that the capacity of uPA to regulate vascular tone contributes to its fibrinolytic activity as well as to other uPA-mediated signal transduction events such as cell adhesion and migration. Identification of vasoactive components in uPA and their receptors will provide insight into the pathophysiology of these disorders and identify novel targets for therapeutic intervention.