Regulation of vasoreactivity by urokinase

描述（申请人摘要）：尿激酶（uPA）是一种多功能的 一种与多种病理生理过程有关的蛋白质， 如癌症、血管生成和炎症。除了它的纤维蛋白溶解作用 活动，我们最近观察到，uPA及其主要片段调节 收缩离体大鼠主动脉环和调节血压。的 uPA介导的血管反应性对纤维蛋白溶解或这些其他反应性的贡献 病理生理事件尚未研究，是本研究的主题。 格兰特.在具体目标1中，我们建议检查uPA的贡献 生长因子结构域和“连接肽”对血管舒张的作用 kringle在血管收缩中的作用及其受uPAR和PM- 1的调节。我们将 探讨低密度脂蛋白相关受体在肝细胞生成中的作用 来自uPA的生物活性片段和B整联蛋白的参与作为潜在的 信号转导-kringle结合蛋白。uPA-Kringle中的元素 调节血管活性的细胞。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 内源性uPA、uPAR和PAl-I对转基因小鼠血压的调节作用 缺乏这些蛋白质。uPA介导的血管收缩性将在 小鼠缺乏PGI 2受体和前列腺素途径中的关键酶， 包括考克斯-1和考克斯-2。在具体目标3中，我们将检查相对于 uPA介导的血管反应性和蛋白水解在模型中的作用 在我们的实验室中发生了肺微栓塞， uPA的作用。我们假设uPA调节血管的能力， 紧张有助于其纤溶活性以及其他uPA介导的 信号转导事件，如细胞粘附和迁移。识别 uPA及其受体中血管活性成分的研究将有助于了解 这些疾病的病理生理学，并确定新的目标， 治疗干预

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.