The Urokinase-CD87 System in Macrophage Activation

尿激酶-CD87 系统在巨噬细胞激活中的作用

• 批准号: 6537149
• 负责人: ROBERT Gary SITRIN
• 金额: $ 26.43万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-07-01 至 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6537149
• 关键词: biological signal transduction; calcium flux; cell adhesion molecules; chemical aggregate; fibrinogen receptors; gene expression; human subject; inflammation; integrins; interleukin 1; laboratory mouse; leukocyte activation /transformation; macrophage; monocyte; phagocytes; phosphorylation; plasminogen activator; receptor; receptor binding; receptor expression; tissue /cell culture; urokinase

DESCRIPTION (Applicant's Abstract): The enzymes, receptors, and inhibitors comprising the plasminogen activator (PA)-plasmin fibrinolytic system contribute importantly to the pathogenesis of inflammation and tissue repair. Evidence is accumulating to indicate that urokinase-type PA (uPA) and uPA receptors (uPAR; CD87) are integral to leukocyte activation, and complex mechanisms have been described whereby uPAR participates in regulating cellular adhesion, migration, and cytokine activation. There is equally compelling evidence that binding uPA to uPAR directly activates signaling pathways, and our recent work has shown that uPAR aggregation, seen during leukocyte adhesion and migration, also initiates activation signaling. Still, our understanding of the mechanisms by which uPAR regulates leukocyte function is fragmentary. The central hypothesis underlying the proposed work is that uPA and uPAR serve pivotal functions in regulating the early events that transition neutrophils and mononuclear phagocytes from quiescent to "activated" phenotypes. The long-term objective of this project is to understand the roles uPA and uPAR play in leukocyte activation signaling, and to characterize the underlying pathways of signal transduction. The short-term objectives are to: i) determine the regulatory roles of uPAR aggregation on leukocyte activation signaling, emphasizing cooperative signaling with adhesion molecules, degranulation, superoxide release, and uPAR turnover; ii) determine whether uPA binding vs. aggregation causes formation of distinctive multiprotein signaling assemblies that partition into specialized lipid-rich domains of the plasma membrane; and iii) determine the role of uPAR in "outside-in" signaling by adhesion molecules, emphasizing signaling intermediates required for adhesion and migration. Thus far, our studies have fortified our hypothesis that uPAR-mediated signaling profoundly affects the function of neutrophils and mononuclear phagocytes. Hopefully, a more complete appreciation of the mechanisms and consequences of uPAR-mediated signaling will create new opportunities for therapeutically manipulating the function of these leukocytes in acute and chronic inflammation, wound healing, and fibrosis.

描述（申请人的摘要）：酶、受体和抑制剂 包含纤溶酶原激活剂（PA）-纤溶酶纤溶系统 对炎症和组织修复的发病机制有重要贡献。 越来越多的证据表明尿激酶型 PA (uPA) 和 uPA 受体（uPAR；CD87）是白细胞激活不可或缺的一部分，并且复杂 已经描述了 uPAR 参与调节细胞的机制 粘附、迁移和细胞因子激活。也有同样引人注目的 有证据表明，uPA 与 uPAR 结合可直接激活信号通路，并且 我们最近的工作表明，在白细胞粘附过程中观察到 uPAR 聚集 和迁移，也启动激活信号。尽管如此，我们的理解 uPAR 调节白细胞功能的机制是不完整的。这 拟议工作的中心假设是 uPA 和 uPAR 服务 调节中性粒细胞转变的早期事件的关键功能 和单核吞噬细胞从静止到“激活”表型。这 该项目的长期目标是了解 uPA 和 uPAR 的作用 在白细胞激活信号传导中发挥作用，并表征潜在的 信号转导途径。短期目标是： i) 确定 uPAR聚集对白细胞激活信号传导的调节作用， 强调与粘附分子的协同信号传导、脱粒、 超氧化物释放和 uPAR 周转； ii) 确定 uPA 结合与否 聚集导致独特的多蛋白信号传导组件的形成 划分为质膜的专门富含脂质的区域；和 iii) 通过粘附确定uPAR在“由外向内”信号传导中的作用 分子，强调粘附和所需的信号中间体 迁移。到目前为止，我们的研究已经证实了我们的假设： uPAR 介导的信号传导深刻影响中性粒细胞和 单核吞噬细胞。希望能有更全面的认识 uPAR 介导的信号传导的机制和后果将创造新的 治疗性操纵这些白细胞功能的机会 急性和慢性炎症、伤口愈合和纤维化。