MONOCYTE/MACROPHAGE REGULATION OF COAGULATION REACTIONS

描述：单核/巨噬细胞在炎症中起关键作用 和动脉粥样硬化的过程。因为凝血酶是一种强有力的效应器 在这些反应中，总体假设是凝血酶 单核/巨噬细胞表面的产生提供了 这些部位的重要生物调节效应分子。 目标是定义约束和动力学参数 导致凝血酶表达的分子事件 并阐明单核/巨噬细胞的细胞机制 调节促凝血剂表型的表达。这将是 实现了以下六个具体目标。1)凝血酶原酶 单核/巨噬细胞的复杂组装功能及其调控 曲面将被定义。膜是如何调节这种复合体的 联合蛋白酶、活化蛋白C/蛋白S失活 复合激动剂激活细胞与多种蛋白质的黏附 底物，特别是层粘连蛋白将被确定。2) 单核/巨噬细胞与细胞外结合的促凝血表型 诸如层粘连蛋白之类的基质底物将根据以下各项确定 组织因子表达，Xa催化的IX裂解，以及 膜结合蛋白水解酶的表达。3)整合素受体 单核细胞与层粘连蛋白结合的介导物将被确定，并 层粘连蛋白受体占位对促凝血剂表型的影响 将会被确定。4)确定IXAlpha形成原因的研究 Xa结合单核细胞不是单核细胞结合Tf/VIIa的底物 将启动复杂的研究，以确定IXAlpha如何 Bound Xa的生产是受监管的。5)Va和Xa的区域 将确定与单核细胞表面的中介独立结合。 6)对Va受体的定义和特性的研究 单核细胞/巨噬细胞将被启动。

DESCRIPTION: Monocytes/macrophages play key roles in inflammatory and atherosclerotic processes. Since thrombin is a potent effector of these responses, the overall hypothesis is that thrombin production at the monocyte/macrophage surface provides an important bioregulatory effector molecule at these sites. Objectives are to define binding and kinetic parameters governing molecular events resulting in expression of thrombin at the monocyte/macrophage surface and to elucidate cellular mechanisms which regulate expression of a procoagulant phenotype. This will be accomplished in six specific aims as follows. 1) The prothrombinase complex assembly function and regulation at the monocyte/macrophage surface will be defined. How this complex is modulated by membrane associated proteases, activated protein C/protein S inactivation complex, agonist activation of cells and adherence to various protein substrates, particularly laminin will be determined. 2) The procoagulant phenotype of monocytes/macrophages bound to extracellular matrix substrates such as laminin will be determined, with respect to tissue factor expression, Xa catalyzed cleavage of IX, and expression of membrane-bound proteases. 3) The integrin receptor that mediates monocyte binding to laminin will be identified and the effect of laminin receptor occupancy on procoagulant phenotype will be determined. 4) Studies to determine why IXalpha formed by Xa bound to monocytes is not a substrate for monocyte-bound TF/VIIa complex will be initiated as will studies to determine how IXalpha production by bound Xa is regulated. 5) the regions of Va and Xa that mediate independent binding to the monocyte surface will be determined. 6) Studies to define and characterize the Va receptor expressed on monocytes/macrophages will be initiated.