ACTIVATION OF PROTHROMBIN

这项研究计划旨在了解凝血酶是如何产生的 以及凝血酶的生成是如何被调节的。 我们对这些问题的态度 来自于与1）相关的四个独立方向的收敛 凝固酶复合物的物理性质， 以及这些复合物如何组装成有效的酶 催化剂的 2)混合多种混凝催化剂的研究 为了试图复制组合催化剂体系的性能 例如与凝血酶的组织因子途径相关的 表情 3)为了研究这个过程， 生物系统（全血），以评估假设的正确性 从纯化系统中提取。 4)试图创造数学 可用于定量定义过程的模型 血液凝固及其调节，以帮助实验设计 1，2，3，并且还有助于评价药理学试剂， 止血和血栓性疾病。 本调查的目的是了解 维生素K依赖性促凝血和抗凝复合物及其制备方法 凝血酶生成过程中的调节。 研究将采用 物理化学技术，包括流体力学和荧光 光谱，（后者在溶液和表面）研究 合成膜和细胞上的复合物。 反应将被跟踪 使用合成和天然基质来监测预稳定性 状态和稳态动力学事件。 天然和重组抑制剂 将用于研究促凝血和抗凝的调节 与凝血酶生成相关的过程。 我们将整合 通过对个别反应的研究获得的详细信息 与从多反应中心系统获得的相同。 的相关性 这些纯化的系统对全血中发生的事件的反应将是 通过我们的系统进行定量评估。 相反，进程指出， 发生在整个血液系统中，将引起适当的注意， 纯化系统分析。 我们期待着开发一个定量的 与药物相关的生物学相关化学评价 在血液凝固过程中同时发生的复杂反应 活动 这些数据在解释正常生理学方面具有重要意义， 在开发方法以纠正凝血病理学相关的 血栓和血友病 我们开发的技术将提供 用于评价潜在药物干预的工具 止血和血栓性疾病。

This research program is aimed at understanding how thrombin is generated and how thrombin generation is regulated. Our approach to these questions comes via the convergence of four separate directions associated with 1) the physical properties of coagulation enzyme complexes, their constituents and how these complexes can assemble into efficient enzyme catalysts. 2) Studies in which multiple coagulation catalysts are mixed to attempt to duplicate the performance of the combined catalyst system such as that associated with the tissue factor pathway of thrombin expression. 3) To study this process in unadulterated minimally modified biological systems (whole blood) to evaluate the correctness of hypotheses derived from purified systems. 4) To attempt to create mathematical models which can be used to define, on a quantitative basis, the process of blood clotting and its regulation both to aid in experimental designs 1, 2, 3, and also to aid in the evaluation of the pharmacologic agents, hemostatic and thrombotic diseases. The aim of the present investigation is to understand the nature of procoagulant and anticoagulant vitamin-K dependent complexes and their regulation during the process of thrombin generation. Studies will employ physical chemistry techniques including hydrodynamics and fluorescence spectroscopy, (the latter both in solution and on surfaces) to study complexes on synthetic membranes and cells. Reactions will be followed using both synthetic and natural substrates to monitor both presteady state and steady state kinetic events. Natural and recombinant inhibitors will be used to study the regulation of procoagulant and anticoagulant processes associated with thrombin generation. We will integrate the detailed information available through studies of individual reactions with that obtained from multi-reaction center systems. The relevance of these purified systems to events occurring in whole blood will be evaluated quantitatively by our system. Conversely, the processes noted to occur in the whole blood system will direct appropriate attention in the purified system analyses. We anticipate developing a quantitative evaluation of the biologically relevant chemistry associated with the complex reactions which occur simultaneously during a blood clotting event. These data have significance in interpreting normal physiology and in developing approaches to correct the coagulation pathology associated with thrombosis and hemophilia. The techniques we develop will provide tools for the evaluation of potential pharmacological intervention in hemostatic and thrombotic disease.