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。我们对这些问题的处理方法 通过与1关联的四个不同方向的汇聚来实现) 凝血酶复合体的物理性质、凝固酶的 以及这些复合体如何组装成有效的酶 催化剂。2)多种混凝催化剂混合的研究 试图复制组合催化剂系统的性能 例如与凝血酶的组织因子途径相关的基因 表情。3)在未掺杂的微改性条件下研究这一过程。 生物系统(全血)评估假说的正确性 从纯化的系统中提取。4)尝试创建数学 可用于在定量的基础上定义过程的模型 凝血及其调节的研究有助于实验设计 1、2、3，并且还帮助评价药理药剂， 止血和血栓性疾病。 目前调查的目的是了解 促凝剂和抗凝剂维生素K依赖的复合体及其 凝血酶生成过程中的调控。研究将雇用 包括流体动力学和荧光在内的物理化学技术 光谱学，(后者既在溶液中又在表面上)研究 合成膜和细胞上的复合体。我们会关注他们的反应 使用合成底物和天然底物来监测稳态期前 状态和稳定状态动力学事件。天然和重组抑制剂 将用于研究促凝剂和抗凝剂的调节 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可获得详细信息 与从多反应中心系统获得的结果相同。的关联性 这些纯化的系统对全血中发生的事件将 由我们的系统进行定量评估。相反，注意到的进程 在整个血液系统中发生将引导适当的注意在 对净化后的系统进行分析。我们预计将开发一种量化的 与癌症相关的生物化学的评价 在血液凝结过程中同时发生的复杂反应 事件。这些数据对解释正常的生理学和 在开发方法来纠正与凝血相关的病理 患有血栓和血友病。我们开发的技术将提供 用于评估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.