Surface Dependent Reactions in Thrombosis and Thrombolysis

描述(由申请人提供)：该计划的总体重点是确定维持血液流动性和凝固性之间平衡的过程的组成部分和机制。与维持血液流动性相关的成分包括血浆、循环血细胞、血管组织及其周围组织的成分。维持或改变血液流动性的过程包括凝血反应、与外周血液和血管细胞相关的促凝血和抗凝功能以及血管-血液纤溶系统。本计划中的项目以一种综合的方式处理与这些过程及其监管相关的全球反应。基本假设是，有助于止血和纤溶的复杂多方面系统的性质体现在系统各个组件的结构、相互作用和反应的详细知识中，并可以从这些详细知识中推断出来。这些研究既集中在由纯化成分重建的系统上，也集中在天然生物材料和生物系统上，包括血栓形成的机制和群体研究。我们的战略是将我们处理这些生物表面上发生的分子和生理相互作用的人才结合起来，并将这些知识与人类健康和疾病联系起来。该计划由四个项目组成：1)凝血酶原的激活，2)静脉血栓栓塞症：基因，风险和管理，3)纤溶级联反应的特性，4)人血小板凝血酶原酶活性的调节。一个行政核心和一个免疫学核心支持这些项目。总体而言，这些项目和核心在它们的目的和它们在化学、细胞和流行病学研究中共享的试剂(天然和重组蛋白质、核酸、合成抑制物、多肽底物、抗体和细胞)方面是综合的，旨在了解 人体血栓形成和止血的过程。建议的研究从分子遗传学、细胞生物学和生物化学的基础研究延伸到人类血栓性疾病和出血性疾病的遗传学和病理机制。拟议的研究计划和过去研究成果的历史证据表明，主要研究人员和实验室之间存在着重要的智力和身体上的互动，这使该计划项目成为一个有效的科学载体。

DESCRIPTION (provided by applicant): The overall focus of this program is aimed at identifying the components of, and the mechanisms for, the processes which maintain the balance between the fluidity and clotting of blood. The components associated with the maintenance of blood fluidity include elements of the plasma, the circulating blood cells, the vascular tissues and their surrounding tissues. The processes responsible for maintaining or altering the fluidity of blood include the coagulation reactions, the pro and anticoagulant functions associated with peripheral blood and vascular cells and the vascular-blood fibrinolytic system. The projects in this Program address, in an integrated fashion, the global reactions associated with each of these processes and their regulation. The fundamental hypothesis is that the properties of the complex multifaceted systems contributing to hemostasis and fibrinolysis are embodied in, and can be deduced from detailed knowledge of the structure, interactions and reactions of the individual components of the systems. The studies focus both upon systems reconstructed from purified components and on natural biomaterials and biosystems, including mechanistic and population studies of thrombophilia. Our strategy is to combine our talents dealing with the molecular and physiological interactions occurring on these biological surfaces and to correlate this knowledge with human health and disease. The program is composed of four projects 1) The Activation of Prothrombin, 2) Venous Thromboembolism: Genes, Risk and Management, 3) Properties of Fibrinolytic Cascade, 4) Regulation of Human Platelet Prothrombinase Activity. An Administrative Core and an Immunology Core support these projects. Overall, these projects and cores are integrated with respect to their purpose and the reagents which they share (natural and recombinant proteins, nucleic acids, synthetic inhibitors, peptide substrates, antibodies and cells) in chemical cellular and epidemiological studies aimed at understanding the processes of human thrombosis and hemostasis. The research proposed extends from fundamental studies of molecular genetics, cell biology and biochemistry to the genetics and mechanisms of the pathology of human thrombotic disease and bleeding disorders. The proposed research program and the historical evidence of past research accomplishments demonstrate that significant interactions, both intellectual and physical, exist between the principal investigators and the laboratories which make this program project grant an effective scientific vehicle.