The Activation of Prothrombin

凝血酶原的激活

• 批准号: 7328145
• 负责人: KENNETH G MANN
• 金额: $ 34.07万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7328145
• 关键词: Affect; Anticoagulants; Antiplatelet Drugs; Binding; Biochemical; Biological; Blood Cells; Blood Circulation; Blood Clot; Blood Platelets; Blood Vessels; Blood capillaries; Blood coagulation; Cessation of life; Coagulation Process; Complex; Condition; Development; Diagnosis; Disease; Endothelial Cells; Endothelium; Fibrinolysis; Film; Fluorescence; Generations; Goals; Health; Hemophilia A; Hemorrhage; Human; Human Biology; In Vitro; Intervention; Knowledge; Medicine; Membrane; Methods; Modeling; New Agents; Pathologic; Pathology; Physiology; Plasma; Program Research Project Grants; Prophylactic treatment; Proteins; Proteome; Prothrombin; Range; Reaction; Risk; Source; System; Techniques; Testing; Thrombin; Thromboplastin; Thrombosis; Time; United States; Venous; Whole Blood; blood coagulation process; capillary; monocyte; research study; response; tool

The goal of this project is to characterizethe physiology and pathology of the blood coagulation system in quantifiable terms. We have developed three approaches for these analyseswhich include: numerical models of the blood coagulation proteome, numerical recapitulations of the blood coagulation proteome using purified proteins, and studies of whole blood in vitro and flowing from microvascular wounds. We seek quantitatively transparent descriptions convergent with the biological/pathologic observations of medicine which can ultimately be useful for the diagnosis, prophylaxis and therapy of human thrombotic and lemorrhagic disease. In the renewal requested, we will evaluate, in the closed blood coagulation systems, the influence of additional components of the plasma proteome on the generation of thrombin and other constituents. Special emphasis will be focused on tissue factor from natural sources, protein S, and cellular contributions by platelets, monocytes and endothelial cells. We will apply our methods to open systems, initially using flow dynamics in two artificial systems, to investigate the binding and presentation of the components of the proteolytic coagulation complexes under conditions of shear ranging from venous to arterial. These experiments will be conducted using total internal reflectance fluorescence and a newly devised tool the Real Time Thrombosis Profiler. Experiments in flow will be quantitatively analyzed using biophysical techniques and evaluated using modern mathematical techniques used to describe flow dynamics. Flow reactions will be studied in systems ranging from artificial capillaries coated with synthetic . membrane films or endothelial cells, and ultimately to human vascular arterial and venous segments. The systems developed will be utilized to evaluate the influence of anticoagulants and antiplatelet agents on the coagulation response. We anticipate the latter studies will provide evidence for identifying control points and the qualities of new agents required for control of these points. Project 1 is integrated with each of the remaining five projects of this program project grant providing both intellectual material and physical support in the collaborative studies of coagulation and fibrinolysis in human biology. Relevance: Venous and arterial blood clots are major health problems in the United States associated with approximately one million deaths each year. Hemorrhagic diseases, especially hemophilia A and B are thankfully less frequent, but still major health issues for those affected. This project seeks to provide fundamental knowledge which will be useful to identify those at risk for thrombotic and bleeding diseases, and provide methods and information that can be useful in the diagnosis, prophylaxis and therapy of bleeding and clotting diseases. ^^

该项目的目标是表征血液凝固系统的生理学和病理学特征 可量化的术语。我们为这些分析开发了三种方法，包括： 凝血蛋白质组模型、凝血蛋白质组数值重演 使用纯化的蛋白质，并对体外全血和微血管伤口流动的全血进行研究。我们寻求 定量透明的描述与医学的生物学/病理学观察相一致 最终可用于人类血栓和血栓性疾病的诊断、预防和治疗 出血性疾病。在更新请求中，我们将在封闭式凝血系统中进行评估， 血浆蛋白质组的其他成分对凝血酶和其他物质产生的影响 选民。特别重点将集中于天然来源的组织因子、蛋白质 S 和细胞 血小板、单核细胞和内皮细胞的贡献。我们将把我们的方法应用于开放系统， 最初在两个人工系统中使用流动动力学，以研究 在从静脉到剪切力的条件下，蛋白水解凝固复合物的成分 动脉。这些实验将使用全内反射荧光和新的 设计了实时血栓分析仪工具。流动实验将使用定量分析 生物物理技术并使用用于描述流动的现代数学技术进行评估 动力学。流动反应将在涂有合成材料的人造毛细血管等系统中进行研究。 膜或内皮细胞，最终到达人体血管动脉和静脉段。这 开发的系统将用于评估抗凝剂和抗血小板剂对 凝血反应。我们预计后面的研究将为识别控制点和 控制这些点所需的新代理的质量。项目 1 与每个项目集成 该计划的其余五个项目提供智力物质和物质支持的项目赠款 在人类生物学中凝血和纤维蛋白溶解的合作研究中。 相关性：静脉和动脉血栓是美国的主要健康问题，与以下疾病相关 每年约有一百万人死亡。出血性疾病，尤其是甲型和乙型血友病 值得庆幸的是，这种情况发生的频率较低，但对受影响的人来说仍然是重大健康问题。该项目旨在提供 有助于识别那些有血栓和出血性疾病风险的人的基础知识， 并提供可用于诊断、预防和治疗的方法和信息 出血和凝血疾病。 ^^