Thrombus Formation In Vivo

体内血栓形成

• 批准号: 7680997
• 负责人: Bruce Furie
• 金额: $ 174.92万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7680997
• 关键词: Address; Adhesions; Animals; Biochemistry; Blood Platelets; CD39 antigen; Cellular biology; Development; Endothelial Cells; Factor IX; Factor XII; Kinetics; Lasers; Life; Mass Spectrum Analysis; Mediating; Microscopy; Modeling; Molecular; Morbidity - disease rate; Mus; Myeloid Cells; Nucleotides; Phase; Physiological; Platelet Activation; Principal Investigator; Process; Program Research Project Grants; Proteins; Role; Series; Signal Transduction; Smooth Muscle Myocytes; Societies; Source; Speed; Technology; Testing; Thromboplastin; Thrombosis; Thrombus; base; in vivo; intravital microscopy; mortality; palmitoylation; prevent; von Willebrand Factor

DESCRIPTION (provided by applicant): This Program Project Grant, entitled "THROMBUS FORMATION IN VIVO" brings four principal investigators to focus on the process of thrombogenesis. This group has pioneered the development of high speed intravital confocal and widefield microscopy to study thrombus formation in a living mouse using the laser induced thrombosis model. Using this technology, they will address a series of critical questions related to the three phases of thrombus formation: initiation, development and propagation. In Project #1 entitled TISSUE FACTOR AND THE INITIATION OF THROMBUS FORMATION, Dr. Bruce Furie will study the physiologic role of tissue factor and the molecular basis of tissue factor activation. He will examine the kinetics of expression of tissue factor forms in cultured endothelial cells and during thrombus formation in a living mouse. The cellular source of tissue factor required during thrombus formation will be evaluated using chimeric mice, MAFIA mice, and genetically altered mice that are deficient in tissue factor in endothelial cells, platelets, myeloid cells or smooth muscle cells. In Project #2 entitled PLATELET PROTEIN PALMITOYLATION AND THROMBUS FORMATION, Dr. Robert Flaumenhaft will evaluate the role of protein palmitoylation in platelet activation and thrombus formation using the mouse thrombosis model, and determine which proteins undergo posttranslational palmitoylation. In Project #3 entitled CD39 AND ITS ROLE IN THROMBOGENESIS, Dr. Simon Robson will test the hypothesis that modulated CD39/NTPDase-1 expression regulates nucleotide-mediated signaling in the vasculature and platelet activation, thus regulating thrombus propagation during thrombus formation in living mice. In Project #4 entitled INITIAL PLATELET ADHESION AND THROMBUS PROPAGATION, Dr. Barbara Furie will study the combined roles of GPVI/PAR4 and PAR4/von Willebrand factor in platelet activation during thrombus formation, the contribution of cellular sources of von Willebrand factor to thrombus development and the role of Factor XII and Factor IX in tissue factor-mediated thrombus propagation. Administrative, Intravital Microscopy and Mass Spectrometry cores support the activities of the four projects. The ability to study the biochemistry and cell biology of thrombus formation in living animals offers opportunities to understand thrombosis and develop strategies for preventing thrombosis, the major cause of morbidity and mortality in Western society.

描述（由申请人提供）： 这项名为“体内血栓形成”的项目资助吸引了四名主要研究人员关注血栓形成的过程。该小组率先开发了高速活体共聚焦和宽视野显微镜，利用激光诱导血栓形成模型来研究活体小鼠的血栓形成。利用这项技术，他们将解决与血栓形成三个阶段相关的一系列关键问题：起始、发展和传播。在题为“组织因子和血栓形成的启动”的项目#1 中，Bruce Furie 博士将研究组织因子的生理作用和组织因子激活的分子基础。他将研究培养的内皮细胞中以及活体小鼠血栓形成过程中组织因子形式的表达动力学。将使用内皮细胞、血小板、骨髓细胞或平滑肌细胞中缺乏组织因子的嵌合小鼠、MAFIA小鼠和基因改造小鼠来评估血栓形成过程中所需的组织因子的细胞来源。在题为“血小板蛋白棕榈酰化和血栓形成”的项目 #2 中，Robert Flaumenhaft 博士将使用小鼠血栓形成模型评估蛋白质棕榈酰化在血小板活化和血栓形成中的作用，并确定哪些蛋白质经历翻译后棕榈酰化。在题为“CD39 及其在血栓发生中的作用”的项目#3 中，Simon Robson 博士将测试这一假设：调节 CD39/NTPDase-1 表达可调节脉管系统和血小板激活中核苷酸介导的信号传导，从而在活体小鼠的血栓形成过程中调节血栓传播。 。在题为“初始血小板粘附和血栓传播”的项目 #4 中，Barbara Furie 博士将研究 GPVI/PAR4 和 PAR4/von Willebrand 因子在血栓形成过程中血小板激活中的综合作用，以及 von Willebrand 因子的细胞来源对血栓形成的贡献以及因子 XII 和因子 IX 在组织因子介导的血栓传播中的作用。行政、活体显微镜和质谱核心支持这四个项目的活动。研究活体动物血栓形成的生物化学和细胞生物学的能力为了解血栓形成和制定预防血栓形成的策略提供了机会，血栓形成是西方社会发病和死亡的主要原因。