BLOOD COAGULATION & FIBRINOLYSIS

血液凝固

• 批准号: 6390805
• 负责人: Nigel Mackman
• 金额: $ 36.78万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-01 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6390805
• 关键词: biological signal transduction; blood coagulation; fibrinolysis; genetic regulation; hemostasis; laboratory mouse; thrombin; thromboplastin; vascular endothelium

The hemostatic balance is regulated by vascular bed-specific endothelial cell signaling pathways. We propose that coronary artery thrombosis arises through local alternations in one or more of these pathways. The overall goal of the Collaborative Program are to elucidate the molecular basis of endothelial cell subtype-specific gene expression in the hear and to identify the critical components of cardiac hemostasis. Dr. Rosenberg will study the role of a platelet-derived growth factor signaling pathway in mediating expression of a gene program within cardiac microvascular endothelial cells that includes tissue factor (TF). He will also optimize a recently developed mouse model of coronary artery thrombosis. Dr. Aird will examine the role of the Egr-1 transcription factor in mediating cardiac-specific hemostasis. He will ask how a single gene can serve to "fine tune" hemostasis according to the local needs of the tissue. Dr. Mackman will evaluate the role of a thrombin-PAR-1 signaling pathway in governing local levels of procoagulant (TF) and fibrinolytic (tissue-type plasminogen activator) molecules within the heart. In addition, he will address the contribution of monocyte-derived TF to cardiac hemostasis. Dr. Housman will use genetic approaches in large populations to identify genotypes which significantly contribute to coronary thrombosis. The three basic science projects are interrelated by several common themes. Each component involves: (1) the study of a cardiac endothelial cell type-specific signaling pathway, (2) the determination of the effects of cell type-specific signaling pathways on global hemostasis (fibrin deposition) (3) the study of TF gene regulation and its role as the initiator of coagulation in the cardiac circulation, and (4) the use of transgenic mouse technology for studying vascular-bed specific hemostasis in the heart. The clinical project will serve as a vital link to validate the role of local hemostatic components in human populations. Dr. Rosenberg provides expertise in both genetic mouse models of hyper- coagulability and in the functional analysis of in vivo hemostasis. Dr. Aird contributes tools for studying vascular bed-specific gene regulation. Dr. Mackman has experience in studying TF gene regulation in cultured cells and animal models. Dr. Housman is an acknowledged expert in human genomics. Taken together, the individual projects and the collaborative efforts promise to provide important insight into the molecular basis of cardiac hemostasis.

止血平衡由血管床特异性内皮细胞信号通路调节。我们认为冠状动脉血栓形成是通过这些途径中的一个或多个发生局部改变而产生的。该合作项目的总体目标是阐明心脏内皮细胞亚型特异性基因表达的分子基础，并确定心脏止血的关键成分。Rosenberg博士将研究血小板衍生生长因子信号通路在介导包括组织因子（TF）在内的心脏微血管内皮细胞内基因程序表达中的作用。他还将优化最近开发的冠状动脉血栓形成小鼠模型。Dr. Aird将研究Egr-1转录因子在介导心脏特异性止血中的作用。他将询问单个基因如何根据组织的局部需要“微调”止血。Mackman博士将评估凝血酶- par -1信号通路在控制心脏内局部促凝剂（TF）和纤溶酶（组织型纤溶酶原激活剂）分子水平中的作用。此外，他将讨论单核细胞来源的TF对心脏止血的贡献。Housman博士将在大量人群中使用遗传方法来确定导致冠状动脉血栓形成的基因型。这三个基础科学项目有几个共同的主题。每个组成部分涉及：(1)研究心脏内皮细胞类型特异性信号通路，(2)确定细胞类型特异性信号通路对全局止血（纤维蛋白沉积）的影响，(3)研究TF基因调控及其作为心脏循环中凝血启动剂的作用，以及(4)使用转基因小鼠技术研究心脏血管床特异性止血。临床项目将成为验证局部止血成分在人群中的作用的重要环节。罗森博格博士在高凝性基因小鼠模型和体内止血功能分析方面提供专业知识。Aird博士为研究血管床特异性基因调控提供了工具。Mackman博士在培养细胞和动物模型中研究TF基因调控方面具有丰富的经验。豪斯曼博士是公认的人类基因组学专家。总的来说，个人项目和合作努力有望为心脏止血的分子基础提供重要的见解。