BLOOD COAGULATION & FIBRINOLYSIS

这种止血平衡受血管床特有的内皮细胞信号通路的调节。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的局部改变而发生的。协作计划的总体目标是阐明HAR中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心脏微血管内皮细胞内包括组织因子(TF)在内的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。艾尔德博士将研究Egr-1转录因子在介导心脏特异性止血中的作用。他会问，单个基因如何根据组织的局部需求来“微调”止血。Mackman博士将评估凝血酶-PAR-1信号通路在调节心脏内局部促凝血剂(TF)和纤溶(组织型纤溶酶原激活剂)分子水平中的作用。此外，他还将介绍单核细胞来源的转铁蛋白在心脏止血中的作用。豪斯曼博士将在大量人群中使用基因方法来确定对冠状动脉血栓形成有显著影响的基因类型。这三个基础科学项目通过几个共同的主题相互联系。每个组成部分包括：(1)心脏内皮细胞类型特异性信号通路的研究，(2)细胞类型特异性信号通路对整体止血(纤维蛋白沉积)的影响的确定，(3)TF基因调控及其在心脏循环中作为凝血起始者的作用的研究，以及(4)利用转基因小鼠技术研究心脏血管床特异性止血。该临床项目将成为验证局部止血成分在人类人群中的作用的重要环节。罗森博格博士在高凝状态的小鼠遗传模型和体内止血的功能分析方面提供了专业知识。艾尔德博士为研究血管床特有的基因调控贡献了工具。麦克曼博士在研究培养细胞和动物模型中的转铁蛋白基因调控方面拥有丰富的经验。豪斯曼博士是公认的人类基因组学专家。综上所述，这些单独的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。

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.