GENETICS OF CORONARY THROMBOSIS

描述（改编自申请人摘要） 止血平衡由血管床特异性内皮细胞调节 信号通路申请人提出冠状动脉血栓形成 通过这些途径中的一个或多个的局部改变而产生。整体 合作计划的目标是阐明 内皮细胞亚型特异性基因在心脏中的表达， 心脏止血的关键成分在这个项目中，罗森伯格博士 将研究血小板衍生生长因子信号通路在 介导心脏微血管内基因程序的表达 内皮细胞，包括组织因子（TF）。他还将优化 最近开发的小鼠冠状动脉血栓形成模型。在这个项目中， Aird博士将研究Egr-1转录因子在介导 心脏特异性止血。他会问一个单一的基因如何能起到“罚款”的作用， 根据组织的局部需要调节”止血。在这个项目中，博士。 Mackman将评估凝血酶-PAR-1信号通路在 控制促凝血剂（TF）和纤溶（组织型）的局部水平 纤溶酶原激活物）分子。另外他还会 探讨单核细胞源性TF对心脏止血的作用。在这 项目，豪斯曼博士将在大规模人群中使用遗传方法， 鉴定显著导致冠状动脉血栓形成基因型。的 三个基础科学项目通过几个共同的 主题.每个组成部分包括：（1）心脏内皮细胞的研究 类型特异性信号通路，（2）确定细胞的作用 类型特异性信号通路对整体止血（纤维蛋白沉积）的影响（3） TF基因调控及其作为凝血启动子作用的研究 在心脏循环中，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 将作为验证局部止血成分在以下方面作用的重要环节： 人类种群。

DESCRIPTION (Adapted from Applicant's Abstract) The hemostatic balance is regulated by vascular bed-specific endothelial cell signaling pathways. The applicants propose that coronary artery thrombosis arises through local alterations in one or more of these pathways. The overall goals of the Collaborative Program are to elucidate the molecular basis of endothelial cell subtype-specific gene expression in the heart and to identify the critical components of cardiac hemostasis. In this project , 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. In this project, Dr. Aird will examine the role of the Egr-l 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. In this project, 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 monocytederived TF to cardiac hemostasis. In this project, 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.