GENETICS OF CORONARY THROMBOSIS

描述(改编自申请人摘要) 血管床特异性内皮细胞调节止血平衡 信号通路。申请人提出冠状动脉血栓形成 通过这些通路中的一条或多条局部改变而发生。整体而言 合作计划的目标是阐明人类免疫缺陷的分子基础 内皮细胞亚型特异性基因在心脏中的表达及鉴定 心脏止血的关键成分。在这个项目中，罗森博格博士 将研究血小板衍生生长因子信号通路在 基因程序在心脏微血管内的介导表达 包括组织因子(TF)在内的内皮细胞。他还将优化一个 最近发展起来的小鼠冠状动脉血栓形成模型。在这个项目中， 艾尔德博士将研究Egr-L转录因子在调节 心脏特异性止血。他会问，单个基因如何才能“很好”？ 根据组织的局部需求调整止血。 Mackman将评估凝血酶-PAR-1信号通路在 控制局部促凝剂(TF)和纤溶(组织型)水平 纤溶酶原激活剂)分子。此外，他还将 阐述单核细胞来源的转铁蛋白在心脏止血中的作用。在这 在这个项目中，Housman博士将在大量人口中使用遗传方法来 确定显著导致冠状动脉血栓形成的基因类型。这个 三个基础科学项目由几个共同的 主题。每个组成部分都涉及：(1)心脏内皮细胞的研究 类型特异性信号通路，(2)细胞效应的测定 全球止血(纤维蛋白沉积)的类型特异性信号通路(3) 凝血因子基因调控及其作为凝血引发剂作用的研究 以及(4)利用转基因小鼠技术 研究血管床在心脏中的特异性止血。临床项目 将成为验证局部止血成分在 人类人口。

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.