GENETICS OF CORONARY THROMBOSIS

冠状动脉血栓形成的遗传学

• 批准号: 6390808
• 负责人: David Housman
• 金额: $ 31.27万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6390808
• 关键词: anticoagulants; biological signal transduction; clinical research; clotting factor; coagulation factor IX; coagulation factor X; coronary occlusion /thrombosis; fibrinopeptide; genetic polymorphism; human subject; immunologic assay /test; protein C; prothrombin; vascular endothelium; zymogens

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.

描述（改编自申请人的摘要） 止血平衡受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 是通过这些途径中的一个或多个的局部改变而产生的。整体 该合作计划的目标是阐明的分子基础 心脏内皮细胞亚型特异性基因表达并鉴定 心脏止血的关键组成部分。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 内皮细胞含有组织因子 (TF)。他还将优化 最近开发的小鼠冠状动脉血栓模型。在这个项目中， Aird 博士将研究 Egr-l 转录因子在介导中的作用 心脏特异性止血。他将询问单个基因如何能够“很好地发挥作用”。 根据组织的局部需要调整“止血。在这个项目中，博士。 Mackman 将评估凝血酶-PAR-1 信号通路在 控制促凝剂 (TF) 和纤溶剂（组织型）的局部水平 纤溶酶原激活剂）心脏内的分子。此外，他还将 解决单核细胞来源的 TF 对心脏止血的贡献。在这个 在该项目中，豪斯曼博士将在大量人群中使用遗传方法来 鉴定对冠状动脉血栓形成有显着影响的基因型。这 三个基础科学项目通过几个共同点相互关联 主题。每个部分涉及：（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 全局止血的类型特异性信号通路（纤维蛋白沉积）(3) TF基因调控及其作为凝血启动子作用的研究 （4）利用转基因小鼠技术 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作用的重要环节 人口。