MOLECULAR BASIS OF CARDIAC-SPECIFIC HEMOSTASIS-COLLABORA

心脏特异性止血的分子基础-COLLABORA

• 批准号: 6662018
• 负责人: Robert D Rosenberg
• 金额: $ 34.8万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 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/6662018
• 关键词: biological signal transduction; gene expression; hemostasis; laboratory mouse; molecular pathology; platelet derived growth factor; thromboplastin; thrombosis; vascular endothelium

The hemostatic balance is regulated by vascular bed-specific endothelial cell signaling pathways. We 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. 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 (Projects 1-3) 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 hypercoagulability 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.

止血平衡受血管特异性内皮细胞信号通路的调节。 我们建议通过在这些途径的一种或多种局部改变冠状动脉血栓形成。 协作计划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的生长因子信号通路在介导包括组织因子（TF）的心脏微血管内皮细胞中介导基因程序表达的作用。他还将优化最近开发的冠状动脉血栓形成小鼠模型。 AIRD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。 他将询问一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信号通路在心脏内部局部水平（TF）和纤维蛋白水解（组织型纤溶酶原激活剂）分子中的局部水平中的作用。 此外，他将解决单核细胞衍生的TF对心脏止血的贡献。 Housman博士将使用大量人群中的遗传方法来识别有助于冠状动脉血栓形成的基因型。 三个基础科学项目（项目1-3）与几个共同的主题相互关联。 每个组件涉及：（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途径对全球止血的影响（纤维蛋白沉积）（3）TF基因调节的研究及其在及（4）在心脏循环中的起始技术的作用，以及（4）在（4）中及（4））的作用。 心。 该临床项目将是验证人群中局部止血成分的作用的重要联系。 Rosenberg博士在高凝性的遗传小鼠模型和体内止血的功能分析中都提供了专业知识。 AIRD博士贡献了研究血管特异性基因调节的工具。 麦克曼博士在研究培养细胞和动物模型中研究TF基因调节方面具有经验。 Housman博士是人类基因组学专家。 综上所述，各个项目和协作努力有望为心脏止血的分子基础提供重要的见解。