BLOOD COAGULATION & FIBRINOLYSIS

血液凝固

• 批准号: 6799980
• 负责人: Nigel Mackman
• 金额: $ 35.46万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 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 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6799980
• 关键词: biological signal transduction; blood coagulation; fibrinolysis; genetic regulation; hemostasis; laboratory mouse; thrombin; thromboplastin; vascular endothelium

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.

止血平衡由血管床特异性内皮细胞信号通路调节。 我们认为冠状动脉血栓形成是通过这些通路中的一个或多个的局部改变而发生的。 该合作项目的总体目标是阐明心脏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博士将研究血小板源性生长因子信号通路在介导心脏微血管内皮细胞（包括组织因子（TF））内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。 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。 他将询问单个基因如何根据组织的局部需要“微调”止血。 Mackman博士将评估凝血酶-PAR-1信号通路在控制心脏内促凝血（TF）和纤溶（组织型纤溶酶原激活剂）分子局部水平中的作用。 此外，他将讨论单核细胞衍生的TF对心脏止血的贡献。 Housman博士将在大规模人群中使用遗传学方法来识别显著导致冠状动脉血栓形成的基因型。 这三个基础科学项目由几个共同的主题相互关联。每个组成部分包括：（1）研究心脏内皮细胞类型特异性信号传导途径，（2）测定细胞类型特异性信号传导途径对整体止血（纤维蛋白沉积）的影响，（3）研究TF基因调控及其作为心脏循环中凝血起始物的作用，和（4）使用转基因小鼠技术研究心脏中血管床特异性止血。 该临床项目将作为验证局部止血成分在人群中作用的重要环节。 Rosenberg博士在高凝性遗传小鼠模型和体内止血功能分析方面提供专业知识。 Aird博士为研究血管床特异性基因调控提供了工具。 Mackman博士在培养细胞和动物模型中研究TF基因调控方面具有丰富的经验。 豪斯曼博士是公认的人类基因组学专家。 总之，个别项目和合作努力承诺提供心脏止血的分子基础的重要见解。

项目成果

Gene-centric meta-analysis of lipid traits in African, East Asian and Hispanic populations.

• DOI: 10.1371/journal.pone.0050198
• 发表时间: 2012
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Elbers CC;Guo Y;Tragante V;van Iperen EP;Lanktree MB;Castillo BA;Chen F;Yanek LR;Wojczynski MK;Li YR;Ferwerda B;Ballantyne CM;Buxbaum SG;Chen YD;Chen WM;Cupples LA;Cushman M;Duan Y;Duggan D;Evans MK;Fernandes JK;Fornage M;Garcia M;Garvey WT;Glazer N;Gomez F;Harris TB;Halder I;Howard VJ;Keller MF;Kamboh MI;Kooperberg C;Kritchevsky SB;LaCroix A;Liu K;Liu Y;Musunuru K;Newman AB;Onland-Moret NC;Ordovas J;Peter I;Post W;Redline S;Reis SE;Saxena R;Schreiner PJ;Volcik KA;Wang X;Yusuf S;Zonderland AB;Anand SS;Becker DM;Psaty B;Rader DJ;Reiner AP;Rich SS;Rotter JI;Sale MM;Tsai MY;Borecki IB;Hegele RA;Kathiresan S;Nalls MA;Taylor HA Jr;Hakonarson H;Sivapalaratnam S;Asselbergs FW;Drenos F;Wilson JG;Keating BJ
• 通讯作者: Keating BJ

An approach to estimate bidirectional mediation effects with application to body mass index and fasting glucose.

一种应用体重指数和空腹血糖来估计双向中介效应的方法。

• DOI: 10.1111/ahg.12261
• 发表时间: 2018
• 期刊: Annals of human genetics
• 影响因子: 1.9
• 作者: Talluri,Rajesh;Shete,Sanjay
• 通讯作者: Shete,Sanjay

Vitamin D, vitamin D binding protein gene polymorphisms, race and risk of incident stroke: the Atherosclerosis Risk in Communities (ARIC) study.

• DOI: 10.1111/ene.12731
• 发表时间: 2015-08
• 期刊: European journal of neurology
• 影响因子: 5.1
• 作者: Schneider AL;Lutsey PL;Selvin E;Mosley TH;Sharrett AR;Carson KA;Post WS;Pankow JS;Folsom AR;Gottesman RF;Michos ED
• 通讯作者: Michos ED

Double genomic control is not effective to correct for population stratification in meta-analysis for genome-wide association studies.

双基因组控制不能有效地纠正全基因组关联研究荟萃分析中的群体分层。

• DOI: 10.3389/fgene.2012.00300
• 发表时间: 2012
• 期刊: Frontiers in genetics
• 影响因子: 3.7
• 作者: Wang,Shudong;Chen,Wenan;Chen,Xiangning;Hu,Fengjiao;Archer,KellieJ;Liu,HbNianjun;Sun,Shumei;Gao,Guimin
• 通讯作者: Gao,Guimin

Genetically elevated fetuin-A levels, fasting glucose levels, and risk of type 2 diabetes: the cardiovascular health study.

• DOI: 10.2337/dc12-2323
• 发表时间: 2013-10
• 期刊: Diabetes care
• 影响因子: 16.2
• 作者: Jensen MK;Bartz TM;Djoussé L;Kizer JR;Zieman SJ;Rimm EB;Siscovick DS;Psaty BM;Ix JH;Mukamal KJ
• 通讯作者: Mukamal KJ