VEIN GRAFT PRESERVATION: THROMBOSIS & NEOINTIMAL DISEASE

静脉移植物的保存：血栓形成

• 批准号: 6638168
• 负责人: YOSHIFUMI NAKA
• 金额: $ 12.89万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6638168
• 关键词: acute disease /disorder; atherosclerosis; biological signal transduction; blood vessel transplantation; cell proliferation; coronary artery; disease /disorder model; fibrin; fibrinolysis; gene expression; genetically modified animals; graft versus host disease; laboratory mouse; model design /development; morphometry; plasminogen activator; plasminogen activator inhibitors; platelets; second messengers; thromboplastin; thrombosis; tissue /organ preservation; transcription factor; venous thrombosis; von Willebrand factor

(Adapted from applicant?s abstract) The development of vein graft atherosclerosis is a major concern for patients undergoing coronary artery bypass grafting. My career plans are to develop as a clinician-scientist through a program of mentored training in vascular biology and hands-on experience using a transgenic murine model of vein graft disease. Recent data shows that the process of saphenous vein harvest from humans results in marked upregulation of P-selectin on the endothelial surface. In murine cardiac grafts, restoration of deficient cAMP or NO/cGMP second messenger pathways at the time of preservation improves endothelial homeostatic properties and suppresses neointimal proliferation. Recruitment of mononuclear phagocytes to postischemic vessels is a key trigger for thrombosis, due to 1) de novo expression of tissue factor (TF), driven by ischemic induction of the transcription factor early growth response gene-1 (Egr-1), as well as 2) by inhibition of fibrinolysis via induction of plasminogen activator inhibitor-1 (PAI-1) and suppression of endogenous PA genes. Mice null for the Egr-1 gene exhibit diminished hypoxic induction of TF expression and reduced intravascular thrombosis; mice null for PAI-1 similarly exhibit reduced accrual of fibrin. These data lead me to hypothesize that; 1) Egr-1 driven induction of TF expression within saphenous veins may be an important mechanism driving early vein graft thrombosis; II) intravascular fibrin accrual is likely to be amplified by suppression of the fibrinolytic axis, which may contribute to neoinitmal proliferation; III) alteration of the preservation milieu,, by restoring deficient second messenger cyclic nucleotides, can result in reduction in vein graft neointimal proliferation. These hypotheses will be tested in a murine model of vein graft disease, using specific gene-deleted mice, basic molecular tools to detect/quantify thrombosis, and histomorphometric image analysis to assess neointimal formation. The current proposal is driven by the applicant?s desire to use a model of vein graft disease as a tool to learn how to undertake basic studies to elucidate mechanisms of early and late vein graft failure.

（根据申请人？静脉移植的发展 动脉粥样硬化是接受冠状动脉成形术的患者的主要关注点 旁路移植术我的职业规划是发展成为一名临床科学家 通过一个血管生物学的指导培训计划， 使用静脉移植疾病的转基因小鼠模型的经验。最近的数据 显示从人体采集隐静脉的过程导致显著的 内皮表面P-选择素的上调。在小鼠心脏 移植物，恢复缺陷的cAMP或NO/cGMP第二信使途径， 保存时间改善了内皮细胞的稳态特性， 抑制新生内膜增生。单核吞噬细胞的募集 缺血后血管是血栓形成的关键触发因素，由于1）新生 组织因子（TF）的表达，由缺血诱导驱动， 转录因子早期生长反应基因-1（Egr-1），以及2）通过 通过纤溶酶原激活物抑制剂-1诱导抑制纤维蛋白溶解 （派-1）和内源性PA基因的抑制。Egr-1基因缺失小鼠 表现出降低的TF表达的低氧诱导， 血管内血栓形成;派-1缺失小鼠类似地表现出降低的 纤维蛋白的积累。这些数据使我假设：1）Egr-1驱动 在隐静脉内诱导TF表达可能是重要的 驱动早期静脉移植物血栓形成的机制; II）血管内纤维蛋白 增加可能通过纤维蛋白溶解轴的抑制而放大， 这可能有助于新生儿增殖; III）改变 通过恢复缺陷的第二信使环 核苷酸，可以导致静脉移植物新生内膜增殖的减少。 这些假设将在静脉移植物疾病的鼠模型中进行测试，使用 特异性基因缺失小鼠，检测/定量的基本分子工具 血栓形成和组织形态学图像分析，以评估新生内膜 阵目前的提案是由申请人推动的吗？的愿望，使用 静脉移植疾病模型作为学习如何进行基础研究的工具 阐明早期和晚期静脉移植失败的机制。