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VEIN GRAFT PRESERVATION: THROMBOSIS & NEOINTIMAL DISEASE

静脉移植物的保存：血栓形成

基本信息

批准号：
6726078
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
项目类别：
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

项目摘要

(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.

（改编自申请人的摘要）静脉移植的发展动脉粥样硬化是接受冠状动脉手术的患者最关心的问题旁路嫁接。我的职业计划是成为一名临床医生科学家通过血管生物学和实践指导培训计划使用静脉移植疾病转基因小鼠模型的经验。近期数据表明从人类身上获取隐静脉的过程会产生显着的结果内皮表面 P-选择素的上调。在小鼠心脏中移植物，恢复缺陷的 cAMP 或 NO/cGMP 第二信使途径保存时间改善内皮稳态特性抑制新内膜增殖。募集单核吞噬细胞缺血后血管是血栓形成的关键触发因素，原因是 1) de novo 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) 通过纤溶酶原激活剂抑制剂-1 的诱导抑制纤维蛋白溶解 (PAI-1) 和内源 PA 基因的抑制。 Egr-1基因无效的小鼠表现出 TF 表达的缺氧诱导减弱并减少血管内血栓形成； PAI-1 无效的小鼠同样表现出减少纤维蛋白的累积。这些数据让我做出这样的假设： 1) Egr-1驱动诱导隐静脉内 TF 表达可能是一个重要的因素早期静脉移植物血栓形成的驱动机制； II) 血管内纤维蛋白通过抑制纤溶轴可能会放大累积量，这可能有助于新生细胞增殖； III) 变更通过恢复有缺陷的第二信使循环来保护环境核苷酸，可导致静脉移植新内膜增殖减少。这些假设将在静脉移植疾病的小鼠模型中进行测试，使用特定基因缺失小鼠，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内膜形成。当前的提案是由申请人希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。