VEIN GRAFT PRESERVATION: THROMBOSIS & NEOINTIMAL DISEASE

(改编自申请者S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的主要担忧。 搭桥手术。我的职业计划是发展成为一名临床医生-科学家 通过血管生物学和实践方面的指导培训计划 静脉移植疾病转基因小鼠模型的使用经验。最新数据 显示从人体采集大隐静脉的过程会导致明显的 内皮细胞表面P-选择素表达上调。在小鼠心脏中 移植物，修复缺陷cAMP或NO/cGMP第二信使通路 保存时间可改善血管内皮细胞的动态平衡特性 抑制新生内膜增殖。单核吞噬细胞募集到 缺血后血管是血栓形成的关键触发因素，因为血管新生 组织因子(TF)在脑缺血诱导中的表达 转录因子早期生长反应基因-1(Egr-1)以及2)通过 纤溶酶原激活物抑制物-1的诱导抑制纤溶作用 (PAI-1)和抑制内源性PA基因。小鼠Egr-1基因缺失 表现为低氧诱导TF表达减弱，并降低 血管内血栓形成；PAI-1基因缺失的小鼠表现为类似的减少 纤维蛋白积累量。这些数据使我假设：1)Egr-1驱动 在隐静脉内诱导TF的表达可能是一个重要的 早期静脉移植物血栓形成的机制：II)血管内纤维蛋白 通过抑制纤溶轴很可能放大累积性， 这可能有助于新生血管的增殖；iii)改变 通过恢复缺失的第二信使环来保护环境 核苷酸，可以导致静脉移植物新生内膜增殖的减少。 这些假说将在静脉移植疾病的小鼠模型中进行测试，使用 特定基因缺失的小鼠，检测/量化的基本分子工具 血栓形成和组织形态计量学图像分析评估新生内膜 队形。目前的提议是由申请者推动的吗？S希望用一个 将静脉移植疾病模型作为学习如何进行基础研究的工具 目的：阐明早期和晚期静脉移植失败的机制。

(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.