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的患者的主要问题绕过嫁接。我的职业计划是发展为临床医生科学家通过一项指导的血管生物学和动手培训的计划使用静脉移植疾病的转基因鼠模型的经验。最新数据表明人类的隐性静脉收获过程导致明显 p-选择素在内皮表面上的上调。在鼠心脏移植物，恢复不足的营地或无/CGMP第二信使途径保存时间改善了内皮稳态特性和抑制新的增殖。招募单核吞噬细胞缺血后血管是血栓形成的关键触发因素，由于1）由缺血性诱导驱动的组织因子（TF）的表达转录因子早期生长反应基因1（EGR-1）以及2）通过诱导纤溶酶原激活剂抑制剂1抑制纤维蛋白溶解（PAI-1）和内源性PA基因的抑制。 EGR-1基因的无小鼠无效表现出TF表达的低氧诱导降低并降低血管内血栓形成； pai-1的小鼠null类似地显示出降低纤维蛋白的应计。这些数据使我假设了这一点。 1）EGR-1驱动诱导大隐静脉内TF表达可能是重要的驱动早期静脉移植血栓形成的机制； ii）血管内纤维蛋白抑制纤维蛋白轴可能会放大应计的，这可能有助于新知识增殖； iii）改变保存环境，通过恢复不足的第二信使循环核苷酸可导致静脉移植物新内膜增殖的减少。这些假设将在使用静脉移植疾病的鼠模型中进行检验特定的基因删除小鼠，基本的分子工具来检测/量化血栓形成和组织形态图像分析，以评估新内膜形成。当前的建议是由申请人驱动的静脉移植疾病的模型作为学习如何进行基础研究的工具阐明早期和晚期移植物衰竭的机制。