VEIN GRAFT PRESERVATION: THROMBOSIS & NEOINTIMAL DISEASE

静脉移植物的保存：血栓形成

• 批准号: 6230018
• 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/6230018
• 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.

(改编自申请人？静脉移植的发展