Thrombotic/Fibrinolytic Balance in Cardiac Transplant Vasculopathy

心脏移植血管病中的血栓/纤溶平衡

• 批准号: 8150064
• 负责人: David J. Pinsky
• 金额: $ 23万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8150064
• 关键词: Affinity; Alloantigen; Allografting; Alteplase; Apolipoprotein E; Area; Automobile Driving; Biological Preservation; Biology; Blood Platelets; Blood Vessels; CCAAT-Enhancer-Binding Proteins; Cardiac; Cells; Clinical Research; Coagulation Process; Coronary; Coronary Arteriosclerosis; Coronary Thrombosis; Crossbreeding; Data; Deposition; Development; Ear; Elements; Engineering; Equilibrium; Exhibits; Fibrin; Fibrinolysis; Functional disorder; Generations; Genes; Genetic; Growth; Heart; Heart Transplantation; Homologous Gene; Human; Hyperlipidemia; Hypoxia; Hypoxia Inducible Factor; Immune; In Situ; Incidence; Indium; Inflammation; Inflammatory; Inherited; Injury; Ischemia; Isogenic transplantation; Knockout Mice; Lead; Mediator of activation protein; Modeling; Molecular; Mus; Mutant Strains Mice; Mutation; Organ; Pathogenesis; Patients; Plasminogen Activator Inhibitor 1; Process; Rodent; Role; Severities; Signal Transduction; Site; System; Techniques; Testing; Thrombin; Thromboplastin; Thrombosis; Thrombus; Tissues; Translating; Transplant Recipients; Transplantation; Vascular Diseases; Vascular Graft; Vascular blood supply; Venous; Wild Type Mouse; allotransplant; cellular development; factor V Leiden; heart allograft; heart preservation; human data; in vivo; inhibitor/antagonist; injured; insight; monocyte; mouse model; mutant; pre-clinical; promoter; research study; response; therapeutic target; thrombolysis; tool; transcription factor; von Willebrand Factor

Transplantation-associated coronary artery disease (TCAD), characterized by progressive neointimal proliferation and luminal obliteration, remains the major impediment to the long-term survival of heart transplant recipients. Clinical studies suggest that inherited thrombophilias, graft vascular thrombosis, and hyperlipidemia contribute to TCAD. Preliminary data show that cardiac preservation or tissue hypoxia elicits secretion of von Willebrand factor (vWF) and expression of tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1), the latter driven by three independent transcriptional motifs in the PAI-1 promoter. Furthermore, in a heterotopic murine vascularized cardiac allotransplant model, TCAD quantified by histomorphometry is significantly reduced in PAI-1 deficient allografts, but exacerbated in tissue plasminogen activator (tPA) null grafts. These data lead us to hypothesize that creation of a fibrin stroma by ischemiadriven thrombosis or inhibited fibrinolysis in the context of ongoing vascular injury, hyperlipidemia, and inflammation, creates a rich matrix driving the development of an occluding neointima. Project 3 for this PPG will elucidate the molecular mechanisms driving thrombus accrual in cardiac allografts. and their role in TCAD pathoqenesis. Aim 1 will elucidate the contribution of thrombosis to TCAD using thrombophilic factor V Leiden mice, mice with a hypomorphic TF mutation, and those with graded levels of vWF. Aim 2 will elucidate the contribution of fibrinolysis to TCAD using mice deficient in PAI-1, tPA, or uPA, as well as mice null for the master switch transcription factor (Egr-1) underlying hypoxic induction of PAI-1. Pharmacological PAI-1 inhibitors will be tested to establish a potential therapeutic target for TCAD where now none exist. Aim 3 will determine the role of background hyperlipidemia as a synergistic mechanism driving thrombosis and TCAD, using apolipoprotein E-deficient hypercholesterolemic mice on thrombophilic or thromboresistant backgrounds. This project will interact with Project 1 in areas of PAI-1 biology and hyperlipidemia, Project 2 in areas of thrombosis, hypofibrinolysis, and hyperlipidemia as triggers for venous vascular injury, Project 4 in areas of new anti-thrombotic target development and genetic modifiers of thrombosis, as well as the three Cores. These studies will provide new insights into powerful mechanisms which obliterate vessels in transplanted hearts, and identify new therapies to keep these critical vessels open.

移植相关冠状动脉疾病（TCAD），特征为进行性新生内膜 增殖和管腔闭塞，仍然是心脏长期存活的主要障碍 移植接受者临床研究表明，遗传性血栓形成倾向，移植血管血栓形成， 高脂血症有助于TCAD。初步数据显示，心脏保存或组织缺氧 血管性血友病因子（vWF）的分泌和组织因子（TF）及纤溶酶原激活物的表达 抑制剂-1（派-1），后者由派-1启动子中的三个独立的转录基序驱动。 此外，在异位鼠血管化心脏同种异体移植模型中，TCAD通过 派-1缺乏的同种异体移植物的组织形态学显著降低，但组织纤溶酶原升高， 活化剂（tPA）无效移植物。这些数据使我们假设缺血诱导的纤维蛋白基质的形成 血栓形成或在持续性血管损伤、高脂血症和 炎症，产生丰富的基质，驱动闭塞性新生内膜的发展。项目3为此 PPG将阐明驱动心脏移植物中血栓积聚的分子机制。以及农村妇女在消除 TCAD发病机制目的1利用血栓形成因子阐明血栓形成在TCAD中的作用 V Leiden小鼠、具有亚型TF突变的小鼠和具有分级水平的vWF的小鼠。目标2将 使用派-1、tPA或uPA缺陷小鼠以及小鼠阐明纤维蛋白溶解对TCAD的贡献 无效的主开关转录因子（Egr-1）的基础缺氧诱导派-1。药理 派-1抑制剂将被测试，以建立一个潜在的治疗靶点TCAD，现在不存在。 目的3将确定背景高脂血症作为驱动血栓形成的协同机制的作用 和TCAD，使用载脂蛋白E缺陷的高胆固醇血症小鼠对血栓形成或血栓抵抗 背景该项目将与派-1生物学和高脂血症领域的项目1、项目2 在血栓形成、纤溶功能减退和高脂血症作为静脉血管损伤的触发因素方面，项目4 在新的抗血栓靶点开发和血栓形成遗传修饰剂领域，以及这三个领域 丹这些研究将提供新的见解，强大的机制，闭塞血管， 移植心脏，并确定新的疗法来保持这些关键血管的开放。