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.

以进行性新生内膜为特征的移植相关冠状动脉疾病(TCAD) 增殖和管腔闭塞仍然是心脏长期存活的主要障碍。 移植受者。临床研究表明，遗传性血栓形成、移植物血管血栓形成和 高脂血症是TCAD的致病因素。初步数据显示，心脏保存或组织缺氧会引起 血管性血友病因子(VWF)的分泌及组织因子(TF)和纤溶酶原激活物的表达 抑制物-1(PAI-1)，后者由PAI-1启动子中三个独立的转录基序驱动。 此外，在异位小鼠带血管同种异体心脏移植模型中，TCAD通过 组织形态计量学在PAI-1缺乏的同种异体移植物中显著减少，但在组织纤溶酶原中恶化 激活剂(TPA)无效移植。这些数据使我们假设，缺血诱导产生了纤维蛋白间质 血栓形成或纤溶抑制与持续的血管损伤、高脂血症和 炎症，创造丰富的基质，推动闭塞的新生内膜的发展。此项目的项目3 PPG将阐明驱动同种异体心脏移植物血栓形成的分子机制。以及他们在 TCAD的发病机制。目的1利用亲血栓因子阐明血栓形成对TCAD的贡献 VLeiden小鼠、Tf基因突变过低的小鼠，以及vWF水平分级的小鼠。目标2将 利用PAI-1、tPA或uPA缺乏的小鼠以及小鼠阐明纤溶在TCAD中的作用 PAI-1低氧诱导下的主开关转录因子(Egr-1)为空。药理作用 PAI-1抑制剂将进行测试，以建立目前尚不存在的TCAD的潜在治疗靶点。 目标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抗血栓形成 背景。该项目将与项目1在PAI-1生物学和高脂血症领域进行互动，项目2 血栓形成、纤溶功能低下和高脂血症是静脉血管损伤的触发因素，项目4 在新的抗血栓靶向开发和血栓形成的遗传修饰物以及三个方面 核心。这些研究将为阻断血管的强大机制提供新的见解。 移植心脏，并找出保持这些关键血管畅通的新疗法。