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.

移植相关的冠状动脉疾病（TCAD），其特征是进行性新自由临界 增殖和腔内闭塞仍然是心脏长期生存的主要障碍 移植接受者。临床研究表明，遗传性血栓形成，移植血管血栓形成和 高脂血症有助于TCAD。初步数据表明心脏保存或组织缺氧引起 von Willebrand因子（VWF）的分泌以及组织因子（TF）和纤溶酶原激活剂的表达 抑制剂1（PAI-1），后者由PAI-1启动子中的三个独立转录基序驱动。 此外，在异位的鼠血管化心脏同酶模型中，TCAD由TCAD量化 在PAI-1缺乏同种异体移植物中，组织形态法显着降低，但在组织纤溶酶原中加剧 激活剂（TPA）无效移植物。这些数据使我们假设通过缺血驱动的创建纤维蛋白基质 在持续的血管损伤，高脂血症和 炎症，创建了一个富含遮挡新内膜的发展的富含矩阵。项目3 PPG将阐明在同种异体移植中驱动血栓累积的分子机制。以及他们在 TCAD病原体。 AIM 1将使用血栓形成因子阐明血栓形成对TCAD的贡献 v莱顿小鼠，具有肌电TF突变的小鼠，vWF水平分级的小鼠。 AIM 2意志 使用缺乏PAI-1，TPA或UPA的小鼠以及小鼠，阐明纤维蛋白溶解对TCAD的贡献 主开关转录因子（EGR-1）的null pai-1低氧诱导。药理 将测试PAI-1抑制剂，以建立现在不存在的TCAD的潜在治疗靶点。 AIM 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缺陷型高胆固醇小鼠在血栓形成或血栓上 背景。该项目将与PAI-1生物学和高脂血症领域的项目1互动，项目2 在血栓形成，低纤维蛋白溶解和高脂血症作为静脉血管损伤的触发因素中，项目4 在新的抗血栓形成靶向发展和血栓形成的遗传修饰剂的地区，以及三个 内核。这些研究将提供有关强大机制的新见解 移植心脏，并确定新疗法以保持这些关键血管的打开状态。