Thrombotic/Fibrinolytic Balance in Cardiac Transplant Vasculopathy

心脏移植血管病中的血栓/纤溶平衡

基本信息

批准号：
8247044
负责人：
David J. Pinsky
金额：
$ 22.77万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-01 至 2013-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8247044
关键词：
Affinity Alloantigen Allografting Alteplase Apolipoprotein E Area Atherosclerosis 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 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 novel pre-clinical promoter research study response therapeutic target thrombolysis tool transcription factor von Willebrand Factor

项目摘要

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），其特征是进行性新生内膜增殖和管腔闭塞，仍然是心脏长期生存的主要障碍移植受者。临床研究表明，遗传性血栓形成倾向、移植血管血栓形成和高脂血症会导致 TCAD。初步数据表明，心脏保存或组织缺氧会引起血管性血友病因子 (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，在异位鼠血管化心脏同种异体移植模型中，TCAD 通过以下方式量化：在 PAI-1 缺陷的同种异体移植物中，组织形态计量学显着降低，但在组织纤溶酶原中加剧激活剂（tPA）无效移植物。这些数据使我们推测，缺血驱动的纤维蛋白基质的产生在持续血管损伤、高脂血症和炎症会产生丰富的基质，驱动闭塞性新内膜的发展。项目3为此 PPG 将阐明同种异体心脏移植物中驱动血栓形成的分子机制。以及他们在其中的作用 TCAD发病机制。目标 1 将利用血栓形成因子阐明血栓形成对 TCAD 的影响 V Leiden 小鼠、具有低效性 TF 突变的小鼠以及具有分级 vWF 水平的小鼠。目标2将使用缺乏 PAI-1、tPA 或 uPA 的小鼠以及小鼠阐明纤溶对 TCAD 的贡献 PAI-1 缺氧诱导的主开关转录因子 (Egr-1) 无效。药理作用将测试 PAI-1 抑制剂，以确定目前不存在的 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 缺陷型高胆固醇血症小鼠来治疗易血栓性或抗血栓性背景。该项目将与项目 1 在 PAI-1 生物学和高脂血症领域互动，项目 2 在血栓形成、纤溶低下和高脂血症领域作为静脉血管损伤的触发因素，项目 4 在新的抗血栓靶点开发和血栓形成基因修饰领域，以及三个领域核心。这些研究将为消除血管的强大机制提供新的见解。移植心脏，并找到新的疗法来保持这些关键血管畅通。