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: 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
• 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

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.

以进行性新内膜为特征的移植相关性冠状动脉疾病（TCAD）