Vascular Remodeling in Transplant Arteriosclerosis

移植动脉硬化的血管重塑

• 批准号: 7433331
• 负责人: CHRISTIANE FERRAN
• 金额: $ 41.27万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-15 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7433331
• 关键词: 3-nitrotyrosine; A Mouse; Adenoviruses; Allografting; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Apoptotic; Arteriosclerosis; Atherosclerosis; Balloon Angioplasty; Blood Vessels; Carotid Arteries; Cell Proliferation; Cessation of life; Chronic; Class; Coagulation Process; Cytoskeleton; Data; Development; Down-Regulation; Endothelial Cells; Exhibits; Functional disorder; Gene Chips; Gene Transfer; Genes; Graft Rejection; Healed; Homing; Hypoxia; Immunohistochemistry; Immunologic Factors; Immunologics; Immunosuppression; Immunosuppressive Agents; In Situ Nick-End Labeling; In Vitro; Inbred BALB C Mice; Inflammation; Inhibition of NF-KB activation; Injury; Intercellular adhesion molecule 1; Invasive; Knockout Mice; Lead; Left; Lesion; Leukocytes; Literature; MHC Class I Genes; Measurement; Medial; Mediating; Modeling; Molecular; Mus; Myosin ATPase; Myosin Heavy Chains; Nitric Oxide; Organ Transplantation; PECAM1 gene; Phenotype; Physiological; Platelet aggregation; Prevention; Prevention approach; Principal Investigator; Production; Proliferation Marker; Protein Overexpression; Proteins; RNA; RNA Interference; Rattus; Reading; Recombinants; Reverse Transcriptase Polymerase Chain Reaction; Role; Series; Smooth Muscle Myocytes; Stem cells; Stimulus; Structure; System; Testing; Therapeutic immunosuppression; Thrombosis; Time; Tissues; Transfection; Transgenic Mice; Transplantation; Treatment Protocols; Tube; Vascular Cell Adhesion Molecule-1; Vascular remodeling; Week; Western Blotting; Work; activating transcription factor; angiogenesis; atheroprotective; base; beta-Galactosidase; cell injury; cell motility; chemokine; cytokine; gain of function; gene therapy; graft failure; healing; in vivo; interest; intima media; kidney allograft; loss of function; migration; mouse model; mutant; neointima formation; neovascularization; novel; novel therapeutics; p65; prevent; progenitor; programs; protective effect; protein expression; research study; response; size

DESCRIPTION (provided by applicant): Transplant associated vasculopathy (TAV) is an accelerated form of atherosclerosis resulting in chronic rejection of vascularized organ grafts and the major cause of graft failure since the advent of novel immunosuppressive regimen. The causes of chronic rejection and TAV are likely multifactorial including immunologic and non- immunologic factors that integrate at the level of the vascular wall leading to a phenotypic switch of endothelial (EC) and smooth muscle cells (SMC), underscoring the development of TAV lesions. Activated EC promote inflammation, coagulation, platelet aggregation and cellular invasion and may lead to EC apoptosis exposing the subendothelial matrix and further promoting thrombosis. In addition, production of cytokines and chemokines by activated EC and invasive leukocytes as well as exposure of the subendothelial matrix provoke a switch in SMC phenotype. Activated SMC (i) promote inflammation and increased synthesis of extra-cellular matrix; (ii) exhibit aberrant proliferation and migration within the neointima and (iii) demonstrate deregulated apoptosis, all culminating in the occlusive vasculopathy of chronic rejection. The pathophysiology of TAV has been recently revisited by the demonstration that injury to the vessel wall of the graft triggers homing of circulating SMC and possibly EC progenitors from the recipient. Understanding the molecular basis for, and preventing the acquisition of, this "pro-atherogenic" EC/SMC phenotype as well as halting the homing of circulating SMC to the neointima are critical for devising new therapeutic approaches for the prevention and treatment of TAV. We have shown that A20 is part of the regulatory cytoprotective response of EC to injury. In EC, in vitro, A20 has a dual anti-apoptotic and anti-inflammatory function supporting its atheroprotective potential. We also demonstrate that A20 is part of the physiologic response of SMC to injury. Overexpression of A20 in SMC inhibits the induction of NF-KB dependent genes implicated in TAV, blocks SMC proliferation and unexpectedly sensitizes neointimal SMC to apoptosis. In vivo, A20 is expressed in EC and SMC of long term surviving rat kidney allografts and is associated with the absence of TAV. In addition, overexpression of A20 in rat carotid artery SMC following balloon angioplasty prevents but also cures neointima formation and promotes healing by increasing re-endothelialization. Based on these findings, we hypothesize that expression of A20 in EC and SMC may beneficially impact TAV. Our aims are to (i) Determine the function of A20 in EC as it pertains to activation, apoptosis and vascular remodeling; (ii) Determine the effect of A20 upon SMC activation, proliferation, phenotype and response to apoptotic stimuli; both aims will include loss and gain of function studies; (iii) Establish a structure/function analysis for A20 in EC and SMC; *[(iv) Evaluate the protective function of A20 against TAV using a mouse model of aortic transplantation. In vivo studies will include gain of function experiments using rAd. mediated transfer of A20 to the aortic graft or alternatively, transgenic mice expressing A20 in their vasculature. They will also include loss of function experiments using aortic allografts from A20 knock-out mice]*.

描述（由申请人提供）：移植相关血管病（TAV）是动脉粥样硬化的加速形式，导致血管化器官移植物的慢性排斥反应，是新型免疫抑制方案出现以来移植物失败的主要原因。慢性排斥反应和TAV的原因可能是多因素的，包括在血管壁水平整合的免疫和非免疫因素，导致内皮细胞（EC）和平滑肌细胞（SMC）的表型转换，强调TAV病变的发展。激活的EC促进炎症、凝血、血小板聚集和细胞侵袭，并可能导致EC凋亡，暴露内皮下基质，进一步促进血栓形成。此外，细胞因子和趋化因子的生产激活EC和浸润性白细胞以及暴露的内皮下基质引起开关SMC表型。活化的SMC（i）促进炎症和细胞外基质合成增加;（ii）在新生内膜内表现出异常增殖和迁移，以及（iii）表现出失调的细胞凋亡，所有这些最终导致慢性排斥的闭塞性血管病。TAV的病理生理学最近已经被证明，移植物血管壁的损伤触发循环SMC和可能的EC祖细胞从受体归巢重新审视。了解这种“致动脉粥样硬化”EC/SMC表型的分子基础并防止其获得以及阻止循环SMC归巢至新生内膜对于设计预防和治疗TAV的新治疗方法至关重要。我们已经表明，A20是EC对损伤的调节性细胞保护反应的一部分。在体外EC中，A20具有双重抗凋亡和抗炎功能，支持其动脉粥样硬化保护潜力。我们还表明，A20是SMC对损伤的生理反应的一部分。A20在SMC中的过表达抑制了与TAV有关的NF-κ B依赖性基因的诱导，阻断了SMC的增殖，并且出乎意料地使新生内膜SMC对凋亡敏感。在体内，A20在长期存活的大鼠同种异体肾移植物的EC和SMC中表达，并且与TAV的缺乏相关。此外，A20在大鼠颈动脉SMC中的过表达在球囊血管成形术后预防但也治愈新生内膜形成，并通过增加再内皮化促进愈合。基于这些发现，我们推测A20在EC和SMC中的表达可能有益于TAV。我们的目标是（i）确定A20在EC中的功能，因为它与激活、细胞凋亡和血管重塑有关;（ii）确定A20对SMC激活、增殖、表型和对细胞凋亡刺激反应的影响;这两个目标将包括功能研究的丧失和获得;（iii）建立EC和SMC中A20的结构/功能分析;*[（iv）使用主动脉移植的小鼠模型评估A20针对TAV的保护功能。体内研究将包括使用rAd的功能获得实验。介导的A20转移到主动脉移植物或在其脉管系统中表达A20的转基因小鼠。它们还将包括使用来自A20敲除小鼠的主动脉同种异体移植物的功能丧失实验]*。