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）：移植相关血管病变（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，并且是自新型免疫抑制疗法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，包括免疫学和非免疫学因素，这些因素在血管壁水平上整合，导致内皮细胞 (EC) 和平滑肌细胞 (SMC) 的表型转换，强调了 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，激活的 EC 和侵袭性白细胞产生细胞因子和趋化因子以及内皮下基质的暴露会引起 SMC 表型的转变。激活的 SMC (i) 促进炎症并增加细胞外基质的合成； (ii) 表现出新内膜内的异常增殖和迁移，(iii) 表现出细胞凋亡失调，所有这些最终导致慢性排斥的闭塞性血管病变。最近有人重新审视了 TAV 的病理生理学，即移植物血管壁损伤会触发循环 SMC 和可能的 EC 祖细胞从受体归巢。了解这种“促动脉粥样硬化”EC/SMC 表型的分子基础并防止其获得，以及阻止循环 SMC 归巢到新内膜对于设计预防和治疗 TAV 的新治疗方法至关重要。我们已经证明 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潜力。我们还证明 A20 是 SMC 对损伤的生理反应的一部分。 SMC 中 A20 的过度表达可抑制 TAV 中涉及的 NF-KB 依赖性基因的诱导，阻断 SMC 增殖并意外地使新内膜 SMC 对细胞凋亡敏感。在体内，A20 在长期存活的大鼠肾同种异体移植物的 EC 和 SMC 中表达，并且与 TAV 的缺失相关。此外，球囊血管成形术后大鼠颈动脉 SMC 中 A20 的过度表达可预防但也可治愈新内膜形成，并通过增加再内皮化促进愈合。基于这些发现，我们假设 EC 和 SMC 中 A20 的表达可能有益地影响 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、表型和对凋亡刺激的反应的影响；这两个目标都将包括功能丧失和获得的研究； (iii) 对 EC 和 SMC 中的 A20 进行结构/功能分析； *[(iv) 使用主动脉移植小鼠模型评估 A20 对 TAV 的保护功能。体内研究将包括使用 rAd 进行功能获得实验。介导A20转移至主动脉移植物或在其脉管系统中表达A20的转基因小鼠。他们还将包括使用 A20 敲除小鼠的同种异体主动脉移植物进行功能丧失实验]*。