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）：与移植相关的血管病（TAV）是一种加速的动脉粥样硬化形式，导致长期拒绝血管的器官移植物，并且是自新的免疫抑制治疗方案出现以来的关节衰竭的主要原因。慢性排斥和TAV的原因可能是多因素的，包括在血管壁的水平上整合的免疫和非免疫学因素，导致内皮（EC）和平滑肌细胞（SMC）的表型转换，强调了TAV病变的发展。活化的EC促进炎症，凝结，血小板聚集和细胞侵袭，并可能导致EC凋亡暴露于下皮基质并进一步促进血栓形成。此外，活化的EC和侵入性白细胞以及暴露于SMC表型中的开关的开关。活化的SMC（i）促进炎症并增加细胞外基质的合成； （ii）新内膜内表现出异常的增殖和迁移，（iii）表现出失调的凋亡，所有这些都在慢性排斥反应的闭塞性血管病中达到顶峰。最近，通过证明了移植物的损伤触发了循环SMC的归巢和可能是受体的EC祖细胞的损伤，TAV的病理生理已被重新审视。了解这种“亲动力” EC/SMC表型的分子基础，并防止获取的习得，并停止将循环SMC归入新的NEINSIMA对于设计新的预防和治疗TAV治疗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EC中，在体外，A20具有双重抗凋亡和抗炎功能，支持其动脉保护潜力。我们还证明A20是SMC对损伤的生理反应的一部分。 SMC中A20的过表达抑制了与TAV有关的NF-KB依赖基因的诱导，阻止了SMC增殖，并意外地将新内膜SMC敏感到凋亡。在体内，A20在EC和长期存活的大鼠肾脏同种异体移植物的EC和SMC中表达，并且与不存在TAV有关。此外，气球血管成形术后大鼠颈动脉SMC中A20的过表达可预防新内膜形成，并通过增加再粘膜化来促进愈合。根据这些发现，我们假设A20在EC和SMC中的表达可能会对TAV产生有益的影响。我们的目的是（i）确定A20在EC中的功能，因为它与激活，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；两种目标都将包括功能研究的损失和增益； （iii）在EC和SMC中为A20建立结构/功能分析； *[（iv）使用主动脉移植的小鼠模型评估A20对TAV的保护功能。体内研究将包括使用RAD的功能实验获得。 A20向主动脉移植物或替代介导的转移，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的功能实验的丧失]*。