MECHANISMS OF ACCELERATED GRAFT ARTERIOSCLEROSIS

这个多学科研究计划的总体目标是 确定加速移植物动脉硬化（阿加）的机制， 为了更好地识别和治疗这种疾病， disorder.目前的假设是血管损伤的各种原因 在移植期间和之后触发多个宿主和供体依赖性 导致阿加的反应。五个项目和三个核心支助单位 将解决这个计划的目标和假设。项目1将 研究血管内皮细胞对损伤的反应如何导致 阿加。本项目的重点将是审查 异源三聚体G蛋白信号通路和细胞毒性淋巴细胞- 介导的Fas过度表达对内皮细胞的凋亡。 项目2将研究巨细胞病毒（CMV）如何促成阿加。在 特别是，非允许性CMV感染的作用和相互作用 CMV基因产物与p53肿瘤抑制基因产物，血小板- 衍生生长因子（PDGF）和转化生长因子β（TGF beta）将被检查。项目3将研究分子的作用 炎症和增殖反应中的介质 关于阿加。该项目的重点将是刺激增长 化合物TGF-β和PDGF，以及抗增殖和血管舒张 复合一氧化氮 项目4将研究补体的作用（C） 和抗体在阿加，重点是对缺血，同种免疫， 自身免疫和病毒（CMV）损伤。特别是早期和晚期C 将分别检查各组分， 特异性主要组织相容性复合体（MHC）和热休克蛋白 (HSP)表位项目5将研究细胞介导免疫的作用 自体（HSP，宿主-MHC），同种异体（供体MHC）和外源性 (CMV)抗原在阿加的发展。 特别是剧目， 环孢素A诱导的自身反应性T细胞的功能和特异性 在调解阿加将被审查。核心A（Core A） 提供行政和统计支持。病理学/临床 核心（核心B）将处理和储存用于研究的人类和动物组织， 并为量化病理变化提供中心资源。的 动物核心（核心C）将提供统一的动物心脏移植， 体内研究。 本计划中检查的每个途径将使用库存的人类 组织，用体外和体内动物模型解剖，和 在分子和细胞水平上定义。分子和细胞 反过来，确定的机制将构成开发新的 诊断和治疗策略，可以转化为 患者

The overall objective of this multidisciplinary research program is to identify the mechanisms of accelerated graft arteriosclerosis (AGA) in heart transplant recipients in order to better identify and treat this disorder. The working hypothesis is that various causes of vascular injury during and after transplantation trigger multiple host and donor dependent responses resulting in AGA. Five projects and three core support units will address the objectives and hypotheses of this program. Project 1 will examine how the response of vascular endothelial cells to injury leads to AGA. The focus of this project will be to examine the role of the heterotrimeric G-protein signaling pathway and of cytotoxic lymphocyte- mediated apoptosis triggered by fas overexpression on endothelial cells. Project 2 will examine how cytomegalovirus (CMV) contributes to AGA. In particular, the role of non-permissive CMV infection and the interaction of CMV gene products with the p53 tumor suppressor gene product, platelet- derived growth factor (PDGF), and transforming growth factor beta (TGF beta) will be examined. Project 3 will examine the role of molecular mediators in the inflammatory and proliferative responses characteristic of AGA. The focus of this project will be on the growth-stimulating compounds TGF-beta and PDGF, and the anti-proliferative and vasodilating compound nitric oxide. Project 4 will examine the role of complement (C) and antibody in AGA, focusing on responses to ischemic, alloimmune, autoimmune and viral (CMV) injury. In particular, early and late C components will be examined separately, as will antibody responses to specific major histocompatibility complex (MHC) and heat shock protein (HSP) epitopes. Project 5 will examine the role of cell-mediated immunity to autologous (HSP, host-MHC), to allogeneic (donor MHC), and to exogenous (CMV) antigens in the development of AGA. In particular, the repertoire, function, and specificity of cyclosporine A-induced autoreactive T-cells in mediating AGA will be examined. The Administrative Core (Core A) will provide administrative and statistical support. The Pathology/Clinical Core (Core B) will process and bank human and animal tissues for study, and provide a central resource for quantifying pathologic changes. The animal core (Core C) will provide uniform animal heart transplants for in vivo studies. Each pathway examined in this Program will be studied using banked human tissues, dissected out with in vitro and in vivo animal models, and defined at the molecular and cellular levels. The molecular and cellular mechanisms identified in turn will form the basis for developing novel diagnostic and therapeutic strategies which can be translated back to patients.