MECHANISMS OF ACCELERATED GRAFT ARTERIOSCLEROSIS

这个多学科研究项目的总体目标是 探讨移植物动脉硬化(AGA)的发病机制 心脏移植受者，以便更好地识别和治疗这一问题 无序。工作假说是血管损伤的各种原因 移植中和移植后触发多个宿主和供体依赖 导致AGA的反应。五个项目和三个核心支持单位 将阐述该计划的目标和假设。项目1将 研究血管内皮细胞对损伤的反应如何导致 阿加。本项目的重点将是研究 异三聚体G蛋白信号通路与细胞毒性淋巴细胞 血管内皮细胞Fas过表达引发的细胞凋亡。 项目2将研究巨细胞病毒(CMV)如何促进AGA。在……里面 特别是，非允许性CMV感染的作用及其相互作用 巨细胞病毒基因产物与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) (测试版)将被检查。项目3将研究分子的作用。 炎症和增殖性反应中的介质特征 AGA的。该项目的重点将放在促进增长的 化合物转化生长因子-β和血小板衍生生长因子及其抗增殖和血管扩张作用 复合一氧化氮。项目4将审查补体的作用(C) 和AGA中的抗体，侧重于对缺血、同种异体免疫、 自身免疫和病毒(CMV)损伤。特别是，早期和晚期的C 成分将被单独检查，抗体反应也将被单独检查 特异性主要组织相容性复合体与热休克蛋白 (HSP)表位。项目5将研究细胞免疫的作用。 到自体(HSP，宿主-MHC)、到异体(供体MHC)和到外源 (CMV)抗原在AGA发生中的作用。尤其是曲目， 环孢素A诱导的自身反应性T细胞的功能和特异性 在调解中，将对AGA进行检查。行政核心(核心A)将 提供行政和统计方面的支持。病理学/临床 CORE(CORE B)将处理和储存人类和动物组织以供研究， 并为量化病理变化提供中心资源。这个 动物核心(核心C)将提供统一的动物心脏移植 活体研究。 本程序中检查的每一条路径都将使用库中的人类进行研究 用体外和体内动物模型解剖出的组织，以及 在分子和细胞水平上被定义。分子和细胞 确定的机制反过来将形成开发小说的基础 诊断和治疗策略可翻译回 病人。

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.