ENDOTHELIAL CELL DYSFUNCTION & APOPOTOSIS IN ACCELERATED GRAFT ARTERIOSCLEROSIS

内皮细胞功能障碍

基本信息

批准号：
6642364
负责人：
NICHOLAS A FLAVAHAN
金额：
$ 49.81万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-05-01 至 2003-04-30
项目状态：
已结题

项目摘要

Accelerated graft arteriosclerOsis (AGA) represents a major obstacle to long term survival of heart transplant recipients. While it has become clear that AGA is a multifactorial problem, the specific mechanisms leading to AGA remain unknown. Because of their pivotal role in the maintenance of vessel homeostasis, endothelial cells (EcS) are likely to represent prime targets in the pathogenesis of AGA. Project 1 is designed to provide in-depth characterization of the process that affects ECs in AGA, from extracellular factors to intracellular molecular pathways that transduce messages to the genome of ECs. By integrating our studies on ECs with other projects of this program, we intend to provide information that will be key to the development of specific strategies to suppress AGA. In AGA, the functional damage to the endothelium is diffuse. Morphologically, areas of endothelial erosion can be found dispersed along the coronary vessels. Several mechanisms of BC ii-jury have been implicated in AGA: (i) oxidative injury resulting from ischemia/reperfusion at the time of surgery; (ii) immunological injuries involving complement activation, processing and presentation of antigens, activation and adhesion of T.lymphocytes, in particular cytolytic T- lymphocytes (CTL), sequestration of monocytes, production of antibodies against allo- or iso-antigens, and dysregulation of the immune system with Cyclosporine A; (iii) injury with CMV-infection/reactivation; and (iv) direct Cyclosporine A toxicity. These various mechanisms could contribute either independently or in concert, to the diffuse abnormalities of ECs in AGA. Particular emphasis will be placed on the following pathway, which will provide the basis for the specific aims of this project: (i) the initial injury results in uncoupling of Gi-2 from its membrane receptors; (ii) the uncoupling of Gi-2 then results in BC dysfunction and overexpression of Fas on the surface of ECs, through a pathway that requires NF-kappaB activation; (iii) overexpression of Fas, in turn, results in the "kiss of death" as CTL bind to the ECs through the interaction of Fas and Fas-ligand present on the CTL surface; (iv) increased BC apoptosis will further aggravate the dysfunctional aspect of the endothelium and promote fibrin production and deposition due to the abnormal presence of phosphatidylserine on the surface of ECs. As a result, the endothelium in these patients is not capable of carrying out its usual functions namely, vasodilation, anti-thrombotic effect, anti- proliferative effect for the cells of the vessel wall, control of the attachment of inflammatory cells, and homeostasis of extracellular protein production, leading to the development of AGA.

加速移植物动脉硬化（AGA）是移植物动脉硬化的一个主要障碍心脏移植受者的长期存活。虽然已经成为明确AGA是一个多因素问题，具体机制导致 AGA 的原因仍不清楚。由于他们在其中的关键作用维持血管稳态，内皮细胞（EcS）可能代表 AGA 发病机制的主要靶点。项目1设计提供影响 EC 的过程的深入特征 AGA，从细胞外因子到细胞内分子途径将信息转导至 EC 基因组。通过整合我们对 EC 的研究与该计划的其他项目一起，我们打算提供以下信息：将是制定抑制 AGA 的具体策略的关键。在 AGA，内皮功能损伤是弥漫性的。从形态学上看，内皮侵蚀区域分布在冠状血管。 BC ii-陪审团的几种机制已被与 AGA 相关的：(i) 氧化损伤手术时缺血/再灌注； (二) 免疫损伤涉及补体激活、抗原加工和呈递， T淋巴细胞的激活和粘附，特别是溶细胞性T淋巴细胞淋巴细胞 (CTL)、单核细胞隔离、抗体产生针对同种异体或同种抗原，以及免疫系统失调环孢素A； (iii) CMV 感染/再激活造成的损伤； (四) 环孢素A的直接毒性。这些不同的机制可能有助于独立或协同地影响 EC 的弥漫性异常阿嘎。将特别强调以下途径：将为该项目的具体目标奠定基础：(i) 最初的损伤导致 Gi-2 与其膜受体解偶联； (ii) Gi-2 解偶联导致 BC 功能障碍， Fas 在 EC 表面过度表达，通过以下途径需要 NF-kappaB 激活； (iii) Fas 的过度表达，当 CTL 通过以下方式与 EC 结合时，导致“死亡之吻” Fas 和 CTL 表面存在的 Fas 配体的相互作用；（四） BC细胞凋亡增加将进一步加剧BC的功能失调内皮细胞并促进纤维蛋白的产生和沉积 ECs 表面异常存在磷脂酰丝氨酸。作为一个结果，这些患者的内皮细胞无法执行其通常的功能是舒张血管、抗血栓作用、抗血栓作用。对血管壁细胞的增殖作用，控制炎症细胞的附着和细胞外蛋白质的稳态的生产，导致了 AGA 的发展。