RAGE AND MECHANISMS OF VASCULAR AND MONOCYTE DYSFUNCTION

持续的内皮和单核吞噬细胞功能障碍是 慢性血管疾病的发病机制。非酶 蛋白质和脂类的糖氧化形成高级糖基化 血管和组织中的终产物(AGEs)在 动脉粥样硬化、糖尿病和肾功能衰竭。AGEs与 内皮细胞和单核细胞上的AGE受体(RAGE)干扰细胞 对血管和组织动态平衡过程至关重要的特性，以及 导致慢性细胞激活。该计划的中心假设 项目是年龄-RAGE介导的内皮细胞和单核细胞的调节 功能损害生理效应器机制并最终在 侵袭性动脉粥样硬化、伤口修复延迟和分辨率受损 局部发炎。使用葡萄糖耐量异常作为刺激 增强年龄形成，我们的初步研究表明， 年龄-RAGE相互作用抑制加速的动脉粥样硬化，改善 伤口愈合，减少软组织的炎症后果 感染。项目1将利用我们最近开发的小鼠模型 加速的动脉粥样硬化与糖耐量异常相关 RAGE在血管病变快速形成中的作用。项目2将 将我们的概念扩展到胰岛素的二次意图创伤模型- AGE-RAGE介导的细胞功能障碍是耐药小鼠的基础 受损的组织修复机制。项目3将重点放在当地 在富含年龄的软组织中的炎症/感染 由细菌感染引发的牙周炎。重叠的宿主反应 动脉粥样硬化、创面修复和局部损伤引发的机制 炎症，内皮细胞和单核细胞的密切参与，如 以及年龄约束对愤怒的核心作用，为 三个项目之间的密切互动。通过合作研究 在每个项目之间，RAGE的贡献将被确定 使用转基因小鼠和突变的RAGE分子。在这个结束的时候 计划项目，我们希望已经生成了新的重要信息 与血管和单核细胞功能障碍相关的加速 动脉粥样硬化、伤口愈合受损和宿主反应受损 到局部炎症，常见于以组织为特征的疾病 年龄的沉积。这些数据应该会为一个新的目标提供洞察力 用于开发未来的治疗剂。

Sustained endothelial and mononuclear phagocyte dysfunction is critical to the pathogenesis of chronic vascular disorders. Non-enzymatic glycoxidation of proteins and lipids forming Advanced Glycation Endproducts (AGEs) in the vasculature and tissues is accelerated in atherosclerosis, diabetes and renal failure. Interaction of AGES with Receptor for AGE (RAGE) on endothelium and monocytes perturbs cellular properties critical to vascular and tissue homeostatic processes, and causes chronic cellular activation. The central hypothesis of the Program Project is that AGE-RAGE-mediated modulation of endothelial and monocyte functions compromises physiologic effector mechanisms and eventuates in aggressive atherosclerosis, delayed wound repair, and impaired resolution of local inflammation. Employing glucose intolerance as the stimulus for enhanced AGE formation, our pilot studies have shown that antagonism of AGE-RAGE interaction suppresses accelerated atherosclerosis, ameliorates wound healing and diminishes inflammatory consequences of soft tissue infection. Project 1 will exploit our recently developed murine model of accelerated atherosclerosis associated with glucose intolerance to probe the role of RAGE in rapid formation of vascular lesions. Project 2 will extend our concept to a secondary intention wound model in insulin- resistant mice in which AGE-RAGE-mediated cellular dysfunction underlies compromised tissues reparative mechanisms. Project 3 will focus on local inflammation/infection in AGE-rich soft tissues using a model of gingivitis triggered by bacterial infection. The overlapping host response mechanisms triggered by atherogenesis, wound repair and local inflammation, the intimate involvement of endothelium and monocytes, as well as the central role of AGE binding to RAGE, provide the basis for close interactions among the three Projects. By collaborative studies between each of the Projects, the contribution of RAGE will be determined using transgenic mice and mutated RAGE molecules. At the end of this Program Project, we expect to have generated new and important information related to vascular and monocyte dysfunction underlying accelerated atherosclerosis, impaired wound healing and the compromised host response to local inflammation common to disorders characterize by tissue deposition of AGEs. These data should provide insight into a novel target for the development of future therapeutic agents.