RAGE AND MECHANISMS OF VASCULAR AND MONOCYTE DYSFUNCTION

持续的内皮细胞和单核吞噬细胞功能障碍对于 慢性血管疾病的发病机制。非酶 蛋白质和脂质的糖基氧化形成晚期糖化 血管和组织中的终产物（AGEs）在 动脉粥样硬化、糖尿病和肾衰竭。AGES与 内皮细胞和单核细胞上的AGE受体（AGE）干扰细胞内的 对血管和组织稳态过程至关重要的性质，以及 导致慢性细胞激活方案的核心假设是 项目是AGE-beta介导的内皮细胞和单核细胞 功能会损害生理效应机制， 侵袭性动脉粥样硬化、伤口修复延迟和消退受损 局部炎症利用葡萄糖耐受不良作为刺激， 增强AGE形成，我们的初步研究表明， AGE-CRP相互作用抑制加速的动脉粥样硬化， 伤口愈合和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， 与葡萄糖耐受不良相关的加速动脉粥样硬化 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中的二次意图伤口模型， AGE-beta介导的细胞功能障碍的耐药小鼠 损害组织修复机制。项目3将侧重于当地 炎症/感染在富含AGE的软组织中使用的模型 由细菌感染引起的牙龈炎。重叠的宿主反应 动脉粥样硬化形成、伤口修复和局部 炎症，内皮细胞和单核细胞的密切参与， 以及AGE结合至E2的中心作用，为以下研究提供了基础： 三个项目之间的密切互动。通过合作研究 在每个项目之间， 使用转基因小鼠和突变的DNA分子。于年底 计划项目，我们希望产生新的和重要的信息 与血管和单核细胞功能障碍有关， 动脉粥样硬化、伤口愈合受损和宿主反应受损 局部炎症常见于以组织 AGEs的沉积。这些数据应该可以提供一个新的目标的洞察力 用于未来治疗药物的开发。

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.