VASCULAR AND MONOCYTE DYSFUNCTION AND LOCAL INFECTION

晚期糖基化终产物（AGEs）的组织和血管沉积， 蛋白质和脂质糖氧化的不可逆产物， 在正常衰老过程中并且由于葡萄糖耐受不良而加速， 动脉粥样硬化和肾功能不全。因此，宿主反应机制 由局部炎症和/或感染引发的， 在这些环境中。细胞对解决此类问题至关重要 炎症灶，尤其是内皮细胞（EC）和单核细胞 吞噬细胞（MP），表达AGEs受体（RECEPTOR for AGEs，RECEPTOR），是一种主要的细胞 AGEs的表面结合位点。随着反政府分子的参与， 引起局部炎症的变化， 牙龈卟啉单胞菌（Pg）在富含AGE的组织中使用葡萄糖不耐受 用来自葡萄糖不耐受小鼠的牙龈卟啉单胞菌类似激发的动物 结果显示AGEs广泛沉积， MP和EC。通过以下途径阻断AGE与细胞凋亡的相互作用： 施用，通过施用截短形式的维生素B1（S1） 跨越细胞外结构域，抑制牙龈炎症， 牙槽骨丢失。我们假设AGEs，通过它们与 内皮细胞和单核细胞增生，主要牙龈组织， 炎症反应导致牙槽骨丢失增加。因此，在本发明中， 葡萄糖不耐受小鼠的牙龈炎提供了一个扩大 我们的概念，年龄-β-介导的细胞活化的基础上，非- 解决和破坏性的炎症。我们的目标是：（1）比较 炎性细胞因子的产生，胶原蛋白的合成和降解， 炎症细胞流入受影响的牙龈组织和程度 葡萄糖不耐受小鼠和正常小鼠的牙槽骨丢失， 感染Pg;（2）确定阻断AGE-CRP相互作用 减轻牙周炎和骨质流失;和（3）使用鼠 转基因（Tg）模型，其中野生型或显性负性突变体是 在EC或MP中选择性过表达，以测试 导致富含AGE的牙龈中的PD。项目将与 项目1和2，并将获得核心的技术援助。 合作互动包括：开发和表征的Tg 小鼠（项目1 - 2和核心C），转录分析 表达和切割的配体结合结构域（项目1 - 2）， 细胞因子分析（项目2）和组织病理学研究（核心B）。

Tissue and vascular deposition of Advanced Glycation Endproducts (AGEs), irreversible products of glycoxidation of proteins and lipids, occur during normal aging and are accelerated by glucose intolerance, atherosclerosis and renal dysfunction. Thus, host response mechanisms triggered by local inflammation and/or infection operate in an AGE-rich environment in these settings. Cells critical to resolution of such inflamed foci, especially endothelial cells (ECs) and mononuclear phagocytes (MPs), express Receptor for AGEs (RAGE), a principal cell surface binding site for AGEs. Consequent to engagement by AGEs, RAGE brings about changes in which local inflammation is initiated by porphyromonas gingivalis (Pg) in AGE-rich tissues using glucose intolerant animals similarly challenged with Pg. Gingiva from glucose-intolerant mice showed extensive deposition of AGEs and increased expression of RAGE in MPs and ECs. Interruption of AGE interaction with cellular RAGE, by administration, by administration of a truncated form of RAGE (sRAGE) spanning the extracellular domain, suppressed gingival inflammation and alveolar bone loss. We hypothesize that AGEs, via their interaction with endothelial and monocyte RAGE, prime gingival tissue for an exaggerated inflammatory response eventuating in enhanced alveolar bone loss. Thus, gingivitis in glucose-intolerant mice provides an opportunity to extend our concept of AGE-RAGE-mediated cellular activation as a basis for non- resolving and destructive inflammation. Our aims are: (1) to compare production of inflammatory cytokines, collagen synthesis and degradation, influx of inflammatory cells into affected gingival tissue and extent of alveolar bone loss in glucose-intolerant and normal mice with/without infection with Pg; (2) to determine how blockade of AGE-RAGE interaction attenuates periodontal inflammation and bone loss; and, (3) to use murine transgenic (Tg) models in which wild-type or dominant negative RAGE is selective over-expressed in ECs or MPs to test the concept that RAGE contributes to PD in AGE-rich gingiva. Project will work closely with Projects 1&2 and will obtain technical assistance from the Cores. Collaborative interactions include: development and characterization of Tg RAGE mice (Projects 1-2 and Core C), transcriptional analysis of RAGE expression and dissection of the RAGE ligand binding domain (Project 1-2), cytokine analysis (Project 2), and a pathologic study of tissues (Core B).