VASCULAR AND MONOCYTE DYSFUNCTION AND LOCAL INFECTION

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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).