Tissue and vascular deposition of Advanced Glycation Endproducts (AGEs), irreversible products of glycoxidation of proteins and lipids, occurs during normal aging and is accelerated by concomitant glucose intolerance or renal failure. Thus, normal host reparative mechanisms, such as those set in motion by wounding must proceed in an environment rich in AGEs. Cells critical to orchestration of wound healing, especially endothelial cells (ECs) and mononuclear phagocytes (MPs), express Receptor for AGE (RAGE), a principal cell surface binding site for AGEs. Consequent to engagement bu AGEs, RAGE brings about changes in cellular functions central to tissue reparative mechanisms triggered during the inflammatory, proliferative and remodeling phases of healing. Pilot studies using a secondary intention would model in glucose intolerant mice, the latter to accelerate AGE deposition, have shown delayed healing compared with control animals. Wound closure in this model is enhanced, almost to levels in euglycemic controls, by local or systemic administration of a truncated hypothesis that AGE binding to RAGE on critical cellular targets, especially ECs and MPs, modulates their participation in reparative processes by promoting sustained activation, leading to a chronic, destructive inflammatory response.
Our specific aims are: (1) to analyze, in the secondary intention wound model, the effect of sRAGE on differences in the reparative response in glucose-intolerant amd euglycemic mice, by monitoring activation of ECs, influx and activation of MPs, production of pro-inflammatory cytokines, growth factors, and the balance of collagen synthesis/degradation; (2) to produce new transgenic murine models for evaluating the contribution of AGE-RAGE interaction to wound healing by cross-breeding transgenic (Tg) mice with targeted overexpression of full- length RAGE or a dominant negative form of the receptor in MPs or ECs with glucose intolerant mice, and to determine the effect on the reparative response: and (3) to identify determinants on RAGE mediating interaction with AGEs. Project 2 will work closely with Projects 1&3 and will obtain technical assistance from the Cores. Collaborative interactions will include: development and characterization of Tg RAGE mice (Projects 1&3 and Core C), collagen/collagenase evaluation (Project 2), transcriptional analysis of RAGE expression (Project 1), and pathologic study of tissues (Core B).
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