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.
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