COBRE P3: ROLE OF HEXOSAMINE BIOSYNTHETIC PATHWAY AND POSTRANSLATIONAL O-GLCNAC

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Of an estimated 20.8 million adults and children in the US that have diabetes, one-third of these patients suffer from severe periodontal disease. The increased severity of periodontal disease in diabetic patients reflects, in part, accelerated tissue degradation and delayed tissue healing. This is postulated to result from an interplay of factors including increased susceptibility to infection, elevated pro-inflammatory cytokines, and hyperglycemia. Matrix metalloproteases (MMP), responsible for the breakdown of collagen, are elevated in response to bacterial challenge and recent evidence suggests that infection and hyperglycemia act synergistically to stimulate the expression and secretion of MMP-1. This synergistic response may explain the exaggerated tissue destruction observed in diabetic patients. Furthermore, the delayed regeneration of the damaged periodontium may stem from an inadequate response to growth factors such as IGF-1. The IGF-1R pathway, which contributes to periodontal ligament cell proliferation, alveolar bone growth, and osteoblast differentiation, is down-regulated by pro-inflammatory cytokines and hyperglycemia. In the studies proposed, we will investigate the role of glucose-induced glycosylation of Ser/Thr residues by N-acetylglucosamine (O-GlcNAc) in the elevated response of resident macrophages to bacterial challenge and in the attenuated response of periodontal ligament cells to IGF-1. Posttranslational O-GlcNAcylation of proteins is postulated to regulate protein function in a manner analogous to phosphorylation. To test whether this modification contributes to the detrimental effects of high glucose, we will manipulate the expression and activity of the enzymes responsible for the incorporation or removal of this monosaccharide from proteins. The purpose of this research project is to determine if inappropriate protein O-GlcNAc glycosylaton resulting from hyperglycemia contributes to the accelerated tissue degradation and delayed healing observed in diabetic patients with periodontal disease. The ultimate goal of this research is to elucidate potential targets of therapeutic intervention to delay the onset or progression of diabetes-associated periodontal disease.