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 COHR: Center for Oral Health Research | Projects | COBRE for Oral Health - Projects - Lauren E. Ball, PhD

Lauren E. Ball, PhD
Project 3: Role of the Hexosamine Biosynthetic Pathway and Posttranslational O-GlcNAc Glycosylation in Complications of Diabetes Pertaining to Oral Health (Start date 7/1/07)

OverviewLauren E. Ball

The purpose of this research project is to determine if inappropriate protein O-GlcNAc glycosylation 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.


We are interested in the mechanisms underlying the onset and progression of complications associated with diabetes. The Diabetes Control and Complications Trial clearly showed that strict control of blood glucose concentration slowed the progression of microvascular complications of diabetes including; blindness, nerve damage, and kidney failure. Recent studies demonstrate that diabetic patients also have an elevated risk of developing periodontal disease. 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.

Under normal conditions 2-3% of the glucose entering the cell is metabolized to UDP-N-acetylglucosamine (UDP-GlcNAc) by the hexosamine biosynthetic pathway. UDP-GlcNAc is the monosaccharide donor for the O-linked glycosylation of serine and threonine residues by N-acetylglucosamine (GlcNAc). This is a dynamic and reversible posttranslational modification occurring on nuclear and cytoplasmic proteins. This modification regulates protein function in a manner analogous to S/T phosphorylation and furthermore may compete with S/T phosphorylation. The enzymes catalyzing the incorporation and removal of GlcNAc from proteins, O-GlcNAc transferase and O-GlcNAcase, respectively, are located in the nucleus and cytoplasm of the cell and are ubiquitously distributed in tissues. Many proteins are O-GlcNAc modified including transcription factors, oncogenes, tumor suppressors, heat shock proteins, nuclear pore proteins, and intracellular signaling molecules. In states of nutrient excess, such as type II diabetes, UDP-GlcNAc levels and the extent of protein O-GlcNAc modification rise. Thus, hyperglycemia-induced O-GlcNAc modification has been proposed to contribute to the microvascular complications (nephropathy, neuropathy, and retinopathy) associated with diabetes and may exacerbate diabetic periodontal disease.

The progression of periodontal disease 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. In the studies proposed, we will investigate the role of O-GlcNAc transferase and O-GlcNAcase in the elevated response of resident macrophages to bacterial challenge following exposure to chronic high glucose.

The delayed regeneration of the damaged periodontium may stem from an inadequate response to growth factors such as IGF-1. The IGF-1 receptor 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 O-GlcNAc modification of proteins in the insulin/IGF-1 signaling pathway and the impact of this modification on the response of periodontal ligament cells to IGF-1.

Selected Publications

  1. Ball, L.E., Berkaw, M.N., Buse, M.G.: Identification of the Major Site of O-Linked {beta}-N-Acetylglucosamine Modification in the C-Terminus of Insulin Receptor Substrate-1. Mol Cell Proteomics. 2006 Feb;5(2):313-23.

  2. Robinson, K.A., Ball, L.E., Buse, M.G.: Reduction of O-GlcNAc protein modification does not prevent insulin resistance in 3T3-L1 adipocytes. Am J Physiol Endocrinol Metab. 2007 Mar; 292(3):E884-90.

  3. Ball, L.E., Garland, D.L., Crouch, R.K, Schey, K.L.: Posttranslational Modifications of Aquaporin 0 in the Normal Human Lens: Spatial and Temporal Occurrence. Biochemistry. 43: 9856-65, 2004.

  4. Ball, L.E., Little, M., Nowak, M.W., Garland, D.L., Crouch, R.K, Schey, K.L.: C-Terminally Truncated Aquaporin 0 (AQP0 1-243) Observed in the Aging Human Lens Remains Functionally Viable. Invest. Ophthalmol. Vis. Sci. 44: 4820-8, 2003.

  5. Ball, L.E., Oatis, J.E. Jr., Dharmisiri, K., Busman, M., Wang, J., Cowden, L., Galijatovic, A., Chen, N., Crouch, R.K., Knapp, D.R.: Mass spectrometric mapping of integral membrane proteins; Application to complete mapping of Bacteriorhodopsins and Rhodopsin. Protein Science. 7: 758-764, 1998.

Additional Publications

  1. Ervin, L.A., Ball, L.E., Crouch, R.K., Schey, K.L.: Phosphorylation and Glycosylation of Bovine Lens MP20. Invest. Ophthalmol. Vis. Sci. 46 (2): 627-35, 2005.

  2. Knapp, D.R, Crouch, R.K., Ball, L.E., Gelasco, A.K., Ablonczy, Z.: Mass Spectrometric Analysis of G Protein-Coupled Receptors. Meth Enzymol. 343: 157-161, 2001.

Additional Information/Links

Dr. Ball's Departmental Web Page