Abstract

Diabetes has now reached epidemic status in the United States, affects 6.5% of the general population, and continues to increase at a very alarming rate. Periodontal disease is referred to as the sixth complication of diabetes. There is a reciprocal relationship between diabetes and periodontal disease where each condition exacerbates the other. We have recently observed that neutrophils and monocytes from diabetic patients contain elevated diacylglycerides (DAG), enhanced activity of protein kinase C (PKC), and can release significantly more superoxide and/or tumor necrosis factor-alpha than cells from healthy individuals. Superoxide, cytokines and matrix metalloproteinases play a significant role in the destruction of periodontal tissues in diabetes. Importantly, certain endogenous, anti-inflammatory lipids that result from transcellular metabolism of arachidonic and eicosapentaenoic acid (lipoxins, resolvins) were found to be highly effective in inhibiting superoxide release from diabetic neutrophils and blocking periodontal disease in a rabbit model. In this proposal, we will: 1) determine the molecular mechanisms responsible for alterations in DAG and PKC in diabetic patients; 2) uncover the biochemical basis for priming of neutrophils/monocytes in diabetes, and determine if this priming is prevented when patients are brought under glycemic control and/or treated for periodontal disease; 3) determine the signal transduction pathways by which advanced glycation end products (AGE) prime neutrophils; and 4) determine if certain endogenous anti-inflammatory lipid mediators (e.g., lipoxins, resolvins) can limit the inflammatory response in diabetes by blocking the enhanced functional responses of neutrophils and monocytes from these patients. Techniques of modern biochemistry, immunology and cell biology will be employed in these investigations. These studies have the potential of leading to better methods of treating periodontal disease and perhaps other complications of diabetes.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE015566-04
Application #
7383929
Study Section
Oral, Dental and Craniofacial Sciences Study Section (ODCS)
Program Officer
Kusiak, John W
Project Start
2005-04-01
Project End
2010-03-31
Budget Start
2008-04-01
Budget End
2009-03-31
Support Year
4
Fiscal Year
2008
Total Cost
$347,987
Indirect Cost

  Institution

Name
Boston University
Department
Dentistry
Type
Schools of Dentistry
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118

  Publications

Damgaard, C; Kantarci, A; Holmstrup, P et al. (2017) Porphyromonas gingivalis-induced production of reactive oxygen species, tumor necrosis factor-?, interleukin-6, CXCL8 and CCL2 by neutrophils from localized aggressive periodontitis and healthy donors: modulating actions of red blood cells and resolvin E1 J Periodontal Res 52:246-254
Zamakhchari, Mai F; Sima, Corneliu; Sama, Kishore et al. (2016) Lack of p47(phox) in Akita Diabetic Mice Is Associated with Interstitial Pneumonia, Fibrosis, and Oral Inflammation. Am J Pathol 186:659-70
Mendes, Reila Tainá; Nguyen, Daniel; Stephens, Danielle et al. (2016) Endothelial Cell Response to Fusobacterium nucleatum. Infect Immun 84:2141-2148
Steffens, Joao Paulo; Coimbra, Leila Santana; Rossa Jr, Carlos et al. (2015) Androgen receptors and experimental bone loss - an in vivo and in vitro study. Bone 81:683-690
Maekawa, Tomoki; Hosur, Kavita; Abe, Toshiharu et al. (2015) Antagonistic effects of IL-17 and D-resolvins on endothelial Del-1 expression through a GSK-3?-C/EBP? pathway. Nat Commun 6:8272
Steffens, Joao Paulo; Wang, Xiaoshan; Starr, Jacqueline R et al. (2015) Associations Between Sex Hormone Levels and Periodontitis in Men: Results From NHANES III. J Periodontol 86:1116-25
Hasturk, Hatice; Abdallah, Rima; Kantarci, Alpdogan et al. (2015) Resolvin E1 (RvE1) Attenuates Atherosclerotic Plaque Formation in Diet and Inflammation-Induced Atherogenesis. Arterioscler Thromb Vasc Biol 35:1123-33
Herrera, Bruno S; Hasturk, Hatice; Kantarci, Alpdogan et al. (2015) Impact of resolvin E1 on murine neutrophil phagocytosis in type 2 diabetes. Infect Immun 83:792-801
Kang, Eun Ha; Lee, Jung Tae; Lee, Hyo-Jung et al. (2015) Chronic Periodontitis Is Associated With Spinal Dysmobility in Patients With Ankylosing Spondylitis. J Periodontol 86:1303-13
Wang, Chin-Wei; Colas, Romain A; Dalli, Jesmond et al. (2015) Maresin 1 Biosynthesis and Proresolving Anti-infective Functions with Human-Localized Aggressive Periodontitis Leukocytes. Infect Immun 84:658-65

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