Diabetes increases the risk of severe infections, including periodontitis. Maintenance of homeostasis and tissue health of the periodontium is complicated by overgrowth of specific pathogens. The innate immune response prevents invasion and limits the complexity of the infection. When disease occurs as a complication of systemic disease as in diabetes, tissue damage results from the host response (phagocyte mediated tissue injury), which provides a microenvironment that favors bacterial growth and the chronicity of the lesion. Dysregulated inflammatory/immune reactions have been implicated in the pathogenesis of the complications of diabetes, particularly periodontitis and cardiovascular diseases. Tissues exposed to the external environment and significant bacteria load, such as the periodontium, are at increased risk. The return of inflamed tissues to health and homeostasis is mediated by endogenous agonists that promote resolution of inflammation. The cellular and molecular mechanisms responsible for the resolution of periodontal inflammation are beginning to be mapped. These same proresolution agonists enhance host cell mediated antibacterial activity. Precursor fatty acid substrates from cells (arachidonic acid) and dietary sources (omega-3 fatty acids) yield lipid mediators (lipoxins and resolvins, respectively) that counter-regulate pro-inflammatory signals. Systematic temporal study of periodontal infection and resolution in tissues of people with diabetes is of paramount importance in the treatment of bacterially initiated periodontal disease. The goal of this competing renewal R01 proposal is to determine the impact of infection in resolution circuits of inflammation in people with diabetes. Our novel hypothesis is that restoration of resolution pathways by exogenous administration of resolving molecules will resolve periodontal inflammation and restore homeostasis modifying the composition of the microflora. In this proposal, we will investigate the mechanism of action of phagocyte interactions in the periodontium invoking innate antimicrobial activity and enhanced clearance of pathogens in people with diabetes.

Public Health Relevance

Diabetes increases the risk of severe infections, including periodontitis. When periodontal disease occurs as a complication of systemic disease as in diabetes, tissue damage results from the host response and the return of inflamed tissues to health is mediated by molecules that promote resolution of inflammation. The goal of this competing renewal R01 proposal is to determine the impact of infection in resolution circuits of inflammation in people with diabetes.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01DE015566-11
Application #
8681200
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Lunsford, Dwayne
Project Start
Project End
Budget Start
Budget End
Support Year
11
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Forsyth Institute
Department
Type
DUNS #
City
Cambridge
State
MA
Country
United States
Zip Code
02142
Mendes, Reila Tainá; Nguyen, Daniel; Stephens, Danielle et al. (2016) Endothelial Cell Response to Fusobacterium nucleatum. Infect Immun 84:2141-8
Damgaard, C; Kantarci, A; Holmstrup, P et al. (2016) Porphyromonas gingivalis-induced production of reactive oxygen species, tumor necrosis factor-α, interleukin-6, CXCL8 and CCL2 by neutrophils from localized aggressive periodontitis and healthy donors: modulating actions of red blood cells and resolvin E J Periodontal Res :
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
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
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
Van Dyke, T E; Hasturk, H; Kantarci, A et al. (2015) Proresolving nanomedicines activate bone regeneration in periodontitis. J Dent Res 94:148-56
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-3β-C/EBPβ pathway. Nat Commun 6:8272
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
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
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 81:683-90

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