Control of inflammation in periodontal regeneration is a major public health problem. Approximately 50% of the population of the United States has some form of periodontal disease and tissue engineering procedures cannot completely restore hard and soft tissues. Control of endogenous inflammation is an absolute requirement for tissue engineering success. There is a critical need for new therapeutics in regeneration that control local inflammation. The long-term goal of this R01 proposal is to utilize natural resolution of inflammation to control local inflammation and accelerate regeneration. Resolvins mediate resolution of inflammation facilitating periodontal regeneration and a return to homeostasis. Our group introduced the novel concept that inflammatory disease may result from a failure of active resolution. Accumulating evidence suggests that agonists of endogenous resolution programs may be the best approach to control inflammation in periodontal regeneration and reconstruction. The Central Hypothesis is that resolution of inflammation pathways and mediators can be harnessed to control inflammation in periodontal tissues enabling regeneration and reconstruction. We have demonstrated that delivery of lipoxins and resolvins greatly enhances tissue regeneration by control of inflammation. Resolvins also have actions beyond control of neutrophils including receptor mediated control of osteoclast and osteoblast function in wound healing and bone regeneration. We will identify key endogenous control mechanisms for bone formation induced by RvE1 using specific RvE1 receptor knock-out (KO) and receptor over-expressing transgenic mice, determine the basis for bone cell responses to RvE1 by elucidation of signal anabolic pathways that promote osteoblast mediated bone formation and limit osteoclast activity, and unravel the complexities of lipid mediator synergy and characterize hetero- specific resolution agonist amplification by determining pro and anti-inflammatory lipid mediator profiles induced by RvE1. Results from these studies will advance our knowledge of mechanisms in natural resolution of inflammation in tissue regeneration to develop novel bioengineering-based strategies targeted for periodontal regeneration. Our experienced research team consists of experts in cell biology, pharmacological biochemistry, animal models and periodontal regeneration that are well positioned to carry out this project.

Public Health Relevance

This proposal addresses the published NIDCR need for new therapies for the control of periodontal inflammation. Approximately 50% of the population of the United States has some form of periodontal disease and tissue engineering procedures cannot completely restore hard and soft tissues. Control of endogenous inflammation is an absolute requirement for tissue engineering success. There is a critical need for new therapeutics in regeneration that control local inflammation. This proposal will identify key control mechanisms for new bone formation induced by the natural mediator, RvE1 and determine the mechanism of action at the molecular, cellular and whole body level.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
1R01DE025020-01
Application #
8861681
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Lumelsky, Nadya L
Project Start
2015-05-01
Project End
2019-04-30
Budget Start
2015-05-01
Budget End
2016-04-30
Support Year
1
Fiscal Year
2015
Total Cost
$495,338
Indirect Cost
$187,400
Name
Forsyth Institute
Department
Type
DUNS #
062190616
City
Cambridge
State
MA
Country
United States
Zip Code
02142
Sima, Corneliu; Montero, Eduardo; Nguyen, Daniel et al. (2018) Author Correction: ERV1 Overexpression in Myeloid Cells Protects against High Fat Diet Induced Obesity and Glucose Intolerance. Sci Rep 8:4143
Mizraji, Gabriel; Heyman, Oded; Van Dyke, Thomas E et al. (2018) Resolvin D2 Restrains Th1 Immunity and Prevents Alveolar Bone Loss in Murine Periodontitis. Front Immunol 9:785
El Kholy, Karim; Freire, Marcelo; Chen, Tsute et al. (2018) Resolvin E1 Promotes Bone Preservation Under Inflammatory Conditions. Front Immunol 9:1300
Van Dyke, T E; Diaz, P I; Moutsopoulos, N et al. (2018) Task Force on Design and Analysis in Oral Health Research: Host-Microbiome Interactions in Dysbiosis. JDR Clin Trans Res 3:6-9
Van Dyke, Thomas E (2017) Pro-resolving mediators in the regulation of periodontal disease. Mol Aspects Med 58:21-36
Papathanasiou, E; Trotman, C A; Scott, A R et al. (2017) Current and Emerging Treatments for Postsurgical Cleft Lip Scarring: Effectiveness and Mechanisms. J Dent Res 96:1370-1377
Sima, Corneliu; Montero, Eduardo; Nguyen, Daniel et al. (2017) ERV1 Overexpression in Myeloid Cells Protects against High Fat Diet Induced Obesity and Glucose Intolerance. Sci Rep 7:12848
Serhan, Charles N (2017) Discovery of specialized pro-resolving mediators marks the dawn of resolution physiology and pharmacology. Mol Aspects Med 58:1-11
Serhan, Charles N (2017) Treating inflammation and infection in the 21st century: new hints from decoding resolution mediators and mechanisms. FASEB J 31:1273-1288
Freire, Marcelo O; Dalli, Jesmond; Serhan, Charles N et al. (2017) Neutrophil Resolvin E1 Receptor Expression and Function in Type 2 Diabetes. J Immunol 198:718-728

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