Oral infections lead to local persistent inflammation that when """"""""uncontrolled"""""""" gives rise to periodontal diseases (PD), a costly public health burden. PD is not only limited to tooth loss and associated loss of self-esteem but also impacts general health. Our recent findings indicate that resolution of inflammation is an active process and reveal an urgent need to clinically navigate this essentially uncharted terrain of infammation-resolution. To address this scientific opportunity and important mission in oral health, a multidisciplinary team of experts is assembled in a new Specialized Center for Research (SCR) configuration that will use new technologies to elucidate the molecular map of oral resolution. Our team and overall project will provide systematic molecular analyses and insights into the integrated host resolution response with focus in oral inflammation and PD-related tissue injury. Recently, we found that human neutrophils (PMN), along with generating the many proinflammatory mediators during inflammation, also generate in exudates novel """"""""proresolving"""""""" lipid mediators (LM) that possess potent anti-inflammatory and tissue protective actions, as well as activate novel anti-microbial mechanisms in mucosal epithelial cells. These ongoing studies give rise to an overarching hypothesis to be tested in four interrelated sub-projects in this SCR requiring a highly integrated approach. The SCR overall novel hypothesis addressed is: Periodontal disease (oral inflammation and tissue injury), certain microbes, surgical anesthesia, and other widely used drugs impact recently uncovered LM resolution pathways essential in host defense and homeostasis. They prolong oral inflammation by disrupting these uncharted resolution circuits. This SCR team consists of 4 sub-projects with complementary expertise and 3 scientific cores needed to map the molecular circuitry of oral resolution with a central theme of novel LM and their actions with PMN, newly uncovered anti-microbial mucosal defense mechanisms, and PMN-mediated destruction of engineered tissue matrices. Our mission's overall goal is to provide these essential molecular coordinates for swift translation to human oral health. Broad long-term objectives are a) to elucidate the map of oral resolution, b) provide molecular map(s) and coordinates to clinicians to improve treatment practices and our national preparedness and biodefense status, and c) provide the basis for new therapeutic approaches using agonists of resolution.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Specialized Center (P50)
Project #
3P50DE016191-05S1
Application #
7944380
Study Section
Special Emphasis Panel (ZDE1-YL (42))
Program Officer
Lunsford, Dwayne
Project Start
2004-09-17
Project End
2011-07-31
Budget Start
2008-08-01
Budget End
2010-07-31
Support Year
5
Fiscal Year
2009
Total Cost
$1,140,000
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
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Winkler, Jeremy W; Uddin, Jasim; Serhan, Charles N et al. (2013) Stereocontrolled total synthesis of the potent anti-inflammatory and pro-resolving lipid mediator resolvin D3 and its aspirin-triggered 17R-epimer. Org Lett 15:1424-7
Gao, Li; Faibish, Dan; Fredman, Gabrielle et al. (2013) Resolvin E1 and chemokine-like receptor 1 mediate bone preservation. J Immunol 190:689-94
Bartold, P Mark; Van Dyke, Thomas E (2013) Periodontitis: a host-mediated disruption of microbial homeostasis. Unlearning learned concepts. Periodontol 2000 62:203-17
Hasturk, Hatice; Kantarci, Alpdogan; Van Dyke, Thomas E (2012) Oral inflammatory diseases and systemic inflammation: role of the macrophage. Front Immunol 3:118
Petasis, Nicos A; Yang, Rong; Winkler, Jeremy W et al. (2012) Stereocontrolled total synthesis of neuroprotectin D1 / protectin D1 and its aspirin-triggered stereoisomer. Tetrahedron Lett 53:1695-1698
Hasturk, Hatice; Kantarci, Alpdogan; Van Dyke, Thomas E (2012) Paradigm shift in the pharmacological management of periodontal diseases. Front Oral Biol 15:160-76
Schif-Zuck, Sagie; Gross, Nufar; Assi, Simaan et al. (2011) Saturated-efferocytosis generates pro-resolving CD11b low macrophages: modulation by resolvins and glucocorticoids. Eur J Immunol 41:366-79
MacManus, Christopher F; Campbell, Eric L; Keely, Simon et al. (2011) Anti-inflammatory actions of adrenomedullin through fine tuning of HIF stabilization. FASEB J 25:1856-64
Serhan, Charles N; Petasis, Nicos A (2011) Resolvins and protectins in inflammation resolution. Chem Rev 111:5922-43

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