Abstract

Periodontal disease initiation and progression occurs as a consequence of the host immune inflammatory response to oral pathogens. Tristetraprolin (TTP) is a zinc finger protein that binds to the ARE of cytokine mRNAs and enhances degradation of the mRNA. TTP is phosphorylated by the p38-MK2 pathway and may serve as a general mechanism of cytokine mRNA regulation. The objective of this application is to determine how TTP and the MK2 pathway modify periodontal disease initiation and progression. Experimental models of periodontitis where TTP is over-expressed show a reduction of pro-inflammatory proteins and reduced amount of LPS-induced alveolar bone loss. Preliminary data for this proposal indicates that mutant mice lacking TTP display an increased amount of periodontal bone loss compared with wild type littermates.
The aims for this proposal are 1) to determine the role of TTP expression/phosphorylation status directs local inflammatory cytokine expression in periodontal disease progression, 2) to determine if TTP will determine the extent of inflammation and alveolar bone loss in experimental models of periodontal disease, and 3) measure TTP expression and phosphorylation status in human periodontal disease progression. These studies will establish the role of a key RNA binding protein in experimental models and human periodontitis. Using genetic models lacking TTP or the key kinase that modulates TTP function, MK2, definitive data relative to TTP biology related to periodontal disease will be gained. Foundation and translational significance of mRNA stability will provide insight into the potential of these proteins to be targeted for future studies that will modify innate immune cytokine expression for therapeutic benefit in the management of chronic periodontitis.

Public Health Relevance

Periodontal disease progression occurs as a consequence of the host immune inflammatory response to oral pathogens. These studies will establish the role of RNA binding proteins needed to mediate inflammatory cytokine mRNA stability. Progress in understanding the role of posttranscriptional cytokine regulation in periodontal inflammation and bone loss may yield new possibilities for treatment of periodontal diseases.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE021423-03
Application #
8499286
Study Section
Oral, Dental and Craniofacial Sciences Study Section (ODCS)
Program Officer
Burgoon, Penny W
Project Start
2011-07-01
Project End
2016-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
3
Fiscal Year
2013
Total Cost
$354,000
Indirect Cost
$114,000

  Institution

Name
Medical University of South Carolina
Department
Dentistry
Type
Schools of Dentistry
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425

  Publications

Novince, Chad M; Whittow, Carolyn R; Aartun, Johannes D et al. (2017) Commensal Gut Microbiota Immunomodulatory Actions in Bone Marrow and Liver have Catabolic Effects on Skeletal Homeostasis in Health. Sci Rep 7:5747
Valerio, M S; Basilakos, D S; Kirkpatrick, J E et al. (2017) Sex-based differential regulation of bacterial-induced bone resorption. J Periodontal Res 52:377-387
Herbert, B A; Novince, C M; Kirkwood, K L (2016) Aggregatibacter actinomycetemcomitans, a potent immunoregulator of the periodontal host defense system and alveolar bone homeostasis. Mol Oral Microbiol 31:207-27
Herbert, Bethany A; Valerio, Michael S; Gaestel, Matthias et al. (2015) Sexual Dimorphism in MAPK-Activated Protein Kinase-2 (MK2) Regulation of RANKL-Induced Osteoclastogenesis in Osteoclast Progenitor Subpopulations. PLoS One 10:e0125387
Valerio, Michael S; Herbert, Bethany A; Basilakos, Dimitrios S et al. (2015) Critical role of MKP-1 in lipopolysaccharide-induced osteoclast formation through CXCL1 and CXCL2. Cytokine 71:71-80
Jin, J; Zhang, X; Lu, Z et al. (2014) Simvastatin inhibits lipopolysaccharide-induced osteoclastogenesis and reduces alveolar bone loss in experimental periodontal disease. J Periodontal Res 49:518-26
Zhang, Xiaoyi; Hyer, J Madison; Yu, Hong et al. (2014) DUSP1 phosphatase regulates the proinflammatory milieu in head and neck squamous cell carcinoma. Cancer Res 74:7191-7
Valerio, Michael S; Herbert, Bethany A; Griffin 3rd, Alfred C et al. (2014) MKP-1 signaling events are required for early osteoclastogenesis in lineage defined progenitor populations by disrupting RANKL-induced NFATc1 nuclear translocation. Bone 60:16-25
Jin, J; Machado, E R; Yu, H et al. (2014) Simvastatin inhibits LPS-induced alveolar bone loss during metabolic syndrome. J Dent Res 93:294-9
Guimarães, Morgana Rodrigues; Leite, Fábio Renato Manzoli; Spolidorio, Luís Carlos et al. (2013) Curcumin abrogates LPS-induced pro-inflammatory cytokines in RAW 264.7 macrophages. Evidence for novel mechanisms involving SOCS-1, -3 and p38 MAPK. Arch Oral Biol 58:1309-17

Showing the most recent 10 out of 27 publications