Periodontal disease is one of the most common chronic infectious diseases of humans and it has been estimated that in the United States alone 100,000,000 people possess measurable periodontal bone loss. Importantly, periodontal disease is increasingly more common in adults as they age suggesting that ontogeny impacts periodontal disease susceptibility and / or inflammatory progression. A myriad of bacteria inhabit the oral cavity;however, Porphyromonas gingivalis has been identified as a primary etiological agent associated with human periodontal disease. Based on two epidemiological studies, the toll-like receptors (TLRs;a group of innate immune receptors that recognize distinct microbial patterns) have been implicated in progression of human periodontal disease. However, to date, experimental studies have not been performed to directly assess the role for TLRs, or the adaptor molecules involved in TLR-mediated signaling in oral bone loss in the context of a specific periodontal disease pathogen. Moreover, there is a lack of knowledge regarding modeling long-term patterns of oral bone loss in response to infection. In this study, we propose 1- To define the role of TLR2 and TLR4 in the age-related innate immune response to P. gingivalis and fimbriae;2- To define the role of MyD88-dependent and MyD88-independent signaling in the age-related innate immune response to P. gingivalis and fimbriae;and 3- To define the roles for the TLR2 and TLR4 receptors and MyD88-dependent and MyD88-independent signaling cascades in age-related oral bone loss patterns in mice in response to P. gingivalis infection. These studies will: 1- elucidate the contribution of ontogeny to the host inflammatory response to P. gingivalis in vitro;2- define the age-related progression of oral bone loss in a murine model in response to P. gingivalis infection;and 3- and assess the contribution of TLR2 and TLR4, as well as TLR adaptor molecules including MyD88 in this response. These studies provide for a thorough examination of the mechanisms underlying the role played by specific TLR receptors to P. gingivalis-elicited inflammation and oral bone loss in the context of age.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Research Project (R01)
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Special Emphasis Panel (ZDE1-YL (20))
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Lumelsky, Nadya L
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Boston Medical Center
United States
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Shaik-Dasthagirisaheb, Y B; Huang, N; Weinberg, E O et al. (2015) Aging and contribution of MyD88 and TRIF to expression of TLR pathway-associated genes following stimulation with Porphyromonas gingivalis. J Periodontal Res 50:89-102
Shaik-Dasthagirisaheb, Yazdani B; Huang, Nasi; Gibson 3rd, Frank C (2014) Inflammatory response to Porphyromonas gingivalis partially requires interferon regulatory factor (IRF) 3. Innate Immun 20:312-9
Shaik-Dasthagirisaheb, Y B; Huang, N; Baer, M T et al. (2013) Role of MyD88-dependent and MyD88-independent signaling in Porphyromonas gingivalis-elicited macrophage foam cell formation. Mol Oral Microbiol 28:28-39
Shaik-Dasthagirisaheb, Yazdani B; Kantarci, Alpdogan; Gibson 3rd, Frank C (2010) Immune response of macrophages from young and aged mice to the oral pathogenic bacterium Porphyromonas gingivalis. Immun Ageing 7:15
Baer, M T; Huang, N; Gibson 3rd, F C (2009) Scavenger receptor A is expressed by macrophages in response to Porphyromonas gingivalis, and participates in TNF-alpha expression. Oral Microbiol Immunol 24:456-63
Gibson 3rd, Frank C; Genco, Caroline A (2007) Porphyromonas gingivalis mediated periodontal disease and atherosclerosis: disparate diseases with commonalities in pathogenesis through TLRs. Curr Pharm Des 13:3665-75