The overall goal of this project is to elucidate interacting endogenous anti-inflammatory pathways that can be harnessed to suppress an over-exuberant host response to periodontal bacteria and other pathogens. Bacteria are initially recognized by Toll-like receptors (TLRs) and other pathogen recognition receptors expressed on innate cells. TLR interaction with microbe-specific molecular patterns induces the innate production of pro- inflammatory cytokines, which direct the intensity and direction of the immune response, leads to recruitment of leukocytes to the site of infection, and the production of an arsenal of anti-bacterial molecules, many of which have the potential to cause the collateral tissue damage that defines destructive inflammatory diseases. There are at least three endogenous anti-inflammatory pathways. The first life cycle of DE017680 focused on the in vitro elucidation of the PI3K/ AKT anti-inflammatory pathway, the key role of GSK3b in this signaling cascade, and the mechanisms by which this pathway regulates the expression of IFNb, IL-1Ra, IL-10 in innate cells in addition to controlling T cell development and proliferation. In addition o the PI3K/ AKT cascade, this renewal will also consider the a7 nicotinic acetylcholine receptor-dependent cholinergic and the Wnt3a anti- inflammatory pathways. Crosstalk between these three pathways will be elucidated, with particular attention paid to the pivotal role of the centra inflammatory mediator, GSK3b, in pathway convergence. While each pathway is efficacious in its own right, therapeutic interventions that maximize the anti-inflammatory potential of convergent signaling events are likely to be particularly potent. To this end, anti-inflammatory signaling events will be exploited using murine models of inflammation (sub-cutaneous chamber) and periodontitis (alveolar bone loss). Therefore, this project will lay the groundwork for the development of novel approaches to the treatment of periodontitis and other inflammatory diseases and identify therapeutic targets that should be readily translatable.
It is the host response to dental plaque that leads to the development of periodontitis, one of the most common infectious diseases in humans that consumes >$14 billion dollars in health costs in the U.S. per annum. We will identify overlapping events between several endogenous mechanisms of inflammatory suppression (the PI3K/AKT/GSK3b; cholinergic; and Wnt3a anti-inflammatory pathways); elucidate specific mechanisms that suppress pro-inflammatory cytokine production in response to bacterial infection; determine anti-inflammatory events that control the release of tissue degrading matrix metalloproteinases; and establish if we can exploit these anti-inflammatory pathways to reduce inflammation and periodontal disease progression in murine models. These data will identify novel potential therapeutic approaches to the control of destructive inflammation.
|Gu, Zhen; Lamont, Gwyneth J; Lamont, Richard J et al. (2016) Resolvin D1, resolvin D2 and maresin 1 activate the GSK3Î² anti-inflammatory axis in TLR4-engaged human monocytes. Innate Immun 22:186-95|
|Yin, Hui; Zhou, Huaxin; Kang, Yi et al. (2016) Syk negatively regulates TLR4-mediated IFNÎ² and IL-10 production and promotes inflammatory responses in dendritic cells. Biochim Biophys Acta 1860:588-98|
|Wang, Huizhi; Graves 2nd, Mark W; Zhou, Huaxin et al. (2016) 2-Amino-4-(3,4-(methylenedioxy)benzylamino)-6-(3-methoxyphenyl)pyrimidine is an anti-inflammatory TLR-2, -4 and -5 response mediator in human monocytes. Inflamm Res 65:61-9|
|Goulas, T; Garcia-Ferrer, I; Hutcherson, J A et al. (2016) Structure of RagB, a major immunodominant outer-membrane surface receptor antigen of Porphyromonas gingivalis. Mol Oral Microbiol 31:472-485|
|Hutcherson, J A; Gogeneni, H; Yoder-Himes, D et al. (2016) Comparison of inherently essential genes of Porphyromonas gingivalis identified in two transposon-sequencing libraries. Mol Oral Microbiol 31:354-64|
|Hutcherson, J A; Bagaitkar, J; Nagano, K et al. (2015) Porphyromonas gingivalis RagB is a proinflammatory signal transducer and activator of transcription 4 agonist. Mol Oral Microbiol 30:242-52|
|Zhou, Huaxin; Gao, Shegan; Duan, Xiaoxian et al. (2015) Inhibition of serum- and glucocorticoid-inducible kinase 1 enhances TLR-mediated inflammation and promotes endotoxin-driven organ failure. FASEB J 29:3737-49|
|Wang, Qian; Sztukowska, Maryta; Ojo, Akintunde et al. (2015) FOXO responses to Porphyromonas gingivalis in epithelial cells. Cell Microbiol 17:1605-17|
|Hutcherson, Justin A; Scott, David A; Bagaitkar, Juhi (2015) Scratching the surface - tobacco-induced bacterial biofilms. Tob Induc Dis 13:1|
|Zhou, Yun; Sztukowska, Maryta; Wang, Qian et al. (2015) Noncanonical activation of Î²-catenin by Porphyromonas gingivalis. Infect Immun 83:3195-203|
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