Periodontal disease initiation and progression occurs as a consequence of the host immune inflammatory response to oral pathogens. The production of inflammatory cytokines is a highly regulated process involving transcriptional and post transcriptional mechanisms. At the post transcriptional level, the presence of adenosine/uridine-rich elements (AREs) in the 3'untranslated region of many cytokine genes, including IL-6, TNF1, and COX-2, targets the mRNA for rapid degradation. As a consequence, cytokine production is repressed. 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. We have recently shown that LPS-induced bone loss in vivo requires p38 signaling in experimental periodontitis. Preliminary data for this proposal indicates that when MK2 is silenced through siRNA significant reduction in LPS-induced cytokine expression is observed. Based upon these data, we hypothesize that selective knockdown of MK2 may offer significant therapeutic benefit in inflammatory periodontal diseases. In this proposal, MK2 siRNA will be evaluated to decrease inflammation in vitro using gene-targeted strategies in macrophages, and in vivo using experimental periodontitis models.
The Specific Aims are: 1) validation of MK2 silencing in cytokine production and posttranscriptional regulation;and 2) in vivo evaluation of MK2 knockdown in an experimental periodontitis model. These studies will determine if siRNA to MK2 can be delivered intraorally as a novel therapeutic that selectively targets cytokine mRNA stability in inflammatory bone loss. Upon accomplishment of these aims, subsequent studies will address optimization of MK2 siRNA, a therapeutic strategy to control periodontal bone loss in infectious animal models of periodontitis. Project Narrative: Periodontal disease progression occurs as a consequence of the host immune inflammatory response to oral pathogens. These studies will establish the role of host immune proteins termed cytokines and the regulation of cytokines by selectively silencing a key signaling molecule needed to mediate inflammatory cytokine mRNA stability. Using established small animal models of experimental periodontitis, we will evaluate the ability of silencing this signaling protein for therapeutic benefit. Progress in understanding the role of posttranscriptional cytokine regulation in periodontal inflammation and bone loss may yield new possibilities for treatment of periodontal diseases and other chronic inflammatory diseases.
| Van Tubergen, Elizabeth; Vander Broek, Robert; Lee, Julia et al. (2011) Tristetraprolin regulates interleukin-6, which is correlated with tumor progression in patients with head and neck squamous cell carcinoma. Cancer 117:2677-89 |
| Li, Qiyan; Yu, Hong; Zinna, Robert et al. (2011) Silencing mitogen-activated protein kinase-activated protein kinase-2 arrests inflammatory bone loss. J Pharmacol Exp Ther 336:633-42 |
| Sartori, R; Li, F; Kirkwood, K L (2009) MAP kinase phosphatase-1 protects against inflammatory bone loss. J Dent Res 88:1125-30 |
| Kirkwood, Keith L; Rossa Jr, Carlos (2009) The potential of p38 MAPK inhibitors to modulate periodontal infections. Curr Drug Metab 10:55-67 |
