The goal of this study is to understand the mechanisms underlying how cell endogenous signaling regulates chronic inflammation and bone loss in periodontitis. Periodontitis is one of the most common inflammatory diseases in humans that results in the destruction of periodontal tissues and alveolar bone, which ultimately lead to teeth loss. It is estimated that majority of adults over the age of 30 suffer from periodontal bone loss. Also, growing evidence suggests that chronic periodontal inflammation is an important risk factor for several pathological disorders including cardiovascular disease, diabetes, atherosclerosis and arthritis. Hence, there is an urgent need to develop novel and efficient therapeutic approaches to treat periodontal disease. Current therapy is hindered by lack of understanding of the mechanisms underlying how cell endogenous positive and negative signaling changes result in the reduction of periodontal tissues functional capacity and contribute to increased incidence of periodontal disease. In our preliminary studies, we found that G?13f/fLysM-Cre mice exhibited severe bone loss with a significant increase in OC number, and marked periodontal ligament (PDL) damage in periodontal disease lesions. We also found overexpression of local G?13 constitutively active form (G?13CA) resulted in reduced periodontal bone loss and inflammation and repaired PDL. Importantly, we demonstrated that G?13 deficiency promoted nuclear factor kappa B (NF-?B) activation through downregulated RhoA and upregulated AKT activity, and that AAV-mediated G?13 overexpression could effectively reduce inflammation with decreased T cells and dendritic cells. Based on our preliminary studies, we hypothesize that Endogenous negative regulators of macrophages, dendritic cells and osteoclasts attenuates periodontitis-induced chronic inflammation and bone loss through the G?13/RhoA/AKT/IKK/NF-?B pathway, and G?13 signaling reduces the risk for periodontal disease.
Three specific aims are proposed to test our hypothesis.
In Aim 1, we will determine the function of G?13 in macrophages, dendritic cells, and OCs in periodontal inflammation and alveolar bone loss in periodontitis by characterizing the phenotypes and pathomechanism through loss-of-function studies.
In Aim 2, we will define the function of G?13 signaling on periodontal inflammation and alveolar bone loss by characterizing the phenotypes and pathomechanism through gain-of-function studies. We will dissect the molecular mechanism of the G?13 signaling function in regulating periodontal inflammation and tissue and bone loss in periodontitis through G?13/RhoA/AKT/IKK/NF- ?B pathway in macrophages, dendritic cells, and OCs in Aim 3. The proposed study will provide important insights into understand the mechanisms underlying how cell endogenous signaling regulates chronic inflammation and bone loss in periodontitis by elucidating the underlying mechanism of G?13 signaling. Insights gained from this study may provide foundation for the ultimate goal of facilitating the design of novel therapeutic approach for periodontal and osteolytic diseases.
Periodontal disease is inefficiently tackled by current therapeutics due to low response rates and adverse side effects; hence, there is an urgent need to develop novel and efficient therapeutic approaches to treat periodontal disease. The proposed study will provide important insights into the negative regulation of bone resorption and inflammation in periodontitis by elucidating the underlying mechanism of G?13 signaling. Hence, the immediate findings of the study will indeed further our understanding of negative regulatory signals in inflammation response and OC activity, and insights gained from this study may also provide foundation for the ultimate long-term goal of facilitating the design of novel therapeutic approach for periodontal and osteolytic diseases.
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