The goal of this study is to understand the mechanisms underlying how cell endogenous signaling regulates chronic inflammation and bone loss in aging-associated 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 results in teeth loss, especially in aged population, and potentially manifests into systemic conditions. Periodontal disease is inefficiently tackled by current therapeutics due to low response rates and adverse side effects presenting a significant challenge in the aging population. However, the mechanism underlying the role of G?13 in inflammation diseases, including periodontal disease, especially under physiological aging and pathological periodontitis, as well as the molecular mechanism by which G?13 regulates periodontal inflammation remains unknown. Current therapy is hindered by lack of understanding of the mechanisms underlying how physiological changes result in an age-associated reduction of periodontal tissues tissue functional capacity and contribute to increased incidence of periodontal disease. In our preliminary studies we found that the expression of G?13) significantly decreases as mice age increases, and we revealed that Gna13f/fLysM-Cre mice exhibited severe bone loss with a significant increase in OC number, and PDL damage in periodontal disease lesions. We also found exacerbated alveolar bone loss and PDL damage associated with Gna13 deficiency in a periodontitis-induced model, while overexpression of local Gna13 constitutively active form (Gna13CA) resulted in reduced periodontal bone loss and inflammation and repaired PDL. Based on our preliminary studies, we hypothesize that G?13 is a master negative regulator that inhibits periodontitis-induced chronic inflammation and bone loss through G?13/RhoA/AKT/IKK/NF-?B pathway and the increased G?13 activate and signaling reduce the risk for age-associated periodontal disease.
Three specific aims are proposed to test our hypothesis.
In Aim 1, we will determine the function of G?13 deficiency in monocytes on exacerbating periodontal inflammation and cementum, periodontal ligament (PDL), and alveolar bone loss by characterizing the phenotypes and pathomechanism of conditional knockout mouse models in aging-associated periodontitis.
In Aim 2, we will define the function of G?13 in monocytes on attenuating periodontal inflammation and periodontal ligament, cementum, and alveolar bone loss by characterizing the phenotypes and pathomechanism of Gna13OE transgenic mouse models and AAV mediated G?13 local overexpression in aging-associated periodontitis. We will dissect the molecular mechanism by which G?13 regulates periodontal inflammation and periodontal tissue and bone loss in age-associated periodontitis through G?13/RhoA/AKT/IKK/NF-?B, and integrins signaling pathways. The proposed study will provide important insights into the negative regulation of bone resorption and inflammation in aged-associated periodontitis by elucidating the underlying mechanism of G?13 signaling.
Periodontal disease is inefficiently tackled by current therapeutics due to low response rate and adverse side effects presenting a significant challenge in the aging population. The proposed study will provide important insights into the negative regulation of bone resorption and inflammation in age-associated 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, especially in sex- and age-associated periodontal disease, 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.
