The role in vivo of Phospholipase A2-IIA (PLA2-IIA) and Notch-1 in the pathogenesis of periodontal disease remain unknown. In this study, using different transgenic and knockout mouse models we seek to validate in vivo the effect of PLA2-IIA and Notch-1 in oral dysbiosis, gingival immunoinflammatory responses, and alveolar bone loss.
(i) To determine the role of PLA2-IIA in Pg-induced oral dysbiosis, inflammation and periodontal disease.(ii) To determine the role of epithelial Notch-1 in Pg-induced PLA2-IIA and periodontitis.(iii) To identify and validate oral epithelial innate responses modulated by Pg through Notch-1 activation.The ongoing studies proposed in this project are a natural extension of our recent findings, which aim to validate in vivo, the role of the Notch-1/PLA2-IIA axis as a potential mechanism for oral dysbiosis and periodontal disease. In addition, these studies will elucidate the impact of Pg-induced N1R activation in Oral epithelial cells (OECs) (besides PLA2-IIA), as an innovative pathway contributing to interfering with host-bacteria homeostatic interactions. We will use the Pg-induced periodontitis oral gavage and ligature models in WT and PLA2-IIA deficient mice, the hPLA2-IIA-Tg mice with their WT littermates, epithelial-specific N1R-deficient mice, as well as OEC cultures to test these hypotheses.
In vivo validation of the role of PLA2-IIA and Notch-1 in the pathogenesis of periodontal disease would provide an important foundation for future pre-clinical studies modulating this pathway as a potential new alternative of host modulation to prevent/treat periodontitis. Moreover, given the demonstrated role of these proteins in other chronic inflammatory diseases such as Cardiovascular Disease, Rheumatoid Arthritis, Alzheimer's Disease, and cancer, positive findings could open new mechanistic pathways that can explain the link between periodontitis and systemic disease.
The study is funded by the National Institute of Health (NIH) and the National Institute of Dental and Craniofacial Research (NIDCR). Grant: DE029498