Research: With advancing age, the immune system undergoes dynamic changes characterized by both impairment of adaptive immunity and activation of low-grade chronic inflammation. This chronic activation of inflammation associated with aging or `inflammaging'. Tristetraprolin (TTP) is an RNA binding protein that post- translationally binds to adenylate-uridylate?rich elements in the 3?-UTR of target mRNAs (including key pro- inflammatory mRNAs e.g. TNF?, COX-2 and IL-6) to promote their rapid turnover. Importantly, the project laboratory has demonstrated that failure to regulate expression of cytokines at the posttranscriptional level contributes to chronic inflammation and spontaneous alveolar bone loss with age in TTP-/- mice compared to age/sex match controls. Thus, TTP expression appears to be essential for alveolar bone homeostasis in an age- dependent manner. Data in this application and recently published data strongly support the concept that macrophages and myeloid-derived suppressor cell (MDSC) populations are expanded with age in TTP-/- mice, with concomitant reduction in lymphocyte populations. Taken together, these results support the notion that TTP may be a critical intrinsic factor of inflammaging and myeloid lineage expansion/differentiation that contributes towards skeletal homeostasis. For this K18 application, it is proposed to use data sets generated already under 5R01DE028258, to examine the role of the microbiome in contributing towards the TTP null hyperinflammatory phenotype and understand if MDSC populations from oral and non-oral sources have different expression profiles by single cell RNA sequencing. Fellowship training plan/environment: The applicant has assembled a strong mentoring team who have a long history of working together and training scientists to become successful independent investigators. The proposed project will allow the applicant to integrate his translation research portfolio with bioinformatics, which will foster the perspectives and skills necessary to continue to be a successful oral biologist.
Periodontal disease progression occurs as a consequence of the host immune inflammatory response to oral pathogens. Progress in understanding the role of posttranscriptional cytokine regulation in periodontal inflammation and bone loss may yield new possibilities for treatment of periodontal diseases. Development of bioinformatic approaches to address questions related to post transcriptional regulation of intra- and extra-oral bone homeostasis will be gained at the end of these studies.
