The impact of the aging immune system on periodontal disease

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Project Summary This is an application for an administrative supplement to an existing Mentored Clinical Scientist Research Career Development Award (K08) awarded to Dr. Daniel Clark. Dr. Clark has been training to establish himself as an investigator in basic science research of osteoimmunology, and this award will provide Dr. Clark with the support and opportunities necessary to reach his career goal of being an independent researcher. In pursuit of his career goal, the K08 award will allow Dr. Clark to: (1) to become an expert in osteoimmunology; (2) develop an independent research program through novel application of osteoimmunology to the investigation of periodontal disease; (3) create a productive and impactful publication record; (4) enhance grant writing skills and create a record of successful utilization of past and current awards. Towards his career goal, Dr. Clark has established a transdisciplinary team to provide their expertise in research training and mentorship in career development. Immune system dysfunction increases with age and is associated with an increased prevalence and severity of inflammatory conditions in elderly populations, including periodontal disease. The cellular and molecular process regulating the inflammatory response that become perturbed by age are unknown. Dr. Clark’s long term goal is to identify cellular and molecular targets for immunomodulatory treatment of periodontal disease. The objective of this proposal is to understand how a key cellular regulator of the innate inflammatory response, macrophages, interacts with mesenchymal stem cells (MSCs) and Th17 cells, to regulate inflammation in bone and how these processes become dysregulated with age. Dr. Clark will utilize primary cell lines from young and old mice and a periodontal disease mouse model to investigate (1) the extent to which macrophages and MSCs interact through triggering receptor expressed on myeloid cells-2 (TREM2) to downregulate inflammation; (2) the extent to which an aged macrophage phenotype drives pathogenic Th17 cell expansion; (3) and demonstrate the effect of immunomodulation with cell-based therapeutics that target age-related perturbations to rejuvenate the immune response in periodontal disease. Further single cell analysis and bioinformatics techniques will produce transcriptomic datasets to identify gene expression signatures associated with aging and inflammatory dysregulation. Findings from this project will improve our understanding of immune regulation in bone, introduce novel targets for therapy, and provide Dr. Clark with a novel independent research program.