The impact of the aging immune system on periodontal disease

免疫系统老化对牙周病的影响

• 批准号: 10471993
• 负责人: Daniel R. Clark
• 金额: $ 16.61万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-17 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10471993
• 关键词: Adult; Affect; Age; Aging; Award; Basic Science; Bioinformatics; Biological; Biology; Biology of Aging; Cell Line; Cell Therapy; Cells; Clinical; Coculture Techniques; Data; Data Set; Dentists; Disease; Disease Progression; Down-Regulation; Elderly; Epithelial Cells; Foundations; Gene Expression Profile; Genetic; Genetic Transcription; Gingiva; Goals; Grant; IL17 gene; Immune; Immune System Diseases; Immune response; Immune system; Immunologist; Infection; Inflammation; Inflammation Mediators; Inflammation Process; Inflammatory; Inflammatory Response; Injury; Innate Immune Response; Interleukin-6; Investigation; K-Series Research Career Programs; Mediating; Mentors; Mentorship; Mesenchymal Stem Cells; Methods; Molecular; Molecular Target; Mus; Pathogenesis; Pathogenicity; Pathologic; Periodontal Diseases; Periodontitis; Pharmacology; Phenotype; Population; Predisposition; Prevalence; Process; Production; Publications; Regulation; Research; Research Personnel; Research Training; Resolution; Scientist; Severities; Severity of illness; Signal Transduction; T-Lymphocyte; TREM2 gene; Techniques; Testing; Tooth structure; Training; Work; Writing; age effect; age related; aged; bone; career; career development; cell age; cellular targeting; clinically significant; cost; cytokine; healing; immunomodulatory strategy; immunomodulatory therapies; immunoregulation; improved; innovation; interleukin-23; macrophage; mouse model; negative affect; new therapeutic target; novel; osteoimmunology; prevent; programs; response; single cell analysis; skills; therapeutic target; transcriptomics

Project Summary This is an application for Dr. Daniel Clark for a Mentored Clinical Scientist Research Career Development Award (K08). 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. Primary mentor Dr. Ralph Marcucio (expert in bone biology) and co-mentor Dr. Mary Nakamura (immunologist and expert in osteoimmunology) will provide foundational training in osteoimmunology, and co-mentor Dr. Yvonne Kapila (leading dentist-scientist and periodontal basic science researcher) will provide expertise and guidance for osteoimmunological applications to periodontal disease research. In addition, collaborators Drs. Marina Sirota, Eben Alsberg, and Saul Villeda will provide their expertise of bioinformatics, cell-based therapeutics, and aging biology respectively. 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.

项目总结