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: 10768043
• 负责人: Daniel R. Clark
• 金额: $ 1.87万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10768043
• 关键词: Administrative Supplement; Age; Aging; Award; Basic Science; Bioinformatics; Cell Communication; Cell Line; Cell Therapy; Cells; Clinical; Data Set; Disease; Elderly; Gene Expression Profile; Goals; Grant; Immune System Diseases; Immune response; Immune system; Inflammation; Inflammatory; Inflammatory Response; Injury; Innate Immune Response; Investigation; K-Series Research Career Programs; Macrophage; Mentors; Mentorship; Mesenchymal Stem Cells; Molecular; Molecular Target; Mus; Pathogenicity; Periodontal Diseases; Phenotype; Population; Predisposition; Prevalence; Process; Productivity; Publications; Regulation; Rejuvenation; Research; Research Personnel; Research Training; Scientist; Severities; TREM2 gene; Techniques; Training; Writing; age related; aged; bone; career; career development; cellular targeting; healing; immunomodulatory therapies; immunoregulation; improved; mouse model; new therapeutic target; novel; osteoimmunology; prevent; programs; single cell analysis; skills; therapeutic target; transcriptomics

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.

项目概要 这是对现有指导临床科学家研究的行政补充申请 授予 Daniel Clark 博士的职业发展奖 (K08) Clark 博士一直在接受培训以确立自己的地位。 作为骨免疫学基础科学研究的研究者，该奖项将为克拉克博士提供 实现成为一名独立研究员的职业目标所需的支持和机会。 根据他的职业目标，K08 奖将使 Clark 博士能够：(1) 成为骨免疫学专家；(2) 发展； 通过骨免疫学的新颖应用来研究的独立研究计划 牙周病；(3) 创造富有成效且有影响力的发表记录；(4) 提高拨款写作技巧； 为了实现他的职业目标，克拉克博士创造了成功利用过去和当前奖项的记录。 建立了一个跨学科团队，提供研究培训和职业指导方面的专业知识 免疫系统功能障碍随着年龄的增长而增加，并且与患病率的增加有关。 以及老年人炎症状况的严重程度，包括牙周病。 克拉克博士的调节因年龄而受到干扰的炎症反应的分子过程尚不清楚。 长期目标是确定牙周免疫调节治疗的细胞和分子靶点 该提案的目的是了解先天性炎症的关键细胞调节因子。 巨噬细胞与间充质干细胞 (MSC) 和 Th17 细胞相互作用，调节炎症 克拉克博士将利用来自骨骼的原代细胞系来研究这些过程如何随着年龄的增长而失调。 年轻和年老小鼠以及牙周病小鼠模型以研究（1）巨噬细胞的程度 和 MSC 通过触发髓样细胞 2 (TREM2) 上表达的受体相互作用来下调 炎症；(2) 衰老的巨噬细胞表型驱动致病性 Th17 细胞扩增的程度； (3) 并证明针对年龄相关的基于细胞的疗法的免疫调节效果 进一步的单细胞分析和扰动以恢复牙周病的免疫反应。 生物信息学技术将产生转录组数据集来识别相关的基因表达特征 该项目的研究结果将提高我们对免疫的理解。 骨骼调节，引入新的治疗靶点，并为克拉克博士提供新颖的独立研究 程序。

项目成果

Periodontal disease as a model to study chronic inflammation in aging.

牙周病作为研究衰老过程中慢性炎症的模型。

• DOI: 10.1007/s11357-023-00835-0
• 发表时间: 2023-06-07
• 期刊: GeroScience
• 影响因子: 5.6
• 作者: M. Bertolini;D. Clark
• 通讯作者: D. Clark

Age-related decrease in periostin expression may be associated with attenuated fracture healing in old mice.

与年龄相关的骨膜素表达下降可能与老年小鼠骨折愈合减弱有关。

• 发表时间: 2023-05
• 作者: Clark, Daniel;Doelling, Jeffrey;Hu, Diane;Miclau, Theodore;Nakamura, Mary;Marcucio, Ralph
• 通讯作者: Marcucio, Ralph

The Contribution of Macrophages in Old Mice to Periodontal Disease.

老年小鼠巨噬细胞对牙周病的贡献。

• 发表时间: 2021-11
• 影响因子: 7.6
• 作者: Clark, D;Halpern, B;Miclau, T;Nakamura, M;Kapila, Y;Marcucio, R
• 通讯作者: Marcucio, R

Frailty, aging, and periodontal disease: Basic biologic considerations.

虚弱、衰老和牙周病：基本的生物学考虑。

• DOI: 10.1111/prd.12380
• 发表时间: 2021-10
• 期刊: Periodontology 2000
• 影响因子: 18.6
• 作者: Clark D;Kotronia E;Ramsay SE
• 通讯作者: Ramsay SE