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.

项目概要 这是丹尼尔·克拉克博士申请指导临床科学家研究职业发展奖的申请 （K08）。克拉克博士一直在接受培训，以确立自己作为基础科学研究的研究者的地位。 骨免疫学，该奖项将为克拉克博士提供实现目标所需的支持和机会 他的职业目标是成为一名独立研究员。为了追求他的职业目标，K08 奖将让 Dr. 克拉克要：（1）成为骨免疫学专家； (2) 制定独立的研究计划 骨免疫学在牙周病研究中的新应用； (3) 创造富有成效的 有影响力的发表记录； (4) 提高补助金写作技巧并创造成功利用过去补助金的记录 以及当前的奖项。为了实现他的职业目标，克拉克博士建立了一个跨学科团队，为他们提供帮助 研究培训和职业发展指导方面的专业知识。主要导师Ralph Marcucio博士（专家 骨生物学博士）和联合导师 Mary Nakamura 博士（免疫学家和骨免疫学专家）将提供 骨免疫学基础培训，共同导师 Yvonne Kapila 博士（领先的牙医科学家和 牙周基础科学研究人员）将为骨免疫学应用提供专业知识和指导 到牙周病研究。此外，合作者博士。玛丽娜·西罗塔、埃本·阿尔斯伯格和索尔·维莱达 将分别提供生物信息学、细胞疗法和衰老生物学方面的专业知识。免疫 系统功能障碍随着年龄的增长而增加，并且与患病率和严重程度的增加有关 老年人群的炎症，包括牙周病。细胞和分子过程 调节因年龄而受到干扰的炎症反应尚不清楚。克拉克博士的长期目标是 确定牙周病免疫调节治疗的细胞和分子靶点。目标 该提案的目的是了解先天炎症反应的关键细胞调节剂巨噬细胞如何 与间充质干细胞 (MSC) 和 Th17 细胞相互作用，调节骨中的炎症以及这些细胞如何 随着年龄的增长，这些过程变得失调。克拉克博士将利用年轻和年老小鼠的原代细胞系和 牙周病小鼠模型研究（1）巨噬细胞和间充质干细胞通过以下方式相互作用的程度 触发髓样细胞 2 (TREM2) 上表达的受体来下调炎症； (2) 程度 衰老的巨噬细胞表型驱动致病性 Th17 细胞扩张； (3) 并演示效果 使用基于细胞的疗法进行免疫调节，针对与年龄相关的干扰，以恢复免疫功能 牙周病的反应。进一步的单细胞分析和生物信息学技术将产生 用于识别与衰老和炎症相关的基因表达特征的转录组数据集 失调。该项目的研究结果将提高我们对骨骼免疫调节的理解，介绍 新的治疗目标，并为克拉克博士提供了一个新颖的独立研究计划。