The impact of the aging immune system on periodontal disease

项目摘要 这是对现有临床科学家导师研究项目的行政补充申请 授予Daniel Clark博士职业发展奖(K08)。克拉克博士一直在接受训练以确立自己的地位 作为一名骨免疫学基础科学研究的研究员，这一奖项将为克拉克博士提供 为实现成为一名独立研究人员的职业目标所需的支持和机会。为了追求 他的职业目标，K08奖将使克拉克博士：(1)成为骨免疫学专家；(2)发展 通过新的骨免疫学应用于骨质疏松症研究的独立研究计划 牙周病；(3)创造有成效和有影响力的出版记录；(4)提高赠款的撰写技巧和 创建成功利用过去和当前奖励的记录。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，提供他们在研究、培训和职业指导方面的专业知识 发展。免疫系统功能障碍随着年龄的增长而增加，并与发病率的增加有关 老年人群中炎症状况的严重性，包括牙周病。蜂窝和 调节炎症反应的分子过程因年龄的变化而变得未知。克拉克医生的 长期目标是确定牙周免疫调节治疗的细胞和分子靶点。 疾病。这项提议的目的是了解先天炎症的一个关键细胞调节因子 巨噬细胞与间充质干细胞(MSCs)和Th17细胞相互作用，调节炎症 以及这些过程如何随着年龄的增长而变得失调。克拉克博士将利用来自 小鼠和老年小鼠及牙周病小鼠模型的研究(1)巨噬细胞 而MSCs通过触发髓系细胞上表达的受体-2(TREM2)下调表达而相互作用 炎症；(2)老化的巨噬细胞表型驱动致病性Th17细胞扩张的程度； (3)并演示了针对年龄相关的细胞疗法的免疫调节效果 使牙周病患者的免疫反应恢复活力的扰动。进一步的单细胞分析和 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签名 与衰老和炎症性失调有关。这个项目的发现将提高我们对免疫的理解 骨的调节，引入新的治疗靶点，并为克拉克博士提供一项新的独立研究 程序。

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.