The impact of the aging immune system on periodontal disease

项目摘要 这是Daniel Clark博士申请临床科学家导师研究职业发展奖的申请书 (K08)。克拉克博士一直在接受培训，以确立自己作为一名基础科学研究人员的地位 这一奖项将为克拉克博士提供必要的支持和机会，以达到 他的职业目标是成为一名独立研究员。在追求他的职业目标的过程中，K08奖将允许Dr。 克拉克：(1)成为骨免疫学专家；(2)通过以下方式发展独立的研究计划 骨免疫学在牙周病研究中的新应用；(3)创造一个多产和 有影响力的出版记录；(4)提高赠款撰写技能，创造成功利用过去的记录 以及目前的奖项。为了实现他的职业目标，克拉克博士建立了一个跨学科的团队，为他们提供 在研究、培训和职业发展指导方面的专业知识。主要导师拉尔夫·马尔库西奥博士(专家 和共同导师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，共同导师伊冯·卡皮拉博士(领先的牙医兼科学家和 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 对牙周病的研究。此外，合作者玛丽娜·西罗塔博士、埃本·阿尔斯伯格博士和索尔·维尔达博士 将分别提供他们在生物信息学、细胞治疗学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，并与增加的患病率和严重程度有关 老年人群的炎症状况，包括牙周病。细胞和分子过程 调控因年龄增长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。目标是 这一建议的目的是了解先天炎症反应的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，调节骨骼的炎症，以及这些 随着年龄的增长，这些过程会变得不受控制。克拉克博士将利用小鼠和老年小鼠的原代细胞系和一种 牙周病小鼠模型研究(1)巨噬细胞与间充质干细胞相互作用的程度 触发髓样细胞上表达的受体-2(TREM2)下调炎症；(2) 衰老的巨噬细胞表型驱动致病性Th17细胞的增殖；(3)并展示了 针对与年龄相关的干扰以恢复免疫的细胞疗法的免疫调节 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 识别与衰老和炎症相关的基因表达特征的转录数据集 监管失调。这个项目的发现将提高我们对骨骼免疫调节的理解，介绍 新的治疗靶点，并为克拉克博士提供了一个新的独立研究计划。

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.