The impact of the aging immune system on periodontal disease

项目摘要 这是丹尼尔克拉克博士申请临床科学家研究职业发展奖的申请表 （K08）。克拉克博士一直在接受培训，以使自己成为一名基础科学研究的调查员。 该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。为了追求他的职业目标，K 08奖将允许博士。 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）建立一个富有成效的， 有影响力的出版记录;（4）提高赠款写作技巧，创造成功利用过去的记录 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， 研究培训和职业发展导师方面的专业知识。主要导师Ralph Marcucio博士（专家 和共同导师玛丽中村博士（免疫学家和骨免疫学专家）将提供 在骨免疫学的基础训练，和共同导师博士Yvonne Kapila（领先的牙科科学家和 牙周基础科学研究员）将为骨免疫学应用提供专业知识和指导 牙周病的研究。此外，合作者Marina Sirota、Eben Alsberg和扫罗Villeda博士 将分别提供生物信息学、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，并与以下疾病的患病率和严重程度增加有关： 老年人群的炎症状况，包括牙周病。细胞和分子过程 调节受年龄干扰的炎症反应是未知的。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。客观 这项建议的目的是了解先天性炎症反应的关键细胞调节因子，巨噬细胞， 与间充质干细胞（MSC）和Th 17细胞相互作用，以调节骨骼中的炎症，以及这些细胞如何与骨髓基质细胞（MSC）和Th 17细胞相互作用， 随着年龄的增长，这些过程变得失调。克拉克博士将利用来自年轻和老年小鼠的原代细胞系和一种 牙周病小鼠模型研究（1）巨噬细胞和MSC相互作用的程度， 髓样细胞上表达的触发受体-2（TREM 2）下调炎症;（2） 老化的巨噬细胞表型驱动致病性Th 17细胞扩增;（3）并证明 用靶向年龄相关扰动的基于细胞的治疗剂进行免疫调节以恢复免疫 牙周病的治疗方法进一步的单细胞分析和生物信息学技术将产生 转录组学数据集，以识别与衰老和炎症相关的基因表达特征 失调该项目的发现将提高我们对骨骼免疫调节的理解， 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.