Development of resident memory T cells in the synovium

项目总结/摘要 类风湿性关节炎（RA）和幼年特发性关节炎（JIA）是关节的慢性自身免疫性疾病 并伴有周期性关节炎发作临床医生早就认识到，每个受影响的人都会发展出一种 受影响关节的个体模式，并且这种模式在疾病缓解期间随时间保持稳定， 照明弹我们最近发现关节炎关节中存在滑膜驻留记忆T细胞（TRM），并显示 它们会引起关节炎相应地，耗尽这些细胞可改善疾病复发， 表明TRM可以作为关节炎治疗的新方法。的长期目标 建议是定义滑膜中TRM发展和维持的介质，并确定这些介质是否 可以在治疗上靶向这些通路以治疗关节炎。 本提案的具体目的是在小鼠和人类研究中利用2种互补方法来确定 滑膜TRM发展的介质。Aim 1利用了一种由美国生物医学会开发的炎症性关节炎小鼠模型， PI以确定滑膜TRM的谱系和分化过程。AIM 2利用人类滑膜类器官 询问滑膜微环境（即滑膜基质细胞）对TRM的影响的系统 形成和生存。我们希望这些研究将确定TRM发展的关键介质， 可能代表炎性关节炎的新治疗靶点。 候选人是医学博士/博士波士顿儿童医院的儿科风湿病专家该提案基于 她的免疫学基础知识，以扩大她的技能到抗体偶联单细胞测序， 生物信息学、人类滑膜的类器官模型和CRISPR基因靶向。该提案包括一个 全面的指导和教学计划，使她能够成功地学习新技能并获得专业知识 在每一个重要的领域。主要导师Peter Nigrovic博士是一位流变学家和 炎症性关节炎的病理生理学。候选人组建了一个K 08咨询委员会， 博士Michael Brenner博士、Rachael Clark博士和Soumya Raychaudhuri博士，他们各自在以下方面具有特定的专业知识： 该提案的各个方面，例如单细胞测序数据的分析，人类滑膜的3D模型， 以及人类疾病中TRM生物学的专业知识。候选人致力于翻译研究的职业生涯 目标是成为一名独立的实验室研究者，专注于自身免疫性疾病的局部机制。 紊乱波士顿儿童医院的拟议研究、培训计划和特殊环境， 布里格姆妇女医院和哈佛医学院将使她能够成功地过渡到一个 独立PI和领导者在这个领域。

Project Summary/Abstract Rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA) are chronic autoimmune diseases of the joint punctuated by periodic arthritis flares. Clinicians have long recognized that each affected person develops an individual pattern of affected joints, and that this pattern remains stable over time through disease remission and flares. We recently identified the presence of synovial resident memory T cells (TRM) in arthritic joints and showed that they mediate arthritis flares. Correspondingly, depleting these cells ameliorates disease recurrence, indicating that TRM can be targeted as a novel approach in arthritis therapy. The long-term objective of the proposal is to define the mediators of TRM development and maintenance in the synovium and determine if these pathways can be therapeutically targeted to treat arthritis. The specific aims of this proposal utilize 2 complementary approaches in mice and human studies to identify the mediators of synovial TRM development. Aim 1 utilizes a mouse model of inflammatory arthritis developed by the PI to define the lineage and differentiation process of synovial TRM. Aim 2 utilizes a human synovial organoid system to interrogate the impact of the synovial microenvironment, namely synovial stromal cells, on TRM formation and survival. We expect that these studies will identify critical mediators of TRM development, which may represent novel therapeutic targets for inflammatory arthritis. The candidate is an M.D./Ph.D. pediatric rheumatologist at Boston Children’s Hospital. This proposal builds upon her foundational knowledge of immunology to extend her skillset into antibody-coupled single cell sequencing, bioinformatics, organoid models of human synovium, and CRISPR gene targeting. The proposal includes a comprehensive mentoring and didactic plan that will allow her to successfully learn new skills and gain expertise in each of these important areas. The primary mentor, Dr. Peter Nigrovic, is a rheumatologist and expert in the pathophysiology of inflammatory arthritis. The candidate has assembled a K08 advisory committee consisting of Dr. Michael Brenner, Dr. Rachael Clark, and Dr. Soumya Raychaudhuri, who each have specific expertise in various aspects of this proposal such as analysis of single-cell sequencing data, 3D models of human synovium, and expertise in TRM biology in human disease. The candidate is committed to a career in translational research with the goal of becoming an independent lab-based investigator focusing on local mechanisms to autoimmune disorders. The proposed studies, training plan, and exceptional environment at Boston Children’s Hospital, Brigham and Women’s Hospital and Harvard Medical School will enable her to successfully transition to an independent PI and leader in this field.