Development of resident memory T cells in the synovium

项目摘要/摘要 类风湿关节炎(RA)和幼年特发性关节炎(JIA)是关节的慢性自身免疫性疾病 不时会出现周期性的关节炎症状。临床医生早就认识到，每个受影响的人都会发展成 受影响关节的个体模式，并且这种模式在疾病缓解和 照明弹。我们最近发现了关节炎关节中滑膜驻留记忆T细胞(TRM)的存在，并显示 它们调节了关节炎的发作。相应地，消耗这些细胞可以改善疾病的复发， 提示TRM可作为治疗关节炎的一种新方法。该计划的长远目标 建议定义滑膜中TRM发育和维持的介质，并确定这些介质是否 这些途径可以在治疗上有针对性地治疗关节炎。 这项建议的具体目标是在小鼠和人体研究中利用两种互补的方法来确定 滑膜TRM发育的介体。Aim 1利用由 PI以确定滑膜TRM的谱系和分化过程。Aim 2利用一种人类滑膜有机物质 用于询问滑膜微环境，即滑膜基质细胞对TRM的影响的系统 形成和生存。我们预计，这些研究将确定TRM发展的关键中介因素， 可能是炎症性关节炎的新治疗靶点。 候选人是波士顿儿童医院的医学博士/博士儿科风湿病专家。这项建议的基础是 她的免疫学基础知识将她的技能扩展到抗体偶联单细胞测序， 生物信息学、人体滑膜器官模型和CRISPR基因打靶。该提案包括一项 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 在这些重要领域中的每一个。主要导师彼得·尼格罗维奇博士是一位风湿病专家，也是 炎症性关节炎的病理生理学。候选人已经组建了一个K08咨询委员会，委员会成员包括 迈克尔·布伦纳博士、瑞切尔·克拉克博士和苏米亚·雷乔杜里博士，他们各自在 这一建议的各个方面，例如单细胞测序数据的分析，人体滑膜的3D模型， 在人类疾病的TRM生物学方面的专业知识。应聘者致力于翻译研究事业 目标是成为一名独立的实验室研究人员，专注于自身免疫的局部机制 精神错乱。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成功过渡到 独立的PI和该领域的领导者。

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.