Development of resident memory T cells in the synovium

滑膜中常驻记忆 T 细胞的发育

• 批准号: 10427963
• 负责人: Margaret Chang
• 金额: $ 17.33万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-04 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10427963
• 关键词: 3-Dimensional; Adoptive Transfer; Advisory Committees; Affect; Antibodies; Antigens; Area; Arthralgia; Arthritis; Attenuated; Autoimmune Diseases; Bioinformatics; Biology; Boston; CD8-Positive T-Lymphocytes; CD8B1 gene; CRISPR/Cas technology; Cells; Cellular Indexing of Transcriptomes and Epitopes by Sequencing; Childhood; Chronic; Chronic Childhood Arthritis; Clustered Regularly Interspaced Short Palindromic Repeats; Coculture Techniques; Coupled; Data; Development; Disease; Disease remission; Doctor of Medicine; Doctor of Philosophy; Effector Cell; Endothelial Cells; Environment; Event; Exhibits; Fatty Acids; Fibroblasts; Flare; Foundations; Functional disorder; Funding; Future; Gene Expression; Gene Expression Profiling; Gene Targeting; Genes; Genetic Transcription; Goals; Head; Homing; Hospitals; Human; Immune; Immunology; Individual; Inflammation; Inflammatory; Inflammatory Arthritis; Institution; Interruption; Joints; Knowledge; Laboratories; Learning; Life; Ligands; Maintenance; Mediating; Mediator of activation protein; Membrane Proteins; Memory; Mentors; Mentorship; Methods; Modeling; Mus; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Organoids; Pathway interactions; Patients; Pattern; Pediatric Hospitals; Periodicity; Peripheral; Persons; Pharmaceutical Preparations; Phenotype; Physicians; Population; Process; RUNX3 gene; Recurrence; Research Personnel; Resistance; Resources; Rheumatoid Arthritis; Role; Scientist; Series; Signal Transduction; Site; Sterility; Stromal Cells; Surface; Synovial Membrane; System; T memory cell; T-Cell Receptor; T-Lymphocyte; TGFBR2 gene; Testing; Therapeutic; Time; Tissue-Specific Gene Expression; Tissues; Training; Translational Research; Woman; Work; arthritis therapy; arthropathies; base; career; chemokine; chronic autoimmune disease; confocal imaging; design; disorder control; experience; human disease; human model; immune activation; insight; joint inflammation; lymph nodes; mRNA Expression; medical schools; migration; mouse model; new therapeutic target; novel strategies; novel therapeutics; prevent; protein expression; ranpirnase; receptor; recruit; residence; rheumatologist; single cell analysis; single cell sequencing; single-cell RNA sequencing; skills; therapeutic target; three-dimensional modeling; transcriptomics; uptake

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.

项目概要/摘要 类风湿性关节炎（RA）和幼年特发性关节炎（JIA）是慢性自身免疫性关节疾病 间或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出现一种 受影响关节的个体模式，并且这种模式随着时间的推移通过疾病缓解和恢复保持稳定 耀斑。我们最近发现关节炎关节中存在滑膜驻留记忆 T 细胞 (TRM)，并表明 他们介导关节炎发作。相应地，消耗这些细胞可以改善疾病复发， 表明 TRM 可以作为关节炎治疗的新方法。该组织的长期目标 建议定义滑膜中 TRM 发展和维护的调节因子，并确定这些调节因子是否 可以针对治疗关节炎的途径进行治疗。 该提案的具体目标是利用小鼠和人类研究中的两种互补方法来确定 滑膜 TRM 发育的介质。目标 1 利用由该公司开发的炎症性关节炎小鼠模型 PI 定义滑膜 TRM 的谱系和分化过程。目标 2 利用人类滑膜类器官 系统询问滑膜微环境（即滑膜基质细胞）对 TRM 的影响 形成和生存。我们期望这些研究将确定 TRM 发展的关键介质， 可能代表炎症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学家。该提案建立在 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、人类滑膜类器官模型和 CRISPR 基因靶向。该提案包括 全面的指导和教学计划将使她能够成功学习新技能并获得专业知识 在每个重要领域。主要导师 Peter Nigrovic 博士是一位风湿病学家和专家 炎症性关节炎的病理生理学。候选人组建了一个 K08 咨询委员会，成员包括 Michael Brenner 博士、Rachael Clark 博士和 Soumya Raychaudhuri 博士在以下领域均拥有特定的专业知识： 该提案的各个方面，例如单细胞测序数据分析、人类滑膜 3D 模型、 以及人类疾病 TRM 生物学方面的专业知识。候选人致力于转化研究事业 目标是成为一名独立的实验室研究者，专注于自身免疫的局部机制 失调。波士顿儿童医院拟议的研究、培训计划和特殊环境， 布莱根妇女医院和哈佛医学院将使她能够成功过渡到 独立PI和该领域的领导者。