Development of resident memory T cells in the synovium

滑膜中常驻记忆 T 细胞的发育

基本信息

批准号：
10601115
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
项目类别：
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/10601115
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 Cell Lineage Cells Cellular Indexing of Transcriptomes and Epitopes by Sequencing Cellular biology 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 Ligands Maintenance Mediating Mediator Membrane Proteins Memory Mentors Mentorship Methods Modeling Mus National Institute of Arthritis, and Musculoskeletal, and Skin Diseases Organoids Pathway interactions Patients Pattern Pediatric Hospitals Periodicals Peripheral Persons Pharmaceutical Preparations Phenotype Physicians Population Process RUNX3 gene Recurrence Recurrent disease Research Personnel Resistance Resources Rheumatoid Arthritis Role Scientist Series Signal Transduction Site Sterility Stromal Cells Surface Synovial Membrane System T memory cell T-Cell Activation T-Cell Development T-Cell Receptor T-Lymphocyte TGFBR2 gene Testing Therapeutic Time Tissue Differentiation Tissue Model Tissue-Specific Gene Expression Tissues Training Translational Research Woman Work arthritis therapy arthropathies 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 receptor recruit residence rheumatologist single cell analysis single cell sequencing single-cell RNA sequencing skills therapeutic target three-dimensional modeling tissue resident memory T cell transcriptomics uptake

项目摘要

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.

项目摘要/摘要类风湿关节炎（RA）和青少年特发性关节炎（JIA）是关节的慢性自身免疫性疾病周期性关节炎耀斑点击。临床医生长期以来已经认识到每个受影响的人都会发展受影响关节的个体模式，并且通过疾病缓解和耀斑。我们最近确定了滑膜居民记忆T细胞（TRM）的存在，并显示它们介导关节炎的耀斑。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。长期目标建议是定义Syromovium中TRM开发和维护的介体，并确定这些是否是否可以热靶向治疗关节炎的途径。该提案的具体目的利用小鼠和人类研究中的两种完整方法来确定滑膜TRM开发的介体。 AIM 1利用了由炎症性关节炎的小鼠模型 PI定义滑膜TRM的谱系和分化过程。 AIM 2利用人类滑膜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开发的关键调解人，这可能代表炎性关节炎的新型治疗靶标。候选人是M.D./ph.d。波士顿儿童医院的小儿风湿病学家。该提议建立在她对免疫学的基本知识将其技能扩展到抗体耦合的单细胞测序中，生物信息学，人类滑膜的器官模型和CRISPR基因靶向。该提案包括一个全面的指导和教学计划，这将使她能够成功学习新技能并获得专业知识在这些重要领域中的每个领域。主要导师彼得·尼格罗维奇（Peter Nigrovic）博士是风湿病学家和专家炎症性关节炎的病理生理。候选人已组建一个K08咨询委员会，该委员会由 Michael Brenner博士，Rachael Clark博士和Soumya Raychaudhuri博士，他们在该建议的各个方面，例如分析单细胞测序数据，人类滑膜的3D模型，和人类疾病中TRM生物学的专业知识。候选人致力于转化研究的职业目的是成为一名基于实验室的独立研究者，专注于自身免疫的本地机制疾病。波士顿儿童医院提议的研究，培训计划和特殊环境， Brigham and妇女医院以及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。