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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：
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
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/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

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.

项目总结/文摘