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:
- 金额:$ 17.33万
- 依托单位:
- 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:
- 关键词:3-DimensionalAdoptive TransferAdvisory CommitteesAffectAntibodiesAntigensAreaArthralgiaArthritisAttenuatedAutoimmune DiseasesBioinformaticsBiologyBostonCD8-Positive T-LymphocytesCD8B1 geneCRISPR/Cas technologyCellsCellular Indexing of Transcriptomes and Epitopes by SequencingChildhoodChronicChronic Childhood ArthritisClustered Regularly Interspaced Short Palindromic RepeatsCoculture TechniquesCoupledDataDevelopmentDiseaseDisease remissionDoctor of MedicineDoctor of PhilosophyEffector CellEndothelial CellsEnvironmentEventExhibitsFatty AcidsFibroblastsFlareFoundationsFunctional disorderFundingFutureGene ExpressionGene Expression ProfilingGene TargetingGenesGenetic TranscriptionGoalsHeadHomingHospitalsHumanImmuneImmunologyIndividualInflammationInflammatoryInflammatory ArthritisInstitutionInterruptionJointsKnowledgeLaboratoriesLearningLifeLigandsMaintenanceMediatingMediator of activation proteinMembrane ProteinsMemoryMentorsMentorshipMethodsModelingMusNational Institute of Arthritis and Musculoskeletal and Skin DiseasesOrganoidsPathway interactionsPatientsPatternPediatric HospitalsPeriodicityPeripheralPersonsPharmaceutical PreparationsPhenotypePhysiciansPopulationProcessRUNX3 geneRecurrenceResearch PersonnelResistanceResourcesRheumatoid ArthritisRoleScientistSeriesSignal TransductionSiteSterilityStromal CellsSurfaceSynovial MembraneSystemT memory cellT-Cell ReceptorT-LymphocyteTGFBR2 geneTestingTherapeuticTimeTissue-Specific Gene ExpressionTissuesTrainingTranslational ResearchWomanWorkarthritis therapyarthropathiesbasecareerchemokinechronic autoimmune diseaseconfocal imagingdesigndisorder controlexperiencehuman diseasehuman modelimmune activationinsightjoint inflammationlymph nodesmRNA Expressionmedical schoolsmigrationmouse modelnew therapeutic targetnovel strategiesnovel therapeuticspreventprotein expressionranpirnasereceptorrecruitresidencerheumatologistsingle cell analysissingle cell sequencingsingle-cell RNA sequencingskillstherapeutic targetthree-dimensional modelingtranscriptomicsuptake
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。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Margaret Chang其他文献
Margaret Chang的其他文献
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{{ truncateString('Margaret Chang', 18)}}的其他基金
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:
10601115 - 财政年份:2022
- 资助金额:
$ 17.33万 - 项目类别:
Galectin-1's effects on dendritic cell function.
Galectin-1 对树突状细胞功能的影响。
- 批准号:
7676449 - 财政年份:2009
- 资助金额:
$ 17.33万 - 项目类别:
Galectin-1's effects on dendritic cell function.
Galectin-1 对树突状细胞功能的影响。
- 批准号:
8323368 - 财政年份:2009
- 资助金额:
$ 17.33万 - 项目类别:
Galectin-1's effects on dendritic cell function.
Galectin-1 对树突状细胞功能的影响。
- 批准号:
8127678 - 财政年份:2009
- 资助金额:
$ 17.33万 - 项目类别:
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