T resident memory cells in arthritis
关节炎中的 T 常驻记忆细胞
基本信息
- 批准号:10609770
- 负责人:
- 金额:$ 42.49万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-07-01 至 2024-05-31
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalAdenovirusesAdultAffectAmericanAnimal ModelAntigensArchivesArthralgiaArthritisAwardBiologyCD8B1 geneCellsCellular biologyCharacteristicsChemicalsChildChronicChronic Childhood ArthritisClinicalCoupledCytometryDataDevelopmentDiseaseDrug EruptionsFlareFlow CytometryFluorescenceFoundationsFresh TissueFunctional disorderFundingGoldHumanImageImmuneImmunityImmunofluorescence ImmunologicIndividualInflammationInflammatoryInflammatory ArthritisInterruptionIntra-Articular InjectionsInvestigationJointsLeadLifeLongterm Follow-upLoxP-flanked alleleMediatingMediator of activation proteinMemoryMetabolismModificationMusNational Institute of Arthritis and Musculoskeletal and Skin DiseasesPatientsPatternPhenotypePopulationPositioning AttributePsoriasisRecurrenceReporterResearchResourcesRheumatoid ArthritisRheumatologyRoleSELL geneSiteSkinStressSurfaceSynovial MembraneSystemT memory cellT-LymphocyteTestingTherapeuticTimeTissuesanakinraarthritis therapybasedesigndisabilitydisorder controlexperimental studyin vivoindividual patientinhibitorirradiationjoint inflammationjoint injurymigrationmouse modelnovelnovel strategiesranpirnaseresponsesingle-cell RNA sequencingskin disordertranscriptome
项目摘要
Project Summary
Inflammatory arthritis in adults and children is often characterized by periods of quiescent activity
followed by disease flares. In any individual patient, the same joints typically flare repeatedly, in a
pattern that usually establishes itself early in disease and then persists for years or decades. The
hypothesis of this proposal is that this “joint-specific memory” reflects the presence of T
resident memory (TRM) cells, whose targeting represents a new approach to arthritis therapy.
TRM are a recently-described subset of long-lived T cells, either CD8 and CD4, that develop in skin
and other tissues as a response to tissue inflammation, persisting for years thereafter to provide
long-lasting site-specific immunity. TRM have never been described in joints. We have now
developed compelling evidence for the presence of these cells in human arthritic synovium using
three orthogonal approaches: single-cell RNAseq, a novel 3-dimensional synovial culture system,
coupled with cytometry by time of flight (CyTOF), and Mantra multidimensional
immunofluorescence imaging. Further, we have developed or adapted three animal models to
develop new murine systems optimized for the study of recurrent, joint-specific, T cell-dependent
inflammatory arthritis.
Building upon these preliminary data, we propose two specific aims. First, we will perform a
comprehensive characterization of human synovial TRM with respect to surface phenotype,
mediators, transcriptome, and metabolism to compare synovial TRM with synovial effector memory
T cells and “gold standard” TRM from human skin. Second, we will use our animal models to
characterize the development and persistence of TRM over time; to test the possibility that these
cells can re-activate arthritis upon antigen-independent triggering as well as antigen exposure; and
employ local depletion to test TRM targeting as a novel approach to durable joint-specific arthritis
therapy.
项目摘要
成人和儿童的炎性关节炎通常以静止活动期为特征
然后是疾病爆发在任何个体患者中,相同的关节通常反复地张开,
这种模式通常在疾病早期建立,然后持续数年或数十年。的
这个提议的假设是,这种“关节特异性记忆”反映了T的存在。
常驻记忆(TRM)细胞,其靶向代表了关节炎治疗的新方法。
TRM是最近描述的长寿命T细胞的子集,CD 8和CD 4,在皮肤中发育
和其他组织作为对组织炎症的反应,持续多年,
持久的位点特异性免疫。TRM从未在关节中描述过。我们现在已经
开发了令人信服的证据,这些细胞存在于人类关节炎滑膜使用
三种正交方法:单细胞RNAseq,一种新的三维滑膜培养系统,
结合飞行时间流式细胞术(CyTOF)和Mantra多维
免疫荧光成像此外,我们已经开发或改造了三种动物模型,
开发新的小鼠系统,优化用于研究复发性,关节特异性,T细胞依赖性
炎性关节炎
在这些初步数据的基础上,我们提出了两个具体目标。首先,我们将执行一个
人滑膜TRM关于表面表型的综合表征,
介质、转录组和代谢,以比较滑膜TRM与滑膜效应记忆
T细胞和来自人类皮肤的“金标准”TRM。其次,我们将使用我们的动物模型,
描述TRM随时间的发展和持续性;测试这些
细胞可以在抗原非依赖性触发以及抗原暴露后重新激活关节炎;以及
采用局部耗竭测试TRM靶向作为持久性关节特异性关节炎的新方法
疗法
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Peter A Nigrovic其他文献
Development of consensus best treatment plans for new-onset systemic juvenile idiopathic arthritis
- DOI:
10.1186/1546-0096-10-s1-a50 - 发表时间:
2012-07-13 - 期刊:
- 影响因子:2.300
- 作者:
Esi M Morgan DeWitt;Timothy Beukelman;Peter A Nigrovic;Karen Onel;Sampath Prahalad;Rayfel Schneider;Matthew Stoll;Carol A Wallace;Yukiko Kimura - 通讯作者:
Yukiko Kimura
Disease characteristics and medication use in a multicenter cohort of children with juvenile idiopathic arthritis (JIA): preliminary analyses from the CARRAnet registry
- DOI:
10.1186/1546-0096-10-s1-a46 - 发表时间:
2012-07-13 - 期刊:
- 影响因子:2.300
- 作者:
Sarah Ringold;Timothy Beukelman;Esi M Morgan DeWitt;Marc Natter;Peter A Nigrovic;Yukiko Kimura - 通讯作者:
Yukiko Kimura
Juvenile idiopathic arthritis is associated with potentially pathogenic glycosylation of IgG
- DOI:
10.1186/1546-0096-10-s1-a5 - 发表时间:
2012-07-13 - 期刊:
- 影响因子:2.300
- 作者:
Altan Ercan;Melissa Hazen;Mary Beth Son;Susan Kim;Fatma Dedeoglu;Robert P Sundel;Robert C Fuhlbrigge;Jing Cui;Nancy A Shadick;Michael E Weinblatt;Michael Spigarelli;David N Glass;Susan D Thompson;Peter A Nigrovic - 通讯作者:
Peter A Nigrovic
Peter A Nigrovic的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Peter A Nigrovic', 18)}}的其他基金
Modulation of neutrophil function through emperipolesis
通过伸入调节中性粒细胞功能
- 批准号:
10091401 - 财政年份:2020
- 资助金额:
$ 42.49万 - 项目类别:
Modulation of neutrophil function through emperipolesis
通过伸入调节中性粒细胞功能
- 批准号:
10656013 - 财政年份:2020
- 资助金额:
$ 42.49万 - 项目类别:
Bridging the gap between GWAS and mechanism in JIA
弥合 GWAS 和 JIA 机制之间的差距
- 批准号:
10064581 - 财政年份:2018
- 资助金额:
$ 42.49万 - 项目类别:
Bridging the gap between GWAS and mechanism in JIA
弥合 GWAS 和 JIA 机制之间的差距
- 批准号:
10675585 - 财政年份:2018
- 资助金额:
$ 42.49万 - 项目类别:
Bridging the gap between GWAS and mechanism in JIA
弥合 GWAS 和 JIA 机制之间的差距
- 批准号:
10622118 - 财政年份:2018
- 资助金额:
$ 42.49万 - 项目类别:
相似海外基金
cGAS-STING Pathway Targeting Replicative Adenoviruses with CD46 Tropism and AFP Promoter Conditional Replication Restriction for the Treatment of Hepatocellular Carcinoma
cGAS-STING 通路靶向具有 CD46 趋向性和 AFP 启动子的复制腺病毒条件性复制限制用于治疗肝细胞癌
- 批准号:
10436626 - 财政年份:2021
- 资助金额:
$ 42.49万 - 项目类别:
Glioma therapy with oncolytic adenoviruses and immunometabolic adjuvants
溶瘤腺病毒和免疫代谢佐剂治疗胶质瘤
- 批准号:
10557162 - 财政年份:2021
- 资助金额:
$ 42.49万 - 项目类别:
Molecular therapy of replication-competent adenoviruses targeting characteristic gene mutations found in mesothelioma
针对间皮瘤中发现的特征基因突变的具有复制能力的腺病毒的分子疗法
- 批准号:
21K08199 - 财政年份:2021
- 资助金额:
$ 42.49万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Glioma therapy with oncolytic adenoviruses and immunometabolic adjuvants
溶瘤腺病毒和免疫代谢佐剂治疗胶质瘤
- 批准号:
10330464 - 财政年份:2021
- 资助金额:
$ 42.49万 - 项目类别:
Structural characterization of nucleoprotein cores of human adenoviruses
人腺病毒核蛋白核心的结构表征
- 批准号:
9807741 - 财政年份:2019
- 资助金额:
$ 42.49万 - 项目类别:
Molecular biology and pathogenesis of fowl adenoviruses
禽腺病毒的分子生物学和发病机制
- 批准号:
41625-2013 - 财政年份:2018
- 资助金额:
$ 42.49万 - 项目类别:
Discovery Grants Program - Individual
The therapeutic strategies with augmented replications of oncolytic adenoviruses for malignant mesothelioma
溶瘤腺病毒增强复制治疗恶性间皮瘤的治疗策略
- 批准号:
18K15937 - 财政年份:2018
- 资助金额:
$ 42.49万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Molecular biology and pathogenesis of fowl adenoviruses
禽腺病毒的分子生物学和发病机制
- 批准号:
41625-2013 - 财政年份:2017
- 资助金额:
$ 42.49万 - 项目类别:
Discovery Grants Program - Individual
Research on detection of novel adenoviruses by genetic methods
新型腺病毒的基因检测研究
- 批准号:
16K09118 - 财政年份:2016
- 资助金额:
$ 42.49万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Exploring the effects of nutrient deprivation on T cells and oncolytic adenoviruses, in order to create immune activators for tumour therapy
探索营养剥夺对 T 细胞和溶瘤腺病毒的影响,以创造用于肿瘤治疗的免疫激活剂
- 批准号:
1813152 - 财政年份:2016
- 资助金额:
$ 42.49万 - 项目类别:
Studentship