T Cell Signaling in Rheumatoid Arthritis
类风湿关节炎中的 T 细胞信号转导
基本信息
- 批准号:8698320
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-04-01 至 2016-03-31
- 项目状态:已结题
- 来源:
- 关键词:AffinityAgingAntigensArthritisAutoantibodiesAutoantigensAutoimmune DiseasesAutoimmune ResponsesBRAF geneBiological MarkersCalibrationCell AgingCell Surface ReceptorsCell SurvivalCellsChronicClassificationCompetenceCross-Sectional StudiesDataDefectDevelopmentDiseaseDisease ManagementDisease remissionElderlyEpidemiologyFailureFc ImmunoglobulinsFeedbackGenetic TranscriptionGoalsHLA-DR4 AntigenHalf-LifeHematopoieticIL7 geneImmuneImmune System DiseasesImmune ToleranceImmunoglobulin GIn VitroIncidenceIndividualInflammationInflammatoryInterleukin-15JAK3 geneKRAS2 geneLeflunomideLifeLongitudinal StudiesLymphopeniaMEKsMethotrexateModelingMolecularNaturePathogenesisPathway interactionsPatientsPeptidesPeripheralPhenotypePhosphorylationPost-Translational Protein ProcessingProcessProductionProphylactic treatmentPsoriatic ArthritisReceptor ActivationRegulationRheumatoid ArthritisRheumatologyRoleSTAT5A geneSerineSignal PathwaySignal TransductionSignaling MoleculeT cell differentiationT-Cell ActivationT-Cell ReceptorT-LymphocyteTNF geneTestingTherapeuticTherapeutic InterventionTissuesUp-Regulationage relatedarthropathiesattenuationclinical practicecytokinedesignimprovedinhibitor/antagonistinsightoverexpressionperipheral tolerancepreventresponsestandard caretherapeutic targettherapy design
项目摘要
DESCRIPTION (provided by applicant):
Rheumatoid arthritis (RA) is a chronic inflammatory disease that manifests predominantly as a destructive arthropathy. In spite of the prominence of the synovial inflammation, autoantibodies are not tissue-specific and are directed against global antigens such as Ig Fc determinants and neoantigens of citrullinated peptides. Additional systemic immunological abnormalities include a defect that can best be summarized as accelerated immune aging. A putative role of age-dependent immune dysfunction in RA pathogenesis resonates with epidemiological data that RA is a disease of the second half of life with increasing incidence in the elderly. We have hypothesized that a defect in regulating T cell activation thresholds contributes to the tolerance failure and possibly also to the accelerated cellular aging. T cell activation thresholds are regulated by the signal strength originating from T-cell receptor (TCR) stimulation and by signals from costimulatory and coinhibitory cell surface receptors. We have found an increased responsiveness of the ERK pathway in RA T cells that is central to TCR calibration and amplifying signal strength and have proposed that mechanisms controlling the Raf-MEK-ERK module in T cells from RA patients have been reset to favor sustained signaling, thereby impairing peripheral immune tolerance. Our preliminary studies have identified several possible mechanisms causing this hyperresponsiveness including the increased transcription of B-RAF and K-RAS and the induction of a positive feedback loop induced by the homeostatic cytokines IL7 and IL15. The objective of the current application is to determine whether a characterization of these signaling abnormalities in individual RA patients is useful for patient classification and treatment design. Specific Aim 1 will explore the hypothesis that subsets of RA patients can be defined which differ in their mechanism to hyperstimulate the ERK pathway. Specific Aim 2 will determine whether the findings are limited to RA or also extend to other frequent arthritides such as psoriatic arthritis. In Specific Aim 3, we will determine whether existing standard (methotrexate, leflunomide or TNF inhibition) and newly emerging treatment approaches such as JAK3 inhibition are able to correct the signaling abnormalities In Specific Aim 4, we will examine the functional consequences of increased ERK responsiveness for T cell tolerance and T cell differentiation.
描述(由申请人提供):
类风湿关节炎(RA)是一种慢性炎症性疾病,主要表现为一种破坏性的关节病变。尽管滑膜炎症突出,但自身抗体不是组织特异性的,并且针对全局抗原,如Ig Fc决定簇和瓜氨酸多肽的新抗原。其他系统性免疫异常包括一种缺陷,最好的概括是免疫老化加速。年龄依赖性免疫功能障碍在类风湿性关节炎发病机制中的作用与流行病学数据一致,即类风湿性关节炎是一种中老年疾病,其发病率在老年人中呈上升趋势。我们假设,调节T细胞激活阈值的缺陷导致耐受性失败,并可能导致细胞加速老化。T细胞激活阈值受来自T细胞受体(TCR)刺激的信号强度以及来自共刺激和共抑制细胞表面受体的信号的调节。我们发现在RA T细胞中ERK通路的反应性增强,这是TCR校准和放大信号强度的核心,并提出控制RA患者T细胞中Raf-MEK-ERK模块的机制已被重置,以利于持续的信号传递,从而损害外周免疫耐受。我们的初步研究已经确定了导致这种高反应性的几种可能机制,包括B-RAF和K-RAS转录增加,以及由稳态细胞因子IL7和IL15诱导的正反馈回路。目前应用的目的是确定单个RA患者的这些信号异常的特征是否对患者分类和治疗设计有用。具体目标1将探索这样的假设,即RA患者的亚群可以被定义为不同的机制,以过度刺激ERK途径。具体目标2将确定研究结果是否仅限于类风湿性关节炎,还是也适用于其他常见的关节炎,如牛皮癣关节炎。在特定的目标3中,我们将确定现有的标准(甲氨蝶呤、来氟米特或肿瘤坏死因子抑制)和新出现的治疗方法(如JAK3抑制)是否能够纠正特定目标中的信号异常。4,我们将检查ERK反应性增加对T细胞耐受和T细胞分化的功能后果。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
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专利数量(0)
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{{ truncateString('JORG J GORONZY', 18)}}的其他基金
Memory T cell development and survival in T cell responses of older individuals
老年人 T 细胞反应中记忆 T 细胞的发育和存活
- 批准号:
9331942 - 财政年份:2017
- 资助金额:
-- - 项目类别:
Memory T cell development and survival in T cell responses of older individuals
老年人 T 细胞反应中记忆 T 细胞的发育和存活
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9904524 - 财政年份:2017
- 资助金额:
-- - 项目类别:
Memory T Cell Development and Survival in T Cell Responses of Older Individuals
老年个体 T 细胞反应中记忆 T 细胞的发育和存活
- 批准号:
10430906 - 财政年份:2017
- 资助金额:
-- - 项目类别:
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