Influence of Age on CD4 T Memory Cells
年龄对 CD4 T 记忆细胞的影响
基本信息
- 批准号:8691644
- 负责人:
- 金额:$ 29.69万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-07-01 至 2018-06-30
- 项目状态:已结题
- 来源:
- 关键词:3&apos Untranslated RegionsATM activationAccountingAdoptive TransferAdultAgeAgingAntigensB-LymphocytesBiological AssayCD4 Positive T LymphocytesCREB1 geneCaM kinase I activatorCell Differentiation processCell physiologyChronicDataE2F1 geneEffector CellElderlyEpigenetic ProcessFeedbackFluorescent ProbesGene ActivationGene ExpressionGene Expression RegulationGenetic EngineeringGenetic TranscriptionHealthHerpes zoster diseaseHeterogeneous-Nuclear Ribonucleoprotein KImmuneImmune responseImmune systemImmunizationIn VitroInfectionInfectious AgentInfluenzaInterventionJUN geneKineticsMAP Kinase GeneMAPK8 geneMediatingMemoryMethylationMicroRNAsMorbidity - disease rateMusMutateNuclearOxygenPathway interactionsPhosphoric Monoester HydrolasesPhosphorylationPopulationPredispositionRecording of previous eventsRegulationReporter GenesRepressionRoleSTK11 geneSignal PathwaySignal TransductionT Cell Receptor Signaling PathwayT cell differentiationT cell responseT-Cell ActivationT-Cell ProliferationT-LymphocyteT-Lymphocyte SubsetsTestingTranscriptTranscriptional RegulationVaccinationVaccinesage effectage relatedagedattenuationbasedemographicsdesignenzyme activityfrailtyimprovedin vivoinhibitor/antagonistinterestmemory CD4 T lymphocytemortalityoverexpressionpromoterpublic health relevanceresearch studyresponsetranscription factor
项目摘要
DESCRIPTION (provided by applicant): The reduced ability of the aging immune system to mount adaptive immune responses compromises the efficacy of vaccinations and increases the morbidity from infections. Adaptive immune responses to exogenous or endogenous threats rely on the rapid expansion of an antigen-specific T cell population and acquisition of effector functions. In studying the effect of age on CD4 T memory cell function, we have identified a negative feedback loop mediated by the dual-specific phosphatase DUSP4 which is overactive in the elderly. DUSP4 is a nuclear phosphatase; its activity peaks two to four days after T cell activation and influences T cell differentiation by controlling nuclear ERK and JNK activity. In th current proposal we examine the hypothesis that the inappropriate activation of this feedback loop impairs T cell differentiation and effector function and that T cell responses in the elderly can be improved by identifying and correcting the mechanism of DUSP4 expression or by directly inhibiting DUSP4 activity. Three specific aims have been designed to test this hypothesis. In Aim 1, we will delineate the effect of DUSP4-mediated feedback loop on the kinetics of nuclear ERK and JNK activity in CD4 memory T cells. In a second step, we will then determine whether the age-associated attenuation of nuclear MAPK activities is universal for T cells or whether it is limited to selected T cell subpopulation depending on their differentiation and their replicative history. In Aim 2, we will explore the mechanisms of increased DUSP4 expression in T cells from the elderly and determine whether the epigenetic or transcriptional control of DUSP4 changes with age. Of particular interest is the hypothesis that increased AMPK activation with age modifies the TCR-induced signaling cascade to favor DUSP4 transcription. In Aim 3, we will examine the functional consequences of increased DUSP4 expression and explore how DUSP4 can be targeted to restore effector cell function.
描述(由申请方提供):衰老免疫系统产生适应性免疫应答的能力降低,影响疫苗接种的有效性,并增加感染的发病率。对外源性或内源性威胁的适应性免疫应答依赖于抗原特异性T细胞群的快速扩增和效应子功能的获得。在研究年龄对CD 4 T记忆细胞功能的影响时,我们已经确定了由双特异性磷酸酶DUSP 4介导的负反馈回路,该磷酸酶在老年人中过度活跃。DUSP 4是一种核磷酸酶;其活性在T细胞活化后2 - 4天达到峰值,并通过控制核ERK和JNK活性来影响T细胞分化。在本提案中,我们研究了这一反馈环的不适当激活损害T细胞分化和效应器功能的假设,并且可以通过鉴定和纠正DUSP 4表达的机制或通过直接抑制DUSP 4活性来改善老年人的T细胞应答。为了检验这一假设,设计了三个具体目标。在目的1中,我们将描述DUSP 4介导的反馈环对CD 4记忆T细胞中核ERK和JNK活性动力学的影响。在第二步中,我们将确定核MAPK活性的年龄相关衰减是否对T细胞是普遍的,或者它是否仅限于选定的T细胞亚群,这取决于它们的分化和它们的复制历史。在目标2中,我们将探索老年人T细胞中DUSP 4表达增加的机制,并确定DUSP 4的表观遗传或转录控制是否随着年龄的变化而变化。特别令人感兴趣的是这样一种假设,即随着年龄的增长,AMPK活化增加,从而改变了TCR诱导的信号级联反应,有利于DUSP 4转录。在目标3中,我们将研究DUSP 4表达增加的功能后果,并探索如何靶向DUSP 4以恢复效应细胞功能。
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:
$ 29.69万 - 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
- 批准号:
9904524 - 财政年份:2017
- 资助金额:
$ 29.69万 - 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:
$ 29.69万 - 项目类别:
microRNA Regulation of T Cell Senescence
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10435599 - 财政年份:2014
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$ 29.69万 - 项目类别:
microRNA Regulation of T Cell Senescence
T 细胞衰老的 microRNA 调控
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10318961 - 财政年份:2014
- 资助金额:
$ 29.69万 - 项目类别:
microRNA Regulation of T Cell Senescence
T 细胞衰老的 microRNA 调控
- 批准号:
10552542 - 财政年份:2014
- 资助金额:
$ 29.69万 - 项目类别:
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