Elucidating the Regulation and Requirement of the NAD salvage pathway in CD8+ T Cell Exhaustion
阐明 CD8 T 细胞耗竭中 NAD 挽救途径的调节和要求
基本信息
- 批准号:10395441
- 负责人:
- 金额:$ 4.68万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-04-01 至 2024-03-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAddressAnabolismAntigensCD28 geneCD3 AntigensCD8-Positive T-LymphocytesCell DeathCell SurvivalCellsCellular Metabolic ProcessCellular biologyChronicClinicalDataDevelopmentEnzymesEpigenetic ProcessFutureGeneticGenetic TranscriptionGoalsHourImmunotherapyInfectionKnock-outLymphocytic choriomeningitis virusMediator of activation proteinMetabolicMetabolismMicroRNAsModelingMolecularMusPathway interactionsPatientsPlayProductionRNARegulationResearchRoleRunningSignal TransductionSignaling MoleculeT-Cell ActivationT-LymphocyteT-Lymphocyte SubsetsTCR ActivationTestingTherapeuticTrainingTranscriptbasecancer immunotherapycancer therapycell typedesignexhaustexhaustionexperienceimmune checkpoint blockadeimprovedin vivonovelpreventprogramsresponseskillstooltranscription factortranslational medicinetreatment responsetumor
项目摘要
Project Summary
The development of checkpoint based cancer immunotherapy has revolutionized cancer treatment in the last
decade. Although many otherwise untreatable patients have seen long term benefit from these therapies, the
long-term benefit for most patients is minimal, highlighting a need for improved treatments. A major goal of
checkpoint based therapies is to reinvigorate chronically stimulated, “exhausted” CD8+ T cells to kill the tumor.
Likewise, a thorough understanding of these chronically stimulated cells and their reinvigoration as compared
to acutely stimulated effector CD8+ T cells will continue to be necessary for future therapeutic discovery. It has
increasingly become appreciated that in addition to epigenetic and transcriptional changes, cell metabolism
plays a critical role in facilitating and determining T cell fate. However, the specific metabolic requirements for
exhausted CD8+ T cells before and after checkpoint based treatment remain unclear. My preliminary studies
suggest that the NAD salvage pathway is a novel mediator of T cell activation and differentiation, which
could be leveraged therapeutically in the context of checkpoint blockade. My data shows that 1) the NAD
salvage pathway is regulated in CD8+ T cells through stimulation of both the TCR and CD28, whose signaling
is known to drive cell fate determination; 2) The NAD salvage pathway is differentially required throughout the
activation of naive CD8+ T cells. During the T cell exit from quiescence, activity of the rate limiting enzyme,
NAMPT, is required for cell survival, proliferation, and function, but not after. I thus hypothesize that that the
NAD salvage pathway is differentially regulated and required in the context of chronic versus acute
antigen stimulation. In this proposal I seek to address this hypothesis by elucidating the specific signaling
mechanisms that induce this pathway in CD8+ T cells (Aim 1) and determining how this pathway is regulated
and required in the context of exhaustion (Aim 2). Completion of these aims will elucidate how different CD8+ T
cell subsets regulate and require the NAD salvage pathway and will mechanistically inform the design of future
immunotherapies designed to reinvigorate exhausted T cells.
项目摘要
基于检查点的癌症免疫疗法的发展在过去已经彻底改变了癌症治疗。
十年尽管许多其他无法治疗的患者已经从这些疗法中获得了长期益处,
对大多数患者的长期益处很小,这突出了对改进治疗的需要。的一个主要目标
基于检查点的疗法是重新激活慢性刺激的、“耗尽的”CD 8 + T细胞以杀死肿瘤。
同样,彻底了解这些长期刺激的细胞和它们的复苏相比,
急性刺激的效应CD 8 + T细胞对于未来的治疗发现将继续是必要的。它有
越来越多地认识到,除了表观遗传和转录变化,细胞代谢
在促进和决定T细胞命运中起关键作用。然而,特定的代谢要求,
在基于检查点的治疗之前和之后耗尽的CD 8 + T细胞仍然不清楚。我的初步研究
提示NAD补救途径是T细胞活化和分化的新介质,
可以在检查点阻断的情况下进行治疗。我的数据显示,1)NAD
补救途径在CD 8 + T细胞中通过刺激TCR和CD 28来调节,TCR和CD 28的信号传导
已知驱动细胞命运决定; 2)NAD补救途径在整个细胞周期中是不同需要的。
初始CD 8 + T细胞的活化。在T细胞从静止期退出期间,限速酶的活性,
NAMPT是细胞存活、增殖和功能所必需的,但不是之后。因此,我假设,
NAD补救途径在慢性与急性的背景下受到不同的调节和需要
抗原刺激在这个建议中,我试图通过阐明特定的信号来解决这个假设。
在CD 8 + T细胞中诱导这一途径的机制(Aim 1),并确定这一途径是如何调节的
在用尽情况下(目标2)。完成这些目标将阐明CD 8 + T的不同之处
细胞亚群调节并需要NAD补救途径,并将机械地告知未来的设计。
免疫疗法旨在重振耗尽的T细胞。
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)
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Lucien Turner其他文献
Lucien Turner的其他文献
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{{ truncateString('Lucien Turner', 18)}}的其他基金
Elucidating the Regulation and Requirement of the NAD salvage pathway in CD8+ T Cell Exhaustion
阐明 CD8 T 细胞耗竭中 NAD 挽救途径的调节和要求
- 批准号:
10577728 - 财政年份:2021
- 资助金额:
$ 4.68万 - 项目类别:
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