Bidirectional metabolic signaling in follicular helper T cell differentiation
滤泡辅助 T 细胞分化中的双向代谢信号
基本信息
- 批准号:10466976
- 负责人:
- 金额:$ 53.63万
- 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:2019-09-19 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:Activated LymphocyteAddressAffinityAmino AcidsAntibody AffinityAntibody FormationAntigensAutoimmune DiseasesB-LymphocytesBiologicalBiological ModelsBiologyCell physiologyCellsCellular ImmunityDefectDistalFRAP1 geneFeedsGTP-Binding ProteinsGeneticGenetic ScreeningGenetic TranscriptionGlucoseGlycolysisGrowthGuanosine Triphosphate PhosphohydrolasesHelper-Inducer T-LymphocyteHeterogeneityHomologous GeneHumoral ImmunitiesImmune System DiseasesImmune signalingImmunoglobulinsImmunologic ReceptorsKnowledgeLinkMediatingMetabolicMetabolic PathwayMetabolismMitochondriaModelingMonomeric GTP-Binding ProteinsMusNutrientOxidative PhosphorylationPathway interactionsPhenotypePost-Translational Protein ProcessingProcessProteinsProteomicsRegulationRoleShapesSignal PathwaySignal TransductionStructure of germinal center of lymph nodeSystemic Lupus ErythematosusSystems BiologyT cell differentiationT cell responseT-Cell ActivationT-Cell ReceptorT-LymphocyteTestingTh1 CellsTherapeuticTranslatingUp-Regulationamino acid metabolismeffector T cellfatty acid biosynthesisglucose metabolismin vivoinnovationinsightinterestmetabolomemitochondrial metabolismmouse geneticsnovelpathogenprogramsreceptorresponsescreeningsingle-cell RNA sequencingtranscription factor
项目摘要
Program Summary/Abstract
Follicular helper T (Tfh) cells provide essential help for B cells and high-affinity antibody production, thereby
linking cellular and humoral immunity. While much emphasis has been placed on immune receptors (e.g.
ICOS) and transcription factors (e.g. Bcl6) required for Tfh differentiation, how signals are transduced from
receptors to transcriptional and biological responses remains poorly defined. Emerging studies reveal nutrient
signaling and metabolic reprogramming as fundamental processes underlying the growth and fate decisions of
activated lymphocytes. However, many questions remain regarding the specific metabolic pathways important
for T cell fate decisions (rather than as a consequence of changes in cellular phenotypes), and how immune
signals intersect with nutrient inputs and metabolic programs. For instance, compared with our knowledge on
glycolytic or Warburg metabolism, the function and regulation of mitochondrial metabolism are much less clear.
We establish that mTOR acts as a key driver of Tfh differentiation by coordinating T cell receptor and ICOS
signaling and glucose metabolism. Through unbiased screens, mouse genetic models and systems biology
approaches in our preliminary studies, we also revealed crucial roles of nutrient signaling and mitochondrial
metabolism in Tfh responses. Our central hypothesis is that the interplay between mTORC1 and nutrient
signaling pathways and mitochondrial metabolic programs orchestrates bidirectional metabolic
signaling and Tfh differentiation. Specifically, we will (1) identify the mechanisms that integrate nutrient and
immune signals in Tfh responses, and (2) establish mitochondrial function and metabolic heterogeneity in Tfh
responses. Importantly, despite the emerging interest in immunometabolism, how nutrient signaling and
mitochondrial metabolism contribute to T cell function remains poorly understood. Building upon our expertise
and innovation that combine genetic and systems biology approaches, we will address fundamental questions
of immunometabolism and Tfh biology. Insights gained from this application may significantly impact our
understanding of Tfh biology and manifest legitimate therapeutic opportunities.
计划摘要/摘要
滤泡辅助 T (Tfh) 细胞为 B 细胞和高亲和力抗体的产生提供必要的帮助,从而
将细胞免疫和体液免疫联系起来。虽然人们非常重视免疫受体(例如
ICOS)和Tfh分化所需的转录因子(例如Bcl6),信号如何从
转录和生物反应的受体仍然不明确。新兴研究揭示营养
信号传导和代谢重编程作为生长和命运决定的基本过程
激活淋巴细胞。然而,关于重要的特定代谢途径仍然存在许多问题。
T 细胞命运决定(而不是细胞表型变化的结果),以及免疫如何
信号与营养输入和代谢程序相交叉。例如,与我们的知识相比
糖酵解或 Warburg 代谢,线粒体代谢的功能和调节尚不清楚。
我们确定 mTOR 通过协调 T 细胞受体和 ICOS 作为 Tfh 分化的关键驱动因素
信号传导和葡萄糖代谢。通过公正的筛选、小鼠遗传模型和系统生物学
在我们的初步研究中,我们还揭示了营养信号传导和线粒体的关键作用
Tfh 反应中的代谢。我们的中心假设是 mTORC1 和营养物质之间的相互作用
信号通路和线粒体代谢程序协调双向代谢
信号传导和 Tfh 分化。具体来说,我们将(1)确定整合营养和营养的机制
Tfh 反应中的免疫信号,以及 (2) 建立 Tfh 中的线粒体功能和代谢异质性
回应。重要的是,尽管人们对免疫代谢产生了兴趣,但营养信号传导和免疫代谢如何发挥作用?
线粒体代谢对 T 细胞功能的贡献仍知之甚少。以我们的专业知识为基础
和结合遗传和系统生物学方法的创新,我们将解决基本问题
免疫代谢和 Tfh 生物学。从该应用程序中获得的见解可能会对我们产生重大影响
了解 Tfh 生物学并明确合法的治疗机会。
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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{{ truncateString('Hongbo Chi', 18)}}的其他基金
Enabling immunotherapy for high-risk Group 3 medulloblastoma via systems immunology
通过系统免疫学对高危 3 组髓母细胞瘤进行免疫治疗
- 批准号:
10714138 - 财政年份:2023
- 资助金额:
$ 53.63万 - 项目类别:
Integrating systems immunology with immunometabolism and cancer immunity
将系统免疫学与免疫代谢和癌症免疫相结合
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10442703 - 财政年份:2021
- 资助金额:
$ 53.63万 - 项目类别:
Integrating systems immunology with immunometabolism and cancer immunity
将系统免疫学与免疫代谢和癌症免疫相结合
- 批准号:
10299800 - 财政年份:2021
- 资助金额:
$ 53.63万 - 项目类别:
2020 Immunometabolism in Health and Disease GRC
2020 健康与疾病中的免疫代谢 GRC
- 批准号:
9912281 - 财政年份:2021
- 资助金额:
$ 53.63万 - 项目类别:
Integrating systems immunology with immunometabolism and cancer immunity
将系统免疫学与免疫代谢和癌症免疫相结合
- 批准号:
10657475 - 财政年份:2021
- 资助金额:
$ 53.63万 - 项目类别:
Bidirectional metabolic signaling in follicular helper T cell differentiation
滤泡辅助 T 细胞分化中的双向代谢信号
- 批准号:
10687027 - 财政年份:2019
- 资助金额:
$ 53.63万 - 项目类别:
Bidirectional metabolic signaling in follicular helper T cell differentiation
滤泡辅助 T 细胞分化中的双向代谢信号
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10020901 - 财政年份:2019
- 资助金额:
$ 53.63万 - 项目类别:
Bidirectional metabolic signaling in follicular helper T cell differentiation
滤泡辅助 T 细胞分化中的双向代谢信号
- 批准号:
10231172 - 财政年份:2019
- 资助金额:
$ 53.63万 - 项目类别:
Bidirectional metabolic signaling in follicular helper T cell differentiation
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