Mitochondrial Membrane Dynamics in Th17 Cells
Th17 细胞的线粒体膜动力学
基本信息
- 批准号:10733013
- 负责人:
- 金额:$ 57.59万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-07-14 至 2028-06-30
- 项目状态:未结题
- 来源:
- 关键词:AddressAntigensAutoimmune DiseasesAutoimmunityCD4 Positive T LymphocytesCD8B1 geneCNS autoimmune diseaseCell DeathCell Differentiation processCell physiologyCellsCellular Metabolic ProcessComplexCrista ampullarisDataDiseaseEffector CellElectron TransportEnvironmentEpigenetic ProcessEventExperimental Autoimmune EncephalomyelitisFailureGenerationsGenesGenetic TranscriptionGoalsGrowthHealthIL17 geneImmuneImmune System DiseasesImmune TargetingImmune responseImmunobiologyImpairmentIn VitroInfectionInflammationInner mitochondrial membraneKnowledgeLeadLinkMalignant NeoplasmsMediatingMembraneMembrane FusionMemoryMetabolicMetabolic PathwayMetabolismMitochondriaMitochondrial DNAMonomeric GTP-Binding ProteinsMorphologyMusOPA1 geneOrganellesOuter Mitochondrial MembraneOutputPathologyPhenotypeProcessProductionProliferatingProtein FamilyProteinsRegulatory T-LymphocyteResistanceRestRoleSTK11 geneShapesSignal TransductionStressStructureT cell differentiationT-Cell ActivationT-LymphocyteT-Lymphocyte SubsetsTh1 CellsTh2 CellsWorkcell growth regulationcell typecytokineenvironmental changeexperimental studyfood consumptiongut homeostasisin vivoinsightmigrationmitochondrial membranemitochondrial metabolismprogramsrespiratoryresponserestrainttherapeutic targettranscription factor
项目摘要
PROJECT SUMMARY
The extensive changes in phenotype and function observed in T cells upon activation are intimately linked to
changes in cellular metabolism. The failure to engage specific and appropriate metabolic programs can impair
or alter T cells, and thus lead to ineffective, or even overexuberant, immune responses. Central to metabolism
are mitochondria, which serve as central hubs of energy generation and biosynthetic activity. Work from our
group and others has provided mechanistic insights into how mitochondrial metabolism is critical to T cell
differentiation and function. However, knowledge about why these organelles change shape to maintain
metabolism, biosynthetic capacity, and function, and in what ways mitochondrial remodeling influences T cell
activation, differentiation, or effector molecule expression is lacking. Investigating how dynamic changes in
mitochondria regulate metabolism to impact CD4+ T cells will enhance our fundamental understanding of
immunobiology and of how to manipulate these cells for disease therapy in the context of cancer, infection, and
autoimmunity. In our initial experiments we found that unlike other Th cell subsets, Th17 cells, a cell type
necessary for maintaining gut homeostasis and implicated in certain types of autoimmunity and inflammation,
had elongated mitochondria in a fused network, as well as tight cristae morphology. These results suggested a
differential role for mitochondrial fusion and the protein OPA1, which mediates both membrane fusion and cristae
morphology, in these cells. OPA1 deletion had no discernible effect on Th1 and Th2 cell differentiation or cytokine
production in vitro, and while Th17 cell differentiation was also unimpaired, IL-17 expression was drastically
reduced. Further, mice with a T cell-specific OPA1 deletion were resistant to developing pathology in
experimental autoimmune encephalomyelitis (EAE), a Th17 cell-mediated autoimmune disease of the central
nervous system. Finally, our data revealed a role for liver kinase B1 (LKB1) in regulating the cellular response
to OPA1-deficiency, and in restraining Th17 cell IL-17 expression when mitochondrial fusion is perturbed. In this
proposal we now seek to understand how mitochondrial dynamics influence the function of diverse CD4+ T cell
subsets. Our overall goal is to dissect the function of OPA1 in Th17 cell effector function, as well as probe its
potential role other CD4+ T cell subsets, and to determine how MM fusion interfaces with LKB1 signaling to
modulate cellular metabolism to limit IL-17 expression in settings of mitochondrial disruption or stress in vitro
and in vivo. To this end, we propose to 1) explore the role of mitochondrial dynamics in CD4+ Th cells, 2)
determine the extent to which LKB1 controls the cellular response to OPA1-deficiency in Th17 cells, and 3)
investigate how metabolic changes upon disrupting mitochondrial fusion lead to dampened Th17 cell function.
项目摘要
活化后在T细胞中观察到的表型和功能的广泛变化与以下密切相关:
细胞代谢的变化。如果不能进行特定和适当的代谢程序,
或改变T细胞,从而导致无效,甚至过度的免疫反应。代谢的中心
线粒体是能量产生和生物合成活动的中心枢纽。从我们的工作
小组和其他人提供了线粒体代谢如何对T细胞至关重要的机制见解。
分化和功能。然而,关于为什么这些细胞器改变形状以维持
代谢,生物合成能力和功能,以及线粒体重塑如何影响T细胞
缺乏激活、分化或效应分子表达。研究动态变化是如何
线粒体调节代谢影响CD 4 + T细胞将增强我们对
免疫生物学以及如何操纵这些细胞用于癌症,感染和
自身免疫在我们最初的实验中,我们发现与其他Th细胞亚群不同,Th 17细胞是一种细胞类型,
对于维持肠道内环境稳定是必需的,并且与某些类型的自身免疫和炎症有关,
具有融合网络中的细长线粒体,以及紧密的嵴形态。这些结果表明,
线粒体融合和介导膜融合和嵴的蛋白质OPA 1的不同作用
在这些细胞中。OPA 1缺失对Th 1和Th 2细胞分化或细胞因子没有明显影响
虽然Th 17细胞分化也未受损,但IL-17表达显著降低,
降低此外,具有T细胞特异性OPA 1缺失的小鼠对发展中的病理学具有抗性,
实验性自身免疫性脑脊髓炎(EAE),一种Th 17细胞介导的中枢神经系统自身免疫性疾病,
神经系统最后,我们的数据揭示了肝激酶B1(LKB 1)在调节细胞反应中的作用。
对OPA 1缺陷的抑制作用,以及在线粒体融合受到干扰时抑制Th 17细胞IL-17表达的作用。在这
我们现在试图了解线粒体动力学如何影响不同的CD 4 + T细胞的功能,
子集我们的总体目标是剖析OPA 1在Th 17细胞效应器功能中的功能,并探讨其在Th 17细胞中的作用。
其他CD 4 + T细胞亚群的潜在作用,并确定MM融合如何与LKB 1信号传导相互作用,
在体外线粒体破坏或应激环境中调节细胞代谢以限制IL-17表达
和体内。为此,我们建议1)探索线粒体动力学在CD 4 + Th细胞中的作用,2)
确定LKB 1控制Th 17细胞中对OPA 1缺陷的细胞应答的程度,和3)
研究线粒体融合破坏后的代谢变化如何导致Th 17细胞功能减弱。
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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Erika L Pearce其他文献
Erika L Pearce的其他文献
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{{ truncateString('Erika L Pearce', 18)}}的其他基金
The Role of the Amino Acid Hypusine in the Maintenance and Function of Tissue-Resident Macrophages
氨基酸马尿苷在组织驻留巨噬细胞的维持和功能中的作用
- 批准号:
10656730 - 财政年份:2023
- 资助金额:
$ 57.59万 - 项目类别:
Phosphorylation of TSC2 (S1365) as a novel Regulator of mTORC1 Signaling in T Cells
TSC2 (S1365) 磷酸化作为 T 细胞中 mTORC1 信号转导的新型调节剂
- 批准号:
10596567 - 财政年份:2021
- 资助金额:
$ 57.59万 - 项目类别:
Phosphorylation of TSC2 (S1365) as a novel Regulator of mTORC1 Signaling in T Cells
TSC2 (S1365) 磷酸化作为 T 细胞中 mTORC1 信号转导的新型调节剂
- 批准号:
10386765 - 财政年份:2021
- 资助金额:
$ 57.59万 - 项目类别:
TUMOR-IMPOSED GLUCOSE RESTRICTIONS ON T CELLS DAMPEN IMMUNITY
肿瘤对 T 细胞施加的葡萄糖限制会削弱免疫力
- 批准号:
8913080 - 财政年份:2014
- 资助金额:
$ 57.59万 - 项目类别:
TUMOR-IMPOSED GLUCOSE RESTRICTIONS ON T CELLS DAMPEN IMMUNITY
肿瘤对 T 细胞施加的葡萄糖限制会削弱免疫力
- 批准号:
9337389 - 财政年份:2014
- 资助金额:
$ 57.59万 - 项目类别:
TUMOR-IMPOSED GLUCOSE RESTRICTIONS ON T CELLS DAMPEN IMMUNITY
肿瘤对 T 细胞施加的葡萄糖限制会削弱免疫力
- 批准号:
9151813 - 财政年份:2014
- 资助金额:
$ 57.59万 - 项目类别:
TUMOR-IMPOSED GLUCOSE RESTRICTIONS ON T CELLS DAMPEN IMMUNITY
肿瘤对 T 细胞施加的葡萄糖限制会削弱免疫力
- 批准号:
8759445 - 财政年份:2014
- 资助金额:
$ 57.59万 - 项目类别:
Metabolic Regulation of CD8 T Cell Memory Development
CD8 T 细胞记忆发育的代谢调节
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$ 57.59万 - 项目类别:
Metabolic Regulation of CD8 T Cell Memory Development
CD8 T 细胞记忆发育的代谢调节
- 批准号:
8650256 - 财政年份:2011
- 资助金额:
$ 57.59万 - 项目类别:
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