Role for gluconeogenic enzyme FBP1 in T cell activation
糖异生酶 FBP1 在 T 细胞激活中的作用
基本信息
- 批准号:10554289
- 负责人:
- 金额:$ 18.47万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-01-24 至 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:AntigensAntioxidantsApoptosisBinding ProteinsBiochemicalBiological AssayCD8-Positive T-LymphocytesCRISPR/Cas technologyCarbonCatalytic DomainCell DeathCell divisionCellsClonal ExpansionCyclic AMPDataDiabetes MellitusDifferentiation AntigensEnsureEnzymesFructoseGelGluconeogenesisGlucoseGoalsHomeostasisHydrolysisImmuneImmune responseImmunoprecipitationImmunotherapyIn VitroInvestigationIsotopesKineticsKnowledgeLabelLengthLipidsMaintenanceMass Spectrum AnalysisMessenger RNAMetabolicMetabolismMethionineModelingMolecularMonitorMutationNADPNatural regenerationNucleotidesNutrientOxidation-ReductionOxidative StressPathway interactionsPentosephosphate PathwayPhasePhosphoric Monoester HydrolasesPhysiologicalPositioning AttributePost-Transcriptional RegulationProductionProliferatingProtein IsoformsProteinsProteomicsReactionReactive Oxygen SpeciesReduced GlutathioneRegulationResearchResistanceRoleSignal PathwaySiteT cell responseT-Cell ActivationT-LymphocyteTestingTracerTranscriptTranslationscancer therapycell preparationcomparativecrosslinkdesignenzyme activityexperienceexperimental studyfructose-6-phosphateglucose metabolismimmunoregulationimprovedinorganic phosphateinsightinterestmutantnovelpreventprogramsresponsetool
项目摘要
SUMMARY
During an immune response, naïve T lymphocytes undergo massive clonal expansion and differentiation and
are required to reprogram their metabolism to meet unexpected high energy and biosynthetic demands. The
metabolic activity generates reactive oxygen species (ROS) and increases intracellular oxidative stress trigger
cell death unless properly regulated. A major biosynthetic pathway that contributes to redox regulation in
proliferative glucose metabolism is the pentose phosphate pathway (PPP) which produces NADPH, a critical
molecule that meets the elevated demand for lipid synthesis and helps neutralize harmful ROS. Although T cells
have several antioxidant pathways in place, less is known about mechanisms that increase the production of
NADPH through the PPP in the metabolically active T cell to prevent excess ROS build up.
Our studies suggest that activated T cells repurpose fructose 1,6-bisphosphatase 1 (FBP1, or FBPase), a key
gluconeogenic enzyme, in a unique way to control oxidative stress. We hypothesize that a constitutively active
short isoform of FBP1 facilitates an increased flux of glucose into the pentose phosphate pathway, to increase
the production of NADPH in T cells as they prepare for rapid proliferation. FBP1, which catalyzes hydrolysis of
fructose-1,6 bisphosphate to fructose-6-phosphate and inorganic phosphate in an irreversible reaction, is one of
three coordinated enzymes in gluconeogenesis, but the only one expressed and active in stimulated T cells.
FBP1 has a carboxy terminal catalytic domain and an inhibitory amino terminal regulatory domain. Preliminary
observations suggest the short isoform may result from utilization of an internal translation initiator methionine.
Aim 1 will determine how FBP1 expression and activity are regulated in T lymphocytes following stimulation by
characterizing the short isoform in activated T cells using biochemical and molecular approaches, investigating
mechanism of regulation of FBP1, through identification of FBP1 mRNA-protein interactions in co-stimulated T
cells, and determining whether the short isoform of FBP1 is enzymatically active. Aim 2 will investigate the
physiological role of FBP1 in activated T lymphocytes using an in vitro activation model, with stable glucose
isotope tracer analysis and enzyme activity assays, while monitoring activation markers, proliferation, ROS,
NADPH and apoptosis, over the course of the activation response. CRISPR/Cas9-generated FBP1 KO and
putative start site mutant T cells will be utilized to determine whether constitutive enzymatic activity is required
for T cell expansion and viability upon stimulation. Finally, signaling pathways impacted by FBP1 activity, will be
identified using comparative proteomic analyses of FBP1 KO and control T cells.
The outlined research has broad implications for immune regulation, proliferative metabolism and maintenance
of redox homeostasis, and will reveal a unique non-gluconeogenic function for FBP1 in T cells The novel,
catalytically active isoform of FBP1 also holds promise as a tool (or target) for immunotherapy, cancer therapy
and diabetes treatment.
总结
项目成果
期刊论文数量(0)
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AMEETA KELEKAR其他文献
AMEETA KELEKAR的其他文献
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{{ truncateString('AMEETA KELEKAR', 18)}}的其他基金
Role for gluconeogenic enzyme FBP1 in T cell activation
糖异生酶 FBP1 在 T 细胞激活中的作用
- 批准号:
10433367 - 财政年份:2022
- 资助金额:
$ 18.47万 - 项目类别:
Bcl-2 protein Noxa in human T cell metabolism and differentiation
Bcl-2蛋白Noxa在人T细胞代谢和分化中的作用
- 批准号:
10197022 - 财政年份:2020
- 资助金额:
$ 18.47万 - 项目类别:
Bcl-2 protein Noxa in human T cell metabolism and differentiation
Bcl-2蛋白Noxa在人T细胞代谢和分化中的作用
- 批准号:
10064173 - 财政年份:2020
- 资助金额:
$ 18.47万 - 项目类别:
Role of a pro-apoptotic Bcl-2 protein in the survival and death of leukemia cells
促凋亡 Bcl-2 蛋白在白血病细胞存活和死亡中的作用
- 批准号:
8460563 - 财政年份:2011
- 资助金额:
$ 18.47万 - 项目类别:
Role of a pro-apoptotic Bcl-2 protein in the survival and death of leukemia cells
促凋亡 Bcl-2 蛋白在白血病细胞存活和死亡中的作用
- 批准号:
8083459 - 财政年份:2011
- 资助金额:
$ 18.47万 - 项目类别:
Role of a pro-apoptotic Bcl-2 protein in the survival and death of leukemia cells
促凋亡 Bcl-2 蛋白在白血病细胞存活和死亡中的作用
- 批准号:
8298981 - 财政年份:2011
- 资助金额:
$ 18.47万 - 项目类别:
Role of a pro-apoptotic Bcl-2 protein in the survival and death of leukemia cells
促凋亡 Bcl-2 蛋白在白血病细胞存活和死亡中的作用
- 批准号:
8835063 - 财政年份:2011
- 资助金额:
$ 18.47万 - 项目类别:
Role of a pro-apoptotic Bcl-2 protein in the survival and death of leukemia cells
促凋亡 Bcl-2 蛋白在白血病细胞存活和死亡中的作用
- 批准号:
8657904 - 财政年份:2011
- 资助金额:
$ 18.47万 - 项目类别:
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