Metabolic control of exit from naïve pluripotency
退出幼稚多能性的代谢控制
基本信息
- 批准号:10625259
- 负责人:
- 金额:$ 5.27万
- 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:2022-04-15 至 2026-04-14
- 项目状态:未结题
- 来源:
- 关键词:ATP Citrate (pro-S)-LyaseAcetatesAcetyl Coenzyme AAcetylationAffectBindingBiochemical ReactionBiological AssayC-terminal binding proteinCell Fate ControlCellsChIP-seqChemicalsChromatinCitratesCompetenceComplexCytoplasmDataDepositionDevelopmentDiseaseEmbryonic DevelopmentEnzymesEquilibriumExcisionExhibitsExperimental GeneticsGene ExpressionGene Expression RegulationGeneticGenetic TranscriptionGenomicsGlucoseGoalsHistone AcetylationLIF geneLaboratoriesLinkMEKsMalatesMass Spectrum AnalysisMeasuresMediatingMemorial Sloan-Kettering Cancer CenterMetabolicMetabolic ControlMetabolic PathwayMetabolismMitochondriaModificationMusNADHOutputOxidation-ReductionPhysiciansProcessPyruvateRegulationReporterReportingResearch ProposalsScientistShapesSignal TransductionSpecific qualifier valueSupplementationTestingTrainingTranscription RepressorWestern BlottingWorkantiportercareercell fate specificationcell typechromatin remodelingcitrate carrierclinical trainingcofactordefined contributiondevelopmental diseaseembryonic stem cellexperimental studygenetic approachgenomic locushistone modificationinsightmutantpharmacologicpluripotencypluripotency factorprogramsself-renewalsensorstem cell differentiationtool
项目摘要
PROJECT SUMMARY
Cellular metabolic pathways exhibit remarkable plasticity across different cell types in both development and
disease. In addition to accompanying changes in cell state, metabolic rewiring has been shown to drive cell fate
decisions programs by altering the chromatin landscape. The deposition of chemical modifications that decorate
chromatin requires the intermediates of metabolic pathways, and several enzymes that remove these marks use
metabolites as part of their enzymatic reaction. Therefore, fluctuations in metabolite levels have the capacity to
shape chromatin to effect cell fate-specific gene expression, but the metabolic changes that drive chromatin
reorganization and the enzymes that mediate metabolic control of cell fate during early development remain
largely unknown. We have previously identified specific metabolites that control self-renewal of mouse embryonic
stem cells (ESCs). Whether metabolism is altered as ESCs exit the self-renewing pluripotent state, and whether
these metabolic changes are required for multi-lineage differentiation remains an open question.
The goal of this research proposal is to characterize the metabolic rewiring that occurs during exit from
naïve pluripotency and to determine the mechanisms by which this rewiring controls mouse ESC
differentiation. Our preliminary data indicate that exit from naïve pluripotency is accompanied by an increase
in the mitochondrial export of citrate. In Aim 1, we will use genetic and pharmacologic approaches to target the
mitochondrial citrate transporter SLC25A1 or the downstream citrate-catabolizing enzyme ATP-citrate lyase to
test the hypothesis that mitochondrially-derived citrate is required for early differentiation. We will investigate
whether this metabolic change regulates cell fate through the deposition of citrate-derived histone acetylation
marks. Preliminary data also shows changes in cellular redox state marked by an increase in the cytosolic
NAD+/NADH ratio during early differentiation. In Aim 2, we will determine if this metabolic change is required for
exit from naïve pluripotency by modulating the NAD+/NADH ratio using pharmacological or genetic tools. Further
experiments will identify the mechanism by which cellular redox state signals to the chromatin landscape to
dictate cell fate. These studies will reveal the mechanisms of metabolic control during exit from naïve pluripotency
and will provide critical insight into how metabolic regulation contributes to changes in cell identity during
embryonic development. The work and training plan outlined in this proposal will be completed in the laboratory
of Dr. Lydia Finley with the co-advisement of Dr. Kristian Helin at Memorial Sloan Kettering Cancer Center and
will ideally prepare the applicant for further clinical training and a career as an independent physician-scientist.
项目总结
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Benjamin Tonnu Jackson其他文献
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{{ truncateString('Benjamin Tonnu Jackson', 18)}}的其他基金
Metabolic control of exit from naïve pluripotency
退出幼稚多能性的代谢控制
- 批准号:
10387708 - 财政年份:2022
- 资助金额:
$ 5.27万 - 项目类别:
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