Defining mechanisms of metabolic-epigenetic crosstalk that drive glioma initiation
定义驱动神经胶质瘤发生的代谢-表观遗传串扰机制
基本信息
- 批准号:10581192
- 负责人:
- 金额:$ 12.42万
- 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:2023-07-01 至 2025-06-30
- 项目状态:未结题
- 来源:
- 关键词:ATAC-seqAddressAdult GliomaAffectBrainBrain NeoplasmsCell Differentiation processCell SeparationCell SizeCellsCentral Nervous System NeoplasmsCessation of lifeChromatinChromatin StructureClinicalCompanionsDNADNA MethylationDataData SetDevelopmentDiseaseEngineeringEnzymesEpigenetic ProcessEvolutionGene ExpressionGene Expression ProfileGene Expression ProfilingGenesGeneticGenetic AnticipationGenetic TranscriptionGenetically Engineered MouseGliomaGliomagenesisGoalsHeterogeneityHumanIn VitroInduced MutationIsocitrate DehydrogenaseKnowledgeLaboratoriesLinkMalignant - descriptorMalignant NeoplasmsMalignant neoplasm of brainMeasuresMetabolicModelingMolecularMolecular AnalysisMusMutationNeurogliaNeuronsNewly DiagnosedOncogenesOncogenicOrganoidsPatternPopulationProcessResistanceSamplingSignal TransductionSpecific qualifier valueSpecimenSystemTestingTimeTissue-Specific Gene ExpressionTissuesUnited StatesWorkalpha ketoglutaratecancer initiationcell fate specificationcell transformationchromatin remodelingcombatepigenomegain of function mutationhistone demethylasehistone methylationin vivoinsightleukemiametabolomemutantmutational statusneuralnew therapeutic targetnovelnovel therapeuticsselective expressionsingle-cell RNA sequencingstandard of carestemstem cellsstem-like celltranscriptometranscriptome sequencingtumor initiationtumorigenesis
项目摘要
PROJECT SUMMARY
Gliomas represent 80% of the 26,000 newly diagnosed cases of malignant brain and central nervous system
tumors in the United States each year and are among the most lethal and treatment-resistant human cancers.
Hot-spot, mono-allelic, gain-of-function mutations in the isocitrate dehydrogenase genes IDH1 and IDH2 are
present in more than 70% of certain subtypes of gliomas, thus representing the genetic hallmark of these
malignant brain tumors. The ‘oncometabolite’ (R)-2-hydroxyglutarate [(R)-2HG], produced by IDH mutant
enzymes, modulates the activities of certain 2-oxoglutarate (2OG) dependent DNA and histone demethylases,
which subsequently promotes neural cell transformation. Accordingly, broad changes in histone and DNA
methylation are strongly associated with IDH mutations in glioma. Despite these discoveries, the precise
molecular mechanisms linking oncometabolite-dependent chromatin remodeling with gliomagenesis remain
obscure. I propose to directly address this knowledge gap and test a new conceptual model to explain
oncometabolite-driven tumorigenesis. In Aim 1, I will perform time-resolved single cell and bulk RNA-seq and
ATAC-seq analyses of the molecular and cellular changes that occur during brain tumor initiation in a novel
genetically engineered mouse (GEM) model of glioma to reveal key mechanisms of (R)-2HG dependent
malignant transformation. In Aim 2, I will conduct integrative analyses of sequencing datasets from human glioma
samples and murine glioma samples from our GEM models to discover functional targets of (R)-2HG in IDH
mutant gliomas. In Aim 3, I will leverage novel mouse brain organoid models to investigate the impact of
oncometabolite activity on neural cell specification during brain development. If successful, my work will provide
a new conceptual framework for understanding the deterministic and stochastic functions of oncometabolite
signaling to chromatin and their influence on cell fate. This advance would deepen our understanding of how
metabolic alterations signal to chromatin in cancer and other diseases. Furthermore, identifying the molecular
processes that functionally link oncometabolites with brain tumor initiation may reveal new therapeutic targets to
combat this disease.
项目总结
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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Yi Xiao其他文献
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