The metabolic-epigenetic axis in memory
记忆中的代谢-表观遗传轴
基本信息
- 批准号:9764788
- 负责人:
- 金额:$ 44.73万
- 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:2019-05-15 至 2024-04-30
- 项目状态:已结题
- 来源:
- 关键词:AbstinenceAcetate-CoA LigaseAcetatesAcetyl Coenzyme AAlcohol abuseAlcoholic beverage heavy drinkerAlcoholsAttentionBehaviorBehavioralBindingBrainCRISPR/Cas technologyCarbonCell NucleusCellsChromatinChromatin LoopCytoplasmDataDepositionDiseaseDorsalEnhancersEnzymesEpigenetic ProcessEthanolFamily memberFutureGene ExpressionGenerationsGenesGeneticGenetic TranscriptionGenomeGenomicsHigher Order Chromatin StructureHippocampus (Brain)Histone AcetylationHistone DeacetylaseHistonesHumanIn VitroInvestigationLearningLinkMass Spectrum AnalysisMediatingMemoryMemory impairmentMental disordersMetabolicMetabolismMitochondriaModelingModificationMolecularMusNeurobiologyNeurogliaNeurologicNeuronal DifferentiationNeuronal PlasticityNeuronsNuclearPathway interactionsPharmaceutical PreparationsPharmacologyPharmacotherapyPhenotypePlayPopulationPost-Translational Protein ProcessingProteinsRegulationRegulatory ElementRegulatory PathwayRelapseRodentRoleSocietiesSubstance Use DisorderTherapeuticTherapeutic InterventionTranscriptTranscriptional RegulationWorkaddictionalcohol behavioralcohol exposurealcohol use disorderbasechromatin modificationchromatin remodelingclassical conditioningcognitive processcravingepigenetic regulationepigenomegenome-widehistone acetyltransferaseimprovedin vivoinhibitor/antagonistknock-downmouse modelneuropsychiatrynovelnovel therapeuticsobject recognitionpreferencepromoterprotein complexrecruitresponsesmall hairpin RNAsmall moleculespatial memorytargeted treatmenttherapeutic targettooltranscriptome sequencing
项目摘要
Abstract
Understanding the molecular machinery underlying learning is critical to improve therapies for memory-related
disorders that continue to burden our society. We recently identified a connection between cellular metabolism,
epigenetic regulation, and memory-related neuronal plasticity. We found that ACSS2, a metabolic enzyme that
generates acetyl-CoA is chromatin-bound in hippocampal neurons and required for long-term spatial memory,
a cognitive process that relies on histone acetylation and gene expression.
While these results established a strong functional link between nuclear acetyl-CoA generation by
ACSS2, histone acetylation, transcription and memory, the exact molecular underpinnings of this metabolic-
epigenetic axis remain to be elucidated. Here we propose to explore this phenomenon in further mechanistic
detail. In particular, we aim to identify ACSS2-associated proteins, examine the mechanism of ACSS2
recruitment to specific genes, and identify higher-order structures that contribute to ACSS2-mediated
transcriptional regulation via chromatin looping. Moreover, we will explore dorsal hippocampal transcriptional
and epigenetic changes that accompany memory formation in a hippocampus-dependent mammalian learning
model (spatial object recognition). We will assess genome-wide changes in transcript abundance and
chromatin accessibility, study the enrichment of histone post-translational modifications, and the re-distribution
of ACSS2 and select histone acetyl marks. Finally, using an array of pharmacological and genetic tools, we will
assess the contribution of ACSS2 to the observed transcriptional, epigenetic and behavioral phenotypes.
In addition, our preliminary data under Aim 3 indicate that ethanol-derived acetyl-groups are rapidly
incorporated into neuronal chromatin in an ACSS2-dependent manner. This remarkably rapid epigenetic
response might underlie alcohol-induced transcriptional and behavioral maladaptations in heavy drinkers.
Indeed, we found that treating primary hippocampal neurons with acetate (the alcohol-derived metabolite and
direct substrate of ACSS2) upregulates learning and memory-related genes and that ACSS2 reduction
eliminates alcohol-related associative learning in conditioned place preference. We will explore hippocampal
transcriptional and epigenetic changes associated with alcohol exposure in mice in vivo and assess the
contribution of ACSS2 to molecular and cellular alterations induced by alcohol. Further, we will assess the
effect of small molecule ACSS2 inhibitors on alcohol-related behaviors, as a basis for future therapeutic
interventions.
Overall, this work will significantly advance the field by characterizing the metabolic-epigenetic axis in
the context of learning neurobiology. Furthermore, we expect our studies to identify efficacious novel
therapeutic avenues for memory impairments and associated neurological and psychiatric conditions.
摘要
项目成果
期刊论文数量(0)
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{{ truncateString('SHELLEY L BERGER', 18)}}的其他基金
Epigenetic regulation by tumor suppressor p53
抑癌基因 p53 的表观遗传调控
- 批准号:
9674890 - 财政年份:2018
- 资助金额:
$ 44.73万 - 项目类别:
Epigenetic regulation of extreme longevity differences in ant castes
蚂蚁种姓极端长寿差异的表观遗传调控
- 批准号:
10222537 - 财政年份:2017
- 资助金额:
$ 44.73万 - 项目类别:
Epigenetic regulation of extreme longevity differences in ant castes
蚂蚁种姓极端长寿差异的表观遗传调控
- 批准号:
10608683 - 财政年份:2017
- 资助金额:
$ 44.73万 - 项目类别:
Epigenetic regulation of extreme longevity differences in ant castes
蚂蚁种姓极端长寿差异的表观遗传调控
- 批准号:
10708181 - 财政年份:2017
- 资助金额:
$ 44.73万 - 项目类别:
Epigenetic Changes associated with Neurodegenerative Diseases
与神经退行性疾病相关的表观遗传变化
- 批准号:
8889810 - 财政年份:2012
- 资助金额:
$ 44.73万 - 项目类别:
Epigenetic Changes associated with Neurodegenerative Diseases
与神经退行性疾病相关的表观遗传变化
- 批准号:
8273529 - 财政年份:2012
- 资助金额:
$ 44.73万 - 项目类别:
Epigenetic Changes associated with Neurodegenerative Diseases
与神经退行性疾病相关的表观遗传变化
- 批准号:
8431739 - 财政年份:2012
- 资助金额:
$ 44.73万 - 项目类别:














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