Cellular signaling in alcoholism
酒精中毒中的细胞信号传导
基本信息
- 批准号:10454864
- 负责人:
- 金额:--
- 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:2019-04-01 至 2024-03-31
- 项目状态:已结题
- 来源:
- 关键词:AcetylationAcuteAddictive BehaviorAlcohol abuseAlcohol consumptionAlcohol dependenceAlcohol withdrawal syndromeAlcoholismAlcoholsAmygdaloid structureAnatomyAnti-Anxiety AgentsAnxietyAnxiety DisordersAttenuatedBehaviorBehavioralBrainBrain-Derived Neurotrophic FactorCREBBP geneCaringCell NucleusChromatinChromatin StructureChronicConvulsionsCytoskeletonDNA MethylationDataDendritic SpinesDevelopmentDrug AddictionDrug abuseE1A-associated p300 proteinEP300 geneEpigenetic ProcessEthanolFutureGene ExpressionGene Expression RegulationGeneral PopulationGenesGenetic TranscriptionHealthHistone AcetylationHistonesInfusion proceduresLysineMedialMediatingMessenger RNAMethylationMicroRNAsMicroarray AnalysisMissionMolecularMotivationPathway interactionsPatientsPharmacotherapyPlayPopulationPost-Transcriptional RegulationPost-Traumatic Stress DisordersProteinsRattusRegulationReportingRiskRoleSignal TransductionSmall Interfering RNAStructureSymptomsSynapsesSynaptic plasticitySynaptophysinTestingTherapeutic AgentsTimeTrans-ActivatorsTranscription CoactivatorTranslational RepressionTremorUntranslated RNAUp-RegulationVeteransWithdrawalWithdrawal Symptomalcohol effectalcohol exposurealcohol use disorderalcoholism therapyanxiety-like behaviorbasechromatin remodelingchronic alcohol ingestiondifferential expressiondrinking behaviorexperimental studyhistone modificationmiRNA expression profilingnegative affectneural circuitnovelpreventproblem drinkerprotein complexpublic health relevancerecruit
项目摘要
Alcohol use disorder (AUD) is a major health concern in the VA population as well as in the general population.
An integral part of the mission of the VA is to provide care for VA patients suffering from alcohol and/or drug
abuse problems. Cessation of chronic ethanol consumption leads to development of negative withdrawal
symptoms that promote increased alcohol drinking and maintain alcohol addictive behaviors. Amygdaloid brain
structures are known to play an important role in anxiety behaviors as well as in alcohol addiction. The
molecular mechanisms, and particularly the role of non-coding microRNAs (miRNAs; 21-23 nt), in specific
neural circuits of the brain that are involved in the development of anxiety-like behaviors during ethanol
withdrawal after chronic ethanol exposure are not well understood. Using microarray analysis, we recently
reported that acute ethanol exposure produces differential miRNA expression in the amygdala. This data
revealed that expression of miRNA-494 (miR-494) was decreased by acute ethanol exposure and its target
gene mRNA levels were increased and involved in the regulation of anxiolytic effects of ethanol. This proposal
will extend these studies and establish the role of miR-494 in the regulation of chromatin and synaptic
remodeling in the amygdala, leading to negative affective state of alcoholism. In addition, this proposal will
identify changes in the expression of other miRNAs during alcohol dependence and then propose experiments
to investigate how these changes in miRNAs coordinate shifts in the expression of target gene pathways that
regulate anxiety-like behaviors during withdrawal after chronic ethanol exposure. We hypothesize that
ethanol withdrawal after chronic exposure will produce differential expression of several miRNAs, and
one of these may be miR-494. The upregulation of miR-494 will induce changes in target genes that
regulate synaptic plasticity and dendritic spines in the amygdala which may underlie the development
of anxiety-like behaviors during ethanol withdrawal. The specific aims of the proposal are: 1) To perform
miRNA expression profiling using a microarray approach in the amygdala of rats during ethanol withdrawal
after chronic ethanol exposure. The emerging miRNAs will be validated and changes in the expression of their
putative target genes will also be examined. 2) To examine if a) miR-494 antagomir infusion in the CeA or
acute ethanol challenge will attenuate anxiety-like behaviors, deficits in the expression (mRNA and protein) of
direct targets (Cbp, p300, Cited2) and indirect targets (Bdnf, Arc, and synaptophysin) as well as deficits in
synapses and dendritic spines in the amygdala of rats during ethanol withdrawal after chronic ethanol
exposure and b) synthetic mimics of miR-494 infused into CeA of control rats will provoke anxiety-like
behaviors and reduce the expression of target genes in the amygdala. 3) To examine if the effects of CeA
infusion of a Cited2 siRNA in control rats will a) produce anxiety-like behaviors, thus mimicking withdrawal-
associated anxiety and b) prevent the anxiolytic effects produced by acute ethanol in control rats. Behavioral
changes will be due to decreased expression of Cited2 and associated reductions in synapses and dendritic
spines in the CeA of rats. The proposed studies will provide new information on the regulation of miRNA
expression and their target genes in the amygdala that may be involved in the abnormal synaptic
plasticity observed during alcohol dependence, and will also identify novel miRNA targets for the
development of potential drugs for the treatment of AUD.
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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{{ truncateString('SUBHASH C. PANDEY', 18)}}的其他基金
Alcohol Research Training in epigenetics and pathophysiology (ARTEP)
表观遗传学和病理生理学酒精研究培训 (ARTEP)
- 批准号:
10188341 - 财政年份:2019
- 资助金额:
-- - 项目类别:
Alcohol Research Training in epigenetics and pathophysiology (ARTEP)
表观遗传学和病理生理学酒精研究培训 (ARTEP)
- 批准号:
10645144 - 财政年份:2019
- 资助金额:
-- - 项目类别:
Alcohol Research Training in epigenetics and pathophysiology (ARTEP)
表观遗传学和病理生理学酒精研究培训 (ARTEP)
- 批准号:
10442535 - 财政年份:2019
- 资助金额:
-- - 项目类别:
Neuronal PARP activity in fetal alcohol spectrum disorders
胎儿酒精谱系障碍中的神经元 PARP 活性
- 批准号:
10152472 - 财政年份:2017
- 资助金额:
-- - 项目类别:
Neuronal PARP activity in fetal alcohol spectrum disorders
胎儿酒精谱系障碍中的神经元 PARP 活性
- 批准号:
9917673 - 财政年份:2017
- 资助金额:
-- - 项目类别:
1/1 NADIA U24 Epigenetic/Molecular Scientific Resource Core
1/1 NADIA U24 表观遗传学/分子科学资源核心
- 批准号:
10686048 - 财政年份:2015
- 资助金额:
-- - 项目类别:
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