Center for Alcohol Research in Epigenetics
表观遗传学酒精研究中心
基本信息
- 批准号:10380644
- 负责人:
- 金额:$ 165.5万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-04-01 至 2025-03-31
- 项目状态:未结题
- 来源:
- 关键词:ATAC-seqAberrant DNA MethylationAlcohol consumptionAlcohol dependenceAlcohol withdrawal syndromeAlcoholismAmygdaloid structureAnatomyAnimal ModelAnimalsAnxietyAreaAutopsyBehavioralBioinformaticsBrainBrain regionCRISPR/Cas technologyCellsChIP-seqCharacteristicsChemicalsChromatinChromatin StructureChronicClustered Regularly Interspaced Short Palindromic RepeatsCommunitiesCommunity OutreachDNADNA MethylationDNA Modification MethylasesDNA Modification ProcessDataData AnalysesDependenceDevelopmentDiseaseElectrophysiology (science)EmotionalEnzymesEpigenetic ProcessFunctional disorderFundingGene ExpressionGene Expression ProfileGene Expression RegulationGeneral PopulationGenesGeneticGenomeGlucocorticoid ReceptorHigh School StudentHippocampus (Brain)Histone AcetylationHistone DeacetylaseHistonesHumanIntakeInvestigationKnowledgeLeadLinkLysineMaintenanceMediatingMedical StudentsMental DepressionMethylationModificationMolecularMolecular BiologyMolecular TargetMotivationMutationNeuroimmuneNeuropeptidesNeurophysiology - biologic functionNeurosciencesNeurotransmittersPathogenesisPathway AnalysisPathway interactionsPatternPharmacotherapyPilot ProjectsPlayPostdoctoral FellowPrefrontal CortexProtein FamilyPsychiatryPublic HealthRNARattusRegulationResearchResearch PersonnelResearch Project GrantsResourcesRewardsRodent ModelRoleScientistSelf AdministrationSignal TransductionSignaling MoleculeSmall Interfering RNAStressSynapsesSystemTestingTimeTissue-Specific Gene ExpressionTranslational ResearchVentral Tegmental AreaVisitWithdrawaladdictionalcohol effectalcohol exposurealcohol researchalcohol use disorderbehavioral phenotypingbrain circuitrychromatin remodelingdemethylationdeter alcohol usedrinkingenvironmental enrichment for laboratory animalsepigenetic markerepigenomeepitranscriptomeepitranscriptomicsgene networkgenome-widegraduate studenthigher educationhistone acetyltransferasehistone methyltransferasehistone modificationhypothalamic-pituitary-adrenal axisinterdisciplinary approachmolecular phenotypeneuroadaptationneurosteroidsneurotrophic factornew therapeutic targetnext generationnoveloutreach programpre-clinical researchproblem drinkersmall hairpin RNAtraining opportunitytranscriptometranscriptome sequencingtranscriptomicsundergraduate studentviral gene deliverywhole genome
项目摘要
Project Summary:
Alcohol use disorder (AUD) can be characterized by a pattern of compulsive alcohol drinking or loss of control
over alcohol drinking. The positive and negative effects of ethanol appear to be regulated by genetic and
epigenetic changes in several key brain regions. Long-term alcohol use causes structural and functional
changes in the prefrontal cortex (PFC), hippocampus, amygdala, and ventral tegmental area of the brain which
may drive behavioral phenotypes, such as anxiety, depression, motivation, and increased alcohol drinking.
Several protein families such as histone deacetylases (HDACs), histone acetyltransferases (HATs), histone
methyltransferases (HMTs), DNA methyltransferases (DNMTs), lysine demethylases, and DNA demethylases
are important players in chromatin remodeling within the genome and are altered by chronic ethanol exposure
and withdrawal. However, the interplay between these different epigenetic modifiers lead to an altered state of
the epigenome and their role in transcriptomic changes associated with adaptations in the reward and stress
systems in the brain (VTA, amygdala, PFC, and hippocampus) during AUD is still unclear. The overall aim of
this Alcohol Research Center is to evaluate the epigenetic and genetic basis of molecular changes in
the brain that underlie behavioral changes in AUD. This P50 application entitled “Center for Alcohol
Research in Epigenetics (CARE)” consists of four highly inter-related preclinical and translational research
projects [research project #1, VTA, (Brodie /Glover), research project #2, Amygdala, (Pandey), research project
#3, Hippocampus, (Lasek) and research project #4, PFC, (Guidotti/Grayson/Gavin)] and two current pilot
projects [pilot project #1 (Epigenetic biomarkers in AUD), and pilot project #2 (Epitranscriptomic modifications in
AUD)], and three Cores [Administrative (Pandey/Lasek), Epigenetics (Grayson/Maienschein-Cline), and
Behavioral Core (Glover/Zhang)]. In addition, the CARE will serve as an important resource and provide a
scientifically enriched environment for training opportunities for the next generation of neuroscientists studying
AUD and will disseminate scientific knowledge of AUD to the general public through a community outreach
program. The primary thematic focus of CARE, as a whole, will be to mechanistically link emerging novel
molecular targets identified by whole-genome approaches (ATAC-seq, ChIP-seq, RNA-seq, and DNA
methylation/demethylation EPIC array) in the proposed brain circuitry to behavioral phenotypes. Mechanistic
approaches (CRISPR-dCas9, shRNA, siRNA, chemogenetic) will be used to manipulate the epigenome
through alterations of either histone acetylation/methylation mechanisms or DNA methylation mechanisms, in
key brain circuitry that regulates behavioral phenotypes associated with AUD (anxiety, depression, motivation,
and alcohol drinking) in order to better understand the pathophysiology of AUD and develop better
pharmacotherapy.
项目摘要:
酒精使用障碍(AUD)的特点是强迫性饮酒或失控的模式
因为喝酒乙醇的积极和消极影响似乎受到遗传和
几个关键大脑区域的表观遗传变化。长期饮酒会导致结构性和功能性损伤
前额叶皮层(PFC)、海马、杏仁核和腹侧被盖区的变化,
可能驱动行为表型,如焦虑、抑郁、动机和饮酒增加。
几种蛋白质家族,如组蛋白脱乙酰酶(HDAC)、组蛋白乙酰转移酶(HAT)、组蛋白乙酰
甲基转移酶(HMT)、DNA甲基转移酶(DNMT)、赖氨酸脱甲基酶和DNA脱甲基酶
是基因组内染色质重塑的重要参与者,并因慢性乙醇暴露而改变
和撤退。然而,这些不同的表观遗传修饰剂之间的相互作用导致了一种改变的状态,
表观基因组及其在与奖励和压力适应相关的转录组变化中的作用
AUD期间大脑中的神经系统(VTA、杏仁核、PFC和海马)的变化仍不清楚。的总体目标
这个酒精研究中心是评估分子变化的表观遗传和遗传基础,
导致AUD行为改变的大脑这个名为"酒精中心"的P50申请
表观遗传学研究(CARE)”由四个高度相关的临床前和转化研究组成
研究项目[研究项目#1,VTA,(Brodie/格洛弗),研究项目#2,杏仁核,(Pandey),研究项目
#3,海马,(Lasek)和研究项目#4,PFC,(Guidotti/Grayson/Gavin)]和两个当前的试点项目
项目[试点项目#1(AUD中的表观遗传生物标志物)和试点项目#2(AUD中的表观遗传修饰)]。
AUD)]和三个核心[管理(Pandey/Lasek),表观遗传学(Grayson/Maienschein-Cline),和
行为核心(格洛弗/张)]。此外,援外社将作为一个重要的资源,
科学丰富的环境,为下一代神经科学家提供培训机会,
AUD,并将通过社区外展活动向公众传播AUD的科学知识
程序. CARE的主要主题重点,作为一个整体,将是机械地连接新兴的小说,
通过全基因组方法鉴定的分子靶点(ATAC-seq、ChIP-seq、RNA-seq和DNA
甲基化/去甲基化EPIC阵列)在所提出的脑回路中的行为表型。机械论
方法(CRISPR-dCas9、shRNA、siRNA、化学遗传学)将用于操纵表观基因组
通过改变组蛋白乙酰化/甲基化机制或DNA甲基化机制,
调节与AUD相关的行为表型(焦虑,抑郁,动机,
和饮酒),以便更好地了解AUD的病理生理学,
药物治疗.
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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SUBHASH C. PANDEY的其他文献
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{{ truncateString('SUBHASH C. PANDEY', 18)}}的其他基金
BLRD Research Career Scientist Award Application
BLRD 研究职业科学家奖申请
- 批准号:
10594004 - 财政年份:2022
- 资助金额:
$ 165.5万 - 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:
10188341 - 财政年份:2019
- 资助金额:
$ 165.5万 - 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:
$ 165.5万 - 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:
$ 165.5万 - 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:
$ 165.5万 - 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:
$ 165.5万 - 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:
$ 165.5万 - 项目类别:
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