Epigenetic regulation of alcohol tolerance and dependence by methyl CpG binding protein 2
甲基 CpG 结合蛋白 2 对酒精耐受性和依赖性的表观遗传调控
基本信息
- 批准号:9133075
- 负责人:
- 金额:$ 36.78万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-06-01 至 2022-05-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAlcohol abuseAlcohol consumptionAlcohol dependenceAlcoholsAutomobile DrivingBindingBinding ProteinsBirdsBrainBrain regionChromatinChronicComplexDNADependenceDevelopmentDown-RegulationEngineeringEthanolExhibitsExperimental DesignsGene ExpressionGene TargetingGenesGenetic TranscriptionHeavy DrinkingImpaired cognitionLeadLiteratureMeasuresMediatingMethyl-CpG-Binding Protein 2MolecularMolecular ProfilingMusMutant Strains MicePathologicPhenotypePhosphorylationRecording of previous eventsRecruitment ActivityRegulationRegulator GenesRegulonRelapseRett SyndromeRoleSiteSubstance AddictionSystems BiologyTestingTranscription Repressor/CorepressorTreatment EfficacyValidationViral Vectoralcohol effectalcohol exposurealcohol use disorderanxiety-like behaviordifferential expressiondrinkingepigenetic regulationfollow-upgene repressiongenetic signaturegenome-wideinnovationmolecular domainmutantnew therapeutic targetnovelnovel therapeuticsprogramsreconstructionsedativesocialtherapeutic targetvalidation studiesvapor
项目摘要
Summary
Long-term alterations in gene expression programs are believed to be key to the development and
progression of alcohol use disorder (AUD). The methyl CpG binding protein 2 (MeCP2), the causative gene of
Rett syndrome, is a protein that binds methylated DNA and, in turn, recruits transcriptional repressors resulting
in persistent down-regulation of gene expression. We observed that MeCP2 mutant mice with reduced
capacity to recruit transcriptional repressors exhibit a robust alcohol–related phenotype characterized by
heightened sensitivity to the sedative effects of alcohol, reduced alcohol intake in limited access 2-bottle choice
and lack of escalation of drinking after passive induction of dependence.
Recent evidence indicates that MeCP2's primary function is to recruit a transcriptional repressor
complex at sites of methylated DNA through a discrete molecular domain. Importantly, MeCP2 has been found
to regulate a specific set of genes – or regulon – rather than broadly affecting gene expression levels, and we
found significant overlap between alcohol-regulated and MeCP2-regulated genes. Thus, in the present project
we will test the overarching hypothesis that MeCP2-regulated genes are key to alcohol's effects and to the
transition to escalated alcohol drinking in the setting of alcohol dependence. To test the sub-hypothesis that
recruitment of transcriptional repressors by MeCP2 is central to its effects on drinking, we will use MeCP2
mutant mice with reduced capacity to recruit transcriptional repressors in comparison with recently introduced
MeCP2 mutant mice with increased capacity to recruit transcriptional repressors, to provide optimal
perturbation of MeCP2 function for the analysis of MeCP2 regulated gene networks. To test the sub-hypothesis
that specific MeCP2 target genes and modulators are key to the transition to escalated drinking associated
with alcohol dependence, we will use a state of the art systems biology strategy that we recently validated for
the reconstruction and interrogation of genome-wide transcriptional interactomes from brain gene expression
profiles. This approach is centered on unbiased identification of transcriptional regulatory relationships from the
gene expression effects of the perturbations under study, rather than what is known from the literature or under
different sets of perturbations. Rather than identifying long lists of differentially expressed genes, this systems
biology strategy identifies and ranks a small number of genes driving the gene signatures associated with the
phenotype. Thus, specific mechanistic hypotheses on the role of MeCP2 in the effects of alcohol are obtained,
and will then be experimentally validated in paradigms of dependent and non-dependent alcohol drinking.
Ultimately, the results of this study will advance our understanding of the molecular mechanisms behind
excessive alcohol drinking in the setting of dependence and will lay the rationale for the exploitation of specific
MeCP2-regulated genes and modulators for the development of novel therapeutic concepts for AUD.
总结
基因表达程序的长期改变被认为是发展的关键,
酒精使用障碍(AUD)。甲基CpG结合蛋白2(MeCP2)是导致
Rett综合征是一种结合甲基化DNA的蛋白质,反过来,招募转录抑制因子,
持续下调基因表达。我们观察到MeCP2突变小鼠,
招募转录抑制因子的能力表现出强大的酒精相关表型,其特征在于
对酒精镇静作用的敏感性提高,在有限的2瓶选择中减少酒精摄入
以及被动诱导依赖后饮酒没有升级。
最近的证据表明MeCP2的主要功能是募集转录抑制因子
通过离散的分子结构域在甲基化DNA的位点形成复合物。重要的是,已经发现MeCP2
调节一组特定的基因--或调节子--而不是广泛地影响基因表达水平,
发现酒精调节基因和MeCP2调节基因之间存在显著重叠。因此,在本项目中,
我们将测试一个总体假设,即MeCP2调节的基因是酒精作用的关键,
在酒精依赖的情况下过渡到逐步增加的饮酒。为了检验子假设,
MeCP2募集转录抑制因子是其对饮酒影响的核心,我们将使用MeCP2
与最近引入的基因突变小鼠相比,
MeCP2突变小鼠具有增加的募集转录抑制因子的能力,以提供最佳的
MeCP2功能的扰动用于分析MeCP2调节的基因网络。为了检验子假设
特定的MeCP2靶基因和调节剂是向饮酒相关的逐步升级过渡的关键,
对于酒精依赖,我们将使用我们最近验证的最先进的系统生物学策略,
脑基因表达全基因组转录相互作用组的重建和研究
数据区.这种方法是集中在公正的识别转录调控关系,从
研究中的扰动对基因表达的影响,而不是从文献中已知的或根据
不同的扰动该系统不是识别一长串差异表达基因,
生物学策略识别并排列了驱动与基因相关的基因签名的少量基因,
表型因此,获得了关于MeCP2在酒精作用中的作用的具体机制假设,
然后将在依赖性和非依赖性饮酒的范例中进行实验验证。
最终,这项研究的结果将促进我们对背后分子机制的理解。
过度饮酒的依赖性,并将奠定理由,利用具体的
MeCP2调节的基因和调节剂用于开发AUD的新治疗概念。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
PIETRO P SANNA其他文献
PIETRO P SANNA的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('PIETRO P SANNA', 18)}}的其他基金
Single nucleus gene expression in moderate and compulsive opioid self-administration in a rodent model of HIV
HIV啮齿动物模型中度和强迫性阿片类药物自我给药的单核基因表达
- 批准号:
10682961 - 财政年份:2023
- 资助金额:
$ 36.78万 - 项目类别:
Transcriptional adaptations driving the intensification of alcohol-seeking in dependent rats undergoing prolonged abstinence
转录适应导致长期戒酒的依赖性大鼠对酒精的渴求加剧
- 批准号:
10540014 - 财政年份:2022
- 资助金额:
$ 36.78万 - 项目类别:
Single nucleus gene expression in moderate and compulsive drug self-administration in a rodent model of HIV
HIV啮齿动物模型中度和强迫性自我给药的单核基因表达
- 批准号:
10592330 - 财政年份:2022
- 资助金额:
$ 36.78万 - 项目类别:
Single nucleus gene expression in moderate and compulsive drug self-administration in a rodent model of HIV
HIV啮齿动物模型中度和强迫性自我给药的单核基因表达
- 批准号:
10454706 - 财政年份:2022
- 资助金额:
$ 36.78万 - 项目类别:
Transcriptional adaptations driving the intensification of alcohol-seeking in dependent rats undergoing prolonged abstinence
转录适应导致长期戒酒的依赖性大鼠对酒精的渴求加剧
- 批准号:
10686229 - 财政年份:2022
- 资助金额:
$ 36.78万 - 项目类别:
An Innovative Approach to Identify Correctors of Metabolic Complications in HIV
一种识别 HIV 代谢并发症校正因子的创新方法
- 批准号:
10395011 - 财政年份:2021
- 资助金额:
$ 36.78万 - 项目类别:
Systems biology of RNA Modifications in HIV/AIDS and Substance Use Disorders
HIV/艾滋病和药物滥用疾病中 RNA 修饰的系统生物学
- 批准号:
10318620 - 财政年份:2018
- 资助金额:
$ 36.78万 - 项目类别:
Identification of small molecules for neurological complications of HIV and substance abuse comorbidity
鉴定治疗 HIV 神经并发症和药物滥用合并症的小分子
- 批准号:
10343707 - 财政年份:2018
- 资助金额:
$ 36.78万 - 项目类别:
Neural substrates of opiate-HIV interactions.
阿片类药物与艾滋病毒相互作用的神经基质。
- 批准号:
9344568 - 财政年份:2016
- 资助金额:
$ 36.78万 - 项目类别:
Cocaine abuse and plasticity in the lateral hypothalamus
可卡因滥用和外侧下丘脑的可塑性
- 批准号:
8989877 - 财政年份:2015
- 资助金额:
$ 36.78万 - 项目类别:
相似海外基金
RII Track-4:NSF: From the Ground Up to the Air Above Coastal Dunes: How Groundwater and Evaporation Affect the Mechanism of Wind Erosion
RII Track-4:NSF:从地面到沿海沙丘上方的空气:地下水和蒸发如何影响风蚀机制
- 批准号:
2327346 - 财政年份:2024
- 资助金额:
$ 36.78万 - 项目类别:
Standard Grant
BRC-BIO: Establishing Astrangia poculata as a study system to understand how multi-partner symbiotic interactions affect pathogen response in cnidarians
BRC-BIO:建立 Astrangia poculata 作为研究系统,以了解多伙伴共生相互作用如何影响刺胞动物的病原体反应
- 批准号:
2312555 - 财政年份:2024
- 资助金额:
$ 36.78万 - 项目类别:
Standard Grant
How Does Particle Material Properties Insoluble and Partially Soluble Affect Sensory Perception Of Fat based Products
不溶性和部分可溶的颗粒材料特性如何影响脂肪基产品的感官知觉
- 批准号:
BB/Z514391/1 - 财政年份:2024
- 资助金额:
$ 36.78万 - 项目类别:
Training Grant
Graduating in Austerity: Do Welfare Cuts Affect the Career Path of University Students?
紧缩毕业:福利削减会影响大学生的职业道路吗?
- 批准号:
ES/Z502595/1 - 财政年份:2024
- 资助金额:
$ 36.78万 - 项目类别:
Fellowship
Insecure lives and the policy disconnect: How multiple insecurities affect Levelling Up and what joined-up policy can do to help
不安全的生活和政策脱节:多种不安全因素如何影响升级以及联合政策可以提供哪些帮助
- 批准号:
ES/Z000149/1 - 财政年份:2024
- 资助金额:
$ 36.78万 - 项目类别:
Research Grant
感性個人差指標 Affect-X の構築とビスポークAIサービスの基盤確立
建立个人敏感度指数 Affect-X 并为定制人工智能服务奠定基础
- 批准号:
23K24936 - 财政年份:2024
- 资助金额:
$ 36.78万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
How does metal binding affect the function of proteins targeted by a devastating pathogen of cereal crops?
金属结合如何影响谷类作物毁灭性病原体靶向的蛋白质的功能?
- 批准号:
2901648 - 财政年份:2024
- 资助金额:
$ 36.78万 - 项目类别:
Studentship
ERI: Developing a Trust-supporting Design Framework with Affect for Human-AI Collaboration
ERI:开发一个支持信任的设计框架,影响人类与人工智能的协作
- 批准号:
2301846 - 财政年份:2023
- 资助金额:
$ 36.78万 - 项目类别:
Standard Grant
Investigating how double-negative T cells affect anti-leukemic and GvHD-inducing activities of conventional T cells
研究双阴性 T 细胞如何影响传统 T 细胞的抗白血病和 GvHD 诱导活性
- 批准号:
488039 - 财政年份:2023
- 资助金额:
$ 36.78万 - 项目类别:
Operating Grants
How motor impairments due to neurodegenerative diseases affect masticatory movements
神经退行性疾病引起的运动障碍如何影响咀嚼运动
- 批准号:
23K16076 - 财政年份:2023
- 资助金额:
$ 36.78万 - 项目类别:
Grant-in-Aid for Early-Career Scientists














{{item.name}}会员




