Novel Transcription Factors in Stimulant and Opiate Action

兴奋剂和阿片类药物作用中的新型转录因子

• 批准号: 10306368
• 负责人: ERIC J. NESTLER
• 金额: $ 25.28万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-15 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10306368
• 关键词: Acute; Animal Model; Architecture; Autopsy; Behavior Control; Behavioral; Big Data; Binding; Binding Sites; Bioinformatics; Biological Assay; Brain; Brain region; CREB1 gene; ChIP-seq; Chromatin; Chronic; Cocaine; Cocaine Dependence; Cocaine use disorder; Complement; Complex; DNA; Data; Data Set; Development; Disease; Drug Addiction; E2F transcription factors; E2F3 protein; Exposure to; Family; Functional disorder; Gene Expression; Genes; Genetic Transcription; Genome; Goals; Human; Investigation; Laboratories; Link; Literature; Maps; Medial; Mediating; Mediator of activation protein; Modeling; Mus; Neurobiology; Neurons; Nucleus Accumbens; Opiate Addiction; Opioid; Persons; Phenotype; Play; Prefrontal Cortex; Program Research Project Grants; Protein Isoforms; Proteins; Public Health; RNA Splicing; RNA analysis; RXR; Recording of previous events; Regulation; Reporting; Rodent; Role; Self Administration; Signal Transduction; Stimulant; Substance Use Disorder; Transcriptional Regulation; Tretinoin; Validation; Work; addiction; base; behavioral genomics; behavioral phenotyping; behavioral response; bone; cell type; chromatin immunoprecipitation; cocaine exposure; cocaine self-administration; deep sequencing; desensitization; drug action; drug of abuse; genome-wide; knock-down; novel; opioid abuse; overexpression; promoter; response; stimulant dependence; transcription factor; transcriptome sequencing; virtual

PROJECT SUMMARY/ABSTRACT– PROJECT 1 Project 1's objective is to characterize several novel transcription factors, not previously implicated in addiction, in mediating the lasting actions of stimulant and opiate drugs of abuse in nucleus accumbens (NAc) and prefrontal cortex (PFC). Virtually all prior studies of transcription factors in addiction have taken a candidate approach. This is in marked contrast to an unbiased approach of using “big data” to deduce, in an open-ended manner, those factors that are most important in mediating specific aspects of the complex addiction phenotype. We utilize this more powerful approach by taking advantage of large-scale RNA-seq and related datasets from rodent addiction models and humans with substance use disorders to identify those factors that appear to play particularly critical roles in drug action. We focus on cell type-specific actions of three of the most highly ranked transcription factors from our PPG’s datasets: E2F3, ZFP189, and RXR. For example, ~25% of all genes that display primed or desensitized changes in expression in NAc as a result of past cocaine self-administration are predicted to be direct targets of E2F3. Based solely on these bioinformatics predictions, we have generated robust preliminary data to validate the importance of each of these transcription factors in drug addiction and now propose to better understand their actions. We will complete characterization of their role in NAc in controlling behavioral responses to cocaine in self- administration assays as well as map their target genes on a genome-wide basis. Both of these efforts will be performed in a cell type-specific manner, as we have evidence for some of the factors playing different roles in different neuronal types in this brain region. This work in animal models will be complemented by studies of humans with cocaine use disorders, where we already have preliminary evidence for their abnormal regulation. We will extend these studies to PFC, where we have found that a different E2F3 splice isoform controls behavioral and genomic responses to cocaine, as well as to opiate models where we know that these factors also show prominent dysregulation. Together, this work will reveal new transcriptional mechanisms underlying cocaine and opiate addiction.

项目摘要/摘要--项目1 项目1‘S的目标是鉴定几个新的转录因子，这些转录因子以前没有涉及到 成瘾，在介导兴奋剂和阿片类药物滥用的持久作用的伏核(NAC) 和前额叶皮质(PFC)。几乎所有先前对转录因子在成瘾中的研究都采取了 候选人进场。这与在一种不带偏见的方法中使用“大数据”来推断形成鲜明对比 以开放的方式，那些在调解复杂的特定方面最重要的因素 成瘾表型。我们利用这种更强大的方法，利用大规模的rna-seq和 来自啮齿动物成瘾模型和患有物质使用障碍的人类的相关数据，以识别这些 在毒品行动中似乎起着特别关键作用的因素。我们关注的是特定于细胞类型的行为 从我们的PPG数据集中排名最高的三个转录因子：E2F3、ZFP 189和RXR。为 例如，在所有显示启动或脱敏的基因中，约25%的基因在NAC中的表达发生变化 过去的可卡因自我给药被预测为E2F3的直接目标。仅基于这些 生物信息学预测，我们已经生成了稳健的初步数据来验证每一个 这些转录因子与药物成瘾有关，现在建议更好地了解它们的作用。我们会 完整表征它们在NAC中控制自身对可卡因的行为反应中的作用 管理部门在全基因组的基础上分析和绘制他们的目标基因。这两项努力都将是 以特定细胞类型的方式进行，因为我们有证据表明一些因素在 这个脑区有不同类型的神经元。在动物模型中的这项工作将得到以下研究的补充 患有可卡因使用障碍的人，我们已经有了他们异常调节的初步证据。 我们将把这些研究扩展到PFC，在那里我们发现不同的E2F3剪接异构体控制 对可卡因的行为和基因组反应，以及对阿片类药物模型的反应，我们知道这些因素 也表现出明显的监管失调。总而言之，这项工作将揭示新的转录机制 可卡因和鸦片成瘾。