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.

项目总结/摘要-项目1 项目1的目标是描述几种新的转录因子，这些转录因子以前没有涉及到转录因子的表达。 成瘾，在介导兴奋性和阿片类药物滥用的持久作用中， 前额叶皮层（PFC）事实上，所有先前关于成瘾中转录因子的研究都采用了 候选方法。这与使用“大数据”进行推断的无偏见方法形成鲜明对比， 开放式的方式，这些因素是最重要的调解具体方面的复杂 成瘾表型我们利用这种更强大的方法，利用大规模的RNA-seq， 从啮齿动物成瘾模型和患有物质使用障碍的人的相关数据集，以确定那些 这些因素似乎在药物作用中起着特别关键的作用。我们专注于细胞类型的特定行动， 我们的PPG数据集中排名最高的三个转录因子：E2 F3，ZFP 189和RXR β。为 例如，在NAc表达中显示引发或脱敏变化的所有基因中， 过去的可卡因自我给药被预测为E2 F3的直接靶点。仅仅基于这些 生物信息学预测，我们已经产生了强大的初步数据，以验证每个重要性， 这些转录因子在药物成瘾中的作用，现在建议更好地了解它们的作用。我们将 完整表征其在NAc中控制自身对可卡因的行为反应的作用， 施用测定以及在全基因组基础上绘制其靶基因。这两项努力将是 以细胞类型特异性的方式进行，因为我们有证据表明一些因素在细胞中起着不同的作用。 不同类型的神经元动物模型的这项工作将得到以下研究的补充： 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，我们发现不同的E2 F3剪接异构体控制着PFC， 行为和基因组对可卡因的反应，以及鸦片模型，我们知道这些因素 也表现出明显的失调。总之，这项工作将揭示新的转录机制， 可卡因和鸦片成瘾