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

基本信息

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
项目类别：
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

项目摘要

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的目标是表征几个新的转录因子，以前未实施成瘾，介导伏隔核（NAC）刺激性和优化滥用药物的持久作用（NAC）和前额叶皮层（PFC）。几乎所有对成瘾中转录因子的先前研究都采用了候选方法。这与使用“大数据”推断出来的公正方法形成鲜明对比。开放式方式，这些因素在调解复合物的特定方面最重要的因素成瘾表型。我们通过利用大规模RNA-Seq和来自啮齿动物成瘾模型和具有物质使用障碍的人类的相关数据集，以识别这些数据集似乎在毒品作用中起着特别关键作用的因素。我们专注于细胞类型的特定动作我们PPG数据集中最高排名最高的转录因子：E2F3，ZFP189和RXR。为了例如，在NAC中显示出启动或脱敏变化的所有基因的约25％过去的可卡因自我管理被预测为E2F3的直接靶标。仅基于这些生物信息学预测，我们已经生成了强大的初步数据，以验证每个数据的重要性这些在药物成瘾中的转录因素，现在提出了更好地了解其行为的建议。我们将完全表征其在NAC中控制对可卡因自我的行为反应中的作用在全基因组的基础上进行给药和映射其靶基因。这两个努力都将是以特定于细胞类型的方式进行，因为我们有证据表明某些因素在该大脑区域的不同神经元类型。动物模型中的这项工作将通过研究可卡因使用障碍的人类，我们已经有针对其异常调节的初步证据。我们将将这些研究扩展到PFC，在那里我们发现不同的E2F3剪接同工型对照行为和基因组对可卡因的反应，以及优化我们知道这些因素的模型还显示出明显的失调。这项工作将共同揭示新的转录机制可卡因并优化成瘾。