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：
10062504
负责人：
ERIC J. NESTLER
金额：
$ 22.68万
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/10062504
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 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 Phenotype Play Prefrontal Cortex Program Research Project Grants Protein Isoforms Proteins Psychostimulant dependence Public Health RNA Splicing RNA analysis RXR Recording of previous events Regulation Reporting Rodent Role Self Administration Signal Transduction 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 cocaine use deep sequencing desensitization drug action drug of abuse genome-wide knock-down novel opioid abuse overexpression promoter response 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 的目标是表征几种新的转录因子，这些转录因子以前未涉及成瘾，介导伏隔核（NAc）滥用兴奋剂和阿片类药物的持久作用事实上，之前所有关于成瘾转录因子的研究都经过了研究。这与使用“大数据”进行推论的公正方法形成鲜明对比。开放式的方式，那些在调解复合体的特定方面最重要的因素我们通过利用大规模 RNA 测序来利用这种更强大的方法。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集，以识别这些我们关注在药物作用中发挥特别关键作用的因素。我们的 PPG 数据集中排名最高的三个转录因子：E2F3、ZFP189 和 RXR。例如，约 25% 的基因在 NAc 中表现出引发或脱敏的表达变化，这是由于仅基于这些，过去的可卡因自我给药预计将成为 E2F3 的直接目标。生物信息学预测，我们生成了可靠的初步数据来验证每个的重要性这些转录因子与药物成瘾有关，现在我们将更好地了解它们的作用。完整表征了它们在 NAc 中控制自我可卡因行为反应的作用管理分析以及在全基因组基础上绘制其目标基因图谱将是这两项工作的重点。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类型中发挥不同的作用该大脑区域的不同神经类型将得到动物模型研究的补充。患有可卡因使用障碍的人类，我们已经掌握了其异常调节的初步证据。我们将这些研究扩展到 PFC，我们发现不同的 E2F3 剪接亚型控制对可卡因以及鸦片模型的行为和基因组反应，我们知道这些因素还显示出显着的失调，这项工作将揭示潜在的新转录机制。可卡因和鸦片成瘾。