Transcriptional Mechanisms of Drug Addiction

项目总结/摘要-总体PPG 这项新的计划项目资助（PPG）利用转录生物学的最新进展，从根本上 增加我们对大脑长期异常的了解，这些异常是兴奋剂和阿片类药物成瘾的基础。 我们的工作集中在与成瘾相关的关键大脑区域的几种特定细胞类型：脑桥核， 背侧纹状体和前额叶皮层PPG由四个项目和三个核心组成，全部位于Mount 西奈PI是各自领域的领导者，他们拥有有效合作的历史，并利用他们的 补充专门知识和方法，以规划拟议研究的多学科课程。项目 1（Eric Nestler）专注于通过自我管理在大脑奖励区域诱导的新型转录因子。 兴奋剂和鸦片。项目2（Paul Kenny）挖掘PPG的复杂数据集，以了解 这些是新发现的一类非编码RNA， 集中在突触上。项目3（Anne Schaefer）关注小胶质细胞在 控制大脑奖励神经元内对滥用药物的转录反应及其行为 后果项目4（Yasmin Hurd）集中于增强子区域的影响，以及它们的 转录和染色质介质，在控制滥用药物的分子和行为适应。 这四个项目都验证了动物在人类死后脑组织中的发现，而人类死后脑组织中的发现， 物质使用障碍被反馈到动物模型中，以阐明所涉及的潜在机制。的 PPG由三个核心提供支持，一个行政核心（Eric Nestler）负责监督和协调PPG 一个动物模型核心（Vanna Zachariou），提供成瘾的动物模型和其他 高级工具（例如，病毒基因转移、可诱导突变小鼠）来操纵感兴趣的个体基因， 特定的细胞类型的目标脑区，从而提供因果关系的证据， 成瘾相关现象的可塑性;以及基因和染色质分析核心（李申），以提供状态- 最先进的方法和生物信息学来表征基因表达的全基因组调控， 成瘾中的染色质修饰这项对药物转录机制的开创性研究 成瘾将有助于推动该领域的重大进展。

PROJECT SUMMARY/ABSTRACT– OVERALL PPG This new Program Project Grant (PPG) utilizes recent advances in transcriptional biology to fundamentally increase our knowledge of the long-lasting abnormalities in brain that underlie stimulant and opiate addiction. Our work focuses on several specific cell types in key addiction-related brain regions: nucleus accumbens, dorsal striatum, and prefrontal cortex. The PPG is composed of four Projects and three Cores all at Mount Sinai. The PIs are leaders in their fields who have an established history of effective collaboration and use their complementary expertise and approaches to chart a multidisciplinary course in the proposed research. Project 1 (Eric Nestler) focuses on novel transcription factors induced in brain reward regions by self-administered stimulants and opiates. Project 2 (Paul Kenny) mines the PPG’s complex datasets to understand the role played by circular RNAs in addiction; these are a newly discovered class of non-coding RNAs some of which, within brain, are concentrated at synapses. Project 3 (Anne Schaefer) focuses on the influence of microglia in controlling transcriptional responses to drugs of abuse within brain reward neurons and their behavioral consequences. Project 4 (Yasmin Hurd) concentrates on the influence of enhancer regions, and their transcriptional and chromatin mediators, in controlling molecular and behavioral adaptations to drugs of abuse. All four projects validate findings from animals in human postmortem brain tissue, while discoveries in human substance use disorders are fed back to animal models to explicate the underlying mechanisms involved. The PPG is supported by three Cores, an Administrative Core (Eric Nestler) to oversee and coordinate PPG operations; an Animal Models Core (Vanna Zachariou) to provide animal models of addiction and other advanced tools (e.g., viral gene transfer, inducible mutant mice) to manipulate individual genes of interest in specific cell types of the targeted brain regions and thereby provide causal evidence linking molecular-cellular plasticity to addiction-related phenomena; and a Gene and Chromatin Analysis Core (Li Shen) to provide state- of-the-art methods and bioinformatics to characterize genome-wide regulation of gene expression and chromatin modifications in addiction. This pioneering investigation of transcriptional mechanisms of drug addiction will help drive major advances in the field.