Transcriptional Mechanisms of Drug Addiction

项目摘要/摘要-总体PPG 这一新的计划项目赠款(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知识，这些异常是兴奋剂和鸦片成瘾的基础。 我们的工作集中在与成瘾相关的关键脑区的几种特定细胞类型上：伏隔核， 背侧纹状体和前额叶皮质。PPG由四个项目和三个核心组成，全部位于芒特 西奈半岛。PI是各自领域的领导者，他们已经建立了有效协作的历史，并使用他们的 补充专业知识和方法，以在拟议的研究中规划多学科课程。项目 1(Eric Nestler)专注于自我给药在大脑奖赏区域诱导的新转录因子 兴奋剂和鸦片类药物。项目2(Paul Kenny)挖掘PPG的复杂数据集以了解角色 由成瘾的环状RNA扮演；这些是新发现的一类非编码RNA，其中一些， 在大脑中，集中在突触上。项目3(Anne Schaefer)专注于小胶质细胞在 在大脑奖赏神经元及其行为中控制药物滥用的转录反应 后果。项目4(Yasmin Hurd)专注于增强子区域的影响，以及他们的 转录和染色质调节因子，控制对滥用药物的分子和行为适应。 所有四个项目都证实了动物在人类死后脑组织中的发现，而在人类中的发现 物质使用障碍被反馈到动物模型，以解释涉及的潜在机制。这个 PPG由三个核心支持，一个管理核心(Eric Nestler)负责监督和协调PPG 行动；一个动物模型核心(Vanna Zachariou)，提供成瘾和其他动物模型 先进的工具(例如，病毒基因转移、可诱导的突变小鼠)来操纵感兴趣的单个基因 目标脑区的特定细胞类型，从而提供将分子-细胞联系起来的因果证据 对成瘾相关现象的可塑性；以及一个基因和染色质分析核心(李申)，提供状态- 最先进的方法和生物信息学来表征全基因组范围的基因表达调控和 成瘾中的染色质修饰。这项对药物转录机制的开创性研究 上瘾将有助于推动该领域的重大进步。

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.