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Transcriptional Mechanisms of Drug Addiction

毒瘾的转录机制

基本信息

批准号：
10306364
负责人：
ERIC J. NESTLER
金额：
$ 182.17万
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/10306364
关键词：
Address Affect Animal Model Animals Automobile Driving Autopsy Back Behavioral Bioinformatics Biology Brain Brain region Cell physiology Chromatin Cicatrix Code Collaborations Complex Corpus striatum structure DNA Modification Process Data Data Set Development Dorsal Drug Addiction Drug Exposure Enhancers Exhibits Female Fiber Functional disorder Gene Expression Gene Expression Regulation Gene Proteins Gene Transfer Genes Genetic Transcription Genome Human Individual Investigation Knowledge Learning Link Mediating Mediator of activation protein Methods Microglia Mining Modeling Molecular Mus Mutant Strains Mice Neurobiology Neuroglia Neurons Nucleus Accumbens Opiate Addiction Opioid Persons Pharmaceutical Preparations Photometry Play Prefrontal Cortex Procedures Program Research Project Grants Proteins Psychiatry Public Health RNA RNA Splicing Recording of previous events Regulation Relapse Research Research Personnel Rest Rewards Rodent Role Self Administration Sex Differences Stimulant Stimulus Structure Substance Use Disorder Synapses Syndrome Tissues Transcriptional Regulation Untranslated RNA Validation Variant Viral Viral Genes Work Yasmin addiction brain reward regions brain tissue cell type chromatin modification chromatin remodeling circular RNA desensitization drug of abuse gene function genome-wide histone modification interest male multidisciplinary multiple datasets neurophysiology neuropsychiatry novel novel strategies operation optogenetics pre-clinical programs response sex stimulant dependence tool transcription factor

项目摘要

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.

项目概要/摘要——总体 PPG 这项新的计划项目拨款 (PPG) 利用转录生物学的最新进展，从根本上增加我们对导致兴奋剂和阿片类药物成瘾的大脑长期异常的了解。我们的工作重点是与成瘾相关的关键大脑区域中的几种特定细胞类型：伏隔核、背侧纹状体和前额皮质。 PPG 由四个项目和三个核心组成，均位于 Mount 西奈半岛。 PI 是各自领域的领导者，他们拥有有效合作的历史，并利用他们的能力互补的专业知识和方法，以在拟议的研究中制定多学科课程。项目 1（Eric Nestler）专注于自我管理在大脑奖励区域诱导的新型转录因子兴奋剂和阿片类药物。项目 2（Paul Kenny）挖掘 PPG 的复杂数据集以了解其角色由环状RNA在成瘾过程中发挥作用；这些是一类新发现的非编码 RNA，其中一些，在大脑内，集中在突触。项目 3（Anne Schaefer）重点研究小胶质细胞对控制大脑奖励神经元内对滥用药物的转录反应及其行为结果。项目 4（Yasmin Hurd）专注于增强子区域的影响及其转录和染色质介质，控制对滥用药物的分子和行为适应。所有四个项目都验证了人类死后脑组织中动物的发现，而人类的发现物质使用障碍被反馈到动物模型中，以解释所涉及的潜在机制。这 PPG 由三个核心支持，其中一个行政核心 (Eric Nestler) 负责监督和协调 PPG 运营;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、诱导突变小鼠）来操纵单个感兴趣的基因目标大脑区域的特定细胞类型，从而提供分子与细胞之间联系的因果证据成瘾相关现象的可塑性；以及基因和染色质分析核心（Li Shen），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过程中的染色质修饰。这项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步。