Center for Alcohol Research in Epigenetics

表观遗传学酒精研究中心

基本信息

批准号：
10613942
负责人：
SUBHASH C. PANDEY
金额：
$ 165.44万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10613942
关键词：
ATAC-seq Aberrant DNA Methylation Alcohol consumption Alcohol dependence Alcohol withdrawal syndrome Alcoholism Amygdaloid structure Anatomy Animal Model Animals Anxiety Area Autopsy Behavioral Bioinformatics Brain Brain region CRISPR/Cas technology Cells ChIP-seq Characteristics Chemicals Chromatin Chromatin Structure Chronic Clustered Regularly Interspaced Short Palindromic Repeats Communities Community Outreach DNA DNA Methylation DNA Modification Methylases DNA Modification Process Data Data Analyses Dependence Development Disease Electrophysiology (science)Emotional Enzymes Epigenetic Process Functional disorder Funding Gene Expression Gene Expression Profile Gene Expression Regulation General Population Genes Genetic Genome Glucocorticoid Receptor High School Student Hippocampus Histone Acetylation Histone Deacetylase Histones Human Intake Investigation Knowledge Lead Link Lysine Maintenance Mediating Medical Students Mental Depression Methylation Modification Molecular Molecular Biology Molecular Target Motivation Mutation Neuroimmune Neuropeptides Neurophysiology - biologic function Neurosciences Neurotransmitters Pathogenesis Pathway Analysis Pathway interactions Pattern Pharmacotherapy Pilot Projects Play Postdoctoral Fellow Prefrontal Cortex Protein Family Psychiatry Public Health RNA Rattus Regulation Research Research Personnel Research Project Grants Resources Rewards Rodent Model Role Scientist Self Administration Signal Transduction Signaling Molecule Small Interfering RNA Stress Synapses System Testing Time Tissue-Specific Gene Expression Translational Research Ventral Tegmental Area Visit Withdrawal addiction alcohol effect alcohol exposure alcohol research alcohol use disorder behavioral phenotyping brain circuitry chromatin remodeling demethylation deter alcohol use drinking environmental enrichment for laboratory animals epigenetic marker epigenome epitranscriptome epitranscriptomics gene network genetic approach genome-wide graduate student higher education histone acetyltransferase histone methyltransferase histone modification hypothalamic-pituitary-adrenal axis interdisciplinary approach molecular phenotype neuroadaptation neurosteroids neurotrophic factor new therapeutic target next generation novel outreach program pre-clinical research problem drinker small hairpin RNA training opportunity transcriptome transcriptome sequencing transcriptomics undergraduate student viral gene delivery whole genome

ATAC-seq Aberrant DNA Methylation Alcohol consumption Alcohol dependence Alcohol withdrawal syndrome Alcoholism Amygdaloid structure Anatomy Animal Model Animals Anxiety Area Autopsy Behavioral Bioinformatics Brain Brain region CRISPR/Cas technology Cells ChIP-seq Characteristics Chemicals Chromatin Chromatin Structure Chronic Clustered Regularly Interspaced Short Palindromic Repeats Communities Community Outreach DNA DNA Methylation DNA Modification Methylases DNA Modification Process Data Data Analyses Dependence Development Disease Electrophysiology (science)Emotional Enzymes Epigenetic Process Functional disorder Funding Gene Expression Gene Expression Profile Gene Expression Regulation General Population Genes Genetic Genome Glucocorticoid Receptor High School Student Hippocampus Histone Acetylation Histone Deacetylase Histones Human Intake Investigation Knowledge Lead Link Lysine Maintenance Mediating Medical Students Mental Depression Methylation Modification Molecular Molecular Biology Molecular Target Motivation Mutation Neuroimmune Neuropeptides Neurophysiology - biologic function Neurosciences Neurotransmitters Pathogenesis Pathway Analysis Pathway interactions Pattern Pharmacotherapy Pilot Projects Play Postdoctoral Fellow Prefrontal Cortex Protein Family Psychiatry Public Health RNA Rattus Regulation Research Research Personnel Research Project Grants Resources Rewards Rodent Model Role Scientist Self Administration Signal Transduction Signaling Molecule Small Interfering RNA Stress Synapses System Testing Time Tissue-Specific Gene Expression Translational Research Ventral Tegmental Area Visit Withdrawal addiction alcohol effect alcohol exposure alcohol research alcohol use disorder behavioral phenotyping brain circuitry chromatin remodeling demethylation deter alcohol use drinking environmental enrichment for laboratory animals epigenetic marker epigenome epitranscriptome epitranscriptomics gene network genetic approach genome-wide graduate student higher education histone acetyltransferase histone methyltransferase histone modification hypothalamic-pituitary-adrenal axis interdisciplinary approach molecular phenotype neuroadaptation neurosteroids neurotrophic factor new therapeutic target next generation novel outreach program pre-clinical research problem drinker small hairpin RNA training opportunity transcriptome transcriptome sequencing transcriptomics undergraduate student viral gene delivery whole genome

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项目摘要

Project Summary: Alcohol use disorder (AUD) can be characterized by a pattern of compulsive alcohol drinking or loss of control over alcohol drinking. The positive and negative effects of ethanol appear to be regulated by genetic and epigenetic changes in several key brain regions. Long-term alcohol use causes structural and functional changes in the prefrontal cortex (PFC), hippocampus, amygdala, and ventral tegmental area of the brain which may drive behavioral phenotypes, such as anxiety, depression, motivation, and increased alcohol drinking. Several protein families such as histone deacetylases (HDACs), histone acetyltransferases (HATs), histone methyltransferases (HMTs), DNA methyltransferases (DNMTs), lysine demethylases, and DNA demethylases are important players in chromatin remodeling within the genome and are altered by chronic ethanol exposure and withdrawal. However, the interplay between these different epigenetic modifiers lead to an altered state of the epigenome and their role in transcriptomic changes associated with adaptations in the reward and stress systems in the brain (VTA, amygdala, PFC, and hippocampus) during AUD is still unclear. The overall aim of this Alcohol Research Center is to evaluate the epigenetic and genetic basis of molecular changes in the brain that underlie behavioral changes in AUD. This P50 application entitled “Center for Alcohol Research in Epigenetics (CARE)” consists of four highly inter-related preclinical and translational research projects [research project #1, VTA, (Brodie /Glover), research project #2, Amygdala, (Pandey), research project #3, Hippocampus, (Lasek) and research project #4, PFC, (Guidotti/Grayson/Gavin)] and two current pilot projects [pilot project #1 (Epigenetic biomarkers in AUD), and pilot project #2 (Epitranscriptomic modifications in AUD)], and three Cores [Administrative (Pandey/Lasek), Epigenetics (Grayson/Maienschein-Cline), and Behavioral Core (Glover/Zhang)]. In addition, the CARE will serve as an important resource and provide a scientifically enriched environment for training opportunities for the next generation of neuroscientists studying AUD and will disseminate scientific knowledge of AUD to the general public through a community outreach program. The primary thematic focus of CARE, as a whole, will be to mechanistically link emerging novel molecular targets identified by whole-genome approaches (ATAC-seq, ChIP-seq, RNA-seq, and DNA methylation/demethylation EPIC array) in the proposed brain circuitry to behavioral phenotypes. Mechanistic approaches (CRISPR-dCas9, shRNA, siRNA, chemogenetic) will be used to manipulate the epigenome through alterations of either histone acetylation/methylation mechanisms or DNA methylation mechanisms, in key brain circuitry that regulates behavioral phenotypes associated with AUD (anxiety, depression, motivation, and alcohol drinking) in order to better understand the pathophysiology of AUD and develop better pharmacotherapy.

项目摘要：酒精使用障碍（AUD）的特征是强迫酒精或失控的模式喝酒。乙醇的积极和负面影响似乎受遗传和几个关键大脑区域的表观遗传变化。长期饮酒会导致结构和功能大脑前额叶皮层（PFC），海马，杏仁核和腹侧段区域的变化可能会推动行为表型，例如焦虑，抑郁，动机和饮酒量增加。几种蛋白质家族，例如组蛋白脱乙酰基酶（HDAC），组蛋白乙酰转移酶（HAT），组蛋白甲基转移酶（HMTS），DNA甲基转移酶（DNMT），赖氨酸脱甲基酶和DNA脱甲基酶是基因组中染色质重塑的重要参与者，并通过慢性乙醇暴露改变了和退出。但是，这些不同的表观遗传修饰剂之间的相互作用导致状态改变表观基因组及其在与奖励和压力中适应相关的转录组变化中的作用在AUD期间，大脑中的系统（VTA，杏仁核，PFC和海马）尚不清楚。总体目的该酒精研究中心是评估分子变化的表观遗传和遗传基础行为构成的大脑在AUD中发生变化。此P50申请名为“酒精中心表观遗传学研究（CARE）”由四个高度相关的临床前和翻译研究组成项目[研究项目＃1，VTA，（Brodie /Glover），研究项目＃2，Amygdala，（Pandey），研究项目＃3，海马，（Lasek）和研究项目＃4，PFC，（Guidotti/Grayson/Gavin）]和两个当前的飞行员项目[试点项目＃1（AUD中的表观遗传生物标志物）和试点项目＃2 AUD]和三个核心[行政（Pandey/Lasek），表观遗传学（Grayson/Maienschein-Cline）和行为核心（Glover/Zhang）]。此外，该护理将作为重要资源，并提供科学丰富的环境，为下一代神经科学家学习的培训机会 AUD并将通过社区宣传将AUD的科学知识传播给公众程序。总体而言，主要的护理主题重点是机械地联系新兴小说通过全基因组方法（ATAC-SEQ，CHIP-SEQ，RNA-SEQ和DNA）识别的分子靶标在拟议的脑电路中，甲基化/脱甲基化史诗阵列）。机理方法（CRISPR-DCAS9，shRNA，siRNA，化学遗传）将用于操纵表观基因组通过改变组蛋白乙酰化/甲基化机制或DNA甲基化机制，调节与AUD相关的行为表型（焦虑，抑郁，动机，和饮酒），以更好地了解AUD的病理生理学并更好地发展药物治疗。