Center for Alcohol Research in Epigenetics

表观遗传学酒精研究中心

• 批准号: 10380644
• 负责人: SUBHASH C. PANDEY
• 金额: $ 165.5万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 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/10380644
• 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 (Brain); 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; 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

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.

项目概要： 酒精使用障碍 (AUD) 的特点是强迫性饮酒或失去控制 过度饮酒。乙醇的正面和负面影响似乎受到遗传和基因的调节。 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受损 大脑前额皮质（PFC）、海马体、杏仁核和腹侧被盖区的变化 可能会驱动行为表型，例如焦虑、抑郁、动机和饮酒增加。 多个蛋白质家族，例如组蛋白脱乙酰酶 (HDAC)、组蛋白乙酰转移酶 (HAT)、组蛋白 甲基转移酶 (HMT)、DNA 甲基转移酶 (DNMT)、赖氨酸脱甲基酶和 DNA 脱甲基酶 是基因组内染色质重塑的重要参与者，并会因长期接触乙醇而改变 和撤回。然而，这些不同的表观遗传修饰剂之间的相互作用导致了状态的改变。 表观基因组及其在与奖励和压力适应相关的转录组变化中的作用 AUD 期间大脑中的系统（VTA、杏仁核、PFC 和海马体）仍不清楚。总体目标是 该酒精研究中心旨在评估酒精分子变化的表观遗传和遗传基础 澳元行为变化背后的大脑。这个名为“酒精中心”的 P50 应用程序 表观遗传学研究 (CARE)”由四项高度相关的临床前和转化研究组成 项目 [研究项目 #1，VTA，（Brodie /Glover），研究项目 #2，Amygdala，（Pandey），研究项目 #3，Hippocampus，（Lasek）和研究项目 #4，PFC，（Guidotti/Grayson/Gavin）] 和两名现任飞行员 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 中的表观转录组修饰） AUD）]，以及三个核心[管理（Pandey/Lasek）、表观遗传学（Grayson/Maienschein-Cline）和 行为核心（格洛弗/张）]。此外，CARE 将作为重要资源并提供 为下一代神经科学家学习提供培训机会的科学丰富环境 AUD 并将通过社区外展向公众传播 AUD 的科学知识 程序。整体而言，CARE 的主要主题焦点将是将新兴小说机械地联系起来 通过全基因组方法（ATAC-seq、ChIP-seq、RNA-seq 和 DNA）鉴定的分子靶点 甲基化/去甲基化 EPIC 阵列）在拟议的大脑电路中的行为表型。机械论 方法（CRISPR-dCas9、shRNA、siRNA、化学遗传学）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），以便更好地了解 AUD 的病理生理学并更好地发展 药物治疗。