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.

项目总结： 酒精使用障碍(AUD)的特征是强迫性饮酒或失控。 因为酗酒。酒精的正面和负面影响似乎是由遗传和 几个关键大脑区域的表观遗传学变化。长期饮酒会导致结构性和功能性 大脑前额叶皮质(PFC)、海马体、杏仁核和腹侧被盖区的变化 可能会导致行为表型，如焦虑、抑郁、动机和酗酒增加。 几个蛋白质家族，如组蛋白脱乙酰酶(HDACs)、组蛋白乙酰转移酶(HATS)、组蛋白 甲基转移酶(HMTs)、DNA甲基转移酶(DNMTs)、赖氨酸去甲基酶和DNA去甲基酶 是基因组内染色质重塑的重要参与者，并会因长期接触酒精而改变 和戒烟。然而，这些不同的表观遗传修饰物之间的相互作用导致了 表观基因组及其在与奖赏和压力适应相关的转录变化中的作用 AUD期间大脑中的系统(VTA、杏仁核、PFC和海马体)仍不清楚。的总体目标 这个酒精研究中心是为了评估分子变化的表观遗传学和遗传学基础。 导致AUD行为变化的大脑。这个P50应用程序的标题是“酒精中心 表观遗传学研究(CARE)“由四项高度相关的临床前和转化性研究组成 项目[研究项目1，VTA(布罗迪/格洛弗)，研究项目2，杏仁核，(潘迪)，研究项目 #3，海马体(Lasek)和研究项目#4，PFC，(Guidotti/Grayson/Gavin)]和目前的两个试点项目 项目[试点项目#1(澳大利亚的表观遗传生物标记物)和试点项目#2(表观转录修饰 AUD)]和三个核心[管理(Pandey/Lasek)、表观遗传学(Grayson/Maienschein-Cline)和 行为核心(格洛弗/张)]。此外，护理将成为一项重要的资源，并提供 科学丰富的环境为下一代神经科学家研究提供培训机会 并会透过社区推广活动，向公众传播有关澳元的科学知识。 程序。作为一个整体，关爱的主要主题焦点将是机械地将新兴小说联系起来 全基因组方法确定的分子靶点(ATAC-SEQ、CHIP-SEQ、RNA-SEQ和DNA 甲基化/去甲基化EPIC阵列)在被提议的大脑回路中对行为表型的影响。机械论 将使用各种方法(CRISPR-dCas9、shRNA、siRNA、化学遗传学)来操纵表观基因组 通过改变组蛋白乙酰化/甲基化机制或DNA甲基化机制，在 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的病理生理机制，更好地发展 药物疗法。