Identifying Brain Epitranscriptomic Changes Associated with Alcohol Use Disorder

识别与酒精使用障碍相关的大脑表观转录组变化

• 批准号: 10343021
• 负责人: Huiping Zhang
• 金额: $ 58.79万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10343021
• 关键词: Adenosine; Adult; Affect; Air; Alcohol consumption; Alcohols; American; Amygdaloid structure; Animal Model; Autopsy; Brain; Brain region; Caucasians; Cell physiology; Cells; Cerebellum; Chronic; Clustered Regularly Interspaced Short Palindromic Repeats; Complex; DNA Methylation; Dependence; Digestion; Disease; Engineering; Environmental Risk Factor; Epigenetic Process; Ethanol; Female; Gene Expression; Genes; Genetic Risk; Genetic Transcription; Genetic Variation; Goals; Guide RNA; Hippocampus (Brain); Human; Immune response; Individual; Lead; Messenger RNA; Methylation; MicroRNAs; Modeling; Modification; Morbidity - disease rate; Morphology; Mus; Neurons; Nucleotides; Nucleus Accumbens; Pathway interactions; Patients; Pharmacological Treatment; Pharmacology; Pilot Projects; Prefrontal Cortex; RNA; RNA Splicing; RNA analysis; RNA methylation; Regulation; Research; Research Design; Resolution; Rewards; Role; Sampling; Self Administration; Signal Transduction; Site; Stimulus; Therapeutic; Tissue Sample; Translating; Translations; Ventral Tegmental Area; addiction; alcohol effect; alcohol exposure; alcohol risk; alcohol use disorder; base; brain tissue; chronic alcohol ingestion; demethylation; design; disorder risk; epitranscriptome; epitranscriptomics; histone modification; innovation; insight; male; methylome; methylomics; mortality; mouse model; novel; nuclease; putamen; transcriptome; transcriptome sequencing; transcriptomics

PROJECT SUMMARY/ABSTRACT Alcohol use disorder (AUD) affects about 4.2% (or 14.1 million) of American adults each year and causes substantial morbidity and mortality. While genetic variation can influence an individual's vulnerability to AUD, chronic alcohol consumption can also lead to alcohol tolerance and dependence, but the underlying mechanism is unclear. There is evidence that that chronic alcohol use alters DNA methylation of specific genes, leading to gene expression changes and possibly an increased risk of AUD. RNA methylation is a common post- transcriptional modification, and it responds rapidly to a variety of stimuli and translates stimulatory signals into cellular activity. We hypothesize that alcohol use alters an individual's RNA methylome (or epitranscriptome), resulting in altered expression of genes involved in AUD-related pathways. The objective of this research is to explore messenger RNA (mRNA) methylomic changes in the brain of AUD subjects and analyze the effect of mRNA methylation on mRNA expression and neuronal activity, thus providing evidence for a new gene expression regulatory mechanism of AUD. To achieve this goal, we propose three specific aims. First, we will profile mRNA methylomic and transcriptomic changes in eight regions (amygdala, caudate, cerebellum, hippocampus, nucleus accumbens, prefrontal cortex, putamen, and ventral tegmental area) of postmortem brains of AUD subjects. Second, we will use chronic intermittent ethanol (CIE)-exposed mice as models to verify AUD-associated brain mRNA methylation and expression changes as well as the correlation of ethanol exposure-induced mRNA methylation and expression changes with the escalation of ethanol self-administration in mice. Third, we will employ a novel epitranscriptome editing approach to investigate the effect of AUD- associated mRNA methylation changes on mRNA expression and neuronal activity. We expect to (1) observe AUD-associated mRNA methylation and expression changes in specific (or across) brain regions; (2) verify AUD- associated mRNA methylation and expression changes by mouse modeling; and (3) confirm the functional role of AUD-associated mRNA methylation in regulating mRNA expression and neuronal activity. Our study design is innovative. AUD-associated mRNA methylation changes will be examined at single-base resolution. An integrative study approach (human postmortem brain studies, mouse modeling, and epitranscriptome editing) will be employed. The proposed research will provide evidence about the influence of brain epitranscriptomic changes on AUD risk. Given that mRNA methylation is dynamic and reversible, mRNAs with differential methylation in the brain of AUD subjects could be potential targets for AUD treatment by pharmacologically altering mRNA methylation status.

项目摘要/摘要 酒精使用障碍（AUD）每年影响约4.2％（或1410万）的美国成年人 大量发病率和死亡率。虽然遗传变异会影响个人对AUD的脆弱性，但 慢性酒精消耗也会导致饮酒和依赖性，但基本机制 不清楚。有证据表明，慢性酒精使用改变了特定基因的DNA甲基化，导致 基因表达变化，可能会增加AUD的风险。 RNA甲基化是一种常见的后 转录修改，它迅速响应各种刺激，并将刺激信号转化为 细胞活性。我们假设酒精的使用改变了个体的RNA甲基甲基（或表演组）， 导致参与AUD相关途径的基因表达改变。这项研究的目的是 探索AUD受试者大脑中的Messenger RNA（mRNA）甲基属性变化，并分析 mRNA甲基化在mRNA表达和神经元活性上，从而提供了新基因的证据 AUD的表达调节机制。为了实现这一目标，我们提出了三个具体目标。首先，我们会的 八个区域的剖面mRNA甲基甲基组和转录组变化（杏仁核，尾状，小脑，小脑， 后尸体的海马，伏隔核，前额叶皮层，壳骨和腹侧对侧面区域） AUD主题的大脑。第二，我们将使用慢性间歇性乙醇（CIE）暴露的小鼠作为模型来验证 听到相关的脑mRNA甲基化和表达变化以及乙醇的相关性 暴露引起的mRNA甲基化和表达随着乙醇自我给药的升级而变化 在老鼠中。第三，我们将采用一种新型的表面参考组编辑方法来研究AUD的影响 相关的mRNA甲基化对mRNA表达和神经元活性的变化。我们希望（1）观察 听觉相关的mRNA甲基化和表达变化在特定（或跨越）大脑区域的变化； （2）验证aud- 相关的mRNA甲基化和通过小鼠建模的表达变化； （3）确认功能作用 在调节mRNA表达和神经元活性中听到的mRNA甲基化。我们的研究设计 是创新的。单基碱分辨率将检查AUD相关的mRNA甲基化变化。一个 综合研究方法（人类后脑研究，小鼠建模和表演组编辑） 将被雇用。拟议的研究将提供有关大脑表面参考组的影响的证据 AUD风险的变化。鉴于mRNA甲基化是动态和可逆的，因此mRNA具有差异 AUD受试者大脑中的甲基化可能是药理上AUD治疗的潜在靶标 改变mRNA甲基化状态。