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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/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，并导致发病率和死亡率很高。虽然遗传变异会影响个体对 AUD 的脆弱性，长期饮酒也会导致酒精耐受和依赖，但其潜在机制尚不清楚。有证据表明，长期饮酒会改变特定基因的 DNA 甲基化，从而导致基因表达变化并可能增加 AUD 风险。 RNA甲基化是一种常见的后处理转录修饰，它对各种刺激做出快速反应，并将刺激信号转化为细胞活动。我们假设饮酒会改变个体的 RNA 甲基化组（或表观转录组），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 受试者大脑中信使 RNA (mRNA) 甲基组的变化并分析其影响 mRNA甲基化对mRNA表达和神经元活性的影响，从而为新基因提供证据 AUD的表达调控机制。为了实现这一目标，我们提出三个具体目标。首先，我们将八个区域（杏仁核、尾状核、小脑、死后的海马体、伏隔核、前额皮质、壳核和腹侧被盖区） AUD 受试者的大脑。其次，我们将使用慢性间歇性乙醇（CIE）暴露小鼠作为模型来验证 AUD相关脑mRNA甲基化和表达变化以及乙醇的相关性暴露诱导的 mRNA 甲基化和表达随着乙醇自我给药的增加而变化在小鼠中。第三，我们将采用一种新颖的表观转录组编辑方法来研究 AUD- 相关的 mRNA 甲基化变化对 mRNA 表达和神经元活性的影响。我们期望 (1) 观察 AUD 相关的 mRNA 甲基化和特定（或跨）大脑区域的表达变化； (2) 验证澳元- 小鼠模型相关的 mRNA 甲基化和表达变化； (3)确认功能作用 AUD 相关 mRNA 甲基化在调节 mRNA 表达和神经元活动中的作用。我们的学习设计是创新的。 AUD 相关的 mRNA 甲基化变化将以单碱基分辨率进行检查。一个综合研究方法（人类死后大脑研究、小鼠建模和表观转录组编辑）将被雇用。拟议的研究将为大脑表观转录组的影响提供证据澳元风险的变化。鉴于 mRNA 甲基化是动态且可逆的，具有差异性的 mRNA AUD 受试者大脑中的甲基化可能是药物治疗 AUD 的潜在目标改变 mRNA 甲基化状态。