Brain microRNA-mRNA regulatory networks and alcohol use disorders

大脑 microRNA-mRNA 调节网络和酒精使用障碍

• 批准号: 9976401
• 负责人: Huiping Zhang
• 金额: $ 35.3万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9976401
• 关键词: 3' Untranslated Regions; Adult; Affect; Age; Alcohol consumption; Alcohols; American; Amygdaloid structure; Autopsy; Bioinformatics; Biological Assay; Biological Models; Biological Process; Brain; Brain region; Cell Line; Cell model; Cerebellum; Computer software; Dependence; Development; Epigenetic Process; European; Gene Expression; Genes; Genetic Variation; Goals; Hippocampus (Brain); Impairment; In Vitro; Knowledge; Lead; Messenger RNA; MicroRNAs; Modeling; Molecular; Morbidity - disease rate; N-Methyl-D-Aspartate Receptors; Neuronal Differentiation; Neurons; Nucleus Accumbens; Occupational; Pathway Analysis; Pathway interactions; Patients; Pharmacological Treatment; Play; Prefrontal Cortex; Race; Reporter; Research; Reverse Transcriptase Polymerase Chain Reaction; Rewards; Role; Smoking History; Subfamily lentivirinae; Technology; Testing; Tissue Sample; Untranslated RNA; Up-Regulation; Ventral Tegmental Area; Western Blotting; addiction; alcohol exposure; alcohol risk; alcohol use disorder; annotation system; base; chronic alcohol ingestion; differential expression; expression vector; human embryonic stem cell; improved; innovation; mRNA Expression; mRNA sequencing; mortality; neuroadaptation; next generation sequencing; novel; novel strategies; novel therapeutic intervention; prediction algorithm; programs; protein expression; putamen; sex; social; stem cells; synaptogenesis; transcriptome; transcriptome sequencing

PROJECT SUMMARY/ABSTRACT Alcohol use disorders (AUDs) are characterized by compulsive and uncontrolled alcohol use, leading to social and occupational impairments. While genetic variation can result in an increased risk of AUDs, chronic alcohol consumption can independently lead to alcohol tolerance and dependence. However, it is unknown how chronic alcohol consumption alters gene expression and leads to neuroadaptations underlying AUDs. There is evidence that small noncoding microRNAs (miRNAs), which regulate target gene (or mRNA) expression at the posttranscriptional level, are abundant in the brain and play important roles in a variety of biological processes such as neuronal differentiation and synapse formation and plasticity. Additionally, each miRNA can regulate the expression of a number of different target mRNAs and each mRNA can be targeted by different miRNAs. Thus, brain miRNAs that regulate the expression of alcohol-responsive mRNAs may act upstream of alcohol- induced neuroadaptations. The objective of the proposed study is to identify dysregulated miRNAs and their target mRNAs in the brains of AUD subjects and generate AUD-associated miRNA-mRNA regulatory networks. The central hypothesis is that AUD-associated miRNAs interact with target mRNAs in reward-related brain regions, forming miRNA-mRNA regulatory networks that are critical for AUD development. This hypothesis will be tested by pursuing three specific aims: (1) identify differentially expressed miRNAs and mRNAs in at least eight reward-related brain regions (prefrontal cortex, nucleus accumbens, ventral tegmental area, hippocampus, amygdala, putamen, caudate, and cerebellum) of AUD subjects using next-generation sequencing (miRNA-Seq and mRNA-Seq); (2) generate AUD-associated miRNA-mRNA regulatory networks in reward-related brain regions using integrated bioinformatics analyses; and (3) refine AUD-associated miRNA- mRNA regulatory networks by validating the predicted miRNA-mRNA pairs using experimental approaches, such as high throughput 3' UTR reporter assays in cell lines and miRNA-mRNA interaction analyses in human embryonic stem cell (hESC)-derived GABAergic cortical neurons (as an in vitro cellular model). The proposed research is significant because it will identify and validate AUD-associated miRNA-mRNA regulatory networks in reward-related brain regions, thus improving our understanding of the epigenetic mechanisms of AUDs. The proposed research is innovative because advanced technologies (such as next-generation sequencing, state- of-the-art bioinformatics programs for miRNA-mRNA network construction, high-throughput 3' UTR reporter assay, and miRNA-mRNA interaction modeling in stem cell-derived neurons) will be used. Our long-term goal is to develop novel pharmacological treatment for AUDs by targeting specific miRNAs and their target genes.

项目总结/摘要 酒精使用障碍（AUDs）的特征是强迫性和不受控制的酒精使用，导致社会性 和职业缺陷。虽然遗传变异可能导致AUD风险增加，但长期饮酒 饮酒可以独立地导致酒精耐受和依赖。然而，不知道如何 慢性酒精消耗改变基因表达，并导致AUDs背后的神经适应。有 有证据表明，调节靶基因（或mRNA）表达的小的非编码microRNAs（miRNAs）在细胞中的表达水平， 在转录后水平，在大脑中丰富，并在各种生物过程中发挥重要作用 例如神经元分化和突触形成以及可塑性。此外，每种miRNA都可以调节 许多不同靶mRNA的表达，并且每种mRNA可以被不同的miRNA靶向。 因此，调节酒精反应mRNAs表达的脑miRNAs可能在酒精反应的上游起作用。 诱导神经适应。这项研究的目的是鉴定失调的miRNAs及其表达。 靶向AUD受试者大脑中的mRNA，并产生AUD相关的miRNA-mRNA调节 网络.中心假设是AUD相关的miRNAs与靶mRNA在奖励相关的转录中相互作用。 大脑区域，形成对AUD发展至关重要的miRNA-mRNA调控网络。这 通过追求三个具体目标来检验假设：（1）鉴定差异表达的miRNAs， 在至少八个与奖励相关的大脑区域（前额叶皮层、丘脑核、腹侧被盖）中的mRNA 区域、海马、杏仁核、壳核、尾状核和小脑） 测序（miRNA-Seq和mRNA-Seq）;（2）在细胞内产生AUD相关的miRNA-mRNA调控网络， 使用综合生物信息学分析与奖励相关的大脑区域;以及（3）改进AUD相关的miRNA- 通过实验方法验证预测的miRNA-mRNA对， 例如细胞系中的高通量3 ′ UTR报告基因测定和人类中的miRNA-mRNA相互作用分析 胚胎干细胞（hESC）衍生的GABA能皮质神经元（作为体外细胞模型）。拟议 这项研究意义重大，因为它将识别和验证AUD相关的miRNA-mRNA调控网络 在奖励相关的大脑区域，从而提高我们对AUDs的表观遗传机制的理解。的 拟议的研究是创新的，因为先进的技术（如下一代测序，国家， 用于miRNA-mRNA网络构建的最先进的生物信息学程序，高通量3' UTR报告基因， 测定和干细胞衍生的神经元中的miRNA-mRNA相互作用建模）。我们的长期目标 目的是通过靶向特异性miRNAs及其靶基因开发治疗AUDs的新药物。

项目成果

Analysis of telomere length variation and Shelterin complex subunit gene expression changes in ethanol-exposed human embryonic stem cells.

• DOI: 10.1016/j.jpsychires.2020.11.027
• 发表时间: 2021-11
• 期刊: Journal of psychiatric research
• 影响因子: 4.8
• 作者: Moazzam M;Yim T;Kumaresan V;Henderson DC;Farrer LA;Zhang H
• 通讯作者: Zhang H

Effect of Prenatal Opioid Exposure on the Human Placental Methylome.

• DOI: 10.3390/biomedicines10051150
• 发表时间: 2022-05-17
• 期刊: Biomedicines
• 影响因子: 4.7

Internet addiction in college students and its relationship with cigarette smoking and alcohol use in Northeast China.

东北地区大学生网络成瘾及其与吸烟、饮酒的关系.

• DOI: 10.1111/appy.12281
• 发表时间: 2017
• 期刊: Asia-Pacific psychiatry : official journal of the Pacific Rim College of Psychiatrists
• 作者: Mei,Songli;Gao,Tingting;Li,Jiaomeng;Zhang,Ying;Chai,Jingxin;Wang,Lingyan;Zhang,Zhao;Zhang,Huiping
• 通讯作者: Zhang,Huiping

Atomoxetine in abstinent cocaine users: Sex differences.

戒除可卡因使用者中的托莫西汀：性别差异。

• DOI: 10.1016/j.dib.2017.08.011
• 发表时间: 2017
• 期刊: Data in brief
• 影响因子: 1.2
• 作者: DeVito,EliseE;Herman,AryehI;Konkus,NoahS;Zhang,Huiping;Sofuoglu,Mehmet
• 通讯作者: Sofuoglu,Mehmet