Gene Expression in the Human Alcoholic Brain

人类酒精大脑中的基因表达

• 批准号: 9257246
• 负责人: Robert A Harris
• 金额: $ 41.63万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9257246
• 关键词: Alcohol Phenotype; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcohols; Algorithms; Alternative Splicing; Alzheimer' s Disease; Amygdaloid structure; Area; Autopsy; Behavioral; Bioinformatics; Biological; Brain; Brain region; Cell Nucleus; Chemicals; Chronic; Clinical Trials; Code; Collaborations; Communities; Complex; Data; Databases; Diagnosis; Disease; Disease Pathway; FDA approved; Funding; Future; Gene Expression; Genes; Genetic; Genomics; Goals; Heavy Drinking; Human; Individual; Link; Malignant Neoplasms; Messenger RNA; MicroRNAs; Microglia; Microinjections; Mining; Modeling; Molecular; Molecular Profiling; Mus; Network-based; Nucleus Accumbens; Pathway Analysis; Pharmaceutical Preparations; Phase; Physical Dependence; Prefrontal Cortex; Preparation; Proteins; Publications; RNA Splicing; Research; Resolution; Role; Sampling; Screening Result; Single Nucleotide Polymorphism; Synaptosomes; System; Technology; Testing; Therapeutic; Transcript; Universities; Untranslated RNA; Variant; Work; alcohol abuse therapy; alcohol research; alcohol risk; base; cohort; craving; design; differential expression; effective therapy; genetics of alcoholism; genome wide association study; human RNA sequencing; human data; human subject; innovation; mouse model; next generation sequencing; novel; novel therapeutics; predictive tools; problem drinker; public health relevance; receptor; success; tissue resource; transcriptome; transcriptome sequencing; treatment strategy

 DESCRIPTION (provided by applicant): During the current period of support we completed next generation sequencing (RNA-Seq) from cohorts of human brain samples obtained from the NSW Tissue Resource Center-University of Sydney. We also defined expression changes of microRNAs (miRNAs) in both human and mouse brain, proposing that miRNA act as "master switches", responsible for many of the changes in gene expression changes and that a single miRNA can alter alcohol consumption. Our previous microarray studies identified potential splice variations in GABAB receptors in human alcoholics and we used RNA-Seq to discover novel, complex splicing of the GABAB1 gene in human brain and showed that chronic alcohol produces additional splicing complexity. We also used our RNA-Seq data to perform a systems network analysis on alcoholics and matched controls across brain regions (prefrontal cortex and basolateral and central amygdala) to define molecular networks based upon lifetime alcohol consumption. We then identified gene networks based on mRNA and microRNA transcriptome profiling that significantly overlap in human alcoholics and mouse models of excessive alcohol consumption. In our proposed studies, we will mine our extensive human RNA-Seq transcriptome profiles in novel and innovative ways to link gene expression changes with genetic differences found in the Collaborative Studies on Genetics of Alcoholism (COGA) studies. We will focus our efforts on identifying candidate FDA approved drugs that can be tested in mouse models of alcohol consumption. Three Specific Aims are proposed: 1) bioinformatics analysis of next generation sequencing and genome-wide association studies will reveal human genes contributing to the risk of alcohol dependence, 2) convergent changes in gene expression between human alcoholics and mouse models of excessive alcohol consumption will be determined using network analysis of synaptoneurosome and microglia genes in the amygdala and prefrontal cortex of both species, and 3) novel therapeutics based on drugs that are in late-phase clinical trials or have existing FDA approval for other purposes will be selected and tested in alcohol drinking models in mice. Identification of effective target compounds in mice will facilitate testing in humans. The repurposing strategy has been used successfully to advance treatment for other diseases but has not been used for alcohol dependence, a disease lacking effective treatment options.

 描述（由申请人提供）：在当前的支持期间，我们对从悉尼大学新南威尔士州组织资源中心获得的一组人脑样本完成了下一代测序 (RNA-Seq)，我们还定义了 microRNA (miRNA) 的表达变化。 ）在人类和小鼠大脑中，提出 miRNA 充当“主开关”，负责基因表达变化的许多变化，并且我们之前的微阵列研究发现了潜在的剪接变异。人类酗酒者中的 GABAB 受体，我们使用 RNA-Seq 发现了人类大脑中 GABAB1 基因的新颖、复杂的剪接，并表明长期饮酒会产生额外的剪接复杂性。我们还使用我们的 RNA-Seq 数据对酗酒者进行系统网络分析。并匹配大脑区域（前额皮质、基底外侧和中央杏仁核）的对照，以定义基于终生饮酒量的分子网络，然后我们根据 mRNA 和 microRNA 转录组分析确定了在饮酒中显着重叠的基因网络。在我们提出的研究中，我们将以新颖和创新的方式挖掘我们广泛的人类酗酒者和过量饮酒的小鼠模型，将基因表达变化与酒精中毒遗传学合作研究（COGA）中发现的遗传差异联系起来。 ）研究的重点是确定 FDA 批准的候选药物，这些药物可以在小鼠饮酒模型中进行测试：1）下一代测序和全基因组关联研究的生物信息学分析将揭示人类基因的贡献。冒着风险酒精依赖的影响，2）人类酗酒者和过度饮酒的小鼠模型之间基因表达的趋同变化将通过对两个物种的杏仁核和前额皮质中的突触神经体和小胶质细胞基因的网络分析来确定，以及3）基于药物的新疗法正在进行后期临床试验或已获得 FDA 批准用于其他目的的药物将被选择并在小鼠饮酒模型中进行测试，鉴定出有效的化合物目标将有助于在人类中进行测试。成功地用于促进其他疾病的治疗，但尚未用于酒精依赖这种缺乏有效治疗选择的疾病。