MicroRNA: targets for medication development in alcoholism

MicroRNA：酒精中毒药物开发的目标

• 批准号: 9057449
• 负责人: R. DAYNE MAYFIELD
• 金额: $ 17.34万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9057449
• 关键词: Address; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcoholism; Alcohols; Behavioral; Brain; Cell Culture Techniques; Chronic; Development; Diagnosis; Disease; Gene Expression; Gene Expression Profile; Genes; Instruction; Mediating; Messenger RNA; MicroRNAs; Modeling; Molecular; Mus; Nature; Nucleus Accumbens; Pattern; Pharmaceutical Preparations; Phenotype; Physical Dependence; Regulation; Reporter; Reverse Transcriptase Polymerase Chain Reaction; Role; Small RNA; System; Testing; Untranslated RNA; Validation; Ventral Tegmental Area; Work; alcohol exposure; alcohol research; alcohol response; alcoholism therapy; base; behavioral genomics; chronic alcohol ingestion; craving; differential expression; drinking; innovation; mRNA Expression; miRNA expression profiling; mouse model; next generation sequencing; novel; overexpression; preference; research study; therapeutic target

PROJECT SUMMARY (See instructions): Chronic alcohol abuse produces lasting changes in brain function that are manifested as tolerance, physical dependence, craving, and other behavioral changes. The Mayfield Project will test the overall hypothesis that these changes are due to the co-ordinated regulation of alcohol-responsive genes by small non-coding RNAs. This Project will explore the role of these regulatory RNAs using several innovative approaches to alcohol research, including profiling of all known miRNAs, next generation sequencing of unique small RNAs, prediction and validation of microRNAs (miRNAs):mRNA target interactions, expression patterns of miRNAs which may act in combination to regulate mRNA expression and delivery of selected alcohol-related miRNAs to brain. Three Specific Aims are proposed: Aim 1 will test the hypothesis that miRNA expression profiling and next generation sequencing will identify unique alcohol-sensitive small RNAs in the nucleus accumbens and ventral tegmental area of mouse brain. Subsequent RT-PCR analysis will validate and define which of these are involved in mediating the effects of alcohol consumption in mouse models. Aim 2 will test the hypothesis that differentially expressed miRNAs are co-ordinately expressed and act in combination by direct interaction with their predicted targets to regulate gene expression. The changes in expression that occur as a result of miRNA regulation are functionally important and may underlie alcohol's actions in the brain. Aim 3 will test the hypothesis that over-expression of select miRNAs in mouse brain, either individually or in combination, will alter drinking phenotypes, and these changes will be correlated with specific patterns of gene expression in the nucleus accumbens and ventral tegmental area of mouse brain.

项目摘要（请参阅说明）： 慢性酒精滥用会导致大脑功能的持久变化，这些变化表现为耐受性，身体依赖，渴望和其他行为变化。梅菲尔德项目将检验总体假设，即这些变化是由于小型非编码RNA对酒精反应基因的协调调节。该项目将使用几种创新的酒精研究方法来探索这些调节性RNA的作用，包括对所有已知的miRNA进行分析，独特的小RNA的下一代测序，microRNAS的预测和验证：mRNA目标相互作用，miRNA的表达模式，这些模式可以通过组合来调节MRNA表达和交付所选的miRNAS rairnas rains-realnas rains rains buninabs buninna，brinaks of Conemination。提出了三个特定的目标：AIM 1将检验以下假设：miRNA表达分析和下一代测序将在伏隔核和小鼠脑的腹侧隔离区域中鉴定出独特的酒精敏感的小RNA。随后的RT-PCR分析将验证并定义哪些参与介导小鼠模型中酒精消耗的影响。 AIM 2将检验以下假设：差异表达的miRNA是协调表达的，并通过直接相互作用与其预测靶标调节基因表达来起作用。由miRNA调节导致的表达变化在功能上很重要，并且可能是酒精在大脑中的作用的基础。 AIM 3将检验以下假设：小鼠大脑中选择的miRNA的过表达，无论是单独或组合，都会改变饮酒表型，并且这些变化将与小鼠脑的振容核和腹侧侧侧的基因表达的特定模式相关。