Role of noncoding RNA in alcohol action

非编码RNA在酒精作用中的作用

• 批准号: 9240749
• 负责人: Gregg E. Homanics
• 金额: $ 52.73万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-05 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9240749
• 关键词: Alcohol consumption; Alcohols; Animal Experiments; Animal Model; Animals; Anti-Inflammatory Agents; Behavioral; Brain; Brain Diseases; Candidate Disease Gene; Cells; Collaborations; Development; Drug Delivery Systems; Drug Targeting; Epigenetic Process; Ethanol; Funding; Gene Expression; Genes; Genetic Engineering; Genetic Vectors; Genetically Engineered Mouse; Goals; Heavy Drinking; Human; Individual; Investigation; Investigational Therapies; Knock-in; Knock-out; Liposomes; Macaca; Methods; MicroRNAs; Modeling; Molecular; Mus; Neuroimmune; Organism; Peripheral; Pharmaceutical Preparations; Phenotype; Production; Proteins; RNA; Rattus; Regulator Genes; Research Personnel; Rodent; Role; Services; Site; Source; Specificity; Stress; Technology; Testing; Toxic effect; Treatment Efficacy; Untranslated RNA; Vesicle; alcohol research; alcohol use disorder; behavioral response; combat; drinking; drinking behavior; effective therapy; exosome; experimental study; gene function; insight; knock-down; knockin animal; knockout animal; mutant; nanoparticle; nanoscale; novel; problem drinker; therapeutic target; transcriptome; transcriptomics

Project Summary Ethanol-induced changes in the brain transcriptome underlie the development and persistence of alcohol use disorder (AUD). INIA-N investigators and others have discovered that ethanol induces specific and dramatic alterations in a highly restricted group of noncoding RNAs (ncRNAs) that includes long ncRNAs (lncRNAs). We posit that these ethanol responsive lncRNAs coordinate AUD brain transcriptomes. Specific Aim 1 will test the hypothesis that individual lncRNAs are key regulators of ethanol drinking. To test this hypothesis, genetically engineered mice with altered expression of lncRNAs will be created and analyzed. Those mutant lines with altered drinking behavior will be scrutinized for mechanistic insight by multiple INIA-N investigators. A barrier to the study of ncRNA function in brain is the dearth of efficient methods of noninvasively delivering ncRNAs and/or ncRNA antagonists to large portions of the brain. Here we posit that intransally administered exosomes (endogenously produced, liposome like nanoparticles) can be harnessed to deliver ncRNA anatagonists or mimics throughout the brain. This approach can also be used to deliver drugs preferentially to brain. Such an approach would target drugs selectively to the desired site of action (brain) while avoiding peripheral toxicities that limit therapeutic efficacy. Because this approach has the dual benefits of target specificity and noninvasiveness, it has tremendous translational potential. Specific Aim 2 will test the hypothesis that exosomes can be harnessed as effective ncRNA/drug delivery vehicles to modulate ethanol drinking. Genetically engineered rodents permit investigation of the involvement of putative ethanol targets in the context of whole animal behavioral responses. Because hypotheses concerning putative ethanol targets must ultimately explain ethanol-induced behavioral phenotypes, whole-animal experiments represent the most rigorous test of relevance. To this end, Specific Aim 3 will create designer mice for both INIA-N and INIA-Stress investigators. Genetically engineered animals will be produced using state of the art CRISPR/Cas9 gene editing technology. This collaborative Specific Aim is the continuation of the INIA-West Genetically Engineered Rodents Core that was funded during the previous project period.

项目概要 乙醇诱导的大脑转录组变化是大脑转录组发展和持续的基础 酒精使用障碍（澳元）。 INIA-N 研究人员和其他人发现乙醇会诱导 一组高度受限的非编码 RNA (ncRNA) 发生了特异性和显着的改变， 包括长 ncRNA (lncRNA)。 我们假设这些乙醇响应性 lncRNA 协调 AUD 脑转录组。 具体目标 1 将检验单个 lncRNA 是关键的假设 乙醇饮用的监管者。 为了验证这一假设，对小鼠进行了基因改造 将创建并分析 lncRNA 的表达。 那些改变饮酒的突变株系 多个 INIA-N 调查员将仔细审查行为以获取机械见解。 研究大脑中 ncRNA 功能的一个障碍是缺乏有效的方法 无创地将 ncRNA 和/或 ncRNA 拮抗剂递送至大脑的大部分区域。在这里我们 假设经内施用外泌体（内源产生的脂质体样纳米颗粒） 可用于在整个大脑中传递 ncRNA 拮抗剂或模拟物。这种方法可以 也可用于优先向大脑输送药物。 这种方法将针对药物 选择性地到达所需的作用部位（大脑），同时避免限制的外周毒性 治疗功效。因为这种方法具有目标特异性和 非侵入性，具有巨大的转化潜力。 具体目标 2 将测试 假设外泌体可以作为有效的 ncRNA/药物递送载体来调节 乙醇饮用。 基因工程啮齿动物允许研究假定的乙醇目标的参与 在整个动物行为反应的背景下。 因为关于假定的假设 乙醇目标必须最终解释乙醇诱导的行为表型、整个动物 实验代表了最严格的相关性测试。 为此，具体目标 3 将创建 为 INIA-N 和 INIA-Stress 研究人员设计的小鼠。基因工程动物将 使用最先进的 CRISPR/Cas9 基因编辑技术生产。 此次合作具体 Aim 是 INIA-West 基因工程啮齿类核心项目的延续，该核心项目是在 上一个项目期间。