Role of noncoding RNA in alcohol action

非编码RNA在酒精作用中的作用

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要乙醇引起的大脑转录组的变化是发展和持久性的基础酒精使用障碍（AUD）。 INIA-N调查人员和其他人发现乙醇诱导在高度限制的非编码RNA（NCRNA）的特定和戏剧性变化中包括长ncRNA（lncRNA）。我们认为这些乙醇响应lncRNA坐标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调节剂。为了检验该假设，经过改变的基因工程小鼠将创建和分析LNCRNA的表达。那些随着饮酒改变的突变线多个INIA-N研究者将仔细检查行为以审查机理洞察力。大脑中NCRNA功能研究的障碍是缺乏有效方法非侵入性将NCRNA和/或NCRNA拮抗剂传递到大脑的大部分。我们在这里认为固定的外泌体（内源产生，像纳米颗粒这样的脂质体）可以利用在整个大脑中传递NCRNA的Anatagonists或模仿。这种方法可以也可用于优先向大脑输送药物。这样的方法将针对药物选择性地到达所需的作用部位（大脑），同时避免了限制的外围毒性治疗功效。因为这种方法具有目标特异性的双重好处，并且无创，它具有巨大的翻译潜力。具体目标2将测试假设外泌体可以利用为有效的NCRNA/药物输送工具调节乙醇喝。基因工程啮齿动物允许研究推定乙醇靶标的参与在整个动物行为反应的背景下。因为关于推定的假设乙醇靶标最终必须解释乙醇诱导的行为表型，全动物实验代表了最严格的相关性测试。为此，特定的目标3将创建 INIA-N和INIA应力调查员的设计师小鼠。基因工程动物将是使用最先进的CRISPR/CAS9基因编辑技术生产。这个协作特定的目的是延续Inia-West基因工程啮齿动物核心，该核心是在此期间资助的上一个项目期。