Long Non-Coding RNA Regulation of Alcohol Drinking Behavior

项目概要/摘要 拟议的独立之路职业发展奖旨在建立在以前的基础上， 候选人的经验，并促进新的科学培训，以了解 酒精使用障碍的神经生物学酒精中毒是一种慢性复发性疾病， 在不同的大脑区域和细胞类型中基因表达的变化。下一代测序 来自死后脑组织的转录组（RNA-seq）显示出协调的动态变化， 表达的基因网络，封装了数百个基因，与酒精使用障碍有关。许多 在人脑的离散区域中所目睹的变化在中枢神经系统中是进化保守的。 中枢神经系统（CNS）在饮酒行为的动物模型。中枢神经系统的分子机制是 由相互作用的蛋白质编码和非编码RNA组成;然而，蛋白质编码基因代表较少 超过总基因组的2%非编码RNA，如长链非编码RNA（lncRNA），是一个丰富的部分， 在哺乳动物转录组中，在巨大的转录网络中具有关键的功能和调节作用。 识别和测试lncRNA在大脑和饮酒行为中的生物学作用 将导致对疾病的更好理解，并可能导致新的药物疗法。期间 在K99培训阶段的建议，候选人将获得新闻技能，量身定制，以补充他的 现有的经验，这将允许调查一个进化保守的lncRNA参与酒精 饮酒行为R博士Adron Harris和R.戴恩·梅菲尔德，他们都是这一领域的专家， 酗酒研究，将直接指导这个项目，并提供援助，为审问的作用，小说 成瘾神经病理学的分子候选者。总体而言，该项目将（1）执行目标- lncRNA的深度测序，并发现受影响的分子网络（2）控制lncRNA表达 以及（3）细胞类型，以辨别分子机制和行为表型 受到lncRNA的影响基于大规模系统的生物信息学方法与直接 在动物模型中对优先候选物的检查将确定lncRNA作为重要的介体， 酒精滥用和依赖。在这个职业发展奖下接受的培训将提供 必要的培训，成为酒精和成瘾研究领域的独立调查员。

Project Summary / Abstract The proposed Pathway to Independence Career Development Award is designed to build upon the previous experience of the candidate and facilitate new scientific training geared towards understanding the neurobiology of an alcohol use disorder. Alcoholism is a chronic relapsing condition that causes widespread changes in gene expression throughout different brain regions and cell-types. Next-generation sequencing of the transcriptome (RNA-seq) from postmortem brain tissue has shown dynamic changes in coordinately expressed gene networks, encapsulating several hundred genes, related to an alcohol use disorder. Many of the changes, witnessed in discrete areas of the human brain, are evolutionary conserved in the central nervous system (CNS) within animal models of alcohol drinking behavior. The molecular machinery of the CNS is comprised of interacting protein-coding and non-coding RNA; however, protein-coding genes represent less than 2% of the total genome. Non-coding RNAs, such as long non-coding RNA (lncRNA), are an abundant part of the mammalian transcriptome, having key functional and regulatory roles over vast transcriptional networks. Identifying and testing the biological role of lncRNAs in the context of the brain and alcohol drinking behavior will lead to an improved understanding of disease, and potentially may lead to new pharmacotherapies. During the K99 training phase of this proposal the candidate will acquire news skills, tailored to complement his existing experience, that will permit the investigation of an evolutionary conserved lncRNA involved in alcohol drinking behavior. Drs. R. Adron Harris and R. Dayne Mayfield, both of whom are experts in the field of alcoholism research, will directly mentor this project and provide assistance for interrogating the role of novel molecular candidates in the neuropathology of addiction. Collectively this project will (1) perform targeted in- depth sequencing of lncRNA, and discover affected molecular networks from (2) controlling lncRNA expression in a specific brain region and (3) cell-types to discern the molecular mechanism and behavioral phenotypes impacted by lncRNA. Integration of large-scale systems-based bioinformatics approaches with direct examination of prioritized candidate(s) in animal models will establish lncRNA(s) as important mediators of alcohol abuse and dependence. The training received under this career development award will provide the necessary training to become an independent investigator in the field of alcohol and addiction research.