Long Non-Coding RNA Regulation of Alcohol Drinking Behavior

长链非编码RNA对饮酒行为的调节

• 批准号: 10395501
• 负责人: Sean P Farris
• 金额: $ 22.37万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10395501
• 关键词: Affect; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcoholism; Alcohols; Animal Model; Area; Autopsy; Award; Bioinformatics; Biological; Biological Testing; Brain; Brain Chemistry; Brain region; Chronic; Code; Complement; Computational Biology; Consumption; Data; Dependence; Development; Diagnostic; Disease; Encapsulated; Etiology; Family; Gene Expression; Gene Expression Regulation; Gene Targeting; Genes; Genetic; Genetic Transcription; Genome; Harvest; Human; In Situ Hybridization; Individual; Investigation; K-Series Research Career Programs; Laboratories; Lasers; Lead; Mediating; Mediator of activation protein; Mental disorders; Mentors; Messenger RNA; Microscopy; Molecular; Molecular Biology; Mosaicism; Mus; Neuraxis; Neurobiology; Neurons; Noise; Participant; Pathway interactions; Personal Satisfaction; Pharmacotherapy; Phase; Population; Proteins; RNA; Regulation; Relapse; Research; Research Personnel; Research Proposals; Role; Self Administration; Societies; System; Testing; Training; Transcript; Transcriptional Regulation; Untranslated RNA; Viral; addiction; alcohol exposure; alcohol response; alcohol testing; alcohol use disorder; base; behavioral phenotyping; brain cell; brain tissue; career development; cell type; chronic alcohol ingestion; design; drinking behavior; epigenetic regulation; experience; gene network; gene regulatory network; genome-wide; human RNA sequencing; improved; insight; knock-down; neurogenomics; neuropathology; new therapeutic target; news; next generation sequencing; novel; response; skills; transcriptome; transcriptome sequencing

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.

项目摘要 /摘要 拟议的独立职业发展途径旨在基于以前的 候选人的经验，并促进新的科学培训，旨在理解 酒精使用障碍的神经生物学。酒精中毒是一种慢性复发状况，导致广泛 整个大脑区域和细胞类型的基因表达的变化。下一代测序 验尸后脑组织的转录组（RNA-SEQ）显示了协调的动态变化 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 这些变化在人脑的离散区域见证 饮酒行为动物模型中的系统（CNS）。中枢神经系统的分子机械是 由相互作用的蛋白质编码和非编码RNA组成；但是，蛋白质编码基因代表较少 总基因组的2％。非编码RNA，例如长的非编码RNA（LNCRNA），是丰富的部分 哺乳动物的转录组，在庞大的转录网络上具有关键功能和调节作用。 在大脑和饮酒行为的背景下识别和测试LNCRNA的生物学作用 将导致对疾病的了解，并可能导致新的药物治疗。期间 该提案的K99培训阶段候选人将获得新闻技能，以补充他 现有的经验，这将允许调查与酒精相关的进化保守的lncRNA 饮酒行为。博士。 R. Adron Harris和R. Dayne Mayfield，他们都是该领域的专家 酒精中毒研究将直接指导该项目，并为询问新颖的作用提供帮助 成瘾神经病理学中的分子候选者。该项目将（1）执行针对性的IN- LNCRNA的深度测序，并从（2）控制lncRNA表达的分子网络发现 在特定的大脑区域和（3）细胞类型中，可以辨别分子机制和行为表型 受lncrna的影响。与直接的基于系统的生物信息学方法的集成 在动物模型中检查优先候选者的优先级候选者将建立LNCRNA作为重要的介体 酗酒和依赖。根据本职业发展奖获得的培训将为 成为酒精和成瘾研究领域的独立研究者的必要培训。