Repeated Binge Drinking and the Genetic Regulation of Corticostriatal Synchrony

反复酗酒与皮质纹状体同步性的基因调控

• 批准号: 10090539
• 负责人: David Nathaniel Linsenbardt
• 金额: $ 24.86万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10090539
• 关键词: Acute; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcoholism; Alcohols; Animals; Area; Award; Behavioral; Behavioral Genetics; Bioinformatics; Blood alcohol level measurement; Brain; Brain region; Cell physiology; Chronic; Computational Biology; Consumption; Data; Data Set; Development; Dose; Electrophysiology (science); Environment; Faculty; Gene Expression; Genes; Genetic; Genetic Predisposition to Disease; Genetic Processes; Genetic Risk; Genetic Transcription; Genomics; Goals; Heavy Drinking; Indiana; Individual; Intake; Interview; Medial; Mediating; Medical; Mentors; Mission; Modeling; Molecular; Mus; National Institute on Alcohol Abuse and Alcoholism; Neurobiology; Nucleus Accumbens; Pathway Analysis; Phase; Physiological; Physiological Adaptation; Physiology; Population; Positioning Attribute; Prefrontal Cortex; Probability; Publishing; Recording of previous events; Regimen; Regulation; Relapse; Reproducibility; Research; Research Personnel; Resources; Rewards; Risk; Role; Series; Severities; Site; Structure; System; Techniques; Time; Training; Universities; Ventral Striatum; Water; academic preparation; addiction; alcohol exposure; alcohol research; alcohol use disorder; binge drinking; bioinformatics tool; career; career development; drinking; experience; genetic analysis; genetics of alcoholism; insight; mouse model; multi-electrode arrays; neuroadaptation; neurophysiology; next generation; next generation sequencing; prevent; programs; recruit; relating to nervous system; skills; symposium; targeted treatment; transcriptome sequencing; treatment strategy

The primary objective of the first two years of the K99/R00 award is to provide the candidate with bioinformatics training in the identification and analysis of brain gene expression networks in preparation for an academic research career in the neurophysiological genetics of alcoholism. The candidates specific goal for the K99 phase of the project is to identify gene networks (and key genes regulating these networks) recruited by repeated binge alcohol consumption within brain areas thought to be involved in loss of control over alcohol consumption - the medial Prefrontal Cortex (mPFC) and the ventral Striatum (vSTR; i.e. nucleus accumbens). The candidate will undertake an intensive training regimen to obtain the necessary skills and expertise to analyze and interpret next-generation sequencing data. He will further his career development by completing semester-long didactic coursework in both next-generation sequencing and bioinformatics, and also by attending intensive short courses on the genetics of addiction, statistical genetics, and network analysis. His career development will also be furthered by attending relevant seminars and seminar series offered through the Indiana University Alcohol Research Center (IARC) and Center for Computational Biology and Bioinformatics (CCBB), and by publishing his research findings, attending scientific conferences, and interviewing for independent faculty positions. The proposed mentoring team includes, Drs. Christopher Lapish, Tatiana Foroud, Yunlong Liu, and Howard Edenberg. These individuals collectively are experts in systems and computational electrophysiology, statistical and bioinformatics analyses, and medical/population genomics and genetics. The long-standing collaborative research environment at IUPUI, in particular the IARC, will provide the candidate the necessary resources to complete the aims as outlined in this proposal. At the start of the 3rd year during the R00 phase of the award, the candidate will establish his new role as an independent faculty researcher where he will continue his research on identifying, validating, and characterizing genes and gene networks regulating the brain circuits associated with repeated excessive alcohol consumption, and genetic risk for such consumption. This will be accomplished by combining newly acquired skills in bioinformatics with his current expertise in behavioral physiology and behavioral genetics. Determining the genetic and neurophysiological causes and consequences of excessive alcohol consumption are directly relevant to the mission of the NIAAA in understanding the neurobiology of alcoholism. Specifically, the proposed studies will reveal how the coordinated activity of networks of genes mediates the physiological functioning of a key brain reward circuit to facilitate repeated excessive alcohol consumption. This will result in a better understanding of why and how alcohol use leads to addiction and will help us develop strategies to prevent and treat excessive drinking.

K99/R 00奖项前两年的主要目标是为候选人提供 在大脑基因表达网络的识别和分析方面的生物信息学培训， 酗酒神经生理遗传学的学术研究生涯。候选人的具体目标是 该项目的K99阶段是确定招募的基因网络（以及调节这些网络的关键基因） 通过在被认为与酒精失控有关的大脑区域内反复酗酒 消耗-内侧前额叶皮质（mPFC）和腹侧纹状体（vSTR;即丘脑核）。 候选人将接受强化培训，以获得必要的技能和专业知识， 分析和解释下一代测序数据。他将通过完成 在下一代测序和生物信息学的一个学期的教学课程，也由 参加关于成瘾遗传学、统计遗传学和网络分析的强化短期课程。他 此外，学员亦会透过以下途径参加有关的研讨会及系列研讨会，以促进职业发展： 印第安纳州大学酒精研究中心（IARC）和计算生物学中心， 生物信息学（CCBB），并通过发表他的研究成果，参加科学会议， 独立教师职位面试。拟议的指导小组包括克里斯托弗博士 Lapish，Tatiana Foroud，Yunlong Liu，and霍华德伊登伯格.这些人都是 系统和计算电生理学，统计和生物信息学分析，以及医学/人口 基因组学和遗传学。IUPUI的长期合作研究环境，特别是IARC， 将为候选人提供必要的资源，以完成本建议书中概述的目标。在 在R 00阶段的第三年开始时，候选人将确立自己的新角色， 独立的教师研究员，他将继续他的研究，识别，验证， 表征基因和基因网络调节与重复过度 酒精消费，以及这种消费的遗传风险。这将通过结合新的 他目前在行为生理学和行为遗传学方面的专业知识，获得了生物信息学方面的技能。 确定过量饮酒的遗传和神经生理原因和后果 直接关系到NIAAA的使命，即了解酒精中毒的神经生物学。具体地说， 这些研究将揭示基因网络的协调活动是如何介导生理学的。 关键的大脑奖励回路的功能，以促进重复过量饮酒。这将导致 更好地了解为什么以及如何使用酒精导致成瘾，并将帮助我们制定策略， 预防和治疗过度饮酒。