Deep Sequencing of CNR1 Gene Network in Substance Dependence

摘要本次导师研究事业发展奖（K01）旨在培养耶鲁大学精神学系初级教员左凌军博士成为物质依赖遗传学（SD）研究领域的独立研究者。培训包括三个主要领域：(1)先进的人类分子遗传学，特别是“Solexa”测序和大麻素受体1 （CNR1）基因网络；(2)神经科学，特别是SD，脑神经网络和大麻素受体与其他SD候选基因蛋白产物的功能关系；(3)高通量序列数据、基因网络数据以及基因与环境相互作用分析的生物信息学和统计学分析方法。为了获得这些培训，左博士的时间将被分配(1)参加课程和研讨会，(2)与导师和联合导师会面，(3)与其他专家互动，主要是(4)研究项目本身。研究计划将集中于CNR1基因网络的深度测序，该网络由CNR1和其他5个生物学相关基因组成。左博士建议通过(1)使用下一代测序方法在相对较大的样本中对目标基因区域进行测序，以及(2)使用多基因模型研究多个功能变体的联合效应，这些功能变体的个体效应可能太弱，无法通过单基因模型检测到。本研究有望阐明SD的CNR1基因网络的遗传变异，这将对SD的病因学研究取得重大进展，也可能有助于开发新的有效的SD治疗和预防策略。

DESCRIPTION (provided by applicant): D Deep sequencing of CNR1 gene network in substance dependence: Abstract This Mentored Research Career Development Award (K01) is to train Dr. Lingjun Zuo, a junior faculty member of Department of Psychiatry at Yale University, to become an independent investigator in the research field on genetics of substance dependence (SD). The trainings include three main areas: (1) advanced human molecular genetics, in particularly in "Solexa" sequencing and cannabinoid receptor 1 (CNR1) gene network; (2) neuroscience, in particularly in SD, brain neural networks and functional relationship between cannabinoid receptor and protein product of other SD candidate genes; and (3) bioinformatic and statistical analytical methods for high-throughput sequence data, gene network data as well as gene x environment interaction analysis. To acquire these trainings, Dr. Zuo's time will be allocated (1) to courses and seminars, (2) to meetings with the mentor and co-mentors, (3) to interactions with other experts, and mainly (4) to the proposed research project per se. The research plan will focus on deep sequencing of CNR1 gene network that consists of CNR1 and five other biologically related genes. Dr. Zuo proposes to identify the potential functional variants underlying SD in this gene network by (1) sequencing the targeted gene regions in a relatively big size of sample using next generation sequencing approach, and by (2) using multiple-gene model to investigate the joint effects of multiple functional variants, which might exert too weak individual effects to be detectable using single-gene model. This proposed study would be promising to elucidate the genetic variants in the CNR1 gene network underlying SD, which would make a major progress in the etiology of SD, and may also be helpful to develop novel and effective treatment and prevention strategies for SD. PUBLIC HEALTH RELEVANCE: Relevance to public health This proposed project will carefully study the effects of cannabinoid receptor 1 gene (CNR1) network on risk for substance dependence (SD) using the next generation deep sequencing technology, which will help us better understand the mechanism for the development of SD. The expected findings would significantly contribute to the improvement of public health.