Pharmacogenetics of alcohol treatment: Topiramate and GRIK1

描述（由申请人提供）：药物遗传学通过描述自然遗传变异在调节治疗反应或不良反应中的作用，有可能为个性化药物治疗决策提供信息。最近的研究表明，用于治疗癫痫的药物托吡酯也能有效地减少酒精使用障碍患者的大量饮酒。基因GRIK1的一种常见变异编码了托吡酯靶向的关键蛋白之一，即Gluk1谷氨酸受体亚基，这种变异与酒精依赖以及托吡酯在治疗重度饮酒者时减少酒精使用的治疗反应有关。该项目将使用从酒精和非酒精受试者捐赠的成人皮肤细胞中获得的重编程多能干细胞在实验室产生的神经细胞，以检查GRIK1遗传变异和酒精与托吡酯联合对体外人类神经细胞中GluK1谷氨酸受体表达和功能的影响。这项工作将采用GRIK1 RNA异构体、反义RNA、RNA编辑和下一代测序的定量基因表达分析，以及药理学分离的含有盐酸盐受体的GluK1的电生理记录。我们预计这项工作的结果将更好地了解酒精受试者对托吡酯治疗的不同反应的生物学基础，从而增加为酒精使用问题患者提供个性化治疗计划的潜力。

DESCRIPTION (provided by applicant): Pharmacogenetics has the potential to inform individualized medication treatment decisions by characterizing the role of natural genetic variation in moderating treatment response or adverse effects. Recent studies have shown that the medication topiramate, which is used to treat epilepsy, is also effective in reducing heavy drinking in patients with alcohol use disorder. A common variation in the gene GRIK1 that encodes one of the key proteins targeted by topiramate, the Gluk1 glutamate receptor subunit, has been associated with alcohol dependence and with treatment response to topiramate for reducing alcohol use in treatment seeking heavy drinkers. This project will use neural cells generated in the laboratory from reprogrammed pluripotent stem cells derived from adult skin cells donated by characterized alcoholic and non-alcoholic subjects to examine the effects of GRIK1 genetic variation and of alcohol combined with topiramate on the expression and function of the GluK1 glutamate receptor in human neural cells in vitro. This work will employ quantitative gene expression assays of GRIK1 RNA isoforms, antisense RNA, RNA editing and next generation sequencing as well as electrophysiology records of pharmacologically isolated GluK1 containing kainate receptors. We anticipate that results from this work will provide a better understanding of the biological basis for differential responses of alcoholic subjects to topiramate treatment and thereby increase the potential to provide individualized treatment planning for persons with alcohol use problems.