Pharmacogenetics of alcohol treatment: Topiramate and GRIK1

描述（由申请人提供）：药物遗传学通过表征自然遗传变异在调节治疗反应或不良反应中的作用，有可能为个体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减少酒精使用障碍患者的大量饮酒。编码托吡酯靶向的关键蛋白之一Gluk1谷氨酸受体亚基的基因GRIK1的常见变异与酒精依赖和对托吡酯的治疗反应有关，托吡酯用于减少寻求治疗的重度饮酒者的酒精使用。该项目将使用在实验室中产生的神经细胞，这些神经细胞来自成人皮肤细胞的重编程多能干细胞，这些细胞由酒精和非酒精受试者捐赠，以研究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编辑和下一代测序以及电生理学记录的分离的GluK1含有红藻氨酸受体的定量基因表达测定。我们预计，从这项工作的结果将提供一个更好的理解的生物学基础，不同的反应，酗酒的主题托吡酯治疗，从而增加了潜在的个人酒精使用问题提供个性化的治疗计划。

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.