Pharmacogenetics of alcohol treatment: Topiramate and GRIK1

酒精治疗的药物遗传学：托吡酯和 GRIK1

基本信息

批准号：
8751105
负责人：
JONATHAN M COVAULT
金额：
$ 23.08万
依托单位：
UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8751105
关键词：
Adult Adverse effects Affect Alcohol abuse Alcohol dependence Alcoholic beverage heavy drinker Alcohols Alleles Alternative Splicing Antisense RNA Attention Biological Biological Assay Cell membrane Cells Chronic Clinical Combined Modality Therapy Data Effectiveness Electrophysiology (science)Epilepsy Ethanol Exposure to Gene Expression Gene Expression Profile Genes Genetic Polymorphism Genetic Variation Genotype Glutamate Receptor Heavy Drinking Homozygote Human In Vitro Individual Kainic Acid Receptors Laboratories Mediating Mediator of activation protein Medical Membrane Messenger RNA Methods Molecular Naltrexone Neurons Ondansetron Patients Pattern Persons Pharmaceutical Preparations Pharmacogenetics Pharmacological Treatment Physiological Pluripotent Stem Cells Production Protein Isoforms Proteins Public Health RNA RNA Editing RNA Sequences RNA Splicing Records Relative (related person)Reporting Research Reverse Transcriptase Polymerase Chain Reaction Role Single Nucleotide Polymorphism Skin Trans-Activators Variant Work alcohol abuse therapy alcohol effect alcohol exposure alcohol use disorder base drinking experience genetic variant induced pluripotent stem cell mRNA Expression next generation next generation sequencing non-alcoholic novel placebo controlled study problem drinker public health relevance reduced alcohol use relating to nervous system response topiramate treatment planning treatment response

项目摘要

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.

描述（由申请人提供）：药物遗传学有可能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来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酗酒。 GRIK1 基因的一个常见变异是托吡酯靶向的关键蛋白之一（Gluk1 谷氨酸受体亚基）的编码，该变异与酒精依赖以及托吡酯在治疗重度饮酒者时减少饮酒的治疗反应有关。该项目将使用在实验室中产生的神经细胞，这些神经细胞是由经过重新编程的多能干细胞产生的，这些干细胞源自特征性酒精和非酒精受试者捐赠的成体皮肤细胞，以检查 GRIK1 遗传变异以及酒精与托吡酯联合对多能干细胞表达和功能的影响。体外人类神经细胞中的 GluK1 谷氨酸受体。这项工作将采用 GRIK1 RNA 同工型、反义 RNA、RNA 编辑和下一代测序的定量基因表达测定，以及药理学分离的含有红藻氨酸受体的 GluK1 的电生理学记录。我们预计这项工作的结果将有助于更好地理解酒精受试者对托吡酯治疗差异反应的生物学基础，从而增加为有酒精使用问题的人提供个体化治疗计划的潜力。