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：
8897927
负责人：
JONATHAN M COVAULT
金额：
$ 18.6万
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 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8897927
关键词：
Adult Adverse effects Affect Alcohol abuse Alcohol dependence Alcoholic beverage heavy drinker Alcohols Alleles Alternative Splicing Antisense RNA Attention Biological Cell membrane Cells Chronic Clinical Combined Modality Therapy Data Effectiveness Electrophysiology (science)Epilepsy Ethanol Exposure to Gene Expression Gene Expression Profile Gene Expression Profiling Genes Genetic Polymorphism Genetic Variation Genotype Glutamate Receptor Health 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 individualized medicine induced pluripotent stem cell mRNA Expression next generation next generation sequencing non-alcoholic novel placebo controlled study problem drinker reduced alcohol use relating to nervous system response topiramate transcriptome sequencing 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性化的药物治疗决定提供信息。最近的研究表明，用于治疗癫痫的托吡酯药物也有效地减少了酒精饮用障碍患者的大量饮酒。基因GRIK1的常见变化，它编码了托吡酯靶向的一种关键蛋白Gluk1谷氨酸受体亚基，与酒精依赖性以及对托吡酯的治疗反应相关，用于减少饮酒，以减少饮酒。该项目将使用由重编程的多能干细胞产生的神经细胞，这些干细胞由成人皮肤细胞衍生而成，这些细胞由成人皮肤细胞通过表征的酒精和非酒精性受试者捐赠，以检查Grik1遗传变异和酒精对托吡酯对人类神经细胞中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，以及含有海藻酸盐受体的药理学分离的GLUK1的电生理记录。我们预计这项工作的结果将更好地理解酒精受试者对托吡酯治疗的差异反应的生物学基础，从而增加为患有酒精使用问题的人提供个性化治疗计划的潜力。