Pharmacogenetics Core

药物遗传学核心

• 批准号: 7648024
• 负责人: Joseph F. Cubells
• 金额: $ 42.42万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7648024
• 关键词: Accounting; Alcohol or Other Drugs use; American; Amino Acid Sequence; Antidepressive Agents; Bioinformatics; Biological Assay; Butyric Acid; Butyric Acids; Candidate Disease Gene; Carrier Proteins; Clinical Pharmacology; Clinical Trials; Cocaine; Cocaine Dependence; Cocaine Users; Computer Simulation; Consult; Consultations; Data; Depressed mood; Development; Disease; Disulfiram; Dopamine; Dopamine-beta-monooxygenase; Education; European; Exons; Facility Construction Funding Category; Faculty; GABA transporter; Genes; Genetic; Genetic Databases; Genetic Polymorphism; Genetic Variation; Genotype; Goals; Grant; Haplotypes; High Pressure Liquid Chromatography; Knowledge; Mediating; Medical; Methadone; Methodology; Methods; Mixed Function Oxygenases; Molecular Genetics; Nomenclature; Outcome Measure; Paranoia; Participant; Patients; Pharmaceutical Preparations; Pharmacogenetics; Pharmacotherapy; Pilot Projects; Placebo Control; Placebos; Plasma; Polymerase Chain Reaction; Population; Promoter Regions; Proteins; Purpose; Randomized; Randomized Clinical Trials; Research; Research Infrastructure; Research Personnel; Restriction Fragment Length Polymorphism Analysis; Sampling; Scanning; Selective Serotonin Reuptake Inhibitor; Series; Sertraline; Single Nucleotide Polymorphism; Standards of Weights and Measures; Statistical Methods; Substance abuse problem; Tandem Repeat Sequences; Testing; Text; Therapeutic; Time; Upper arm; Work; base; design; dopamine transporter; double-blind placebo controlled trial; expectation; gabapentin; gamma-Aminobutyric Acid; genetic variant; inhibitor/antagonist; innovation; neurotransmission; novel; programs; promoter; prospective; response; reuptake; serotonin transporter; size; therapeutic target; tiagabine; transmission process; uptake

The goal of the Pharmacogenetics CORE of this Medications Development Unit Center (MDU) is to integrate molecular genetics into the design and execution of clinical trials of pharmacotherapies for cocaine dependence. We will employ prospective genotyping to stratify participants by genotype at the DBH locus in Project 1 and at the serotonin transporter locus in Project 2. This CORE has five Specific Aims. (1) In Project 1we will stratify prospective subjects bygenotype at a functional promoter polymorphism regulating levels of dopamine beta hydroxylase (DBH) and then enter them into a placebo controlled randomized clinical trial of disulfiram for cocaine dependence. (2) In Project 2 we will stratify prospective subjects by genotype at a functional promoter polymorphism regulating 5-HTTPLR and then enter them into a placebo controlled randomized clinical trial of sertraline for cocaine dependence. (3) For both Projects 1 and 2 we will identify novel single nucleotide polymorphisms (SNPs) in the GAT-1 gene (SLC6A12), which encodes the GABA transporter protein, GAT-1. The GAT-1 is the therapeutic target of tiagabine, which is compared to placebo in both Projects. We will test for an association between GAT-1 haplotypes and response to tiagabine. (4) We will establish an infrastructure for genotyping known non-synonymous SNPs at GAD-65 and GAD-67, and at the 5-HTTPLR. (5) We will provide technical consultation and support for genotype- based analyses in the current MDUand for other NIDA-sponsored trials for substance-use treatments at Yale. The facilities supported by this CORE will consult on genetic approaches (including statistical genetics) to clinical trials by all the faculty in the Division of SubstanceAbuse. The integration of molecular genetics and clinical pharmacology promises to advance the field of substance abuse treatment by generating innovative hypotheses and introducing new genetic and neuro-proteinomic methodologies as they evolve for other types of medical disorders besides substanceabuse.

该药物开发单元中心（MDU）的药物遗传学核心的目标是 将分子遗传学整合到可卡因药物疗法的临床试验的设计和执行 依赖。我们将利用前瞻性基因分型来通过基因型在DBH基因座进行分层 在项目1和项目2中的5-羟色胺转运蛋白基因座中。该核心具有五个特定的目标。 （1）英寸 项目1WE将在调节功能启动子多态性下对前瞻性受试者进行分层。 多巴胺β羟化酶（DBH）的水平，然后将其输入安慰剂控制的随机分配 可卡因依赖性二硫仑的临床试验。 （2）在项目2中，我们将根据 调节5-HTTPLR的功能启动子多态性的基因型，然后进入安慰剂 可卡因依赖性的舍曲林的对照随机临床试验。 （3）对于两个项目1和2我们 将确定GAT-1基因（SLC6A12）中新型的单核苷酸多态性（SNP），该核苷酸（SLC6A12）编码 GABA转运蛋白GAT-1。 GAT-1是tiagabine的治疗靶标，可以比较 在两个项目中安慰剂。我们将测试GAT-1单倍型与对响应之间的关联 tiagabine。 （4）我们将建立用于GAD-65上已知非同义SNP的基因分型的基础架构 和GAD-67，以及5-HTTPLR。 （5）我们将为基因型提供技术咨询和支持 - 基于当前MDUAND的基于NIDA赞助的试验的物质使用治疗的分析 耶鲁 该核心支持的设施将咨询遗传方法（包括统计 遗传学）对属性分裂的所有教师进行临床试验。分子的整合 遗传学和临床药理学有望通过 产生创新的假设，并引入新的遗传和神经蛋白质组学方法论 除了替代药物外，它们还为其他类型的医学疾病而发展。