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.

药物开发单位中心（MDU）药物遗传学核心的目标是 将分子遗传学纳入可卡因药物治疗临床试验的设计和执行 依赖我们将采用前瞻性基因分型，以分层的基因型在DBH位点的参与者 在项目1和项目2中的5-羟色胺转运体位点。这个核心有五个具体目标。(1)在 项目1我们将按照基因型对潜在的受试者进行分层，基因型在一个功能性启动子多态性调节 多巴胺β羟化酶（DBH）水平，然后将其输入安慰剂对照随机 双硫仑治疗可卡因依赖的临床试验(2)在项目2中，我们将对潜在受试者进行分层， 在调节5-HTTPLR的功能性启动子多态性的基因型，然后将其输入安慰剂 舍曲林治疗可卡因依赖的随机对照临床试验(3)对于项目1和项目2， 将在GAT-1基因（SLC 6A 12）中鉴定新的单核苷酸多态性（SNP），该基因编码 GABA转运蛋白GAT-1 GAT-1是噻加宾的治疗靶点， 两个项目中的安慰剂。我们将检测GAT-1单倍型与对 噻加宾。(4)我们将建立一个基础设施，用于对GAD-65位点上已知的非同义SNP进行基因分型 和GAD-67以及5-HTTPLR。(5)我们将提供基因分型的技术咨询和支持- 基于当前MDU和其他NIDA申办的药物使用治疗试验的分析， 耶鲁 该核心小组支持的设施将就遗传方法（包括统计方法）提供咨询。 遗传学）的药物滥用部门的所有教师的临床试验。分子整合 遗传学和临床药理学有望推进物质滥用治疗领域， 产生创新的假设，并引入新的遗传和神经蛋白质组学方法， 除了药物滥用外，它们还进化为其他类型的医学疾病。