Pharmacogenetics Core

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依赖药物治疗临床试验的设计和执行。我们将采用前瞻性基因分型，分层参与者的基因型在DBH基因座和5-羟色胺转运蛋白基因座。这个核心有五个具体目标。(1)我们将在调节多巴胺β羟化酶（DBH）水平的功能性启动子多态性上按基因型对前瞻性受试者进行分层，然后将其纳入双硫仑治疗可卡因依赖的安慰剂对照随机临床试验。(2)我们将按调节5-HTTPLR的功能性启动子多态性的基因型对前瞻性受试者进行分层，然后将他们纳入舍曲林治疗可卡因依赖的安慰剂对照随机临床试验。(3)我们将在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，与安慰剂相比。我们将测试GAT-1单倍型和对噻加宾的反应之间的关联。(4)我们将建立一个基础设施，用于对GAD-65和GAD-67以及5-HTTPLR的已知非同义SNP进行基因分型。(5)我们将为目前MDU中基于基因型的分析和耶鲁大学其他NIDA赞助的物质使用治疗试验提供技术咨询和支持。该CORE支持的设施将咨询药物滥用司所有教师对临床试验的遗传方法（包括统计遗传学）。分子整合 遗传学和临床药理学有望通过产生创新假设并引入新的遗传学和神经蛋白质组学方法来推进药物滥用治疗领域，因为它们在药物滥用以外的其他类型的医学疾病中不断发展。

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 and at the serotonin transporter locus. This CORE has five Specific Aims. (1) We will stratify prospective subjects by genotype 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) 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) 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. 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 MDU and 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 Substance Abuse. 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 substance abuse.