Antidepressent Response and Gene Expression

描述(申请人提供)：抑郁症估计每年花费650亿美元，而任何给定的抗抑郁药物治疗(ADT)只在大约一半的病例中有效。尽管ADT明显需要改进，但在理解反应机制方面只取得了一些进展。最近的证据表明，抗抑郁反应(ADR)可能依赖于5-羟色胺转运体(SERT)基因序列中一个多态的启动子区域。这种多态(5-HTTLPR)对几种细胞因子和激酶信号具有不同的敏感性。 试点基因芯片数据现在已经表明，在慢性抗抑郁药物治疗(ADT)的外围，一些相同的细胞因子和激酶信号发生了变化。这一开发项目将使最初的临床基础设施能够开发必要的实验室和临床程序，以测试作为抗抑郁治疗(ADT)功能而研究外围基因表达的可行性和应用。 本实验将利用Affymetrix HG-U 133a基因芯片芯片检测25例抑郁症患者在S-西酞普兰治疗8周前后和10例抑郁症患者在安慰剂治疗8周前后的淋巴细胞基因表达谱。这些受试者的RNA将被收集在分开的样本中，并在分开的副本中分析ADT和安慰剂的效果。我们预计，调控SERT隔离的基因、在5HTTLPR上有差异作用的转录因子以及一系列共同调控的基因，包括那些具有5HTTLPR 44碱基对多态性的共同序列的基因，可能会在ADT中表达。表达SERT的淋巴细胞具有不同于ADT的SERT转运动力学特征。这将评估该方法在未来的资金提案中的实用性，以分析这些患者的基因表达，并最终研究100名抑郁症患者的ADR表型，以及100名年龄、性别和种族匹配的对照。

DESCRIPTION (provided by applicant): Depression is estimated to cost 65 billion dollars yearly, whereas any given antidepressant treatment (ADT) is only effective in approximately half of all cases. Despite the obvious need for improvement of ADT, only some progress has been made in understanding the mechanisms of response. Recent evidence has revealed that antidepressant response (ADR) may be dependent upon a polymorphic promoter region in the serotonin transporter (SERT) gene sequence. This polymorphism (5-HTTLPR) is differentially sensitive to several cytokine and kinase signals. Pilot gene chip data has now shown that some of these same cytokine and kinase signals change in the periphery with chronic antidepressant treatment (ADT). This developmental project will enable the initial clinical infrastructure to develop the necessary laboratory and clinical procedures to test the feasibility and application of studying gene expression in the periphery as a function of antidepressant treatment (ADT). The experiment will examine gene expression patterns in lymphocytes using Affymetrix HG-U 133A GeneChip microarrays in 25 depressed patients before and after 8 weeks treatment with s-citalopram, and 10 depressed patients before and after 8 weeks treatment with placebo. RNA from these subjects will be collected in split sample and analyzed for ADT vs. placebo effects in split duplicate. We anticipate that genes that regulate SERT sequestration, transcription factors with differential action at the 5HTTLPR, and sets of co-regulated genes, including those with consensus sequences to the 5HTTLPR 44 base pair polymorphism may be expressed with ADT. Lymphocytes, which express SERT, will be characterized for SERT transport kinetics, which differ with ADT. This will assess the utility of the approach for a future funding proposal to analyze gene expression in those patients, and ultimately study 100 depressed patients phenotyped for ADR and 100 age, sex, and race matched controls.