Systems Genetics of Fluoxetine-Induced Neurogenesis and Antidepressant Response

描述（由申请人提供）： 在这个项目中，候选人建议阐明临床前系统中重要的抗抑郁反应表型的遗传基础，即来自协作杂交（CC）小鼠系的重组近交系杂交（RIX）。实验将使用氟西汀（百忧解），一种高度处方的抗抑郁药进行。虽然氟西汀没有严重的副作用，但只有约50%的患者出现治疗反应。首先，我们将成年雄性RIX暴露于人样稳态浓度的氟西汀（250暴露，250对照笼交配），并评估啮齿动物中与抗抑郁反应相关的两种表型的变化：尾部悬挂试验中的行为绝望和海马神经发生的定量测量。对于这些性状中的每一个，我们将使用现有的基因组数据进行全基因组关联映射和途径分析。其次，我们使用新的和强大的方法来评估海马齿状回转录组和甲基化组（下一代测序技术）来完善这些关联。第三，我们通过产生预期显示出高或低氟西汀敏感性的新动物（N=10 RIX各）来测试这些遗传和分子生物标志物的预测有效性。该临床前系统药物基因组学项目旨在确定调节小鼠对氟西汀反应的关键基因。后续工作将在人类临床试验样本中检查这些候选基因。

DESCRIPTION (provided by applicant): In this project, the candidate proposes to elucidate the genetic basis of important antidepressant response phenotypes in a pre-clinical system, recombinant-inbred intercrosses (RIX) from the Collaborative Cross (CC) mouse lines. Experiments will be performed using fluoxetine (Prozac), a highly prescribed antidepressant. While fluoxetine does not have major side effects, only about 50% of patients experience a therapeutic response. First, we will expose adult male RIX to human-like steady state concentrations of fluoxetine (250 exposed, 250 control cage mates) and assess changes in two phenotypes relevant to antidepressant response in rodents: behavioral despair in the tail suspension test and quantitative measures of hippocampal neurogenesis. For each of these traits, we will use existing genomic data to conduct genome-wide association mapping and pathway analysis. Second, we refine these associations using new and powerful ways to assess the hippocampal dentate gyrus transcriptome and methylome (next generation sequencing technologies). Third, we test the predictive validity of these genetic and molecular biomarkers by generating novel animals expected to show high or low fluoxetine sensitivity (N=10 RIX each). This pre-clinical systems pharmacogenomics project is powered to identify key genes regulating response to fluoxetine in mice. Follow- up work will then examine these candidate genes in human clinical trial samples.