PNAS2013-11-02 11:56 PM

Human genome–guided identification of memory-modulating drugs 记忆调节药物的人类基因导向识别

Abstract In the last decade there has been an exponential increase in knowledge about the genetic basis of complex human traits, including neuropsychiatric disorders. It is not clear, however, to what extent this knowledge can be used as a starting point for drug identification, one of the central hopes of the human genome project. The aim of the present study was to identify memory-modulating compounds through the use of human genetic information. We performed a multinational collaborative study, which included assessment of aversive memory—a trait central to posttraumatic stress disorder—and a gene-set analysis in healthy individuals. We identified 20 potential drug target genes in two genomewide-corrected gene sets: the neuroactive ligand–receptor interaction and the long-term depression gene set. In a subsequent double-blind, placebo-controlled study in healthy volunteers, we aimed at providing a proof of concept for the genome-guided identification of memory modulating compounds. Pharmacological intervention at the neuroactive ligand–receptor interaction gene set led to significant reduction of aversive memory. The findings demonstrate that genome information, along with appropriate data mining methodology, can be used as a starting point for the identification of memory-modulating compounds. 论文摘要 我们对包括神经精神性障碍在内的基因层面有关复杂人类特性的所知在过去十年中呈现指数级增长。然而作为人类基因工程中的最大愿景之一,我们仍然不知究竟需要对这一领域探究到何种程度,才能开辟将之运用在药物识别中的新里程。当前的研究目标是为了通过运用人类基因信息来辨别那些对记忆起调控作用的化合物。为此我们进行了多国研究合作,其中包括了对负面记忆的评估鉴定-着重针对创伤后应激障碍的特性-以及对健康个体进行的基因集合的分析。我们在两个修正的全基因组的集合中确定了20个潜在的药物靶基因:分别为神经活性配体-受体相互作用的基因组集合和长期抑郁的基因组集合。在随后对健康志愿受测者进行的双盲安慰剂控制研究试验中,我们目标于为那些对记忆起调控作用的化合物的基因引导识别提供概念性的证明。我们发现试验中对神经活性配体-受体相互作用的基因集所进行的药理性干预使得那些负面记忆得到显著抑制。借助于恰当的数据挖掘技术手段,这些研究证明了基因信息可以被用作识别那些对记忆起调控作用的化合物的新用途。

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