Srivastava PK, van Eyll J, Godard P, Mazzuferi M, Delahaye-Duriez A, Steenwinckel JV, et al. A systems-level framework for drug discovery identifies Csf1R as an anti-epileptic drug target. Nat Commun. 2018;9(1):3561. doi:10.1038/s41467-018-06008-4. The identification of drug targets is highly challenging, particularly for diseases of the brain. To address this problem, we developed and experimentally validated a general computational framework for drug target discovery that combines gene regulatory information with causal reasoning ("Causal Reasoning Analytical Framework for Target discovery"-CRAFT). Using a systems genetics approach and starting from gene expression data from the target tissue, CRAFT provides a predictive framework for identifying cell membrane receptors with a direction-specified influence over disease-related gene expression profiles. As proof of concept, we applied CRAFT to epilepsy and predicted the tyrosine kinase receptor Csf1R as a potential therapeutic target. The predicted effect of Csf1R blockade in attenuating epilepsy seizures was validated in 3 preclinical models of epilepsy. These results highlight CRAFT as a systems-level framework for target discovery and suggest Csf1R blockade as a novel therapeutic strategy in epilepsy. The CRAFT is applicable to disease settings other than epilepsy.

中文翻译：

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研究抗癫痫药物发现的新方法。

Srivastava PK，van Eyll J，Godard P，Mazzuferi M，Delahaye-Duriez A，Steenwinckel JV等。用于药物发现的系统级框架将Csf1R识别为抗癫痫药的目标。Nat Commun。2018; 9（1）：3561。doi：10.1038 / s41467-018-06008-4。药物靶标的鉴定非常具有挑战性，特别是对于脑部疾病。为了解决这个问题，我们开发并实验验证了用于药物靶标发现的通用计算框架，该框架将基因调控信息与因果推理相结合（“目标发现的因果推理分析框架” -CRAFT）。使用系统遗传学方法并从目标组织的基因表达数据开始，CRAFT提供了一个预测框架，用于识别对疾病相关基因表达谱具有方向特定影响的细胞膜受体。作为概念的证明，我们将CRAFT应用于癫痫病并预测酪氨酸激酶受体Csf1R是潜在的治疗靶点。在3种临床前癫痫模型中验证了Csf1R阻断在减轻癫痫发作中的预期作用。这些结果突出了CRAFT作为靶标发现的系统级框架，并建议Csf1R阻断是癫痫的一种新型治疗策略。CRAFT适用于癫痫以外的疾病。在3种临床前癫痫模型中验证了Csf1R阻断在减轻癫痫发作中的预期作用。这些结果突出了CRAFT作为靶标发现的系统级框架，并建议Csf1R阻断是癫痫的一种新型治疗策略。CRAFT适用于癫痫以外的疾病。在3种临床前癫痫模型中验证了Csf1R阻断在减轻癫痫发作中的预期作用。这些结果突出了CRAFT作为靶标发现的系统级框架，并建议Csf1R阻断是癫痫的一种新型治疗策略。CRAFT适用于癫痫以外的疾病。