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基因网络推断和主调节器分析确定了与雌激素相关的受体 (ERRγ) 作为酒精使用障碍 (AUD) 的治疗标

Irene Lorrai, Riccardo Maccioni, Itzamar Torres

bioRxiv : the preprint server for biology

|November 26, 2025

概括

主调节器分析确定了与雌激素相关的受体 (ERRγ) 是酒精依赖的关键驱动因素. 用GSK4716准ERRγ有效降低了临床前模型中的酒精消费和寻找行为.

科学领域:

神经科学是一个神经科学.
遗传学遗传学是一个
药理学药理学是指药理学的学科.

背景情况:

仅差异基因表达不足以预测转录因子活性和相关的表型.
酒精依赖个体前额叶皮层 (PFC) 的基因网络失调需要进行更深入的调查.
系统生物学方法为复杂的基因调节网络提供了新的见解.

研究的目的:

确定与酒精依赖相关的PFC中基因网络失调的关键调控驱动因素.
功能性验证与雌激素相关的受体 (ERRγ) 作为酒精使用障碍 (AUD) 的潜在治疗标.

主要方法:

采用系统生物学方法,包括基因网络推断和主调节器分析 (MRA).
在小鼠中使用了暗中饮酒 (DID) 和慢性间歇性蒸汽暴露 (CIE) 模型.
在各种强化计划下,评估了老鼠的酒精自我管理.
在临床前模型中使用ERRγ激动剂GSK4716.

主要成果:

与雌激素相关的受体 (ERRγ) 被确定为具有酒精依赖史的人的PFC中的高级主调节器 (MR).
在小鼠 (DID和CIE模型) 和老鼠 (操作性自我管理) 中,GSK4716显著降低了酒精消耗.
GSK4716防止了酒精条件下的位置偏好,而不影响机动或糖摄入量,表明了特异性.
在非依赖性和依赖性动物模型中观察到药物的有效性.

结论:

转录组范围内的基因调节网络分析有效地识别了酒精依赖的可用药物调节剂.
ERRγ在调节过度饮酒和寻求行为方面发挥着重要作用.
ERRγ调制代表了酒精使用障碍 (AUD) 的有前途的治疗策略.

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