发育早期的药物治疗可以激活核受体，对药物代谢产生长期影响。但目前的相关研究多是围绕单一核受体激活，核受体网络的调控作用鲜有报道。我们前期研究发现，新生鼠苯巴比妥（PB）暴露对II相酶UGTs表达产生长期影响，并且核受体网络及表观遗传修饰参与UGT1A1发育表达的转录调控。由此推测：发育早期的药物暴露可激活CAR-HNF1A/HNF4A调控网络，并产生表观遗传记忆，长期诱导II相酶表达，持续影响成年后的药物代谢。本课题采用人源化小鼠hUGT1作为模型动物、PB作为模型药物拟研究：1）新生鼠PB暴露激活核受体网络对UGTs诱导表达的长期影响；2）该长期诱导表达对成年后药物代谢及疗效的影响；3）核受体网络参与诱导表达的表观遗传机制。该研究首次探讨核受体网络参与调控药物暴露对II相酶的长期诱导作用，可填补早期药物暴露对II相酶长期影响的认知不足，并为解释成年人群药物反应个体差异提供新的视角。

Accumulated evidences have indicated that drug treatment of neonates and infants can result in activation of nuclear receptor and a permanent change of liver drug metabolism. To date, studies concerning this field have focused on the activation of single nuclear receptor, and the regulation of nuclear receptor networks remain elusive. Our preliminary studies have suggested that phenobarbital（PB）exposure in early-life resulted in permanent induction of phase II enzymes UGT1A1 in mice and nuclear receptor regulatory networks and epigenetic modifications involved in the developmental regulation of UGT1A1. Based on these results, we hypothesize that exposure to PB during neonatal period activates CAR-HNF1A/HNF4A nuclear receptor network to trigger epigenetic modifications, which can permanently induce the expression of phase II enzymes in adult and disturb therapeutic efficacy. In the current study, we use phenobarbital as a model drug and hUGT1 mouse as an in vivo model to demonstrate: 1) CAR-HNF1A/HNF4A nuclear receptor network regulating permanent change of phase II enzymes UGTs induced by phenobarbital exposure in neonatal mice; 2) the long-term impacts of PB exposure at early life on therapeutic efficacy; 3) the role of epigenetic memory in the long-term impacts of CAR-HNF1A/HNF4A nuclear receptor network at early life on UGTs expression. This project will focus on mechanism of nuclear receptor network regulating permanent change of phase II enzymes induced by phenobarbital exposure in neonatal mice, which will fill the knowledge gaps on long-term effects of phase II enzymes on drug exposure in early-life and provide a new perspective to explain the inter-individual difference in adults.