胆汁缺乏诱发新生仔猪肝源性腹泻，易导致新生仔猪死亡，造成生猪产业巨大损失。肝脏功能紊乱，胆酸合成减少是其发生的主要原因，但潜在的分子机制尚不明确。申请人前期工作中发现视黄酸相关孤儿核受体RORγ作为调控胆固醇代谢新的转录因子，靶向胆固醇、胆酸代谢关键基因，招募组蛋白修饰相关辅助因子，激活胆固醇、胆酸的合成。因此，本项目旨在阐明RORγ在新生仔猪肝源性腹泻发生过程中对胆酸合成的调节作用及分子机制。通过RNA-seq转录组筛选出在胆酸合成通路中决定了肝源性腹泻发生的特异性靶标基因；采用ChIP-seq全基因组学分析证明RORγ与特异基因之间的靶向性；在体外建立类器官模型，通过敲除和过表达系统对RORγ靶向调节特异基因进行功能验证，并通过激动剂验证激活RORγ增强仔猪肝脏类器官中胆酸合成的假说。该研究结果将从理论上丰富对肝源性腹泻发生机制的认识，为防治新生仔猪肝源性腹泻提供新的思路。

Biliary deficiency induced-Newborn Piglet Hepatogenic Diarrhea (NPHD) results in the death of neonatal piglets and causes huge losses to the pig industry. Liver dysfunction, like the synthetic blockade of bile acids, is the predominant event to cause the NPHD. However, the underlying molecular mechanism is still unclear. Previously, we found a novel transcription factor of cholesterol metabolism, retinoic-acid-receptor-related orphan nuclear receptor RORγ, can directly bind to the key genes, to activate the synthesis of cholesterol and bile acids by recruiting the key factors of histone modification. Therefore, the present project is aiming to elucidate how RORγ functions on cholesterol and bile acids synthesis and to understand the potential mechanism during the development of NPHD. Firstly, we will define the signature genes that drive bile acids synthesis in NPHD when compare to that of control using RNA-seq. Moreover, ChIP-seq is used to demonstrate whether RORγ directly binds to and activates the selected signature genes. Furthermore, RORγ actions on bile acid synthesis will be validated in an organoid model by knockout associated with ectopic expression. Finally, we will verify the hypothesis that small-molecule agonists activate RORγ to rescue the bile acids synthesis in the organoids of NPHD. Taken together, these results will theoretically enrich the understanding of the pathogenesis and provide a new opportunity for effective prevention and therapy of NPHD.