谷胱甘肽前体NAC通过调控TNFα-TNFR2通路抑制胆道闭锁的机制研究

胆道闭锁（Biliary Atresia, BA）是一种新生儿的严重肝胆疾病，是儿童肝移植最常见的适应症，目前仍缺乏有效的治疗药物。申请人前期研究发现，谷胱甘肽代谢途径基因在胆道闭锁患儿肝脏中表达显著下调，谷胱甘肽前体N-乙酰半胱氨酸（N-acetyl cysteine, NAC）可以在胆道闭锁小鼠模型中抑制胆管损伤和炎症反应发生，因此NAC可能成为潜在的胆道闭锁治疗药物。但是，其中机制还尚不清楚。本项目中，首先我们将利用患儿数据深入分析谷胱甘肽代谢途径相关的调控通路。初步结果显示，TNFα-TNFR2炎症通路在患儿肝脏中被激活，同时与谷胱甘肽代谢途径负相关，提示该通路在胆道闭锁中的重要性。进一步，我们将利用小鼠模型和体外细胞模型研究NAC对TNFα通路、通路下游免疫细胞的激活、炎症反应和胆管损伤的作用及调控，从而揭示NAC抑制胆道闭锁的分子机制，为临床治疗提供新的理论基础。

Biliary atresia (BA) is a serious neonatal liver disease and the most common indication for liver transplant in children. Currently, there is no successful drug for this disease. In our previous publication, we found that glutathione metabolism pathway was significantly down-regulated in the livers of patients with BA and that glutathione precursor N-acetyl cysteine (NAC) suppressed biliary injury and inflammation, suggesting NAC is a potential drug for BA. However, the molecular mechanism of how NAC suppresses biliary injury and inflammation remains unknown. In this project, we will first analyze glutathione metabolism associated pathways using patient data; Our preliminary result suggested that TNFα-TNFR2 pathway were activated in patient’s livers and negatively correlated with glutathione metabolism, indicating an essential role of TNFα-TNFR2 pathway in BA; Next, we will employ BA mouse model and in-vitro culture system to investigate how NAC regulates TNFα-TNFR2 pathway, activation of its downstream cell types, inflammation and biliary injury. Thus, this project will unveil the molecular mechanisms by which NAC suppresses biliary atresia, providing a novel molecular basis to treat BA.