关于建立胆道毒素诱导新型胆道闭锁动物模型的研究

Biliary atresia (BA) is the most common cause of obstructive jaundice in children, and is the most common indication of liver transplantation in children. It is mainly characterized by progressive inflammation in both intrahepatic and extrahepatic bile ducts and hepatic fibrosis, and most BA patients will die due to liver failure within a year. Current researches are limited by the timing of surgical treatment, which cannot explain its definite pathogenesis, so the development and application of BA animal model are particularly urgent and important. Conventional rotavirus-induced BA model restricts the mechanism of BA liver fibrosis in-depth study, because of the short survival time of model mice (2-3 weeks) and unobvious cirrhosis, In recent years, biliary toxins (biliatresone) have been shown to selectively induce zebrafish extrahepatic biliary atresia, so we hypothesized that bile ducts may be used in the construction of a novel biliary atresia model. In this study, we designed the animal model of biliary atresia, which was similar to that of human biliary atresia, and had a prolonged survival time. The completion of this project will provide a clinical, standard, repeatable and controllable experimental animal model for the further study of the pathogenesis and prevention of BA, and promote the development of BA research.

胆道闭锁（biliary atresia，BA）是新生儿长期梗阻性黄疸的最常见原因，亦是儿童肝移植最常见适应症，主要以肝内外胆管进行性炎症和肝纤维化为主要特征，大多数BA患儿在一年内会因肝功能衰竭而死。研究多受限于手术治疗时机，无法明确其具体发病机制，所以BA动物模型的开发和应用显得尤为重要。以往常用的轮状病毒诱导BA模型，由于模型小鼠生存时间短（2-3周），肝纤维化不明显，而极大限制了BA肝纤维化机制的深入研究。近年发现胆道毒素（胆闭素，biliatresone）可选择性诱发斑马鱼肝外胆道闭锁模型，因此，我们推测胆闭素可能用于新型胆道闭锁模型的构建。本课题拟通过人工合成胆闭素活性物质，制作与人类胆道闭锁临床实际相近，且生存时间较长的胆道闭锁小鼠动物模型。本项目的完成将为进一步研究BA的发病机制、防治方法提供符合临床实际的、标准的、可重复的、可控的实验动物模型，推动BA研究的发展。

胆道闭锁（biliary atresia，BA）是儿童梗阻性黄疸最常见的原因，主要以肝内外胆管进行性炎症和肝纤维化为主要特征。研究多受限于手术治疗时机，无法明确其具体发病机制，所以BA动物模型的开发和应用显得尤为重要。近年发现胆道毒素（胆闭素，biliatresone）可选择性诱发斑马鱼肝外胆道闭锁模型，因此，我们推测胆闭素可能用于新型胆道闭锁模型的构建。本课题通过人工合成胆闭素活性物质，制作与人类胆道闭锁临床实际相近，且生存时间较长的胆道闭锁小鼠动物模型。本课题合成胆闭素具有胆道毒性，可诱导斑马鱼胆道发生胆道闭锁；胆闭素的深入研究将为探讨胆道闭锁发病机制提供新的切入点。大剂量合成胆闭素对孕鼠和胎鼠具有致死性；合成胆闭素可成功诱导新生小鼠发生胆道闭锁；根据新生小鼠体重选择干预时间点和胆闭素剂量可一定程度提高小鼠胆道闭锁成模率。