Beclin1调控斑马鱼胆汁酸代谢的机制研究

肝脏的细胞组成和生理功能在进化上是保守的，斑马鱼具有胚胎学和影像学的优势，可作为研究肝脏时小鼠模型的有益补充。胆汁酸是由肝脏合成并分泌的，胆汁酸代谢紊乱可导致包括胆汁酸淤积在内的多种疾病。细胞自噬是一种古老的细胞内稳态维持系统，可与溶酶体融合降解冗余蛋白质和受损细胞器。Beclin1是细胞自噬发生过程中的重要基因，其基因敲除小鼠在胚胎早期死亡。我们的前期研究发现beclin1敲除的斑马鱼可存活至幼鱼，在7.5dpf后肝脏出现组织结构和细胞形态的变化。有趣的是，我们意外地发现突变体有明显的肝内胆汁淤积。本课题拟从胆汁酸合成及调控、胆管堵塞与肝肠循环、胆汁酸转运蛋白及其他自噬相关基因等方面研究Beclin1调控斑马鱼胆汁酸代谢的机制，同时关注突变体死亡原因及beclin1的下游基因。

The liver is conserved in cell composition and biological function among vertebrates during evolution. Compared to mouse, Zebrafish have advantages on fast embryogenesis and ease of imaging, and can be used a good supplement to mouse model to study liver. Bile acid is produced and secreted by liver, dys-regulation of bile acid homeostasis will lead to several kinds of diseases including cholestasis. Autophagy is an ancient self-digestive mechanism in eukaryotic cells delivering cytoplasmic materials into the lysosome for degradation. The cargoes include damaged organelles, aberrant proteins and other cellular contents. Beclin1 (Atg6) is essential for autophagosome formation, knock-out of Beclin1 in mouse results in early embryonic lethality. In our previous studies, we found that beclin1 zebrafish mutant could survive to larval stage, and the liver of mutant became abnormal in tissue structure and cellular morphology. Interestingly, severe intrahepatic homeostasis was revealed in the mutant. The project proposes to study the mechanism of Beclin1 in the regulation of bile acid homeostasis on the following aspects: the regulation of bile acid synthesis, the potential obstruction of secretary channel, localization of bile acid transporters and other autophagy-related genes. The reason of larval death of the mutant and downstream genes of beclin1 will also be investigated.