SNX7通过影响c-FLIPs水平调节肝脏发育的分子机制研究

In the preliminary work,we identified SNX7,a novel vesicular trafficing gene enriched in the liver,was required for zebrafish early liver development.knock down of SNX7 expression by morpholino-injection severely inhibits the specification and maturation of hepatoblast.Inhibition of SNX7 specifically activates the death receptor apoptosis pathway, and c-FLIPs was identified as the crucial molecular in the process.In this proposal,we plan to analyse the physiological functions of SNX7 based on the knock-out mouse model as well as in-vitro hepatic differentiation system,investigate the molecular mechnisams involved, especially how SNX7 impacts the early embryonic liver development and hepatoblast fate determination through the regulation of c-FLIPs.Our objective is to reveal the function and mechanism of SNX7-c-FLIPs cascade in vivo and in vitro.This study is likely to improve our understanding about hepatoblast specificaiton and cell fate determination during liver development.

前期研究证明与细胞内膜泡运输密切相关的基因SNX7在斑马鱼胚胎肝脏发育早期有特异性的高表达，且对于早期肝脏的发育是必需的。由morpholino所介导的SNX7特异性敲降强烈地抑制肝祖细胞的特化和成熟过程。分子水平检测表明抑制SNX7的表达激活死亡受体信号通路，而c-FLIPs则是这一过程中的关键效应分子。本项目计划在基因敲除小鼠动物模型和体外定向分化肝细胞模型的基础上研究其具体的分子机制，特别是SNX7如何通过影响c-FLIPs的表达水平调节早期胚胎肝脏发育和肝祖细胞命运决定。本研究项目致力于揭示SNX7-cFLIPs级联信号在体内和体外系统中的生理功能和及其分子机制，预期研究成果将有助于我们加深对肝脏发育过程中肝祖细胞特化和细胞命运决定过程的理解。