乙肝表面抗原(HBsAg)是慢性乙肝的标志，也是重要的致病因子，对人群危害严重。但HBsAg难以清除是本领域的难点问题。我们的前期工作证实HBsAg能结合并外迁GRP78蛋白，降低内质网内GRP78蛋白，此过程与肝细胞持续损伤密切相关。GRP78能结合内质网跨膜信号分子调控其活化，发挥抗细胞损伤作用。因此我们假设在HBsAg诱导的细胞损伤中，HBsAg竞争性破坏GRP78与跨膜分子的结合，而活化下游分子。本课题将利用细胞模型和小鼠模型研究HBsAg对GRP78和ATF-6，XBP1分布和结合的影响，以及后二者调控NFκB入核及下游基因活化变化；并通过回补GRP78，干扰HBsAg诱发的内质网信号变化，验证GRP78通过稳定内质网跨膜信号发挥抗HBsAg诱导的肝细胞损伤作用的假设，阐明HBsAg导致肝损伤的分子机制，据此寻求对慢性乙肝的早期防治，避免严重肝病的发生。

Hepatitis B surface antigen (HBsAg) is not only the serum marker of chronic hepatitis B (CHB), but also an important causative factor of liver diseases. However，the clearance of HBsAg is one of the most difficult problems in HBV field. The aim of this study is to demonstrate the molecular mechanism of liver injury induced by HBsAg to find out an effective treatment of CHB in early stage. In our previous study, it has been proved that the amount of GRP78 in endoplasmic reticulum (ER) was decreased due to the HBsAg-induced protein secretion, which plays a role in liver injury. It was also reported that GRP78 could bind to ER transmembrane signaling factors and adjust their activities to resist the liver injury. Therefore, we propose that the binding of GRP78 to transmembrane factors could be inhibited by competitive bind of HBsAg. In this study, we will employ the animal model and cell model to investigate the influence of HBsAg to the distribution and binding of GRP78 and ATF-6 or XBP1. Furthermore, we will investigate how ATF-6 and XBP1 induce the entrance of NFκB to nucleus followed by activating the downstream genes. Then, it will be determined whether restoration of GRP78 can block the changes of ER transmembrane signaling. Finally, it will be tested if GRP78 can resist HBsAg induced liver injury via stabilizing endoplasmic reticulum transmembrane signaling factors.