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乙型肝炎表面抗原(HBsAg)持续阳性是控制乙肝中难以解决的重大问题。本研究通过揭示HBsAg致病机制的基础研究,寻找抑制或清除HBsAg的新途径。通过建立有可比性的HBsAg转基因鼠和稳定表达细胞系及相应对照,进行比较转录组学和蛋白质组学研究,发现了HBsAg在HBV慢性感染中的一些新致病机制。其中包括:HBsAg促进肝细胞内CypA分泌,后者可趋化炎症细胞在HBsAg阳性灶周围浸润;在细胞模型中,HBsAg分泌可引起胞内GRP78蛋白下降,导致肝细胞抗凋亡能力减弱;发现HBsAg在细胞中可上调截短的LEF1基因的表达,缺乏活化全长LEF1促成瘤和增殖活性;而肝癌组织中LEF1则倾向于核内分布,并活化Wnt下游基因Cyclin D1与c-myc,有促肿瘤活性。在转基因鼠和细胞模型中都发现了物质和能量代谢相关的基因发生变化,并与临床慢性乙肝患者表现相符。研究中有关CypA的发现提供了抑制HBsAg的新途径;有关代谢的变化提出了改变饮食内容与习惯可能有利于HBsAg阳性感染者的预后。
The persistent positive of hepatitis B surface antigen (HBsAg) is a major problem in the control of hepatitis B that is difficult to solve. In this study, by revealing the basic research of pathogenic mechanism of HBsAg, looking for a new way to inhibit or eliminate HBsAg. Through the establishment of a comparable HBsAg transgenic mouse and stable expression of cell lines and the corresponding control, comparative transcriptomics and proteomics studies, found HBsAg in HBV chronic infection in some of the new pathogenesis. These include: HBsAg promotes the secretion of CypA in hepatocytes, which chemotactic inflammatory cells infiltrate around the HBsAg-positive foci; in the cellular model, HBsAg secretion causes a decrease in intracellular GRP78 protein, leading to diminished hepatocyte apoptosis; HBsAg up-regulates the expression of truncated LEF1 gene in the cells and lacks the activation-promoting full-length LEF1 to promote tumorigenesis and proliferation. However, LEF1 in liver cancer tends to be distributed in the nucleus and activates Wnt downstream genes Cyclin D1 and c-myc Tumor activity. Both genes and energy metabolism-related genes were found to be altered in transgenic mice and cell models, consistent with the performance of clinical chronic hepatitis B patients. The discovery of CypA in the study provides new avenues of inhibiting HBsAg; changes in metabolism have suggested that changing dietary content and habits may be beneficial to the prognosis of HBsAg-positive individuals.