ATR介导的DNA损伤通路在截短型表面抗原增强HBV致病性中的作用及机制研究

乙肝病毒表面抗原（HBsAg）截短可导致HBV致病性改变，我们的研究显示截短型HBsAg能增强HBV致瘤性，其机制可能与ATR介导的DNA损伤通路有关。. 本项目拟利用裸鼠荷瘤模型，通过观察阻断ATR通路对截短型HBsAg促瘤作用的影响，了解其是否通过ATR介导的DNA损伤通路增强HBV致病性；通过研究ATR-CHK1/SMC1通路对宿主细胞周期的影响，以及ATR-SMC1对"端粒维持机制"的作用，阐明ATR通路关键分子在截短型HBsAg增强HBV致病性中的分子机制；利用临床肝癌组织标本，研究截短型HBsAg的产生情况，分析其与ATR通路关键分子表达水平的相关性，从而深入了解截短型HBsAg在肝癌发生中的作用和机制。. 本研究将有助于阐明截短型HBsAg在增强HBV致病性中的分子机制，并为寻找HBV相关肝癌治疗的新靶点提供参考。

Truncated hepatitis B virus surface antigen (HBsAg) promotes HBV pathogenicity. Our previous study suggested that truncated HBsAg might enchance HBV tumorigenicity through ATR-dependent DNA damage response signaling pathway. . In this study, the xenograft implantation nude mouse model and the specific pathway inhibitor will be utilized to analyze the role of the ATR-dependent pathway in HBsAg-promoted HBV pathogenicity; the role of ATR-CHK1/SMC1 pathway on host cell cycle, and the role of ATR-SMC1 pathway on telomere maintenance will be analyzed to elucidate the molecular mechanism of how the truncated HBsAg utilizes the ATR-dependent pathway to promote HBV pathogenicity; furthermore, the expression of the truncated HBsAg and its association with the key molecules of the ATR-dependent pathway will be analyzed in clinical HBV-related hepatocellular carcinoma tissues, thus consolidating our findings from the cell and mouse models.. This study will help to elucidate the molecular mechanism of the truncated HBsAg-promoted HBV tumorigenicity, thus providing new targets for the treatment of hepatocellular carcinoma.