HEPATITIS B VIRUS AND HEPATOCELLULAR CARCINOMA

慢性B型肝炎病毒（HBV）感染是一个重要的危险因素 在肝细胞癌（HCC）的发展中。 我们提出了一个模型 HBV在HCC中的作用，来自我们的研究表明， 反式激活因子X蛋白（HBx）与XAP-1/UV-DDB相互作用， 参与核苷酸切除修复（NER）的蛋白质， 表达抑制正常NER。 我们假设HBx与XAP-1结合， 为HBV的生命周期提供了一种功能， 削弱了DNA修复，无意中促进了 HCC。 我们将使用几种方法测试模型， （1）HBx对细胞DNA修复的影响。 的 负责抑制NER的HBx结构域将使用 突变HBx蛋白。 着色性干皮病（XP）患者的成纤维细胞 将用于确定HBx是否通过抑制DNA合成， 与XAP-1有关的信号通路。 HBx对突变频率的影响将是 使用我们的HBV X转基因小鼠进行测试。 HBx可能 干扰DNA修复需要改变p53介导的途径 将被审查。 (2)研究功能之间的相互作用 细胞XAP-1和HBx蛋白在肝脏中使用小鼠模型。 鼠 XAP-1将被克隆。 细胞DNA修复试验将测量功能性 HBx-XAP-1蛋白相互作用在HBV X肝脏中的作用 转基因小鼠 HBx表达在肝再生过程中的作用 会得到考验 (3)DNA修复蛋白XAP-1作用的确定 HBV的生命周期 XAP-1在HBV部分损伤修复中的作用 将测试双链DNA基因组。 一组HBx突变蛋白 将用于调查HBx中XAP-1的要求 反式激活 该计划建立在我们的HBV相关HCC模型的基础上， 间接作用人肿瘤病毒的新作用机制， 如HBV。 这些实验将为HBV对人类的影响提供新的见解。 肝细胞、病毒复制和HCC的发展。

Chronic infection with hepatitis B virus (HBV) is an important risk factor in the development of hepatocellular carcinoma (HCC). We present a model for the role of HBV in HCC, derived from our demonstration that the HBV transactivator X protein (HBx) interacts with XAP-1/UV-DDB, a cellular protein involved in nucleotide excision repair (NER), and that HBx expression inhibits normal NER. We hypothesize that HBx binds XAP-1 to provide a function to the HBV life cycle, and that the protein interaction cripples DNA repair and inadvertently contributes to the development of HCC. We will test the model utilizing several approaches and the following specific aims: (1) Effect of HBx on cellular DNA repair. The domains of HBx responsible for inhibition of NER will be mapped using mutant HBx proteins. Fibroblasts from Xeroderma pigmentosum (XP) patients will be used to determine whether HBx inhibits DNA synthesis through a pathway involving XAP-1. The effect of HBx on mutation frequency will be tested utilizing our HBV X transgenic mice. The possibility that HBx interference of DNA repair requires alteration of a p53-mediated pathway will be examined. (2) Investigation of functional interactions between cellular XAP-1 and HBx proteins in the liver using a mouse model. Murine XAP-1 will be cloned. Cellular DNA repair assays will measure functional effects of HBx-XAP-1 protein interactions within the livers of HBV X transgenic mice. The effect of HBx expression during liver regeneration will be tested. (3) Determination of a role for DNA repair protein XAP-1 in the HBV life cycle. A role for XAP-1 in the repair of the HBV partial double-stranded DNA genome will be tested. A panel of HBx mutant proteins will be used to investigate the requirement for XAP-1 in HBx transactivation. The proposed program builds on our model of HBV-related HCC and suggests a novel mechanism of action for indirect-acting human tumor viruses such as HBV. The experiments will provide new insights into HBV effects on hepatocytes, viral replication, and the development of HCC.