HEPATIC CARCINOGENESIS INDUCED BY HEPATITIS B VIRUS PreS2 MUTANT

乙型肝炎病毒PreS2突变体诱发肝癌

• 批准号: 7246015
• 负责人: Tien-Sze Benedict Yen
• 金额: $ 47.51万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7246015
• 关键词: HEPATIC; CARCINOGENESIS; INDUCED; HEPATITIS; VIRUS

Long-term objectives: Hepatitis C virus (HCV) is one of the most important causes of hepatocellular carcinoma. The long-term goal of this proposal is to understand the mechanism of hepatocarcinogenesis by hepatitis C virus, specifically focusing on the role of the viral core protein. Rationale: Our previous findings on HCV-infected Raji cells and HCV core protein-transgenic mice have suggested several pathways for HCV-induced hepatocarcinogenesis, including the possible role of inflammation and of the inhibition of DMAdamage repair by HCV proteins. Furthermore, the activation of toll-like receptor 4 (TLR4) by HCV NS5A protein suggested possible synergism between HCV and alcohol/diabetes since the latter induces enhanced sensitivity to endotoxin. These are novel mechanisms of viral oncogenesis by a cytoplasmic RNA virus. Specific aims: In this subproject, we will use both culture cell lines infected by HCV in vitro and HCV core protein-transgenic mice to explore the potential mechanisms of HCV oncogenesis. Three specific aims are proposed: 1) Establish the importance of inflammation in HCV oncogenesis. The effects of HCV infection on NFkB and IKKbeta in HCV infection will be studied in cultured cell lines and in IKKbeta-conditional knockout mice. Furthermore, transgenic mice expressing HCV proteins in B cells will be generated to examine the possible effect of inflammatory cytokines on oncogenesis. 2) Using NS5A-transgenic mice, which have enhanced TLR4 expression, we will study the possible synergism between HCV and alcohol/diabetes. Core/NS5A transgenic-TLR4-/- mice will be generated, and the tumor incidence induced by alcohol/obesity will be compared with the core/NS5A Tg mice to assess the role of TLR4. 3) Study the mechanism of inhibition of DMAdamage-repair by HCV. The DMAdamage sensor and response complexes will be studied in HCV-infected cells or cells expressing HCV core protein. Various DMA repair pathwayswill be studied. Finally proteomic analysis in HCV-infected and core- or NS3- expressing cells will be performed to identify other potential target proteins of HCV. These studies are expected to generate knowledge on the possible mechanism of HCV oncogenesis.

长期目标：丙型肝炎病毒（HCV）是引起肝细胞性肝癌的最重要原因之一， carcinoma.这项提案的长期目标是通过以下方式了解肝癌发生的机制： 丙型肝炎病毒，特别关注病毒核心蛋白的作用。 基本原理：我们先前在HCV感染的Raji细胞和HCV核心蛋白转基因小鼠上的发现， 提出了HCV诱导的肝癌发生的几种途径，包括 炎症和HCV蛋白对DMAdamage修复的抑制。此外，激活 Toll样受体4（TLR 4）通过HCVNS 5A蛋白表达，提示HCV和 酒精/糖尿病，因为后者诱导对内毒素的敏感性增强。这些都是新的机制， 细胞质RNA病毒引起的病毒致癌。具体目标：在这个子项目中，我们将使用两种培养细胞 HCV核心蛋白转基因小鼠，以探讨HCV感染的可能机制。 HCV肿瘤发生。提出了三个具体目标：1）建立炎症在HCV中的重要性 肿瘤发生HCV感染对NFkB和IKK β在HCV感染中的影响将在体外培养中研究。 细胞系和IKK β条件性敲除小鼠中。此外，表达HCV蛋白的转基因小鼠 将产生B细胞中的细胞因子，以检查炎性细胞因子对肿瘤发生的可能影响。（二） 使用具有增强的TLR 4表达的NS 5A转基因小鼠，我们将研究可能的协同作用。 HCV和酒精/糖尿病之间的联系将产生Core/NS 5A转基因-TLR 4-/-小鼠，并且肿瘤细胞将被转染。 将酒精/肥胖诱导的发病率与核心/NS 5A Tg小鼠进行比较，以评估 TLR4。3)探讨HCV抑制DNA损伤修复的机制。DMAdamage传感器和 将在HCV感染的细胞或表达HCV核心蛋白的细胞中研究应答复合物。各种 DMA修复途径将被研究。最后，HCV感染和核心蛋白或NS 3蛋白的蛋白质组学分析， 表达细胞中的蛋白质，以鉴定HCV的其他潜在靶蛋白。这些研究 预期将产生关于HCV肿瘤发生的可能机制的知识。