Hepatitis HBx-Mediated Pathogenesis

HBx 介导的肝炎发病机制

• 批准号: 6928570
• 负责人: BETTY L SLAGLE
• 金额: $ 30.14万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6928570
• 关键词: biomarker; cancer risk; cell cycle; clinical research; cofactor; hepatitis B; hepatitis B virus group; hepatocellular carcinoma; pathologic process; protein structure function; transcription factor; virus infection mechanism; virus protein; virus replication

DESCRIPTION (provided by applicant): Chronic infection with HBV is a major risk factor in the development of hepatocellular carcinoma (HCC), and is responsible for over 1 million deaths each year. We have established an HCC cofactor role in transgenic mice that express the HBV regulatory protein (HBx) driven by the human alpha-l-anti-trypsin regulatory sequences (ATX mice). Our recent studies indicate that the cofactor role involves the ability of HBx to deregulate hepatocyte cell cycle controls. Although HBx is essential for virus replication in vivo, the function that it provides is not known. We hypothesize that the essential role of HBx during viral replication is to prepare hepatocytes to become competent to support all steps in virus replication. In the present application, we will explore the effects of HBx on G0 hepatocytes and their transition through early G1, using markers that distinguish these stages of the cell cycle. We additionally hypothesize that HBx holds nondividing cells at a G1 restriction point, and will use RNA inhibition to examine candidate proteins through which HBx may exert this effect. We will also explore the effect of HBx on hepatocyte G0/G1 transition in vivo, and in the presence of the AFBl-induced hotspot p53 mutation. Finally, the livers of ATX mice contain decreased levels of Caspase-3, and we will test the hypothesis that in response to cytotoxic cytokines, HBx inhibits apoptosis as a means of protecting hepatocytes from immune-mediated cell death. HBx is the sole regulatory protein encoded by HBV, we expect it will provide more than one critical role during the virus life cycle. The proposed program builds on our model of HBx-related HCC that indicates an important contribution of HBx effects on cell cycle control. The planned studies examine HBx function in nondividing liver cells, and the results obtained will provide important insight into the rational development of new therapies to treat chronic HBV infection. Our results will also reveal fundamental virus-host interactions that may extend to other viruses that replicate in the liver.

描述(申请人提供)：慢性感染乙肝病毒是发展为肝细胞癌的主要危险因素，每年导致超过100万人死亡。我们已经在由人α-L-抗胰蛋白酶调节序列(ATX小鼠)驱动的表达HBx的转基因小鼠中建立了肝细胞癌辅助因子作用。我们最近的研究表明，辅因子作用涉及HBx解除对肝细胞周期调控的能力。尽管HBx对体内病毒复制是必不可少的，但它提供的功能尚不清楚。我们假设，HBx在病毒复制过程中的重要作用是准备肝细胞，使其能够支持病毒复制的所有步骤。在目前的应用中，我们将使用区分细胞周期这些阶段的标记来探索HBX对G0期肝细胞的影响以及它们通过早期G1期的过渡。我们还假设HBx将未分裂的细胞保持在G1限制点，并将使用RNA抑制来检查HBx可能通过其发挥这一作用的候选蛋白质。我们还将探讨HBx在体内对肝细胞G0/G1转变的影响，以及在AFB1诱导的热点P53突变存在的情况下。最后，ATX小鼠的肝脏中Caspase-3水平降低，我们将检验这一假设，即HBX在回应细胞毒性细胞因子时抑制细胞凋亡，以此作为保护肝细胞免受免疫介导的细胞死亡的一种手段。HBx是唯一由乙肝病毒编码的调节蛋白，我们预计它将在病毒生命周期中发挥不止一个关键作用。建议的方案建立在我们的HBx相关肝癌模型的基础上，表明HBx效应在细胞周期控制中的重要贡献。计划中的研究检查了HBx在未分裂的肝细胞中的功能，所获得的结果将为合理开发治疗慢性乙肝病毒感染的新疗法提供重要的见解。我们的结果还将揭示基本的病毒与宿主的相互作用，这种相互作用可能延伸到在肝脏复制的其他病毒。