Hepatitis HBx-Mediated Pathogenesis

HBx 介导的肝炎发病机制

• 批准号: 6572895
• 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/6572895
• 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（由申请人提供）：HBV慢性感染是肝细胞癌（HCC）发展的主要风险因素，每年导致超过100万人死亡。我们已经在表达由人α-l-抗胰蛋白酶调节序列驱动的HBV调节蛋白（HBx）的转基因小鼠（ATX小鼠）中确定了HCC辅因子的作用。我们最近的研究表明，辅因子的作用涉及HBx的能力，解除对肝细胞周期的控制。虽然HBx是病毒在体内复制所必需的，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使肝细胞准备好支持病毒复制的所有步骤。在本申请中，我们将探索HBx对G 0肝细胞的影响及其通过早期G1的过渡，使用区分细胞周期这些阶段的标志物。我们还假设HBx在G1限制点保持非分裂细胞，并将使用RNA抑制来检查HBx可能发挥这种作用的候选蛋白。我们还将探讨HBx对体内肝细胞G 0/G1转换的影响，以及在AFBL诱导的热点p53突变的存在下。最后，ATX小鼠的肝脏含有降低水平的Caspase-3，我们将测试的假设，在响应细胞毒性细胞因子，HBx抑制细胞凋亡作为一种手段，保护肝细胞免疫介导的细胞死亡。HBx是HBV编码的唯一调节蛋白，我们预计它将在病毒生命周期中发挥多个关键作用。该计划建立在我们的HBx相关HCC模型的基础上，该模型表明HBx对细胞周期控制的重要贡献。计划中的研究检查了HBx在非分裂肝细胞中的功能，所获得的结果将为合理开发治疗慢性HBV感染的新疗法提供重要的见解。我们的研究结果还将揭示基本的病毒-宿主相互作用，这些相互作用可能延伸到在肝脏中复制的其他病毒。