Role of Hepatitis B virus X protein in HBV replication.

乙型肝炎病毒 X 蛋白在 HBV 复制中的作用。

• 批准号: 7534001
• 负责人: Michael J Bouchard
• 金额: $ 31.48万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-12-01 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7534001
• 关键词: Address; Affect; Apoptosis; Apoptotic; Biological; Calcium; Calcium Signaling; Cell Cycle; Cell Line; Cell Nucleus; Cells; Chronic; Chronic Hepatitis B; Complex; Conflict (Psychology); Development; Dyes; Hepadnaviridae; Hepatitis B; Hepatitis B Virus; Hepatitis B X-Protein; Hepatoblastoma; Hepatocyte; Human; Human Virus; Immune; Individual; Infection; Link; Liver neoplasms; Malignant neoplasm of liver; Mediating; Mitochondria; Molecular; Outcome; Pathology; Pathway interactions; Permeability; Physiology; Primary carcinoma of the liver cells; Process; Proteins; Rattus; Regulation; Reporting; Research Personnel; Risk; Role; Signal Pathway; Signal Transduction; Signal Transduction Pathway; System; Viral; Viral Proteins; Virus Diseases; Virus Replication; Voltage-Dependent Anion Channel; Woodchuck; Woodchuck Hepatitis B Virus; Work; base; calcium indicator; cell growth regulation; cell transformation; cell type; inhibitor/antagonist; interest; programs; protein activation; protein expression; research study; transcription factor

The association between hepatocellular carcinoma (HCC) and chronic infection with the human hepatitis B virus (HBV) has generated considerable interest in understanding how infection with HBV increases the risk for liver cancer. Based on studies in woodchucks infected with the woodchuck hepatitis virus, it is assumed that the X protein (HBx) of all mammalian hepadnaviruses, including human HBV, is essential for viral replication. There is also evidence that HBx contributes to the development of HCC. HBx activates many cellular signaling cascades; however, how this is accomplished is unclear. Most studies that sought to identify the essential role of HBx during HBV replication, and understand how HBx regulates cellular signaling pathways, were performed in liver cell lines derived from liver tumors. The use of immortalized or transformed hepatocytes suffers from its lack of biological relevance compared to authentic hepatocytes. We have demonstrated that a key activity of HBx is regulation of cellular calcium signaling pathways. This proposal aims to understand key activities of HBx using cultures of primary rat hepatocytes and to determine how these activities influence hepatocyte physiology and HBV replication. Studies in AIM 1 will characterize the molecular mechanism of HBx activation of calcium signaling pathways in hepatocytes and how this influences HBV replication. Studies in AIM 2 will focus on the interaction between HBx and mitochondria and how this impacts hepatocyte physiology and HBV replication. AIM 3 specifically focuses on regulation of apoptosis by HBx expressed alone or during HBV replication. Although the fundamental activities of HBx are likely preserved in hepatocytes as compared to transformed cells, the magnitude, duration and complexity of these activities may differ in primary hepatocytes. Result from studies in primary rat hepatocytes should more accurately reflect the state of an authentic infected cell, clarify the disparate HBx activites that have been reported, and provide a more sophisticated understanding of the role of HBx during HBV replication.

肝细胞癌（HCC）与人类肝炎的慢性感染之间的关联 病毒（HBV）对了解HBV感染如何增加风险产生了极大的兴趣 用于肝癌。基于在感染木肝炎病毒感染的木屑的研究中，假定 包括人HBV在内的所有哺乳动物肝病毒的X蛋白（HBX）对于病毒至关重要 复制。也有证据表明，HBX有助于HCC的发展。 HBX激活了许多 细胞信号传导级联；但是，如何实现这一目标尚不清楚。大多数试图 确定HBX在HBV复制过程中的基本作用，并了解HBX如何调节细胞 信号通路在源自肝肿瘤的肝细胞系中进行。不朽或 与真实的肝细胞相比，转化的肝细胞缺乏生物学相关性。我们 已经证明HBX的关键活性是调节细胞钙信号通路。这 提案旨在使用原发性肝细胞的培养物了解HBX的关键活动，并确定 这些活动如何影响肝细胞生理和HBV复制。 AIM 1的研究将表征 肝细胞中钙信号通路的HBX激活的分子机制以及如何 影响HBV复制。 AIM 2的研究将重点放在HBX和线粒体之间的相互作用上 以及这如何影响肝细胞生理和HBV复制。 AIM 3专门针对监管 HBX的凋亡单独或HBV复制期间。尽管HBX的基本活动是 与转化的细胞相比，可能保留在肝细胞中，幅度，持续时间和复杂性 这些活动在原发性肝细胞中可能有所不同。原发性大鼠肝细胞的研究应 更准确地反映一个真实受感染的细胞的状态，阐明具有不同的HBX激活物 已有报道，并对HBX在HBV复制中的作用提供了更复杂的理解。