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。

基本信息

批准号：
7727373
负责人：
Michael J Bouchard
金额：
$ 31.15万
依托单位：
DREXEL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-12-01 至 2011-08-18
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7727373
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

项目摘要

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）与人类乙型肝炎慢性感染之间的关联乙型肝炎病毒（HBV）引起了人们对了解乙型肝炎病毒感染如何增加风险的极大兴趣用于肝癌。根据对感染土拨鼠肝炎病毒的土拨鼠的研究，假设所有哺乳动物肝炎病毒（包括人类 HBV）的 X 蛋白 (HBx) 对于病毒的形成至关重要复制。还有证据表明 HBx 有助于 HCC 的发展。 HBx 激活许多细胞信号级联；然而，这是如何实现的尚不清楚。大多数研究试图确定 HBx 在 HBV 复制过程中的重要作用，并了解 HBx 如何调节细胞信号通路，是在源自肝肿瘤的肝细胞系中进行的。使用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 的一个关键活性是细胞钙信号通路的调节。这该提案旨在利用原代大鼠肝细胞培养物了解 HBx 的关键活性，并确定这些活动如何影响肝细胞生理学和 HBV 复制。 AIM 1 的研究将表征 HBx 激活肝细胞钙信号通路的分子机制及其作用机制影响乙肝病毒的复制。 AIM 2 的研究将重点关注 HBx 和线粒体之间的相互作用以及这如何影响肝细胞生理学和 HBV 复制。 AIM 3 特别关注监管 HBx 单独表达或在 HBV 复制过程中表达导致细胞凋亡。尽管 HBx 的基本活动是与转化细胞相比，肝细胞中可能保留的程度、持续时间和复杂性这些活性在原代肝细胞中可能有所不同。原代大鼠肝细胞的研究结果应更准确地反映真实感染细胞的状态，澄清不同的 HBx 活动已报道，并提供了对 HBx 在 HBV 复制过程中的作用的更深入的了解。