Regulation of Hepatitis B Virus Transcription

乙型肝炎病毒转录的调控

• 批准号: 6572137
• 负责人: Alan McLachlan
• 金额: $ 63.34万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-15 至 2005-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6572137
• 关键词: DNA replication; RNA biosynthesis; biological signal transduction; chronic disease /disorder; circular DNA; epitope mapping; genetic transcription; genetically modified animals; hepatitis B; hepatitis B virus group; hormone receptor; immunocytochemistry; in situ hybridization; laboratory mouse; microinjections; tissue /cell culture; transcription factor; virus RNA; virus infection mechanism; virus replication

DESCRIPTION (provided by applicant): Hepatitis B virus (HBV) infection is a worldwide health problem. It is estimated that there are 200 to 500 million HBV chronic carriers in the world for whom, to date, there is no reliable treatment. HBV causes both acute and chronic liver disease and the estimated relative risk of primary hepatocellular carcinoma (PHC) in chronic HBV carriers is approximately 100 times greater than in uninfected individuals. Therefore, effective treatments for chronic HBV infection are required. In cell culture, nuclear hormone receptors have been shown to be essential for HBV pregenomic RNA synthesis and viral biosynthesis. Using a HBV transgenic mouse model of chronic HBV infection, the potential critical role of the nuclear hormone receptors, HNF4 and RXR-alpha plus PPAR-alpha, in regulating HBV transcription and replication in vivo will be investigated. If these nuclear hormone receptors are essential for viral biosynthesis in vivo, these ligand-dependent transcription factors should represent important targets for the development of antiviral agents. In addition, altering the level of expression of the HNF3 isoforms in cell culture and in vivo has been shown to inhibit HBV replication. The role of modulating cellular signal transduction pathways in determining the level of expression of the HNF3 isoforms in vivo and inhibiting HBV transcription and replication will be examined. Understanding the cellular targets of the signal transduction pathways that inhibit HBV synthesis should permit the rational design of antiviral agents. The transgenic mouse model of chronic HBV infection will be used to understand the role of transcriptional regulation in the generation and maintenance of HBV covalently closed circular (CCC) DNA in vivo. Inhibition of HBV CCC DNA synthesis is essential to viral clearance and the prevention of primary hepatocellular carcinoma in man. All of these studies are aimed at identifying possible targets for therapeutic intervention in chronic HBV infection.