Regulation of Hepatitis B Virus Transcription

描述(申请人提供)：乙肝病毒感染是一个世界性的健康问题。据估计，世界上有2亿至5亿慢性乙肝病毒携带者，到目前为止，还没有可靠的治疗方法。乙肝病毒可导致急性和慢性肝病，慢性乙肝携带者患原发性肝细胞癌(PHC)的估计相对风险约为未感染患者的100倍。因此，需要对慢性乙肝病毒感染进行有效的治疗。在细胞培养中，核激素受体被证明是乙肝病毒前基因组RNA合成和病毒生物合成所必需的。利用慢性乙肝病毒感染的转基因小鼠模型，将研究核激素受体HNF4和RXRpha加PPARpha在体内调节乙肝病毒转录和复制的潜在关键作用。如果这些核激素受体对体内病毒的生物合成是必不可少的，那么这些配体依赖的转录因子应该是抗病毒药物开发的重要靶点。此外，改变HNF3亚型在细胞培养和体内的表达水平已被证明可以抑制乙肝病毒的复制。调节细胞信号转导通路在决定体内HNF3亚型表达水平和抑制乙肝病毒转录和复制方面的作用将被检验。了解抑制乙肝病毒合成的信号转导通路的细胞靶点应该有助于合理设计抗病毒药物。转基因小鼠慢性乙肝病毒感染模型将被用来了解转录调控在体内产生和维持乙肝病毒共价闭合环(CCC)DNA中的作用。抑制HBVccDNA的合成对于清除病毒和预防人类原发性肝细胞癌是必不可少的。所有这些研究的目的都是确定乙肝病毒感染治疗干预的可能靶点。

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 RXRalpha plus PPARalpha, 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 HBV infection.