Regulation of Hepatitis B Virus Transcription

描述（由申请人提供）：B肝炎病毒（HBV）感染是一个全球性的健康问题。据估计，世界上有2亿至5亿HBV慢性携带者，迄今为止，没有可靠的治疗方法。HBV引起急性和慢性肝病，慢性HBV携带者中原发性肝细胞癌（PHC）的估计相对风险约为未感染个体的100倍。因此，需要有效治疗慢性HBV感染。在细胞培养中，已显示核激素受体对于HBV前基因组RNA合成和病毒生物合成是必需的。使用慢性HBV感染的HBV转基因小鼠模型，将研究核激素受体HNF 4和RXR-α加PPAR-α在体内调节HBV转录和复制中的潜在关键作用。如果这些核激素受体是体内病毒生物合成所必需的，那么这些配体依赖性转录因子应该是开发抗病毒剂的重要靶点。此外，改变HNF 3同种型在细胞培养物和体内的表达水平已显示出抑制HBV复制。调节细胞信号转导途径在确定体内HNF 3亚型表达水平和抑制HBV转录和复制中的作用将被检查。了解抑制HBV合成的信号转导途径的细胞靶点应该允许抗病毒药物的合理设计。慢性HBV感染的转基因小鼠模型将用于了解体内HBV共价闭合环（CCC）DNA的产生和维持中转录调控的作用。抑制HBV CCC DNA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。所有这些研究都旨在确定慢性HBV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 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.