Regulation of Hepatitis B Virus Transcription

描述（申请人提供）：乙型肝炎病毒（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，迄今尚无可靠的治疗方法。HBV可引起急性和慢性肝病，慢性HBV携带者患原发性肝细胞癌（PHC）的相对危险度估计约为未感染个体的100倍。因此，需要对慢性HBV感染进行有效治疗。在细胞培养中，核激素受体已被证明是HBV基因组前RNA合成和病毒生物合成所必需的。利用HBV转基因小鼠慢性HBV感染模型，研究核激素受体HNF4和rxr - α + 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，那么这些依赖配体的转录因子应该是开发抗病毒药物的重要靶点。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HBV复制。将研究调节细胞信号转导通路在体内决定HNF3亚型表达水平和抑制HBV转录和复制中的作用。了解抑制HBV合成的信号转导途径的细胞靶标应该允许合理设计抗病毒药物。该转基因小鼠慢性HBV感染模型将用于了解转录调控在体内HBV共价闭合环（CCC） DNA的产生和维持中的作用。抑制HBV CCC DNA合成对病毒清除和预防人类原发性肝细胞癌至关重要。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.