Dr. Ou proposes to study three aspects of the HBV pathogenesis and its replication cycle: core protein phosphorylation, C gene transcription controls, and the role of the X gene in replication.
Aim 1 will evaluate the model that core protein phosphorylation blocks virus assembly. Virions will be analyzed for phosphorylation; virus infection will be reconstituted with core proteins mutated to block phosphorylation at specific residues. Viral regulation, packaging efficiency, and virion production will be analyzed.
Aim 2 deals with transcriptional regulation of the core gene, which actually encodes both precore and core proteins by initiating from two different transcription start sites. The study will focus on a critical regulatory site that binds COUP, HNF4, PPAR-RXR, and when mutated, HNF1. Preliminary studies have also characterized an upstream negative regulatory element (NRE) that binds RFX1/MDBP1 and MIBP1. The NRE will be further analyzed in Aim 3. Finally, Aim 4 will evaluate whether the X protein activates cell cycle-dependent genes to support HBV regulation. For these studies, a transgenic mouse will be constructed to incorporate a functional HBV genome, but with a defective X gene.
| Lin, Wen-Jye; Li, Jie; Lee, Yi-Fen et al. (2003) Suppression of hepatitis B virus core promoter by the nuclear orphan receptor TR4. J Biol Chem 278:9353-60 |
