HBV cccDNA的转录调控：FoxO4的功能和机制研究

共价闭合环状DNA(cccDNA)是乙型肝炎病毒（HBV）生活周期中的关键环节。抑制或清除cccDNA是治疗慢性乙型肝炎（CHB）的关键。 我们的预实验结果发现HBV感染可导致FoxO4分子表达的明显下调，而FoxO4的表达可明显抑制cccDNA介导的HBV转录与复制，另外我们还发现FoxO4可与固有免疫分子TRIM22相互作用。本研究拟在cccDNA细胞模型和动物模型上进一步确证FoxO4对HBV cccDNA的转录抑制作用；在机制方面重点关注FoxO4对HBV cccDNA表观遗传修饰的作用以及对抗HBV固有免疫应答活化的影响；另外还将探究HBV对FoxO4表达的负向调控机制；为CHB的治疗提供新的策略与靶标。

Covalently closed circular DNA (cccDNA) plays a key role in the life cycle of Hepatitis B virus (HBV). The difficulty in eliminating or silencing cccDNA poses as a main obstacle for the therapy of chronic HBV infection (CHB). Our primilary data showed that HBV infection led to the downregulation of FoxO4. Overexpression and knockdown experiments demonstrated that FoxO4 displayed an inhibitory effect on cccDNA-driven HBV transcription and replication. Of interest, it was found that FoxO4 could interact with the innate antiviral protein TRIM22. In present investigation, we will further confirm the inhibitory effect of IFI16 on cccDNA transcription and HBV replication both in HBV cell model and animal model. Mechanically, we will pay attention to the effect of FoxO4 on the epigenetic modification of cccDNA, and also the activation of anti-HBV innate immune response. Additionally,the mechanisms whereby HBV downregulates the protein level of FoxO4 may also be evaluated.This study may help to design new strategy against CHB.