丙型肝炎病毒核心蛋白上调IL-32诱导狨猴肝脏炎症的分子机制

丙型肝炎病毒（HCV）核心蛋白（core）在宿主细胞增殖、DNA合成、细胞凋亡、肝炎与肝癌中均起到重要作用，但其诱导肝炎的分子机制仍未阐明。前期我们以HCV完整结构蛋白或完整囊膜蛋白替换GBV-B的相应蛋白构建了两种HCV/GBV-B嵌合病毒感染狨猴模型，呈现出典型的病毒性肝炎的特征。我们观察到含有HCV core的嵌合病毒感染狨猴后引起的肝炎程度更显著。通过转录组分析及Huh7细胞验证，发现可能与core通过PI3K途径上调IL-32相关。HCV core是如何诱导肝炎发生的？本课题将利用HCV-core/GBV-B嵌合病毒体外感染狨猴肝细胞系与体内感染狨猴模型，分析HCV core与细胞信号蛋白相互作用的位点，揭示core如何通过PI3K途径上调IL-32，进而又如何引起肝炎的分子机制。本课题将充分阐明HCV core在肝炎发生过程中所起的关键作用，为丙型肝炎防治提供新的思路和靶标。

The core protein of hepatitis C virus (HCV core) plays an important role in host cell proliferation, DNA synthesis, apoptosis, hepatitis and hepatocellular carcinoma, but the molecular mechanism of its induction of hepatitis was still unclear. Previously, we established HCV whole structural proteins CE1E2p7/GBV-B and whole envelope proteins E1E2p7/GBV-B chimeric viruses infected marmoset models, presenting typical viral hepatitis characteristics. We observed that the liver histopathological changes of marmosets infected with chimeric virus containing HCV core were more significant. Through transcriptome analysis and Huh7 cell verification, we found that it may be related to the up-regulation of IL-32 by core through PI3K pathway. But how did core induce hepatitis? In this study, we will use HCV-core/GBV-B chimeric virus to infect hepatocyte lines of marmosets and in vivo infection model to analyze the site of core-cell signaling protein interaction, elucidate how core induced IL-32 up-regulation through PI3K pathway, and how IL-32 up-regulation caused hepatitis. This topic will deeply help us to understand and analyze the role of core in the process of hepatitis, and provide new ideas and targets for the prevention and treatment of hepatitis C.