TRANSGENIC MOUSE MODEL FOR STUDY OF VIRAL HEPATITIS C

虽然丙型肝炎病毒(丙型肝炎病毒)是发病率和 在世界范围内，病毒的细胞病变效应的作用仍然存在 不清楚。丙型肝炎病毒结构蛋白的生物合成及其功能研究 致病作用，表达1b型丙型肝炎病毒结构的转基因小鼠 蛋白质(核心、E1和E2)是用肝脏特异的 推动者。在多个品系中检测到丙型肝炎病毒转基因的表达 经Northern印迹分析，丙型肝炎病毒特异性逆转录酶-聚合酶链 RT-PCR和Western免疫印迹。免疫组织化学 分析显示核心蛋白主要存在于细胞质中。 偶尔有核染色，细胞质和细胞膜都有 E2蛋白在转基因肝脏中的表达。在六个月内 随着年龄的增长，所有转基因血统的肝脏在组织学上都保持正常。 因此，丙型肝炎病毒结构蛋白在这种情况下不是直接的细胞病变 动物模型。我们的实验室也在培育转基因小鼠 全长丙型肝炎病毒基因组，并正在开发一种可诱导的 利用四环素诱导系统表达丙型肝炎病毒转基因。 这些动物不仅将提供一个有用的动物模型来解决 丙型肝炎病毒基因的免疫致病机制和细胞病变潜能问题 产品还可以研究丙型肝炎病毒在体内的复制。

Although hepatitis C virus (HCV) is a leading cause of morbidity and mortality worldwide, the role of viral cytopathic effects remains unclear. To study the biosynthesis of HCV structural proteins and their pathogenic role, transgenic mice expressing type 1b HCV structural proteins (core, E1 and E2) have been constructed using liver-specific promoters. Expression of HCV transgenes was detected in several lines by Northern blot, HCV-specific reverse transcriptase-polymerase chain reaction (RT-PCR), and Western immunoblotting. Immunohistochemical analysis revealed a predominately cytoplasmic presence of core protein with occasional nuclear staining, and both cytoplasmic and membrane expression of the E2 protein in the transgenic livers. At six months of age, the livers of all transgenic lineages remain histologically normal. Therefore HCV structural proteins are not directly cytopathic in this animal model. Our laboratory are also generating transgenic mice with full-length HCV genome and are developing a system for inducible expression of HCV transgenes using the tetracycline-inducible system. These animal will provide a useful animal model not only to address issues of immunopathogenesis and cytopathic potential of HCV gene products but also to study HCV replication in vivo.