Establishment of laboratory transgenic mouse strains for hepatitis C virus infection

丙型肝炎病毒感染实验室转基因小鼠品系的建立

基本信息

批准号：
09358018
负责人：
YONEKAWA Hiromichi
金额：
$ 16.51万
依托单位：
Tokyo Metropolitan Organization for Medical Research
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1999
项目状态：
已结题

项目摘要

The hepatitis C virus (HCV) is the major causative agent of non-A/non-B hepatitis. A major characteristic of HCV infection is the extremely high (up to 80%) risk of chronicity; in addition, chronic infection of HCV can frequently leads to liver cirrhosis and hepatocellular carcinoma. An important issue regarding the pathogenesis of HCV-associated liver lesions is to determine whether HCV proteins might have a direct effect on cellular phenotype. however, little was known about this respect. To address this question, we tried to establish animal model for HCV. Introducing an efficient Cre/loxP conditional transgenesis, we created several lines of transgenic mice with HCVcDNA (nucleotides 294-3435). After administration of adenovirus that expresses Cre recombinase, the HCV genome introduced as a transgene can express several HCV-specific core proteins in most hepatocytes of the transgenic mice. Moreover, pathological changes and elevated level of serum alanine animotransferase suggested that liver injury occurred in the transgenic mice that express the HCV transgene. A CD4 and CD8 positive cells depletion assay normalized both the serum alanine aminotransferase increases and the pathological changes in the liver. These results suggested that HCV proteins are not directly cytopathic and that the host immune response plays a pivotal role in HCV infection. Thus, this HCV cDNA transgenic mouse provides a powerful tool with which to investigate the immune responses and pathogenesis of HCV infection.

丙型肝炎病毒（HCV）是非A/非B肝炎的主要病因。 HCV感染的主要特征是慢性病的高风险（高达80％）。此外，慢性感染HCV经常会导致肝硬化和肝细胞癌。关于HCV相关肝病变的发病机理的一个重要问题是确定HCV蛋白是否可能对细胞表型有直接影响。但是，关于这方面知之甚少。为了解决这个问题，我们试图为HCV建立动物模型。引入了有效的CRE/LOXP条件转基因，我们用HCVCDNA创建了几行转基因小鼠（核苷酸294-3435）。在施用表达CRE重组酶的腺病毒后，作为转基因引入的HCV基因组可以在大多数转基因小鼠的大多数肝细胞中表达几种HCV特异性核心蛋白。此外，病理变化和血清丙氨酸Animottransferase的水平升高表明，肝损伤发生在表达HCV转基因的转基因小鼠中。 CD4和CD8阳性细胞的耗尽测定使血清丙氨酸氨基转移酶的增加和肝脏的病理变化归一化。这些结果表明，HCV蛋白不是直接的细胞病变，并且宿主免疫反应在HCV感染中起关键作用。因此，该HCV cDNA转基因小鼠提供了一种强大的工具，可以利用研究HCV感染的免疫反应和发病机理。