PATHOGENESIS OF GROUND GLASS CELLS IN HEPATITIS B

乙肝病毒明显与肝细胞癌有关 癌症，但致癌的机制却知之甚少。一 最近的转基因小鼠研究加强了这种可能性，即 细胞坏死和再生在很大程度上有助于 致癌。在慢性乙肝病毒感染中，经常出现 所谓的毛玻璃细胞，也就是肝细胞 细胞内保留的聚集在细胞内的乙肝表面蛋白 内质网。转基因小鼠中的毛玻璃细胞可能会导致 足够的肝细胞损伤和再生以诱导 肝细胞癌。已知磨砂玻璃电池是由 过表达的乙肝病毒大表面蛋白，但分子 在慢性感染期间导致这种过度表达的事件有 未知。我们的假设是，在这个过程中出现的乙肝病毒基因组突变 慢性感染是导致毛玻璃细胞的主要原因之一。在.期间 这个项目的头3年，我们一直在详细研究 乙肝病毒的顺式元件，调节表面基因的表达。结果, 我们已经确定了乙肝病毒基因组的区域，当这些区域发生突变时，可以 导致较大的表面蛋白相对过度表达，因此 培养细胞表面蛋白在细胞内的滞留。 有趣的是，这些区域在慢性前列腺癌过程中经常发生突变。 感染。因此，对于建议的续订，我们希望生成乙肝病毒 模拟自然产生的乙肝病毒基因组的克隆 这些区域。我们将首先确认这些克隆导致 培养细胞表面蛋白在细胞内的滞留。我们会 然后产生含有突变基因组的转基因小鼠，并寻找 毛玻璃细胞的出现、肝炎和肝细胞 癌症。预计这些研究将导致新的 对毛玻璃细胞发病机制的见解，并最终 乙肝病毒感染中的肝细胞癌。

Hepatitis B virus (HBV) is clearly associated with hepatocellular carcinomas, yet the mechanism of carcinogenesis is poorly understood. One possibility, strengthened by recent transgenic mouse studies, is that cellular necrosis and regeneration contribute significantly to carcinogenesis. In chronic HBV infection, there is frequent appearance of so-called ground glass cells, which are hepatocytes with intracellularly retained HBV surface proteins aggregated in the endoplasmic reticulum. Ground glass cells in transgenic mice can cause sufficient hepatocellular damage and regeneration to induce hepatocellular carcinoma. Ground glass cells are known to result from over-expression of the HBV large surface protein, but the molecular events that lead to such over-expression during chronic infection are unknown. Our hypothesis is that HBV genomic mutations that arise during chronic infection comprise one major cause of ground glass cells. During the first 3 years of this project, we have been studying in detail the cis-elements of HBV that regulate surface gene expression. As a result, we have identified regions of the HBV genome, which when mutated, can cause relative over-expression of large surface proteins and hence intracellular retention of surface proteins in cultured cells. Interestingly, these regions are frequently mutated during chronic infection. Therefore, for the proposed renewal, we wish to generate HBV clones that simulate naturally occurring HBV genomes with mutations in these regions. We will first confirm that these clones cause intracellular retention of surface proteins in cultured cells. We will then generate transgenic mice containing mutant genomes, and look for the appearance of ground glass cells, hepatitis, and hepatocellular carcinomas. It is anticipated that these studies will lead to new insights on the pathogenesis of ground glass cells, and ultimately of hepatocellular carcinoma in HBV infection.