PATHOGENESIS OF CHRONIC HEPATITIS AND HEPATOMA

丙型肝炎病毒（HCV）是美国慢性肝炎、肝硬化和肝细胞癌的主要原因。HCV是一种RNA病毒，其在宿主肝细胞中持续存在，逃避宿主免疫反应并导致癌症的机制尚不清楚。我们最近发现，HCV的E2包膜蛋白可以激活细胞grp78和grp94基因的转录，这可能是通过与Gro78（BiP0.由于已经发现Grp78或Grp94的细胞水平增加可以保护细胞免受细胞毒性T淋巴细胞的杀伤并增加转化细胞的致瘤性，因此我们的发现指出了HCV诱导的慢性感染和致癌的发病机制的可能机制。事实上，我们已经获得了HCV E2蛋白保护细胞死亡的初步证据。因此，我们希望扩展我们的研究结果，研究E2蛋白激活Grp78表达的机制，以确认E2蛋白对细胞死亡的影响，并探讨这两种现象之间的联系。我们提出的实验可能为HCV如何导致肝脏疾病提供新的见解，并可能指向针对这种重要的新兴病原体的新的治疗途径。

Hepatitis C virus (HCV) is a major cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma in the US. The mechanism by which HCV, an RNA virus, persists in the host hepatocyte, evades the host immune response, and causes cancer is unclear. We have recently found that the E2 envelope protein of HCV can activate the transcription of the cellular grp78 and grp94 genes, possibly by a stale interaction with Gro78 (BiP0. Since increased cellular levels of Grp78 or Grp94 have been found to protect the cell against killing by cytotoxic T- lymphocytes and increase the tumorigenicity of transformed cells, our findings point to a possible mechanism for the pathogenesis of HCV- induced chronic infection and carcinogenesis. Indeed, we have obtained preliminary evidence that HCV E2 protein protects against cell death. Therefore, we wish to extend our results to study the mechanism by which E2 protein activates Grp78 expression, to confirm the effect of E2 protein on cell death, and to probe the connection between the two phenomena. Our proposed experiments may provide new insights on how HCV causes liver diseases, and possibly point towards novel avenues of therapy against this important emerging pathogen.