Hepatitis C Virus NS5a Protein and Oxidative Stress

描述(申请人提供)：丙型肝炎病毒(丙型肝炎病毒)是慢性肝炎和肝硬变的主要病原体之一。肝组织中的丙型肝炎病毒感染与肝细胞癌的发生有关。据估计，美国约有400万人感染了丙型肝炎病毒。该病毒的RNA基因组编码一个由3010个氨基酸组成的多蛋白。丙型肝炎病毒RNA基因组由5‘端和3’端的独特序列和结构组成，这是病毒翻译和复制所必需的基本特征。RNA基因组编码三种结构蛋白和至少六种非结构蛋白。作为一种非结构蛋白，NS5A已经引起了人们极大的兴趣，这主要是因为它被认为在干扰素抵抗中发挥了作用。在这个应用中，我们建议研究与丙型肝炎病毒NS5A相关的功能。丙型肝炎病毒RNA基因组的翻译和复制功能与内质网膜有关。内质网中的这些活动诱导了内质网应激和内质网过载反应。内质网应激导致未折叠蛋白应答(UPR)，导致整个宿主内质网伴侣蛋白的激活。内质网超载反应似乎涉及两个第二信使，钙和活性氧物种。它们的活性最终导致转录因子的激活和移位到细胞核，从而与同源DNA序列结合并调节基因表达。核转录因子-kappaB和STAT-3就是被磷酸化激活并转运到细胞核的两种转录因子。因此，我们拟探讨丙型肝炎病毒NS5A激活内质网信号转导通路的机制。这些研究有可能提供与慢性肝病发病机制直接相关的信息，包括其进展为与丙型肝炎病毒感染相关的肝细胞癌。

DESCRIPTION (provided by applicant): Hepatitis C virus (HCV) is one of the leading causative agents of chronic hepatitis and cirrhosis. HCV infection of liver is associated with the development of hepatocellular carcinoma. It is estimated that about 4 million people in the US are infected with HCV. The RNA genome of this virus encodes a polyprotein of 3010 amino acids. HCV RNA genome consists of unique sequences and structures at its 5' and 3' termini, which are essential features required for viral translation and replication. The RNA genome codes for three structural proteins and at least six nonstructural proteins. One of the nonstructural proteins, NS5A has generated significant levels of interest due largely to its suggested role in interferon-resistance. In this application, we propose to investigate the functions associated with the HCV NS5A. Translation and replication functions of the HCV RNA genome are associated with the ER membrane. These activities in the ER induce ER stress and ER overload responses. ER stress leads to unfolded protein response (UPR), which leads to activation of whole host of ER chaperone proteins. The ER overload response appears to involve two second messengers, calcium and reactive oxygen species. Their activities ultimately lead to the activation and translocation of transcription factors to the nucleus whereupon they bind cognate DNA sequences and regulate gene expression. NF-kappaB and STAT-3 are two such transcription factors which are activated by phosphorylation and are transported to nucleus. Herein, we propose to investigate the mechanism of activation of ER-nucleus signal transduction pathway by the HCV NS5A. These studies have the potential to provide information of direct relevance to the chronic liver disease pathogenesis including its progression to hepatocellular carcinoma associated with the HCV infection.