FUSE Binding Protein As a Cellular Effector of HCV Replication

描述(申请人提供)：慢性感染丙型肝炎病毒(丙型肝炎病毒)，这是重型肝炎的主要原因，通常发展为肝硬变(LC)和肝细胞癌(肝癌)。丙型肝炎病毒复制和致病的分子机制尚不清楚。我们最近发现了一种细胞因子，融合蛋白(FUSE Binding Protein，FBP)，它能与丙型肝炎病毒3‘端非编码区特异地相互作用，刺激丙型肝炎病毒复制。已知FBP与c-myc原癌基因富含嘧啶的远上游元件(FUSE)相互作用，激活c-myc转录。C-myc针对大约10%的转录基因，协调许多重要的细胞过程，包括增殖、生长和分化。C-myc在慢性丙型肝炎病毒感染的细胞中也持续升高，在受LC和肝癌影响的细胞中也是如此。我们的初步结果表明，FBP在有慢性丙型肝炎病史的肝细胞癌中过度表达，而在其他无慢性丙型肝炎病史的肝细胞癌中明显缺失。我们建议研究FPB在丙型肝炎病毒复制中的作用机制，以及它在丙型肝炎病毒相关致病机制中的可能作用。 公共卫生相关性：这项建议的主要目的是阐明融合结合蛋白(FBP)介导的刺激丙型肝炎病毒复制的机制及其在HC相关发病机制中的意义。这些研究将有助于描绘丙型肝炎病毒-纤维结合蛋白相互作用如何影响感染丙型肝炎病毒的患者，并确定其中任何一种相互作用是否代表治疗干预的目标。

DESCRIPTION (provided by applicant): Chronic infection by hepatitis C virus (HCV), which is the leading cause of severe hepatitis, often develops into liver cirrhosis (LC) and hepatocellular carcinoma (HCC). The molecular mechanisms underlying HCV replication and pathogenesis are poorly understood. We have recently identified a cellular factor, FUSE binding protein (FBP) that specifically interacts with HCV 3'NTR and stimulates HCV replication. FBP is known to interact with the pyrimidine-rich far-upstream element (FUSE) of the c-myc proto-oncogene and activate c-myc transcription. C-myc targets approximately 10% of transcribed genes and coordinates many essential cellular processes, including proliferation, growth, and differentiation. C-myc also is consistently elevated in chronically HCV-infected cells, as well as in cells affected by LC and HCC. Our preliminary results have indicated that FBP is overexpressed in HCC with a history of chronic hepatitis C (CHC) but conspicuously absent in other HCC without CHC history. We propose to investigate the mechanisms whereby FPB acts in HCV replication and it possible role in HCV associated pathogenesis. PUBLIC HEALTH RELEVANCE: The major purpose of this proposal is to elucidate the mechanism of FUSE binding protein (FBP)- mediated stimulation of HCV replication and its implication on HC associated pathogenesis. These studies will help delineate how HCV-FBP interactions affect patients infected with HCV, and to determine whether any of these interactions represent targets for therapeutic intervention.