FUSE Binding Protein As a Cellular Effector of HCV Replication

描述（申请人提供）：慢性丙型肝炎病毒（HCV）感染，是严重肝炎的主要原因，常发展为肝硬化（LC）和肝细胞癌（HCC）。HCV复制和发病机制的分子机制尚不清楚。我们最近发现了一种细胞因子，FUSE结合蛋白（FBP），它特异性地与HCV 3'NTR相互作用并刺激HCV复制。已知FBP与c-myc原癌基因的富嘧啶远上游元件（FUSE）相互作用并激活c-myc转录。C-myc靶向约10%的转录基因，并协调许多基本的细胞过程，包括增殖、生长和分化。C-myc在慢性hcv感染细胞以及LC和HCC感染细胞中也持续升高。我们的初步结果表明，FBP在有慢性丙型肝炎（CHC）病史的HCC中过表达，但在其他无CHC病史的HCC中明显不存在。我们建议研究FPB在HCV复制中的作用机制及其在HCV相关发病机制中的可能作用。

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.