FUSE Binding Protein As a Cellular Effector of HCV Replication

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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.