FUSE Binding Protein As a Cellular Effector of HCV Replication

描述（由申请人提供）：丙型肝炎病毒（HCV）的慢性感染是重型肝炎的主要原因，通常会发展为肝硬化（LC）和肝细胞癌（HCC）。HCV复制和发病机制的分子机制知之甚少。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原癌基因的富含嘧啶的远上游元件（FUSE）相互作用并激活c-myc转录。C-myc靶向大约10%的转录基因，并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HCV感染的细胞以及受LC和HCC影响的细胞中也持续升高。我们的初步研究结果表明，FBP在有慢性丙型肝炎（CHC）病史的HCC中过表达，但在无CHC病史的其他HCC中明显缺失。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。 公共卫生相关性：本研究的主要目的是阐明FUSE结合蛋白（FBP）介导的刺激HCV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述HCV-FBP相互作用如何影响HCV感染患者，并确定这些相互作用中是否有任何一种代表了治疗干预的靶点。

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.