Novel regulatory mechanisms control IFNL3 expression during HCV infection

HCV 感染过程中控制 IFNL3 表达的新调控机制

• 批准号: 8611757
• 负责人: Ram Savan
• 金额: $ 43.5万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8611757
• 关键词: 3' Untranslated Regions; Affect; Antiviral Agents; Antiviral Response; Binding Proteins; Cleaved cell; Combined Modality Therapy; Data; Elements; Figs - dietary; Gene Expression; Genes; Genetic Polymorphism; Hepatitis C; Hepatitis C virus; Hepatocyte; Immune; Immune response; Infection; Interferons; Introns; Laboratories; Linkage Disequilibrium; Mediating; Messenger RNA; MicroRNAs; Modeling; Molecular; Myosin ATPase; Nature; Outcome; Outcome Study; Pathway interactions; Patients; Positioning Attribute; Post-Transcriptional Regulation; RNA-Binding Proteins; Regulation; Regulon; Signal Pathway; Signal Transduction; Single Nucleotide Polymorphism; Structure; Variant; Viral; base; genetic regulatory protein; genome wide association study; hepatitis C virus NS3 protein; improved; mRNA Expression; mRNA Stability; mRNA Transcript Degradation; new therapeutic target; novel; prevent; public health relevance; response

DESCRIPTION (provided by applicant): Hepatitis C virus (HCV) infects over 150 million people worldwide. Interferon (IFN)-based therapy is the mainstay platform for treatment of HCV wherein improving IFN response rates remains paramount to achieving global sustained virological response. Genome-wide association studies (GWAS) have identified three single nucleotide polymorphisms (SNPs) near the interferon lambda 3 (IFNL3 also known as IL28B) gene that strongly associate with HCV patient response to therapy and natural clearance of infection. However, the functional polymorphism mediating these associations is still unknown. We have found that a 3'UTR polymorphism (rs4803217) dictates IFNL3 expression by altering mRNA stability through the recruitment of HCV-induced microRNAs (miRNAs) and AU-rich element (ARE)-binding proteins (ARE-BP). Our preliminary data show that expression of the rs4803217 T variant is repressed by the induced miRNAs and AU-rich element mediated decay, whereas a single T>G polymorphism rescues this suppression. This proposal aims to identify the specific ARE sequences and ARE-BP that function with miRNAs in the post-transcriptional "regulon" acting on IFNL3 variants. We will study the pathways that influence this regulon, namely the ability of HCV to induce host miRNAs in hepatocytes. Finally, we will investigate how the IFNL3 regulon affects the interferon-mediated antiviral response to HCV. This proposal will likely identify new therapeutic targets that can be manipulated in order to control HCV infection.

描述（由申请人提供）：丙型肝炎病毒（HCV）在全球范围内感染了超过1.5亿人。干扰素（IFN）基于基于IFN的治疗是治疗HCV的主要平台，其中提高IFN反应率仍然对实现全球持续的病毒学反应至关重要。全基因组关联研究（GWAS）已经鉴定出三个单核苷酸多态性（SNP）附近的干扰素兰伯达3（IFNL3也称为IL28B）基因，它们与HCV患者对治疗的反应密切相关，并自然而然地关联。但是，介导这些关联的功能多态性仍然未知。我们发现3'UTR多态性（RS4803217）通过募集HCV诱导的MicroRNA（miRNA）和富含AU的元素（are）结合蛋白（are-bp）来改变mRNA稳定性，从而决定IFNL3的表达。我们的初步数据表明，rs4803217 t变体的表达受到诱导的miRNA和富含Au的元素介导的衰减的抑制作用，而单个T> G多态性则挽救了这种抑制。该建议旨在识别特定的是序列和是BP，在作用于IFNL3变体的后“调节”中与miRNA一起起作用。我们将研究影响这种调节的途径，即HCV在肝细胞中诱导宿主miRNA的能力。最后，我们将研究IFNL3调节子如何影响干扰素介导的抗病毒对HCV的反应。该建议可能会确定可以操纵的新治疗靶标，以控制HCV感染。