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Roles for hepatitis C virus-derived circular RNAs in infected cells

丙型肝炎病毒衍生的环状 RNA 在受感染细胞中的作用

基本信息

批准号：
10309048
负责人：
PETER SARNOW
金额：
$ 23.62万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10309048
关键词：
Address Affect Amber Antiviral Agents Antiviral Response Autologous Back Binding Sites Biochemical Bioinformatics Biological Biological Assay Biological Markers C-terminal CRISPR/Cas technology Catalytic Domain Cell Nucleus Cells Cirrhosis Code Cytoplasm Differentiation and Growth Disease Ectopic Expression Endoplasmic Reticulum Eukaryotic Cell Exonuclease Flaviviridae Fluorescent in Situ Hybridization Gene Expression Generations Genetic Genetic Transcription Genome Goals Growth Hepatitis C virus Hepatocyte Human Immune response Immunoprecipitation Individual Infection Internal Ribosome Entry Site Kinetics Label Laboratories Lead Ligase Liver Malignant - descriptor Mass Spectrum Analysis Mission Monitor Movement Nuclear Nuclear RNA Nucleotides Oligonucleotides Open Reading Frames Organoids Outcome Pathogenesis Patients Peptide Hydrolases Peptides Polymerase Predisposition Process Production Proteins Public Health RNA RNA Splicing RNA Viruses RNA replication Research Resistance Ribosomal RNA Ribosomes Rice Role Small Interfering RNA Terminator Codon Testing Transfer RNA Translations United States National Institutes of Health Viral Virus Virus Diseases cell growth circular RNA combat endonuclease endoplasmic reticulum stress gene function genomic RNA inhibitor/antagonist innovation mRNA Precursor member migration novel novel virus patient population polypeptide prevent response tRNA Ligase viral RNA

项目摘要

While novel direct-acting antivirals (DAA) against hepatitis C virus (HCV), such as anti-polymerase and anti- proteinase compounds are effective in many patients, these treatments are still very expensive and not available to most of the 170 million people world-wide infected with HCV. In addition, it is not known whether every patient population will respond to the current DAA treatments. Thus, it is significant to continue to search for new compounds that target both HCV and viral host susceptibility factors to combat virus infection. An astonishing recent discovery made by our laboratory revealed that the HCV genomic RNA is processed during viral infection to yield hundreds of different virus-derived circular RNAs (circRNAs). These circRNAs are generated from all parts of the 10,000-nucleotide viral RNA genome, including circRNAs that contain the viral internal ribosome entry site (IRES). It is hypothesized that these circRNAs present a novel class of viral RNA species that likely display novel functions in infected and uninfected bystander cells. Because these viral circRNAs are predicted to be long-lived they could also have important roles as biomarkers. Thus, exploring the pro- and anti-viral effects of the HCV-derived circular RNAs is a significant venue of research and will point to new Achilles’ heels in RNA viruses. The long-term goals of this application are to explore the roles for the identified viral circRNAs in pro- and anti-viral responses. Two specific aims are proposed to accomplish these goals. First, the mechanism by which the viral circRNAs are generated is being investigated. The hypothesis is that HCV subverts a cellular splicing mechanism that modulates the unfolded protein response in the endoplasmic reticulum. Secondly, it will be examined whether highly abundant circRNAs and IRES-containing circRNAs have functional roles on HCV gene expression in infected cells. The functions of IRES-circRNA translation products in the viral infectious cycle will be examined both in cultured liver cells and human liver organoids that can be infected with autologous HCV. The expected outcomes of this application will address fundamental aspects about the functions of novel circular HCV-derived RNAs in the viral infectious cycle. This proposed research is innovative because it will examine whether novel virus-derived circRNAs can be targeted in antiviral approaches in RNA virus-infected cells.

虽然针对丙型肝炎病毒（HCV）的新型直接作用抗病毒剂（DAA），如抗聚合酶和抗蛋白酶化合物在许多患者中是有效的，但这些治疗仍然非常昂贵，并且对于全世界感染HCV的1.7亿人中的大多数人来说是不可用的。此外，尚不清楚是否每个患者群体都会对当前的DAA治疗作出反应。因此，继续寻找靶向HCV和病毒宿主易感因子的新化合物以对抗病毒感染是重要的。我们实验室最近的一项惊人发现表明，HCV基因组RNA在病毒感染期间被加工，产生数百种不同的病毒衍生环状RNA（circRNA）。这些circRNA由10，000个核苷酸的病毒RNA基因组的所有部分产生，包括含有病毒内部核糖体进入位点（IRES）的circRNA。据推测，这些circRNA呈现了一类新的病毒RNA种类，其可能在感染和未感染的旁观者细胞中显示出新的功能。由于这些病毒circRNA被预测为长寿命的，因此它们也可以作为生物标志物发挥重要作用。因此，探索HCV衍生的环状RNA的促病毒和抗病毒作用是一个重要的研究场所，并将指出RNA病毒的新阿基里斯之踵。本申请的长期目标是探索所鉴定的病毒circRNA在促病毒应答和抗病毒应答中的作用。为实现这些目标，提出了两个具体目标。首先，正在研究病毒circRNA产生的机制。该假说认为HCV破坏了调节内质网中未折叠蛋白反应的细胞剪接机制。其次，将检查高度丰富的circRNA和含有IRES的circRNA是否对感染细胞中的HCV基因表达具有功能作用。IRES-circRNA翻译产物在病毒感染周期中的功能将在培养的肝细胞和可被自体HCV感染的人肝类器官中进行检查。本申请的预期结果将解决有关新型环状HCV衍生RNA在病毒感染周期中的功能的基本方面。这项拟议的研究是创新的，因为它将研究新的病毒衍生的circRNA是否可以在RNA病毒感染的细胞中的抗病毒方法中靶向。