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：
10442607
负责人：
PETER SARNOW
金额：
$ 19.68万
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 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10442607
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 Persons 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 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药物 (DAA)，例如抗聚合酶和抗蛋白酶化合物，对许多患者有效，但这些治疗方法仍然非常昂贵，全世界 1.7 亿人口中的大多数人无法获得这些治疗方法此外，尚不清楚是否每个患者群体都会对当前的 DAA 治疗产生反应，因此，继续寻找针对 HCV 和病毒宿主易感因素的新化合物具有重要意义。我们实验室最近的一项惊人发现表明，HCV 基因组 RNA 在病毒感染过程中被加工，产生数百种不同的病毒衍生环状 RNA (circRNA)，这些 circRNA 由 10,000 个核苷酸的病毒的所有部分产生。 RNA 基因组，包括含有病毒内部核糖体进入位点 (IRES) 的 circRNA 人们重新认识到，这些 circRNA 代表了一类新的病毒 RNA 物种，可能在感染和未感染的情况下表现出新的功能。由于这些病毒 circRNA 预计寿命较长，因此它们也可能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领域。该应用的长期目标是探索已识别的病毒 circRNA 在促病毒和抗病毒反应中的作用，以实现这些目标。由此正在研究病毒产生的 circRNA。假设 HCV 颠覆了调节内质网中未折叠蛋白反应的细胞剪接机制。其次，将检查高丰度的 circRNA 和含有 IRES 的 circRNA 是否对 HCV 具有功能作用。将在培养的肝细胞和可感染的人类肝类器官中检查 IRES-circRNA 翻译产物在病毒感染周期中的功能。该应用的预期结果将解决病毒感染周期中新型环状 HCV 衍生 RNA 的功能的基本问题，这项研究具有创新性，因为它将检查新型病毒衍生 circRNA 是否可以作为抗病毒方法的靶标。在RNA病毒感染的细胞中。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Virus-derived circular RNAs populate hepatitis C virus-infected cells.

病毒衍生的环状 RNA 聚集在丙型肝炎病毒感染的细胞中。

DOI：
10.1073/pnas.2313002121
发表时间：
2024-02-06
期刊：
Proceedings of the National Academy of Sciences of the United States of America
影响因子：
11.1
作者：
Qian M Cao;Pakpoom Boonchuen;Tzu;Shaohua Lei;Kunlaya Somboonwiwat;P. Sarnow
通讯作者：
P. Sarnow