In-depth study of antiviral RNA silencing in Caenorhabditis elegans

秀丽隐杆线虫抗病毒RNA沉默的深入研究

• 批准号: 9403202
• 负责人: Rui Lu
• 金额: $ 28.53万
• 依托单位: LOUISIANA STATE UNIV A&M COL BATON ROUGE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9403202
• 关键词: Address; Alleles; Animal Model; Antiviral Agents; Antiviral Therapy; Biogenesis; Biological Models; Biological Process; Caenorhabditis elegans; Cell Differentiation process; Cells; DNA Sequence Alteration; Detection; Development; Double-Stranded RNA; Gene Expression Regulation; Gene Silencing; Genes; Genetic; Genetic Screening; Homologous Gene; Human; Interferons; Invaded; Invertebrates; Light; Longevity; Mammalian Cell; Mammals; Mediating; Mus; Mutation; N-terminal; Natural Immunity; Nematoda; Plants; Play; Proteins; RNA Helicase; RNA Interference; Regulation; Research; Resistance; Role; Small Interfering RNA; Study models; Transcript; Undifferentiated; Viral; Viral Drug Resistance; Viral Genome; Virus; Virus Diseases; Virus Replication; Work; antiviral immunity; fight against; fungus; gene function; human disease; improved; novel; novel strategies; pathogen; response; sensor; treatment strategy; viral RNA; viral detection; virus development

PROJECT SUMMARY Antiviral RNA silencing (AvRS), also referred to as antiviral RNA interference (RNAi), acts as a major antiviral innate mechanism in fungi, plants, and invertebrates. Recent observations suggest that AvRS is also active in undifferentiated mouse cells and appears to be essential for developing mouse babies to fight against lethal viral pathogen. Virus destruction in AvRS is guided by small interfering RNAs derived from viral double-stranded RNAs (dsRNAs), usually the replication intermediates. Therefore, genetic mutations that accumulate in the viral genome during the term of virus replication do not confer resistance to AvRS. Hence, mechanistic study of AvRS holds promise for developing novel strategies for the treatment of viral infection caused human diseases. In mammals, interferon mediated antiviral immunity represents a major innate immunity against viral infection. This antiviral immunity is often triggered upon the detection of invading viral RNAs by three closely related RNA helicases termed RIG-I-like RNA helicases (RLHs). Among these three RLHs, RIG-I and MDA5 detect virus-produced double-stranded RNAs (dsRNAs) in a sequence- independent manner and, thus, are also resistant to genetic changes within the viral genome. Thus, findings from the study of RLH mediated virus detection is also expected to facilitate the development of novel antiviral therapies. Increasing evidence suggests that RIG-I also plays essential role in regulating mammal development. Currently, it remains to be an open question how RIG-I regulates development in mammals Viruses naturally infect and trigger AvRS in Caenorhabditis elegans, making C. elegans an ideal model organism for the study of AvRS. Compared to other model organism, C. elegans has so far the most, in terms of type species, genes identified as key components of AvRS. Because of its short life span and genetic tractability, C. elegans also allows for rapid identification of novel AvRS genes for in-depth study of AvRS. More importantly, accumulating evidence suggests that worm RLHs contribute to both AvRS, by acting as a virus sensor, and worm development. Thus, C. elegans as a model system would serve us well in addressing the question how the virus detection function of RLHs is regulated and how RLHs contribute to the regulation of development. This application seeks to work on (1) genetic and functional characterization of the candidate AvRS genes isolated from a random genetic screen; (2) mechanistic study of worm AvRS initiation; (3) mechanistic study of viral transcript destruction by worm AvRS. Findings from the proposed research are expected to not only improve our understanding of worm AvRS but also facilitate our study on the regulation of RLH function in virus detection and the regulation of development by RIG-I in mammals.

项目摘要 抗病毒RNA沉默（AvRS），也称为抗病毒RNA干扰（RNAi）， 真菌、植物和无脊椎动物中的主要抗病毒先天机制。最近的观察表明， AvRS在未分化的小鼠细胞中也有活性，似乎对发育中的小鼠至关重要。 婴儿对抗致命的病毒病原体。AvRS中的病毒破坏由小干扰 来源于病毒双链RNA（dsRNA）的RNA，通常是复制的中间产物。 因此，在病毒复制期间在病毒基因组中积累的基因突变 不会对AvRS产生耐药性。因此，对AvRS机理的研究有望为开发 用于治疗病毒感染引起的人类疾病的新策略。 在哺乳动物中，干扰素介导的抗病毒免疫代表了主要的先天免疫， 病毒感染这种抗病毒免疫通常在检测到入侵的病毒RNA时被触发， 三种密切相关的RNA解旋酶称为RIG-I样RNA解旋酶（RLH）。这三 RLH、RIG-I和MDA 5检测病毒产生的双链RNA（dsRNA）， 独立的方式，因此也对病毒基因组内的遗传变化具有抵抗力。因此，在本发明中， RLH介导的病毒检测研究的结果也有望促进 新的抗病毒疗法。越来越多的证据表明，RIG-I也发挥着重要作用， 调节哺乳动物的发育。目前，RIG-I如何调节仍然是一个悬而未决的问题， 哺乳动物发育 病毒自然感染并触发秀丽隐杆线虫中的AvRS，使C.一个理想的优雅 研究AvRS的模式生物。与其他模式生物相比，C.到目前为止， 大多数，在模式物种方面，基因被确定为AvRS的关键组成部分。因为它的寿命很短 跨度和遗传易处理性，C.线虫还允许快速鉴定新的AvRS基因， 深入研究AvRS。更重要的是，越来越多的证据表明， 通过充当病毒传感器，对AvRS和蠕虫的发展都有贡献。因此，C.优雅作为一个 模型系统将很好地解决RLH病毒检测功能的问题 以及RLH如何对发育的调节做出贡献。 本申请旨在研究（1）候选人的遗传和功能特征 （2）蠕虫AvRS启动机制的研究; (3)蠕虫AvRS破坏病毒转录物的机制研究。建议的调查结果 研究预计不仅可以提高我们对蠕虫AvRS的理解， RLH在病毒检测中的功能调控及RIG-I对发育的调控研究 在哺乳动物中。