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.

项目概要 抗病毒 RNA 沉默 (AvRS)，也称为抗病毒 RNA 干扰 (RNAi)，其作用如下： 真菌、植物和无脊椎动物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很活跃，并且似乎对于小鼠的发育至关重要 婴儿对抗致命的病毒病原体。 AvRS 中的病毒破坏是由小干扰引导的 源自病毒双链 RNA (dsRNA) 的 RNA，通常是复制中间体。 因此，在病毒复制期间，病毒基因组中积累的基因突变 不赋予 AvRS 抗性。因此，AvRS 的机制研究有望为开发 治疗由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是针对病毒的主要先天免疫。 病毒感染。这种抗病毒免疫通常是在检测到入侵的病毒 RNA 时触发的 三种密切相关的 RNA 解旋酶，称为 RIG-I 样 RNA 解旋酶 (RLH)。这三者之中 RLH、RIG-I 和 MDA5 检测病毒产生的双链 RNA (dsRNA)，其序列如下： 独立的方式，因此也能抵抗病毒基因组内的遗传变化。因此， RLH 介导的病毒检测研究结果也有望促进该技术的发展 的新型抗病毒疗法。越来越多的证据表明 RIG-I 在 调节哺乳动物的发育。目前，RIG-I 如何监管仍然是一个悬而未决的问题 哺乳动物的发育 病毒自然感染秀丽隐杆线虫并引发 AvRS，这使得秀丽隐杆线虫成为理想的选择 AvRS 研究的模型生物。与其他模式生物相比，秀丽隐杆线虫迄今为止 大多数，就模式物种而言，基因被确定为 AvRS 的关键组成部分。由于其寿命短 由于跨度和遗传易处理性，秀丽隐杆线虫还可以快速识别新的 AvRS 基因 深入研究AvRS。更重要的是，越来越多的证据表明蠕虫 RLH 通过充当病毒传感器，对 AvRS 和蠕虫病毒的发展做出贡献。因此，线虫作为 模型系统将很好地帮助我们解决 RLH 的病毒检测功能如何发挥作用的问题 受到监管以及 RLH 如何促进发展监管。 该申请旨在研究 (1) 候选者的遗传和功能特征 从随机遗传筛选中分离出的 AvRS 基因； (2)蠕虫AvRS启动机制研究； (3)蠕虫AvRS破坏病毒转录本的机制研究。拟议的调查结果 研究预计不仅能增进我们对蠕虫 AvRS 的了解，而且有助于我们 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。