tRNA-derived RNA Fragments (tRFs) and their Functions in Respiratory Syncytial Virus (RSV) Infection

tRNA 衍生的 RNA 片段 (tRF) 及其在呼吸道合胞病毒 (RSV) 感染中的功能

• 批准号: 9384979
• 负责人: Xiaoyong Bao
• 金额: $ 38.75万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-01 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9384979
• 关键词: Algorithms; Antiviral Agents; Biochemistry and Cellular Biology; Biogenesis; Bioinformatics; Biological; Biological Process; Bronchiolitis; Cellular biology; Cleaved cell; Code; Collaborations; Communicable Diseases; Communities; Complex; Computer Analysis; Data; Development; Epithelial Cells; Exhibits; Expression Profiling; Failure; Family; Foundations; Future; Gene Expression Regulation; Genes; Genetic Transcription; Glycine decarboxylase; Goals; Human; Human Genetics; Immune response; Immunoprecipitation; Infant; Knowledge; Length; Lower Respiratory Tract Infection; Lower respiratory tract structure; Lung; Malignant Neoplasms; Mediating; Methodology; MicroRNAs; Molecular; Molecular Biology; Molecular Virology; Morbidity - disease rate; Nucleotides; Organism; Play; Pneumonia; Preventive; Prokaryotic Cells; Protein Biochemistry; Proteins; Public Health; Publications; Publishing; RNA; RNA Biochemistry; RNA-Induced Silencing Complex; Regulation; Regulator Genes; Research; Resources; Respiratory Syncytial Virus Infections; Respiratory syncytial virus; Respiratory syncytial virus RSV proteins; Role; System; Techniques; Testing; The Sun; Therapeutic; Transfer RNA; Untranslated RNA; Vaccines; Viral; Virus Replication; angiogenin; apolipoprotein B mRNA editing enzyme; apolipoprotein E receptor 2; biological systems; cellular targeting; data integration; design; early childhood; endonuclease; experience; experimental study; human disease; in vitro Assay; infancy; innovation; insight; mortality; nervous system disorder; novel; novel strategies; nuclease; polypeptide; protein expression; public health relevance; response; reverse genetics; structural biology; virology; virus host interaction

 DESCRIPTION (provided by applicant): Recent discoveries on small non-coding RNAs (sncRNAs) have significantly advanced human genetics and molecular biology, largely due to the identification of a fundamental role of sncRNAs as gene regulators. tRNA- derived RNA Fragments (tRFs) represent a recently discovered sncRNA family that is quickly being recognized as ubiquitously expressed in organisms ranging from prokaryotes to humans; however, tRFs' biological functions and the mechanism(s) underlying them are largely unknown. Respiratory syncytial virus (RSV) is the single most common cause of lower respiratory tract illness in infants. Our recent publication has shown that the sncRNAs most highly induced by RSV belong to the tRF family. Notably, at least the two most abundant RSV-inducible tRFs have a gene trans-silencing function that is mechanistically distinct from that of miRNAs, and one of these two, called tRF5-GluCTC, promotes RSV replication and regulates genes at a post-transcriptional level. The biogenesis of this tRF is also specific, and mediated by a particular endonuclease (angiogenin, ANG), and not by other nucleases. However, the molecular mechanisms underlying the biological functions and induction of tRF5-GluCTC are not known. Our central hypothesis in this project is that the RSV-induced tRF5-GluCTC is not a random by-product of tRNA degradation, but rather a functional molecule important for host-RSV interactions. This project will focus on exploring the molecular mechanisms underlying the regulatory effects of tRF5-GluCTC on RSV replication, and the host responses thereto. Our experiments will identify the targets of tRF5-GluCTC in RSV- infected airway epithelial cells (Aim 1), determine the viral factor(s) controlling the trans-silencing activity of tRF5- GluCTC (Aim 2), and define the viral component(s) contributing to ANG-mediated biogenesis of tRFs (Aim 3). Preliminary data suggest that the RSV proteins N and P will be a focus of Aims 2 and 3, respectively. The overall goal of this project is to use a combination of molecular virology, protein and RNA biochemistry, and cellular and structural biology techniques to elucidate tRF-mediated regulatory mechanisms for both RSV replication and the host responses it elicits. This novel regulation should provide a key new perspective on RSV-host interactions and undoubtedly facilitate the discovery of new gene regulatory mechanisms in response to RSV infection. Our results on antiviral target identification, targeting mechanisms, and tRF biogenesis will also provide new insights important for the design of preventive and therapeutic strategies for RSV infection. Given the early stage of studies on tRFs, the knowledge and techniques obtained in this study on tRF5-GluCTC will be important for exploring the functions of other tRFs in various biological systems, and therefore will broadly benefit the research community.

 描述（由适用提供）：关于小型非编码RNA（SNCRNA）的最新发现具有显着先进的人类遗传学和分子生物学，这在很大程度上是由于鉴定了SNCRNA作为基因调节剂的基本作用。 tRNA衍生的RNA片段（TRF）代表了一个最近发现的SncRNA家族，该家族迅速被认为是在从原核生物到人类的生物中普遍表达的。但是，TRF的生物学功能和基础的机制在很大程度上是未知的。呼吸突触病毒（RSV）是婴儿下呼吸道疾病的最常见原因。我们最近的出版物表明，RSV诱导的SNCRNA属于TRF家族。值得注意的是，至少两个最丰富的RSV诱导的TRF具有机械上与miRNA不同的基因反式函数，而这两个（称为TRF5-GLUCTC）中的一个促进了RSV复制，并在文字后水平上促进了基因。该TRF的生物发生也是特定的，并由特定的内切酶（血管葡萄蛋白，ANG）而不是其他核系统介导。但是，尚不清楚生物学功能和诱导生物学功能的分子机制。我们在该项目中的中心假设是RSV诱导的TRF5-Gluctc不是tRNA降解的随机副产品，而是对host-rsv相互作用很重要的功能分子。该项目将着重于探索TRF5-Gluctc对RSV复制的调节作用和宿主反应的调节作用的分子机制。我们的实验将确定在RSV感染的气道上皮细胞中TRF5-Gluctc的靶标（AIM 1），确定控制TRF5- GLUCTC的转置式活性的病毒因子（AIM 2）（AIM 2），并定义了导致TRF的Ang Ange GenofeS（SAIM）的病毒成分（S）。初步数据表明，RSV蛋白N和P分别是目标2和3的重点。该项目的总体目标是将分子病毒学，蛋白质和RNA生物化学以及细胞和结构生物学技术的结合使用，以阐明RSV复制及其宿主反应的TRF介导的调节机制。这种新颖的调节应为RSV-host相互作用提供一个关键的新观点，无疑支持发现新基因调节机制，以响应RSV感染。我们关于抗病毒靶标，靶向机制和TRF生物发生的结果 还将为设计RSV感染的预防和治疗策略的设计提供新的见解。鉴于对TRF的研究的早期阶段，这项研究中有关TRF5-GluctC获得的知识和技术对于探索各种生物系统中其他TRF的功能至关重要，因此将广泛地使研究界受益。