Discovery and Function of Higher-Order RNA Structure

高阶RNA结构的发现和功能

• 批准号: 10220064
• 负责人: Kevin M Weeks
• 金额: $ 50.63万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-09 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10220064
• 关键词: Area; Automobile Driving; Base Pairing; Biological; Biological Process; Biology; Cells; Chemistry; Dengue; Ebola; Elements; Emerging Communicable Diseases; Encapsulated; Genome; Ligands; Messenger RNA; Methods; Pathogenicity; Proteins; RNA; RNA Viruses; RNA analysis; Role; Structural Protein; Structure; Technology; Translating; Untranslated RNA; Viral; Vision; Work; ZIKA; base; chikungunya; drug development; genetic regulatory protein; mammalian genome; new technology; novel; novel therapeutics; pathogenic virus; small molecule; viral RNA

SUMMARY RNA functions as the central conduit of information exchange in all cells, a role encapsulated in two critical observations. First, a large fraction of emerging infectious diseases are caused by RNA viruses including Ebola, Chikungunya, Zika, and Dengue. Second, a much larger fraction of the mammalian genome is transcribed into diverse kinds of non-coding RNAs (~70%) than is translated into protein (1- 2%). The functions of messenger, non-coding, and viral RNAs are governed by the linear sequence, base-paired secondary structure, higher-order tertiary structure, and quaternary interactions involving proteins and small molecules. Overall, our understanding of the number and complexity of RNA structures and how RNA structure drives diverse biological functions is very limited. Most methods developed to date for analyzing RNA structure in high-throughput ways do not measure structure in a definitive and accurate way, making it difficult to define broad principles for interrelationships between RNA structure and function. We seek to understand the fundamental roles of RNA structure in all areas of biology by pursuing a two-pronged approach involving (1) inventing, developing, and rigorously validating highly accurate chemistry-based technologies for discovery of novel RNA structures and the networks of interactions between RNAs and proteins and then (2) applying these technologies to problems of broad importance. Here we propose to interrogate the structures and interaction partners of the pathogenic Dengue RNA virus and the Xist long non-coding RNA. Throughout this work, we will focus on in-cell analysis of native viral and endogenous RNAs. This work is expected to have long-term impact for three broad reasons. First, RNA elements with higher-order folds and extensive protein networks are likely to be harbingers of function. Second, there are likely to be structural folds that are different from the relatively limited classes of structures that have been analyzed to date. Third, RNA elements with higher-order folds also contain clefts and crevices that are ideal targets for small- molecule ligands – and novel drugs – that modulate biological function by targeting RNA.

概括 RNA充当所有细胞中信息交换的中心管道，这一作用封装在两个细胞中 批判性观察。首先，大量的新兴传染病是由RNA病毒引起的 包括埃博拉病毒，奇肯尼亚，寨卡病毒和登革热。第二，哺乳动物的一小部分 基因组被转录为非编码RNA（约70％）的潜水员类型，而不是翻译成蛋白质（1- 2％）。信使，非编码和病毒RNA的功能由线性序列控制， 碱基对二级结构，高阶三级结构和涉及第四纪相互作用 蛋白质和小分子。总体而言，我们对RNA的数量和复杂性的理解 结构以及RNA结构如何驱动潜水员生物学功能非常有限。大多数方法 迄今为止开发用于以高通量方式分析RNA结构的开发 确定而准确的方式，使得很难为之间的相互关系定义广泛的原则 RNA结构和功能。我们试图了解所有领域RNA结构的基本作用 通过追求涉及（1）发明，发展和严格的两种供电方法，通过生物学 验证高度准确的基于化学的技术，以发现新的RNA结构和 RNA和蛋白质之间的相互作用网络，然后（2）将这些技术应用于 重要性的问题。在这里，我们建议询问结构和互动伙伴 致病性登革RNA病毒和XIST长的非编码RNA的通过这项工作，我们将 专注于对天然病毒和内源性RNA的细胞内分析。预计这项工作将有长期 影响有三个广泛的原因。首先，具有高阶折叠和广泛蛋白质的RNA元素 网络可能是功能的预兆。其次，可能有结构折叠 与迄今已分析的相对有限类别的结构不同。第三，RNA 具有高阶折叠的元素还包含裂缝和缝隙，这是小型的理想目标 分子配体和新型药物 - 通过靶向RNA调节生物学功能。