Discovery and Function of Higher-Order RNA Structure

高阶RNA结构的发现和功能

基本信息

批准号：
10727073
负责人：
Kevin M Weeks
金额：
$ 7.66万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-06-09 至 2027-05-31
项目状态：
未结题

项目摘要

SUMMARY RNA functions as the central conduit of information exchange in all cells. RNA molecules encode this information in both their primary sequences and in complex structures that form when RNA folds back on itself. A consistent theme from our MIRA-supported work to date is that biological function mediated by RNA structure is ubiquitous in both eubacterial and eukaryotic organisms. The broad and fundamental importance of RNA structure is clear, but there remains a profound knowledge gap: We generally have only rudimentary understanding of RNA structure across vast regions of most messenger and non-coding RNAs. We need to move beyond modeling RNA structure to directly detecting through-space structural communication and interactions in cells. Our lab takes a near-unique approach, simultaneously focusing on experimental simplicity and directness and on extensive validation in model systems. In essentially every instance where we have applied rigorous and quantitative technologies to study RNA structure-function interrelationships, new insights regarding biological regulatory mechanisms have emerged. We have also shown that RNA elements with higher- order structures are more likely to contain high-information-content clefts and pockets that bind small molecules, broadly informing a vigorous field of RNA-targeted drug discovery. This work is designed to have sustained long-term impact by pursuing three overarching opportunities. First, the project focuses on development of decisive, concise, and broadly implementable technologies for discovering and assessing higher-order structure in RNA. Second, this project applies these direct and experimentally concise methods to challenges of broad importance, from identification of structures essential for replication of pathogenic viruses to understanding how RNA conformational ensembles govern transcriptional gene regulation and pre-mRNA splicing. Third, understanding the propensity of RNA to form higher-order structures – and often clefts and pockets – opens up the possibility of targeting these motifs with small molecules, an opportunity we will exploit with the long-term goal of inventing facile and straightforward strategies for creating RNA-targeted therapeutics.

概括 RNA 是所有细胞中信息交换的中心管道，RNA 分子对此进行编码。其初级序列和 RNA 折叠时形成的复杂结构中的信息迄今为止，我们 MIRA 支持的工作的一个一致主题是生物功能介导。 RNA结构在真细菌和真核生物中普遍存在。 RNA 结构的根本重要性是显而易见的，但仍然存在深刻的知识差距：我们通常对大多数生物体广大区域的RNA结构只有初步的了解我们需要超越 RNA 结构建模，直接建模。我们的实验室采用了近乎独特的方法来检测细胞中的空间结构通讯和相互作用。方法，同时注重实验的简单性和直接性以及广泛性模型系统中的验证基本上在我们应用严格和可靠的每个实例中。研究 RNA 结构与功能相互关系的技术、新的定量见解我们还发现，RNA 元件具有更高的生物调节机制。秩序结构更有可能包含高信息含量的裂缝和口袋，这些裂缝和口袋结合小这项工作旨在为 RNA 靶向药物发现的蓬勃发展领域提供广泛的信息。通过追求三个总体机会来产生持续的长期影响首先，该项目的重点是。开发决定性的、简洁的和广泛可实施的技术来发现和其次，该项目通过实验直接应用这些结构。简明的方法应对广泛重要的挑战，从识别必要的结构开始致病病毒的复制以了解 RNA 构象集合如何控制第三，了解 RNA 的倾向。形成高阶结构——通常是裂缝和口袋——开启了针对这些结构的可能性具有小分子的基序，我们将利用这个机会来实现发明简单且易于使用的长期目标创建 RNA 靶向疗法的简单策略。

项目成果

期刊论文数量（23）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Piercing the fog of the RNA structure-ome.

DOI：
10.1126/science.abk1971
发表时间：
2021-08-27
期刊：
Science (New York, N.Y.)
影响因子：
0
作者：
Weeks KM
通讯作者：
Weeks KM

Pervasive Regulatory Functions of mRNA Structure Revealed by High-Resolution SHAPE Probing.

DOI：
10.1016/j.cell.2018.02.034
发表时间：
2018-03-22
期刊：
Cell
影响因子：
64.5
作者：
Mustoe AM;Busan S;Rice GM;Hajdin CE;Peterson BK;Ruda VM;Kubica N;Nutiu R;Baryza JL;Weeks KM
通讯作者：
Weeks KM

Visualization of lncRNA and mRNA Structure Models Within the Integrative Genomics Viewer.

综合基因组学查看器中 lncRNA 和 mRNA 结构模型的可视化。