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充当所有细胞中信息交换的中心管道。 RNA分子编码此在其主要序列和复杂的结构中，当RNA折叠后形成的复杂结构中的信息本身。迄今为止，我们由Mira支持的工作中的一个一致的主题是介导的生物功能通过RNA结构在真菌和真核生物中无处不在。宽阔和 RNA结构的基本重要性很明显，但是仍然存在深刻的知识差距：我们通常只有对大多数广阔地区RNA结构的基本理解 Messenger和非编码RNA。我们需要超越建模RNA结构到直接检测通过空间结构通信和细胞中的相互作用。我们的实验室几乎很独特方法，轻松专注于实验性的简单性和直接性，并广泛地关注模型系统中的验证。在本质上，我们应用严格和研究RNA结构 - 函数相互关系的定量技术，有关的新见解已经出现了生物调节机制。我们还表明，具有较高的RNA元素订单结构更有可能包含较小的高信息包含裂缝和口袋分子，广泛地告知了一个易于RNA靶向的药物发现。这项工作旨在通过寻求三个总体机会，从而持续了长期影响。首先，该项目重点关于果断，简洁和可广泛实施技术的开发，以发现和评估RNA中的高阶结构。其次，该项目在实验中采用这些直接和实验简洁的方法是从确定必不可少的结构来挑战的挑战病原病毒的复制以了解RNA构象如何控制转录基因调控和前mRNA剪接。第三，了解RNA对形成高阶结构，通常是裂缝和口袋 - 打开了针对这些的可能性带有小分子的图案，我们将以发明便利和的长期目标利用机会创建靶向RNA的疗法的直接策略。

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。