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CAREER: Shape-based differentiation of RNA elements using small molecules

职业：使用小分子对 RNA 元件进行基于形状的区分

基本信息

批准号：
1750375
负责人：
Amanda Hargrove
金额：
$ 65万
依托单位：
Duke University
依托单位国家：
美国
项目类别：
Standard Grant
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-01 至 2024-05-31
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1750375&HistoricalAwards=false
关键词：
CAREER Shape based differentiation RNA

项目摘要

With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Professor Amanda Hargrove of Duke University to investigate critical differences in the shape of regulatory RNA structures through the development of novel technologies. The central dogma of molecular biology has long stated that DNA codes for RNA, which codes for protein, which then carries out a cell's important functions; but there is a rapidly growing appreciation for the functions of RNA itself in fundamental biology. At the same time, there is a pressing need for new techniques to investigate these functions, including how RNA interacts with other molecules. In this work, Hargrove and coworkers develop new technology to meet this need using pattern-based recognition, which is similar to human's sense of taste, wherein a handful of receptors can identify a wide range of flavors based on how the components of those flavors differentially interact with the receptors. In this application, small organic molecules are used as receptors to evaluate different "flavors" of RNA structure and rapidly reveal how the shape of RNA corresponds to its function. The assay developed will be widely accessible for future investigations into the classification of RNA functional motifs, and the library of small molecule receptors and their properties will be a publicly available and searchable database. The knowledge and technology produced provide the basis for novel, fundamental discoveries into the structure and function of regulatory RNAs and thus, the central dogma of molecular biology, which impacts all areas of life, from the environment to human health. These innovative technologies push the limits of differential sensing to include structural biology, paving the way for the structure-based classification of additional biomacromolecules. This research integrates with the educational plans of the PI to: 1) implement research-based experiments and collaborative projects among diverse undergraduate and high school students throughout North Carolina; 2) increase student understanding of noncovalent interactions via accessible visualization and application activities; 3) introduce students to interdisciplinary research and real-world applications of chemistry and chemical biology; and 4) increase student engagement in the study of STEM fields. The long-term research goal of the PI is to establish guiding principles for small molecule and protein recognition of RNA and to use these principles for the development of chemical probes for RNA structure and function. The CAREER research objective is to draw upon exquisitely tunable small molecules to develop timesaving and simple technologies that elucidate critical principles in RNA recognition and related function. The identification of functional yet non-protein coding RNA (ncRNA) sequences has led to a revolution in molecular biology, yet myriad questions surround the molecular function of ncRNA. These knowledge gaps include the driving principles behind ncRNA molecular interactions, particularly the influence of three-dimensional shape, and how these interactions guide ncRNA-dependent processes. Fundamental investigations of ncRNA biochemistry are hindered by challenges in molecular characterization, including the intensive time and expertise required to determine 3D RNA structure. Using techniques recently developed in the lab of the PI, the proposed work addresses a number of fundamental molecular questions, including: 1) How does shape influence small molecule:RNA recognition? 2) What RNA structural elements can small molecule receptors differentiate? 3) How do varying environmental conditions impact this differentiation? 4) How do base modifications influence RNA recognition? 5) Can arrays of small molecules differentiate functional RNA elements in a manner comparable to or better than proteins? These novel, small molecule-based methods for understanding RNA recognition provide ready access to chemical insights that reveal both the fundamental principles of small molecule:RNA recognition and the pivotal role RNA shape plays in regulating key cellular functions, ultimately leading to new knowledge in the ncRNA field.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

通过这一奖项，化学系的生命过程化学项目资助杜克大学的Amanda Hargrove教授通过开发新技术来研究调控RNA结构形状的关键差异。长期以来，分子生物学的中心教条一直认为，DNA编码RNA，而RNA编码蛋白质，然后蛋白质执行细胞的重要功能；但人们对RNA本身在基础生物学中的功能的认识正在迅速增长。与此同时，迫切需要新的技术来研究这些功能，包括RNA如何与其他分子相互作用。在这项工作中，哈格罗夫和他的同事开发了一种新技术，利用基于模式的识别来满足这一需求，这种识别类似于人类的味觉，其中少数几个感受器可以根据这些味道的成分与感受器的不同相互作用来识别各种味道。在这一应用中，有机小分子被用作受体来评估RNA结构的不同“味道”，并快速揭示RNA的形状如何与其功能相对应。开发的分析方法将广泛用于未来对RNA功能基序分类的研究，小分子受体及其性质的库将成为一个公开可用和可搜索的数据库。产生的知识和技术为对调控RNA的结构和功能的新的基本发现提供了基础，从而成为影响从环境到人类健康的所有生活领域的分子生物学的中心教条。这些创新技术将差异传感的极限推向了结构生物学，为更多生物大分子的基于结构的分类铺平了道路。这项研究与PI的教育计划相结合，以：1)在北卡罗来纳州不同的本科生和高中生中实施研究型实验和合作项目；2)通过可访问的可视化和应用活动增加学生对非共价相互作用的理解；3)向学生介绍化学和化学生物学的跨学科研究和现实世界应用；以及4)增加学生对STEM领域的研究。PI的长期研究目标是建立小分子和蛋白质识别RNA的指导原则，并将这些指导原则用于开发RNA结构和功能的化学探针。该职业的研究目标是利用微妙可调的小分子来开发节省时间和简单的技术，阐明RNA识别和相关功能的关键原理。功能但非蛋白质编码的RNA(NcRNA)序列的鉴定引发了分子生物学的一场革命，然而ncRNA的分子功能却存在着无数的问题。这些知识差距包括ncRNA分子相互作用背后的驱动原理，特别是三维形状的影响，以及这些相互作用如何指导ncRNA依赖的过程。NcRNA生物化学的基础研究受到分子表征方面的挑战的阻碍，包括确定3D RNA结构所需的密集时间和专业知识。利用PI实验室最近开发的技术，这项拟议的工作解决了许多基本的分子问题，包括：1)形状如何影响小分子：RNA识别？2)小分子受体可以区分哪些RNA结构元素？3)变化的环境条件如何影响这种分化？4)碱基修饰如何影响RNA识别？5)小分子阵列能否以与蛋白质相当或更好的方式区分功能RNA元素？这些新的、基于小分子的理解RNA识别的方法提供了随时获取化学见解的途径，揭示了小分子的基本原理：RNA识别和RNA形状在调节关键细胞功能中所起的关键作用，最终导致了ncRNA领域的新知识。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

R-BIND 2.0: An Updated Database of Bioactive RNA-Targeting Small Molecules and Associated RNA Secondary Structures.

DOI：
10.1021/acschembio.2c00224
发表时间：
2022-06-17
期刊：
ACS CHEMICAL BIOLOGY
影响因子：
4
作者：
Donlic, Anita;Swanson, Emily G.;Chiu, Liang-Yuan;Wicks, Sarah L.;Juru, Aline Umuhire;Cai, Zhengguo;Kassam, Kamillah;Laudeman, Chris;Sanaba, Bilva G.;Sugarman, Andrew;Han, Eunseong;Tolbert, Blanton S.;Hargrove, Amanda E.
通讯作者：
Hargrove, Amanda E.

Driving factors in amiloride recognition of HIV RNA targets