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.

有了这个奖项，化学部门的化学过程计划是为杜克大学的Amanda Hargrove教授提供资金，以通过开发新技术来调查监管RNA结构形状的关键差异。长期以来，分子生物学的中心教条表明，DNA代码为RNA，该RNA代码为蛋白质，然后执行细胞的重要功能。但是，人们对RNA本身在基本生物学中的功能的迅速欣赏。同时，需要新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，Hargrove及其同事开发了新技术，以使用基于模式的识别来满足这种需求，这与人类的口味相似，其中少数受体可以根据这些口味的成分与受体的不同相互作用，从而鉴定出广泛的口味。在此应用中，小有机分子用作评估RNA结构的不同“风味”的受体，并迅速揭示RNA的形状与其功能的对应。开发的分析将被广泛访问，以便将来对RNA功能基序的分类进行研究，并且小分子受体及其性能的库将是公开可用且可搜索的数据库。所产生的知识和技术为调节性RNA的结构和功能提供了新颖的基本发现，因此，分子生物学的核心教条影响了从环境到人类健康的生活的所有领域。这些创新的技术将不同传感的限制推向了结构生物学，从而掩盖了基于结构的其他生物百片分子的道路。这项研究与PI的教育计划集成到：1）在北卡罗来纳州的各种本科生和高中生中实施基于研究的实验和协作项目； 2）通过可访问的可视化和应用活动提高学生对非共价互动的理解； 3）向学生介绍化学和化学生物学的跨学科研究和现实应用； 4）增加学生参与STEM领域的研究。 PI的长期研究目标是建立针对RNA的小分子和蛋白质识别的指导原则，并将这些原理用于开发RNA结构和功能的化学问题。职业研究目标是利用可调节的小分子来开发延时和简单的技术，以阐明RNA识别和相关功能中的关键原理。功能性但非蛋白质编码RNA（NCRNA）序列的鉴定导致了分子生物学的革命，但围绕NCRNA分子功能的无数问题。这些知识差距包括NCRNA分子相互作用的驱动原理，尤其是三维形状的影响，以及这些相互作用如何指导NCRNA依赖性过程。 NCRNA生物化学的基本研究受到分子表征挑战的阻碍，包括确定3D RNA结构所需的密集时间和专业知识。拟议的工作使用最近在PI实验室中开发的技术解决了许多基本分子问题，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）不同的环境条件如何影响这种差异？ 4）基础修饰如何影响RNA识别？ 5）小分子的阵列可以以与蛋白质相当或更好的方式区分功能性RNA元件吗？这些新型的基于小分子的基于理解RNA识别的方法可以及时访问化学见解，这既揭示了小分子的基本原理：RNA识别和关键作用RNA在调节性的关键细胞功能中起着重要的作用，最终导致NCRNA领域的新知识，这反映了NSF的智力阶级的支持。标准。

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