Collaborative Research: Uncovering How Riboswitches Exploit Out-of-Equilibrium RNA Folding Pathways to Make Genetic Decisions

合作研究:揭示核糖开关如何利用非平衡 RNA 折叠途径做出遗传决策

基本信息

  • 批准号:
    1914596
  • 负责人:
  • 金额:
    $ 15.45万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
    Continuing Grant
  • 财政年份:
    2019
  • 资助国家:
    美国
  • 起止时间:
    2019-08-15 至 2023-07-31
  • 项目状态:
    已结题

项目摘要

This work will uncover new principles by which riboswitch RNAs exploit out-of-equilibrium RNA folding and ligand binding to make genetic decisions. The tools developed will also be applicable to understanding the role of co-transcriptional folding and assembly of ribozymes, regulatory RNA structures within non-coding and coding RNAs, and assembly of RNA-protein complexes such as the ribosome and spliceosome. These studies will also contribute understanding of the physical principles of out-of- equilibrium co-transcriptional RNA folding, help address long-standing questions about how dynamic RNA structures coordinate genetic processes, and shed light on how natural RNAs exploit out-of- equilibrium mechanisms to efficiently fold on extremely rugged free-energy landscapes. Since co-transcriptional RNA folding happens every time an RNA is synthesized, the broader impacts of this research include developing general principles and techniques that can be used to understand a wide array of fundamental cellular processes from gene expression to regulation. The study of riboswitches also has several broader impacts towards societal goals, since they can be used as biosensors within new molecular diagnostics, and they are important targets for new classes of antibiotics. Broader impacts of integrated research and education will come from a multi-pronged plan including conducting demonstrations of riboswitch diagnostics to school-age groups, mentorship of undergraduate researchers, and delivering hands-on tutorials of computational RNA folding approaches to broader scientific communities.The overarching goals of this proposal are to: (i) Uncover detailed mechanisms of how ligand binding bifurcates out-of-equilibrium RNA cotranscriptional folding pathways to enact genetic decisions in riboswitch RNAs; and (ii) Develop and apply new hybrid experimental-computational frameworks that can reconstruct RNA cotranscriptional folding pathways at the secondary and tertiary structure levels. The education plan focuses on integrating this research into hands-on demonstration activities targeted towards school age children, undergraduate researcher mentorship, and hands-on training tutorials for the broader scientific community. The post-genomic era has ushered in a new appreciation that RNAs play central roles in regulating, maintaining and defending the genomes of all organisms. However, a critical knowledge gap remains: we have relatively little understanding of the dynamic folding pathways that RNAs undergo as they are being synthesized during transcription, thus hindering our fundamental understanding of how RNA structures enact critical cellular functions such as catalysis, gene expression regulation, and cellular sensing. To address this gap, the PIs recently innovated and validated a hybrid experimental-computational approach that uses high-throughput RNA structure chemical probing data with computational algorithms to generate two and three-dimensional models of RNA cotranscriptional folding pathways. One central objective of this proposal is to extend this approach to incorporate more complex RNA structures and interactions such as pseudoknots relevant to a broad range of functional cellular RNAs. The second is to uncover biophysical principles of how out-of-equilibrium RNA fluctuations during cotranscriptional folding influence RNA function. The latter will be pursued through the use of riboswitch RNAs as model systems, which make ligand-mediated genetic decisions, use the dynamic formation of broadly utilized RNA structures to do so, and have broader impact relevance for fundamental biology and biotechnologies.This project is being jointly supported by the Physics of Living Systems program in the Division of Physics and the Molecular Biophysics program in the Division of Molecular and Cellular Biosciences.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.
这项工作将揭示核糖开关RNA利用失衡RNA折叠和配体结合来做出遗传决策的新原理。开发的工具也将适用于理解的作用,共转录折叠和组装的核酶,非编码和编码RNA内的调控RNA结构,以及装配的RNA-蛋白质复合物,如核糖体和剪接体。这些研究还将有助于理解失衡共转录RNA折叠的物理原理,帮助解决长期存在的关于动态RNA结构如何协调遗传过程的问题,并阐明天然RNA如何利用失衡机制在极其崎岖的自由能景观上有效折叠。由于每次合成RNA时都会发生共转录RNA折叠,因此这项研究的更广泛影响包括开发可用于理解从基因表达到调控的各种基本细胞过程的一般原理和技术。核糖开关的研究也对社会目标产生了一些更广泛的影响,因为它们可以在新的分子诊断中用作生物传感器,并且它们是新型抗生素的重要靶标。综合研究和教育的更广泛的影响将来自一个多管齐下的计划,包括对学龄组进行核糖开关诊断的演示,对本科研究人员的指导,以及向更广泛的科学界提供计算RNA折叠方法的实践教程。(i)揭示配体结合如何分叉失衡RNA共转录折叠途径以在核糖开关RNA中制定遗传决策的详细机制;和(ii)开发和应用新的混合实验-计算框架,可以在二级和三级结构水平上重建RNA共转录折叠途径。教育计划的重点是将这项研究纳入针对学龄儿童的实践演示活动,本科研究人员指导,以及更广泛的科学界的实践培训教程。后基因组时代带来了一种新的认识,即RNA在调节、维持和保护所有生物体的基因组方面发挥着核心作用。然而,一个关键的知识差距仍然存在:我们对RNA在转录过程中合成时所经历的动态折叠途径的了解相对较少,从而阻碍了我们对RNA结构如何发挥关键细胞功能(如催化,基因表达调控和细胞传感)的基本理解。为了解决这一差距,PI最近创新并验证了一种混合实验-计算方法,该方法使用高通量RNA结构化学探测数据和计算算法来生成RNA共转录折叠途径的二维和三维模型。该提案的一个中心目标是扩展这种方法以纳入更复杂的RNA结构和相互作用,例如与广泛的功能性细胞RNA相关的假结。第二个目标是揭示在共转录折叠过程中失衡的RNA波动如何影响RNA功能的生物物理学原理。后者将通过使用核糖开关RNA作为模型系统来实现,该系统做出配体介导的遗传决策,利用广泛使用的RNA结构的动态形成来实现这一目标,该项目由物理学系生命系统物理学项目和分子生物物理学系分子生物物理学项目联合支持,细胞生物科学。该奖项反映了NSF的法定使命,并被认为值得通过使用基金会的知识价值和更广泛的影响审查标准进行评估。

项目成果

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Alan Chen其他文献

Seat-Belt Use In US Counties: Limited Progress Toward Healthy People 2020 Objectives.
美国各县的安全带使用情况:实现 2020 年健康人民目标的进展有限。
  • DOI:
  • 发表时间:
    2017
  • 期刊:
  • 影响因子:
    9.7
  • 作者:
    Jacob E. Sunshine;L. Dwyer;Alan Chen;A. Mokdad
  • 通讯作者:
    A. Mokdad
Autonomous Helicopter Tracking and Localization Using a Self-surveying Camera Array
使用自测相机阵列进行自主直升机跟踪和定位
711: AUTOLOGOUS INTERNAL RECIRCULATION OF DISTAL INTESTINAL CONTENT MITIGATES LIVER AND GUT INJURY IN A NOVEL PIGLET SHORT BOWEL SYNDROME MODEL
  • DOI:
    10.1016/s0016-5085(22)60430-x
  • 发表时间:
    2022-05-01
  • 期刊:
  • 影响因子:
  • 作者:
    Chelsea Hutchinson;Johan van Nispen;Ashish Samaddar;Marcus Voigt;Mustafa Nazzal;Aakash Nagarapu;Alan Chen;Jeffery Bettag;Joseph R. Krebs;John Long;Sonali Jain;Chandrashekhara Manithody;Ajay K. Jain
  • 通讯作者:
    Ajay K. Jain
Home Treatment – das virtuelle Bett
家庭治疗 – das Virdlle Bett
  • DOI:
    10.1007/s15016-016-5600-x
  • 发表时间:
    2016
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Bryana L. Schantz;Emma R. Toner;Mackenzie L. Brown;Nikki Kaiser;Alan Chen;S. Adhikari;S. Hoeppner;Eric Bui;Naomi M. Simon;K. Szuhany
  • 通讯作者:
    K. Szuhany
EP1212: A HISTOPATHOLOGICAL ASSESSMENT OF TOTAL PARENTERAL NUTRITION DRIVEN IMMUNE DYSFUNCTION IN A NOVEL NEONATAL PIG MODEL
  • DOI:
    10.1016/s0016-5085(22)63773-9
  • 发表时间:
    2022-05-01
  • 期刊:
  • 影响因子:
  • 作者:
    Alan Chen;Chelsea Hutchinson;Sherri Besmer;Stephen Bruno;Aakash Nagarapu;Maurya Akula;Trent Davids;Akhil Kumar;Loren Po;Megan Tersteeg;Taylor Soukup;Sonali Jain;John Long;Ajay K. Jain
  • 通讯作者:
    Ajay K. Jain

Alan Chen的其他文献

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{{ truncateString('Alan Chen', 18)}}的其他基金

CAREER: Predicting high-resolution RNA tertiary structures using an experimentally callibrated force-field for RNA folding
职业:使用实验校准的 RNA 折叠力场预测高分辨率 RNA 三级结构
  • 批准号:
    1651877
  • 财政年份:
    2017
  • 资助金额:
    $ 15.45万
  • 项目类别:
    Continuing Grant

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Cell Research
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Cell Research
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    2010
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Cell Research (细胞研究)
  • 批准号:
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    2008
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    专项基金项目
Research on the Rapid Growth Mechanism of KDP Crystal
  • 批准号:
    10774081
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    2007
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    45.0 万元
  • 项目类别:
    面上项目

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