Molecular Determinants of Regulatory Hierarchy for Bacterial Small RNAs
细菌小RNA调控层次的分子决定因素
基本信息
- 批准号:9900794
- 负责人:
- 金额:$ 31.72万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-08-01 至 2022-03-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAffinityBacterial PhysiologyBase PairingBindingBiochemicalCell physiologyDataDevelopmentEscherichia coliFoundationsGene ExpressionGene Expression RegulationGenesGenetic TranscriptionGenetic TranslationGenomicsGoalsHealthHomeostasisHumanImageIndividualIronKineticsLightMapsMediatingMessenger RNAMetabolic stressMetabolismMethodsMicrobeModelingMolecularOutcomePhenotypePhysiologicalPlayPoriferaProcessRNARNA BindingRegulationRegulonResearchResistanceResolutionRibosomal RNARoleSignal TransductionSmall RNAStarvationStressTechniquesTestingTransfer RNATranslational RegulationTranslationsVirulenceWorkbacterial fitnessbasebiological adaptation to stresscombatcommensal bacteriagenome-wide analysisimaging platformin vivo ModelinnovationinsightmRNA StabilitymRNA Transcript Degradationnovelnovel therapeutic interventionpathogenpathogenic bacteriaresponsescreeningsugar
项目摘要
PROJECT SUMMARY
Small RNAs (sRNAs) are numerous and carry out intricate regulatory mechanisms, yet their specific roles in
bacterial physiology and virulence remain by and large mysterious. Our previous work with two model E. coli
sRNAs, SgrS and RyhB, shed light on some of the roles played by sRNAs in bacterial physiology and stress
responses and uncovered novel molecular mechanisms of regulation. We showed that a single sRNA can
base pair with numerous mRNA targets, and promote the rapid degradation of these mRNAs, with important
consequences for key processes including sugar transport and metabolism (SgrS) and iron homeostasis
(RyhB). We defined a novel class of competitors, so-called “sponge” RNAs that bind and modulate the ability of
sRNAs to regulate their mRNA targets. In the current proposal, we build on these preliminary studies to
address several questions with broad relevance to the sRNA field. 1) What kinetic parameters define sRNA
interactions with their targets? Our preliminary data indicate that for SgrS, the target search (where the
sRNA finds the appropriate target) is rate limiting and that this parameter is quantitatively different for each
distinct sRNA-target interaction. In Aim 1, we will use a novel super-resolution imaging platform that we
developed to further interrogate SgrS and RyhB interactions with target mRNAs and define general principles
governing sRNA-mRNA interactions. 2) How do sponge RNAs affect the regulatory efficiency of an sRNA
on many different targets? Regulation by sRNAs varies from strong effects on some targets to weak effects
on other targets. This sets up a regulatory hierarchy that we propose is central to sRNA-mediated control of
bacterial stress responses. In Aim 2, we use quantitative parameters defining sRNA regulatory efficiency and
determine how these parameters are impacted by the presence and absence of sponge RNAs, which compete
with mRNAs for binding to sRNAs. 3) What are the physiological impacts of sponge-mediated regulation
of sRNA activity and how prevalent is this level of control? Our preliminary data suggest that sponge
RNAs help tune sRNA activity so that sRNAs are only able to act on target mRNAs under the appropriate
stress conditions. Though very few have been discovered, we postulate that sponge RNAs are abundant, and
that they may be widely used to control many bacterial sRNAs. In Aim 3, we will address both of these issues
by examining the physiological consequences of sponge-mediated control of both SgrS and RyhB activity and
by conducting genome-wide analyses to identify and characterize novel targets and sponge RNAs for a variety
of bacterial sRNAs. The diverse set of techniques that we have developed and optimized will allow us to
interrogate sRNA interactions with target mRNAs on a global scale and at the level of single RNA molecules.
This will allow us to generate quantitative models for in vivo regulation by sRNAs and elucidate an extensive
sRNA regulatory network to produce an sRNA interaction map of greater precision than ever before.
项目摘要
小RNA(sRNA)数量众多,并执行复杂的调控机制,但它们在细胞内的特定作用,
细菌的生理学和毒性大体上仍然是个谜。我们以前的工作与两个模型E。杆菌
sRNAs,SgrS和RyhB,揭示了sRNAs在细菌生理学和应激中所起的一些作用
反应和发现新的分子调控机制。我们发现单个sRNA可以
与许多mRNA靶点配对,并促进这些mRNA的快速降解,
对糖转运和代谢(SgrS)和铁稳态等关键过程的影响
(RyhB).我们定义了一类新的竞争者,即所谓的“海绵”RNA,它们结合并调节蛋白质的表达能力。
sRNAs调节其mRNA靶点。在目前的建议中,我们在这些初步研究的基础上,
解决与sRNA领域广泛相关的几个问题。1)什么动力学参数定义sRNA
与目标的互动?我们的初步数据表明,对于SgrS,目标搜索(其中
sRNA找到合适的靶标)是速率限制性的,并且该参数对于每一种sRNA来说在数量上是不同的。
不同的sRNA-target相互作用。在Aim 1中,我们将使用一种新型的超分辨率成像平台,
开发用于进一步询问SgrS和RyhB与靶mRNA的相互作用并定义一般原则
控制sRNA-mRNA相互作用。2)海绵RNA如何影响sRNA的调节效率
针对不同的目标sRNA的调节作用从对某些靶点的强作用到弱作用不等
其他目标。这建立了一个调控层次,我们认为这是sRNA介导的控制的核心。
细菌应激反应在目标2中,我们使用定义sRNA调控效率的定量参数,
确定这些参数如何受到海绵RNA的存在和不存在的影响,
用mRNA与sRNA结合。3)海绵介导的调节有哪些生理影响
以及这种控制水平有多普遍?我们的初步数据显示海绵
RNA有助于调节sRNA活性,使得sRNA仅能够在适当的条件下作用于靶mRNA。
应力条件虽然很少被发现,我们假设海绵RNA是丰富的,
它们可以广泛用于控制许多细菌sRNA。在目标3中,我们将解决这两个问题
通过检查海绵介导的SgrS和RyhB活性控制的生理后果,
通过进行全基因组分析,以确定和表征各种新的靶标和海绵RNA,
细菌sRNAs的。我们开发和优化的各种技术将使我们能够
在全球范围内和单个RNA分子水平上询问sRNA与靶mRNA的相互作用。
这将使我们能够生成sRNA体内调控的定量模型,并阐明广泛的
sRNA调控网络,以产生比以往任何时候都更精确的sRNA相互作用图。
项目成果
期刊论文数量(20)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
MS2-Affinity Purification Coupled with RNA Sequencing in Gram-Positive Bacteria.
MS2 亲和纯化与革兰氏阳性细菌中的 RNA 测序相结合。
- DOI:10.3791/61731
- 发表时间:2021
- 期刊:
- 影响因子:0
- 作者:Mercier,Noémie;Prévost,Karine;Massé,Eric;Romby,Pascale;Caldelari,Isabelle;Lalaouna,David
- 通讯作者:Lalaouna,David
Molecular call and response: the physiology of bacterial small RNAs.
- DOI:10.1016/j.bbagrm.2011.07.013
- 发表时间:2011-10
- 期刊:
- 影响因子:4.7
- 作者:Richards, Gregory R.;Vanderpool, Carin K.
- 通讯作者:Vanderpool, Carin K.
Small RNA-mediated activation of sugar phosphatase mRNA regulates glucose homeostasis.
- DOI:10.1016/j.cell.2013.03.003
- 发表时间:2013-04-11
- 期刊:
- 影响因子:64.5
- 作者:Papenfort K;Sun Y;Miyakoshi M;Vanderpool CK;Vogel J
- 通讯作者:Vogel J
A Prophage-Encoded Small RNA Controls Metabolism and Cell Division in Escherichia coli.
- DOI:10.1128/msystems.00021-15
- 发表时间:2016-01
- 期刊:
- 影响因子:6.4
- 作者:Balasubramanian D;Ragunathan PT;Fei J;Vanderpool CK
- 通讯作者:Vanderpool CK
The small RNA SgrS controls sugar-phosphate accumulation by regulating multiple PTS genes.
- DOI:10.1093/nar/gkq1219
- 发表时间:2011-05
- 期刊:
- 影响因子:14.9
- 作者:Rice JB;Vanderpool CK
- 通讯作者:Vanderpool CK
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Carin K Vanderpool其他文献
Carin K Vanderpool的其他文献
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{{ truncateString('Carin K Vanderpool', 18)}}的其他基金
Analysis of the Molecular Determinants of Regulatory Hierarchy of a Bacterial Sma
细菌 Sma 调控层次的分子决定因素分析
- 批准号:
8708113 - 财政年份:2010
- 资助金额:
$ 31.72万 - 项目类别:
Analysis of the Molecular Determinants of Regulatory Hierarchy of a Bacterial Sma
细菌 Sma 调控层次的分子决定因素分析
- 批准号:
8115806 - 财政年份:2010
- 资助金额:
$ 31.72万 - 项目类别:
Analysis of the Molecular Determinants of Regulatory Hierarchy of a Bacterial Sma
细菌 Sma 调控层次的分子决定因素分析
- 批准号:
8309247 - 财政年份:2010
- 资助金额:
$ 31.72万 - 项目类别:
Analysis of the Molecular Determinants of Regulatory Hierarchy of a Bacterial Sma
细菌 Sma 调控层次的分子决定因素分析
- 批准号:
8514636 - 财政年份:2010
- 资助金额:
$ 31.72万 - 项目类别:
Analysis of the Molecular Determinants of Regulatory Hierarchy of a Bacterial Sma
细菌 Sma 调控层次的分子决定因素分析
- 批准号:
7862045 - 财政年份:2010
- 资助金额:
$ 31.72万 - 项目类别:
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