Developing novel technologies to address fundamental questions about second messenger signaling
开发新技术来解决有关第二信使信号传导的基本问题
基本信息
- 批准号:9296950
- 负责人:
- 金额:$ 7.22万
- 依托单位:
- 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:2017-01-01 至 2018-12-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAdenosine MonophosphateAreaBacteriaBacterial PhysiologyBehaviorBiological ProcessBiosensorCellsChemicalsChemotaxisCollaborationsCommunitiesCore FacilityCuesCyclic AMPCyclic GMPCytosineDetectionDevelopmentEnvironmentEquilibriumEukaryotaEukaryotic CellExhibitsExplosionFlow CytometryFluorescence MicroscopyGene Expression RegulationGenomicsGrantGuanosineGuanosine MonophosphateHeterogeneityHome environmentIcebergIntracellular Second MessengerLaboratoriesLifeLife StyleLiquid ChromatographyMass Spectrum AnalysisMeasurementMeasuresMetalsMethodsMichiganMicrobial BiofilmsMicrobiologyMolecularNamesNucleotidesNutrientPathway interactionsPentasPeriodicityPhenotypePhylogenetic AnalysisPlayPopulationPositioning AttributeProtocols documentationPublishingPyrimidineRNARenaissanceReporterRepressionResearchRibonucleotidesRoleSecond Messenger SystemsSensitivity and SpecificitySignal TransductionSignaling MoleculeSourceSystemTechnologyTestingTransfer RNATreesUniversitiesUridine MonophosphateVariantbasecell motilityenvironmental changegenetic elementinorganic phosphateinterestmechanotransductionnew technologynovelresponsesensorsingle cell technologytandem mass spectrometrytranscription factor
项目摘要
Developing technologies to address fundamental questions about second messenger signaling
Summary
Microbiology has witnessed a renaissance in the field of nucleotide-derived second messenger signaling during
the last decade. These intracellular signal molecules allow bacteria to sense and adapt to changing
environmental conditions. The second messengers cyclic adenosine monophosphate (cAMP) and guanosine
penta/tetra phosphate (p/ppGpp) have long been studied for their roles in gene regulation, catabolite repression,
and the stringent response. However, the appreciation for another second messenger, cyclic diguanosine
monophosphate (c-di-GMP) and its role in motility and biofilm formation has recently exploded. Moreover, three
new bacterial second messengers (cyclic diadenosine monophosphate (c-di-AMP), cyclic guanosine
monophosphate (cGMP), and now cyclic GMP-AMP (cGAMP)) have been recently discovered in bacteria. It is
clear that cAMP and p/ppGpp were merely the tip of the proverbial second messenger iceberg. Growing evidence
in eukaryotes suggests that the pyrimidine ribonucleotide derivatives, cyclic cytosine monophosphate (cCMP)
and cyclic uridine monophosphate (cUMP), can be detected and have biological functions, but these signals
have not been detected or studied in bacteria. With this recent explosion of interest in second messengers, there
remains fundamental questions to be addressed, and this proposal will test two novel hypotheses about second
messenger signaling in bacteria. First, we hypothesize that bacteria utilize pyrimidine-derived second
messengers. My laboratory has developed rapid, sensitive liquid chromatography tandem mass spectrometry
(LC-MS/MS) methods to quantify c-di-GMP, c-di-AMP, and pGpG (the breakdown product of c-di-GMP) in over
twenty bacterial species using the world-class mass spectrometry core facility at Michigan State University. In
this grant, we propose to develop LC-MS/MS protocols to quantify all known nucleotide-derived second
messengers and the novel pyrimidine second messengers cCMP, cUMP, and c-di-UMP. We will then extract
nucleotides from different bacterial species across the bacterial phylogenetic tree and measure the presence
and concentration of these nucleotide-based second messengers. Our second hypothesis is that c-di-GMP
displays phenotypic heterogeneity in bacterial populations. This hypothesis will be tested by developing species-
specific RNA biosensors to quantify c-di-GMP in diverse bacteria at the single-cell level. This proposal will test
fundamental hypotheses about bacterial second messenger signaling and develop new LC-MS/MS and single-
cell reporter technologies that will catalyze new areas of bacterial second messenger research.
开发技术来解决有关第二信使信号传导的基本问题
概括
微生物学见证了核苷酸衍生的第二信使信号传导领域的复兴
过去十年。这些细胞内信号分子使细菌能够感知并适应变化
环境条件。第二信使环磷酸腺苷(cAMP)和鸟苷
五磷酸/四磷酸 (p/ppGpp) 长期以来一直在研究其在基因调控、分解代谢物抑制、
以及严厉的回应。然而,另一种第二信使环二鸟苷的升值
单磷酸盐(c-di-GMP)及其在运动和生物膜形成中的作用最近得到了爆发。此外,三
新的细菌第二信使(环二腺苷一磷酸(c-di-AMP)、环鸟苷
最近在细菌中发现了单磷酸盐 (cGMP),以及现在的环 GMP-AMP (cGAMP)。这是
显然,cAMP 和 p/ppGpp 只是众所周知的第二信使冰山一角。越来越多的证据
在真核生物中,嘧啶核糖核苷酸衍生物,环胞嘧啶单磷酸 (cCMP)
和环尿苷单磷酸(cUMP),可以被检测到并具有生物学功能,但这些信号
尚未在细菌中检测或研究。随着最近人们对第二信使的兴趣激增,
仍然是有待解决的基本问题,该提案将测试关于第二个的两个新假设
细菌中的信使信号。首先,我们假设细菌利用嘧啶衍生的第二个
使者。我的实验室开发了快速、灵敏的液相色谱串联质谱仪
(LC-MS/MS) 方法可对 c-di-GMP、c-di-AMP 和 pGpG(c-di-GMP 的分解产物)进行超过
使用密歇根州立大学世界一流的质谱核心设施检测二十种细菌。在
这笔赠款,我们建议开发 LC-MS/MS 协议来量化所有已知的核苷酸衍生的第二
信使和新型嘧啶第二信使 cCMP、cUMP 和 c-di-UMP。然后我们将提取
来自整个细菌系统发育树中不同细菌物种的核苷酸并测量其存在
以及这些基于核苷酸的第二信使的浓度。我们的第二个假设是 c-di-GMP
显示细菌群体的表型异质性。这一假设将通过发展中的物种来检验——
特异性 RNA 生物传感器可在单细胞水平上量化多种细菌中的 c-di-GMP。该提案将测试
关于细菌第二信使信号传导的基本假设并开发新的 LC-MS/MS 和单
细胞报告技术将促进细菌第二信使研究的新领域。
项目成果
期刊论文数量(0)
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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CHRISTOPHER M WATERS其他文献
CHRISTOPHER M WATERS的其他文献
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{{ truncateString('CHRISTOPHER M WATERS', 18)}}的其他基金
Sex differences in ASK1-mediated pulmonary fibrosis
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Exploring cyclic di-nucleotide signaling across the tree of life
探索生命树中的环状二核苷酸信号传导
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10721144 - 财政年份:2021
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Exploring cyclic di-nucleotide signaling across the tree of life
探索生命树中的环状二核苷酸信号传导
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10385949 - 财政年份:2021
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Exploring cyclic di-nucleotide signaling across the tree of life
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10547744 - 财政年份:2021
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$ 7.22万 - 项目类别:
Exploring cyclic di-nucleotide signaling across the tree of life
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10553896 - 财政年份:2021
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Biophysical Mechanisms of Hyperoxia-Induced Lung Injury
高氧引起的肺损伤的生物物理机制
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10614659 - 财政年份:2020
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10374099 - 财政年份:2020
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From structure to systems: Understanding cyclic di-GMP control of transcription
从结构到系统:了解转录的环状二 GMP 控制
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9102193 - 财政年份:2015
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From structure to systems: Understanding cyclic di-GMP control of transcription
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8887427 - 财政年份:2015
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