A Novel high resolution MS platform for high-throughput screening of G protein-coupled receptors
用于高通量筛选 G 蛋白偶联受体的新型高分辨率 MS 平台
基本信息
- 批准号:10636377
- 负责人:
- 金额:$ 34.23万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-06-15 至 2027-03-31
- 项目状态:未结题
- 来源:
- 关键词:Adaptor Signaling ProteinAddressAgonistAmino Acid MotifsAmino AcidsAntibodiesBiologicalBiological AssayBiologyCXC chemokine receptor 3CXCR3 geneCell physiologyClinicalCollectionComplexCoupledDataData AnalysesDetectionDevelopmentDimensionsDiseaseDoseDrug ScreeningDrug TargetingFDA approvedFamilyG Protein-Coupled Receptor SignalingG-Protein-Coupled ReceptorsGTP-Binding ProteinsHeterotrimeric GTP-Binding ProteinsInflammatoryIonsIsomerismLigandsMass Spectrum AnalysisMembraneModernizationPathway interactionsPatternPeptide LibraryPeptidesPharmaceutical PreparationsPharmacologyPhosphopeptidesPhosphorylated PeptidePhosphorylationPhosphorylation SitePhosphotransferasesPlayProcessProtein RegionProteinsProteomicsReagentReproducibilityResearchResolutionRoleSamplingSignal TransductionSiteSpecificitySpectrometrySpeedStructureSystemT cell regulationT-Cell ActivationT-LymphocyteTechnologyTestingTimeTransducersTravelUnited States National Institutes of Healthantagonistbeta-arrestincell preparationchemokinecomputerized data processingdesigndrug developmentdrug discoveryexperiencehigh throughput screeningimprovedinformatics toolion mobilitymass spectrometernovelnovel strategiesoverexpressionphosphoproteomicsprogramsreceptorrecruitresponsescreeningsmall moleculesmall molecule librariesultra high resolution
项目摘要
Summary: Mass spectrometry (MS) has proven invaluable in studying the mechanisms of cellular
signaling as MS platforms can directly provide amino acid residue site-specific phosphorylation
data compared to traditional antibody-based approaches. However, limitations exist in current
MS approaches in generating confident site-specific phosphorylation quantification. This is
particularly evident in complex multi-phosphorylated protein motifs, where the detection of
isomeric multi-phosphorylated peptides easily overwhelms any prediction scoring approach that
is simply based upon the fragmentation spectra. There are many biological examples of
hyperphosphorylated regions, where they are associated with receptor/ligand interactions,
including G-protein coupled receptors (GPCRs), membrane receptors that are the most common
targets for FDA-approved drugs. For accurate site-specific quantification of protein
hyperphosphorylation we propose a transdisciplinary approach using ultrahigh resolution Ion
Mobility Separation (IMS) integrated with highly accurate and sensitive MS and MS/MS spectra
to enable the confident characterization of hyperphosphorylated GPCR ensembles with greatly
improved sensitivity, and speed. We will use multi-level Structures for Lossless Ion Manipulations
(SLIM) technology (SLIM-Orbitrap platform) to fully characterize phosphorylation of
GPCR/antagonist interactions utilizing CXCR3, which plays a central role in inflammatory
diseases through its regulation of T cell function as an initial test case. We plan to first integrate
ultrahigh resolution IMS with an advanced Orbitrap MS platform for unambiguous decoding of
hyperphosphorylated sites, evaluate the SLIM-Orbitrap MS platform for resolving
hyperphosphorylated protein regions, and finally, perform comprehensive site-specific
phosphoproteomics for GPCRs through screening of activated T cells with dose-responses of
chemokine and small-molecule CXCR3 biased agonists.
摘要:质谱法(MS)已被证明在研究细胞凋亡机制方面是非常宝贵的。
作为MS平台的信号传导可以直接提供氨基酸残基位点特异性磷酸化
与传统的基于抗体的方法相比。然而,目前存在局限性。
MS方法在产生可信的位点特异性磷酸化定量。这是
在复杂的多磷酸化蛋白质基序中尤其明显,其中检测到
异构的多磷酸化肽容易克服任何预测评分方法,
仅仅是基于碎片光谱。有很多生物学上的例子
高度磷酸化的区域,在那里它们与受体/配体相互作用相关,
包括G蛋白偶联受体(GPCR),最常见的膜受体,
FDA批准的药物的目标。用于蛋白质的精确位点特异性定量
过度磷酸化我们提出了一种使用超高分辨率离子的跨学科方法
迁移率分离(IMS)集成了高精度和高灵敏度的MS和MS/MS光谱
为了使过度磷酸化的GPCR集合的可靠表征具有极大的
提高了灵敏度和速度。我们将使用多能级结构进行无损离子操作
(SLIM)技术(SLIM-Orbitrap平台),以充分表征
利用CXCR 3的GPCR/拮抗剂相互作用,CXCR 3在炎症反应中起核心作用。
通过其调节T细胞功能的疾病作为初始测试案例。我们计划首先整合
具有先进Orbitrap MS平台的高分辨率IMS,
高度磷酸化位点,评估SLIM-Orbitrap MS平台用于解析
高度磷酸化的蛋白质区域,最后,进行全面的位点特异性
通过筛选具有以下剂量反应的活化T细胞的GPCR磷酸蛋白质组学
趋化因子和小分子CXCR 3偏向激动剂。
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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Jon Jacobs其他文献
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{{ truncateString('Jon Jacobs', 18)}}的其他基金
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- 批准号:
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- 资助金额:
$ 34.23万 - 项目类别:
PSP Omics Center of Acute to Chronic Pain Signatures
PSP 组学中心急性至慢性疼痛特征
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PSP Omics Center of Acute to Chronic Pain Signatures
PSP 组学中心急性至慢性疼痛特征
- 批准号:
10231045 - 财政年份:2019
- 资助金额:
$ 34.23万 - 项目类别:
PSP Omics Center of Acute to Chronic Pain Signatures
PSP 组学中心急性至慢性疼痛特征
- 批准号:
10459355 - 财政年份:2019
- 资助金额:
$ 34.23万 - 项目类别:
PSP Omics Center of Acute to Chronic Pain Signatures
PSP 组学中心急性至慢性疼痛特征
- 批准号:
9812788 - 财政年份:2019
- 资助金额:
$ 34.23万 - 项目类别:
PSP Omics Center of Acute to Chronic Pain Signatures
PSP 组学中心急性至慢性疼痛特征
- 批准号:
10611136 - 财政年份:2019
- 资助金额:
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