Project 1: Discovery of proteins with altered abundance and stability
Project 1: Discovery of proteins with altered abundance and stability
批准号:
10359192
负责人:
Michael MacCoss
金额:
$47.17万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
未结题
起止时间:
2020-02-15 至 2025-01-31
关键词:
AdoptedAlzheimer&aposs disease pathologyAlzheimer&aposs disease related dementiaAmyloidAmyloid FibrilsAmyloid beta-42Apolipoprotein EBiological AssayBiological MarkersBrainCategoriesCellsCholesterol HomeostasisClinicalDataDetectionDevelopmentDifferential DiagnosisDigestionDiseaseEnzyme-Linked Immunosorbent AssayExtracellular FluidFailureFunctional disorderHumanHybridsIndividualInterneuronsLipoproteinsMass Spectrum AnalysisMeasuresMethodsModificationMolecular WeightMonitorNerve DegenerationNeurobiologyNeurodegenerative DisordersPathogenesisPathogenicityPathologyPeptide HydrolasesPeptidesPerformancePredispositionProcessProtein IsoformsProteinsProteomeProteomicsRNA SplicingReactionReproducibilityResearchRoleSamplingSourceSymptomsTechnologyTemperatureTrypsinValidationVariantbasebrain cellcandidate markerclinical diagnosisclinical practicecohortcomorbidityextracellular vesiclesfallsimprovedinhibitormisfolded proteinnervous system disorderneuroinflammationnext generationparticleprogramsprotein foldingprotein misfoldingrecruitsulfated glycoprotein 2tau Proteinstau-1thermal stresstranslational proteomics
中文摘要
摘要
尽管脑脊液Aβ42、tau、磷酸化tau水平与潜在的AD之间存在关联
病理学方面,临床诊断的生物标记物准确性的衡量标准在不同研究之间差别很大。考虑到
其他神经退行性疾病可出现类似AD的临床症状,AD患者
经常合并病理,需要额外的标记物来帮助鉴别诊断和
辨别混合的病理。在过去的十年中,许多候选生物标志物已经被识别出来,反映了
包括胆固醇代谢、神经炎症和淀粉样蛋白在内的一系列病理生理过程
正在处理。然而,已在临床实践中采用或在大范围内独立验证的很少。
队列1.
MacCoss实验室和其他实验室一直在开创下一代蛋白质组学方法的发展
作为经典随机质谱学方法的替代方法。这些新方法提供了一种
目标蛋白质组学战略和全球蛋白质组学战略的混合体。虽然质谱学数据是在一个
以无偏见的方式,以有针对性的策略分析数据,其中分析特定的多肽,尽管分析的是1000个
利用先验信息。因此,可重复的目标、吞吐量和基于MS/MS的自信
并行反应监测(PRM)的量化可以与经典发现方法的能力相结合
定性检测数以千计的蛋白质。这些新的方法是基于系统收集的质量
光谱数据可以提供类似的量化品质因数,并可以类似于
临床化验。
尽管蛋白质组学技术取得了进步,但大多数试图发现新的脑脊液标志物的努力要么
使用1)随机抽样方法(例如,数据相关采集),但量化特征不佳
表现,2)小样本队列,3)完全关注总脑脊液,4)忽略蛋白质处理,以及5)
没有考虑蛋白质的错误折叠或稳定性。本项目在合作研究范围内的目的
方案是将我们的方法提升到另一个水平--将真正的定量方法应用于大井
描述了队列的特征,并将其扩展到功能相关的子群体。
我们有一种脑脊液测定仪,可以从完全分离的物质中以数字形式测定>;1050蛋白质。
日内/日间精密度、线性度、LOD/LOQ等优点。此外,我们还可以使用这种分析方法来
脑脊液蛋白质组的子集,以评估神经生物学的功能相关方面,包括数量
部分溶液或脑脊液颗粒,完整的蛋白质相对分子质量和蛋白质稳定性。最后,我们有足够的吞吐量
将这些分析应用到足以消除观察是由异常引起的可能性的范围内
亚群。
英文摘要
Abstract
Despite the association between the levels of CSF Aβ42, tau, phosphorylated tau and underlying AD
pathology, measures of biomarker accuracy for clinical diagnosis vary widely between studies. Given that
other neurodegenerative conditions can present with AD-like clinical symptoms, and individuals with AD
frequently have comorbid pathologies, additional markers are needed that can aid in differential diagnosis and
identify mixed pathologies. Over the last decade, many candidate biomarkers have been identified, reflecting a
range of pathophysiological processes including cholesterol metabolism, neuroinflammation and amyloid
processing. However, few, have been adopted in clinical practice or been validated in large independent
cohorts1.
The MacCoss lab and others have been pioneering the development of next generation proteomics methods
as an alternative to the classic stochastic mass spectrometry-based methods. These new methods offer a
hybrid between a targeted and global proteomics strategy. While mass spectrometry data is collected in an
unbiased way, the data is analyzed in a targeted strategy where specific peptides, albeit 1000s are analyzed
using prior information. Thus, the reproducible targeting, throughput, and confident MS/MS-based
quantification of parallel reaction monitoring (PRM) can be combined with classical discovery methods' ability
to qualitatively detect thousands of proteins. These new methods based on systematically collected mass
spectrometry data can offer similar quantitative figures of merit and can be validated in analogous fashion to
clinical assays.
Despite advances in proteomics technologies, most attempts at discovering new CSF markers have either
used 1) stochastic sampling methods (e.g. data dependent acquisition) with poorly characterized quantitative
performance, 2) small sample cohorts, 3) focused entirely on total CSF, 4) ignored protein processing, and 5)
did not consider protein misfolding or stability. The purpose of this project within the cooperative research
program is to take our methods to another level – apply true quantitative methods to large well
characterized cohorts and extend them to functionally relevant subpopulations.
We have a CSF assay that can measure >1050 proteins from completely unfractionated material with figures
of merit of within/between day precision, linearity, LOD/LOQ, etc... Furthermore, we can use this assay on
subsets of the CSF proteome to assess functionally relevant aspects of the neurobiology including quantity as
part of solution or CSF particles, intact protein MW, and protein stability. Finally, we have enough throughput
to apply these analyses on a scale sufficient to eliminate the chance that an observation is due to an aberrant
subpopulation.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Seattle Quant: A Resource for the Skyline Software Ecosystem
-
批准号:10609502
-
项目类别:
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资助金额:$111.38万
-
财政年份:2021
-
负责人:Michael MacCoss
-
依托单位:
Seattle Quant: A Resource for the Skyline Software Ecosystem
-
批准号:10400105
-
项目类别:
-
资助金额:$111.38万
-
财政年份:2021
-
负责人:Michael MacCoss
-
依托单位:
Seattle Quant: A Resource for the Skyline Software Ecosystem
-
批准号:10189938
-
项目类别:
-
资助金额:$111.38万
-
财政年份:2021
-
负责人:Michael MacCoss
-
依托单位:
Project 1: Discovery of proteins with altered abundance and stability
-
批准号:10573256
-
项目类别:
-
资助金额:$48.48万
-
财政年份:2020
-
负责人:Michael MacCoss
-
依托单位:
Next Generation Translational Proteomics for Alzheimer's and Related Dementias
-
批准号:10573244
-
项目类别:
-
资助金额:$314.46万
-
财政年份:2020
-
负责人:Michael MacCoss
-
依托单位:
Core 1: Administrative Core
-
批准号:10573245
-
项目类别:
-
资助金额:$5.64万
-
财政年份:2020
-
负责人:Michael MacCoss
-
依托单位:
Next Generation Translational Proteomics for Alzheimer's and Related Dementias
-
批准号:10359187
-
项目类别:
-
资助金额:$314.46万
-
财政年份:2020
-
负责人:Michael MacCoss
-
依托单位:
Core 1: Administrative Core
-
批准号:10359188
-
项目类别:
-
资助金额:$11.34万
-
财政年份:2020
-
负责人:Michael MacCoss
-
依托单位:
The biofilm matrix of P. aeruginosa
-
批准号:10579223
-
项目类别:
-
资助金额:$53.99万
-
财政年份:2019
-
负责人:Michael MacCoss
-
依托单位:
The biofilm matrix of P. aeruginosa
-
批准号:10330563
-
项目类别:
-
资助金额:$56.71万
-
财政年份:2019
-
负责人:Michael MacCoss
-
依托单位:
The Chorus Project: A Sustainable Cloud Solution for Mass Spectrometry Data
-
批准号:9216498
-
项目类别:
-
资助金额:$29.36万
-
财政年份:2017
-
负责人:Michael MacCoss
-
依托单位:
Systematic and Comprehensive Sampling of Peptides in Mixtures by Tandem Mass Spectrometry
-
批准号:8850241
-
项目类别:
-
资助金额:$19.38万
-
财政年份:2015
-
负责人:Michael MacCoss
-
依托单位:
Systematic and Comprehensive Sampling of Peptides in Mixtures by Tandem Mass Spectrometry
-
批准号:9052745
-
项目类别:
-
资助金额:$22.73万
-
财政年份:2015
-
负责人:Michael MacCoss
-
依托单位:
Self Correcting Nanoflow LC-MS for Clinical Proteomics
-
批准号:8840976
-
项目类别:
-
资助金额:$37.43万
-
财政年份:2013
-
负责人:Michael MacCoss
-
依托单位:
Self Correcting Nanoflow LC-MS for Clinical Proteomics
-
批准号:8558710
-
项目类别:
-
资助金额:$35.59万
-
财政年份:2013
-
负责人:Michael MacCoss
-
依托单位:
Skyline Targeted Proteomics Environment
-
批准号:8217996
-
项目类别:
-
资助金额:$37.98万
-
财政年份:2011
-
负责人:Michael MacCoss
-
依托单位:
Skyline Targeted Proteomics Environment
-
批准号:8915218
-
项目类别:
-
资助金额:$38.63万
-
财政年份:2011
-
负责人:Michael MacCoss
-
依托单位:
DEVELOPMENT OF CUSTOM FAIMS ELECTRONICS
-
批准号:8365834
-
项目类别:
-
资助金额:$0.95万
-
财政年份:2011
-
负责人:Michael MacCoss
-
依托单位:
OPTIMIZATION OF NANOFLOW LC FOR IMPROVED PEAK CAPACITY AND PEPTIDE IDS
-
批准号:8365816
-
项目类别:
-
资助金额:$0.95万
-
财政年份:2011
-
负责人:Michael MacCoss
-
依托单位:
WORM EJACULOMICS
-
批准号:8365857
-
项目类别:
-
资助金额:$0.65万
-
财政年份:2011
-
负责人:Michael MacCoss
-
依托单位: