Vibrational spectroscopy with metasurface optics (VISMO) for high-throughput identification of protein post-translational modifications
超表面光学振动光谱 (VISMO) 用于蛋白质翻译后修饰的高通量鉴定
基本信息
- 批准号:10761601
- 负责人:
- 金额:$ 28.99万
- 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:2023-09-22 至 2024-09-21
- 项目状态:已结题
- 来源:
- 关键词:Amino Acid SequenceAmino AcidsAntigensArthritisAutoimmune DiseasesBindingBiological AssayBiological MarkersBiological ProcessBiological Response Modifier TherapyCatalogsCell Signaling ProcessCell physiologyCellsChargeChemicalsComplementDetectionDevelopmentDiabetes MellitusDiagnosisDimensionsDiseaseDisease PathwayEnzyme-Linked Immunosorbent AssayEtiologyFingerprintFluorescenceFoundationsGrowthHealthHealth TransitionHumanImmune responseImmunoassayIndividualInflammationIonsKineticsLabelLegal patentLengthLigandsLocationMalignant NeoplasmsMass Spectrum AnalysisMeasurementMeasuresMetabolicMethodologyMethodsMissionModernizationMonitorNanostructuresNerve DegenerationNeurodegenerative DisordersNoiseNucleic AcidsNucleic acid sequencingNutrientOpticsPathway interactionsPeptide Sequence DeterminationPeptidesPhasePhysiologyPost-Translational Protein ProcessingPosttranslational Amino Acid ModificationPropertyProteinsProteomeProteomicsPumpkinsRaman Spectrum AnalysisRegulationResearch PersonnelResolutionSamplingSignal TransductionSmall Business Innovation Research GrantSpectrum AnalysisSpeedStructureTechnologyTertiary Protein StructureTherapeuticTimeTreatment Efficacyanalogcell typechemical cleavageimprovedinsightinterestmachine learning algorithmminiaturized sensornovel sequencing technologynovel therapeuticsparallelizationpreventprotein aminoacid sequenceprotein functionprotein profilingprotein protein interactionprotein structuresensorsingle moleculesmall moleculesuccesssynthetic peptidetherapeutic developmenttranscriptometreatment response
项目摘要
Project Summary/Abstract
Proteins are critical to a wide array of cellular processes - from cell signaling to immune responses, nutrient
transport, growth, and metabolic regulation. Proper function of proteins depends sensitively on the type,
location, and abundance of post-translational modifications (PTMs). Aberrations in PTM properties can
degrade protein function and compromise the physiology and function of the cells in which they reside. Indeed,
altered PTMs have been implicated in a variety of diseases, including cancers, auto-immune diseases,
neurodegenerative diseases, and inflammation. Nucleic acid sequencing gives almost no insight into PTM
attributes, and sensitive and high-throughput characterization and quantification of PTMs remains a daunting
challenge for mass spectroscopy (MS) and immunoassays. Pumpkinseed is developing an optics-based and
label-free approach to measure protein PTMs, termed Vibrational Spectroscopy with Metasurface Optics
(VISMO). VISMO offers high-speed analysis of millions of proteins – including their sequence, structure, and
interactions – with three key advantages over other proteomics solutions: (1) In a label-free format, we
uniquely identify each molecule via its vibrational scattering spectra, rather than relying on lower-resolution
fluorescent tagging. (2) Using nanostructured Si chips, we create highly efficient optical resonators that both
dramatically amplify the signal-to-noise ratio – even for very low abundance biomarkers – and increase sample
throughput, with simultaneous measurement of ~3 million proteins per square centimeter. (3) We use
cutting-edge machine learning (ML) algorithms to dissect information-rich features from the vibrational spectra,
including the wavenumbers that correspond to the primary, secondary, and tertiary structure of the protein, as
well as changes related to protein or small-molecule binding. Our Phase I proposal will develop this
revolutionary platform for sensitive, high-throughput, and high-resolution protein detection, including their
abundance, sequence, and PTMs. Aim 1 develops sensors that enable sensitive, few-to-single-molecule
spectroscopy, builds our catalog of spectra for particular amino acids, short peptide sequences, and PTMs;
and develops machine learning (ML) algorithms that provide interpretability to each molecule’s optical
scattering signature. Aim 2 advances our methods for protein sequencing using chemical cleavage and our
patented ‘sequencing by subtraction’ methodology. Phase I results will form the foundation of our Phase II
proposal, with potentially far-reaching impacts on whole-proteome sequencing and protein-profiling of the vast
repertoire of cell types. Biotherapeutic companies and academic researchers studying intact, native proteins
will value the high-resolution that Pumpkinseed’s platform offers compared to existing ELISA-type assays, and
the higher-sensitivity and throughput compared to traditional mass spectrometry. Our approach provides a new
methodology for probing protein structure and interactions in order to reveal new dimensions of disease
etiology and distinct opportunities for new therapeutic development.
项目总结/文摘
项目成果
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