Dataset Information

The development of a novel zeolite-based assay for efficient and deep plasma proteomic profiling.

ABSTRACT: Plasma proteins are considered the most informative source of biomarkers for disease diagnosis and monitoring. Mass spectrometry (MS)-based proteomics has been applied to identify biomarkers in plasma, but the complexity of the plasma proteome and the extremely large dynamic range of protein abundances in plasma make the clinical application of plasma proteomics highly challenging. We designed and synthesized zeolite-based nanoparticles to deplete high-abundance plasma proteins. The resulting novel plasma proteomic assay can measure approximately 3000 plasma proteins in a 45 min chromatographic gradient. Compared to those in neat and depleted plasma, the plasma proteins identified by our assay exhibited distinct biological profiles, as validated in several public datasets. A pilot investigation of the proteomic profile of a hepatocellular carcinoma (HCC) cohort identified 15 promising protein features, highlighting the diagnostic value of the plasma proteome in distinguishing individuals with and without HCC. Furthermore, this assay can be easily integrated with all current downstream protein profiling methods and potentially extended to other biofluids. In conclusion, we established a robust and efficient plasma proteomic assay with unprecedented identification depth, paving the way for the translation of plasma proteomics into clinical applications.

SUBMITTER: Li N

PROVIDER: S-EPMC11007927 | biostudies-literature | 2024 Apr

REPOSITORIES: biostudies-literature

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The development of a novel zeolite-based assay for efficient and deep plasma proteomic profiling.

Li Nan N Huang Jingnan J He Shangwen S Zheng Qiaocong Q Ye Feng F Qin Zhengxing Z Wang Dong D Xiao Ting T Mao Mengyuan M Zhou Zhenhua Z Tang Tingxi T Zhang Longshan L Wang Xiaoqing X Wang Yingqiao Y Lyu Ying Y Liu Laiyu L Dai Lingyun L Wang Jigang J Guan Jian J

Journal of nanobiotechnology 20240410 1

Plasma proteins are considered the most informative source of biomarkers for disease diagnosis and monitoring. Mass spectrometry (MS)-based proteomics has been applied to identify biomarkers in plasma, but the complexity of the plasma proteome and the extremely large dynamic range of protein abundances in plasma make the clinical application of plasma proteomics highly challenging. We designed and synthesized zeolite-based nanoparticles to deplete high-abundance plasma proteins. The resulting no ...[more]

PMID: 38600601

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Project description:Plasma biomarkers that reflect molecular states of the cardiovascular system are central for clinical decision making. Routinely used plasma biomarkers include troponins, natriuretic peptides, and lipoprotein particles, yet interrogate only a modest subset of pathways relevant to cardiovascular disease. Systematic profiling of a larger portion of circulating plasma proteins (the plasma proteome) will provide opportunities for unbiased discovery of novel markers to improve diagnostic or predictive accuracy. In addition, proteomic profiling may inform pathophysiological understanding and point to novel therapeutic targets. Obstacles for comprehensive proteomic profiling include the immense size and structural heterogeneity of the proteome, and the broad range of abundance levels, as well. Proteome-wide, untargeted profiling can be performed in tissues and cells with tandem mass spectrometry. However, applications to plasma are limited by the need for complex preanalytical sample preparation stages limiting sample throughput. Multiplexing of targeted methods based on capture and detection of specific proteins are therefore receiving increasing attention in plasma proteomics. Immunoaffinity assays are the workhorse for measuring individual proteins but have been limited for proteomic applications by long development times, cross-reactivity preventing multiplexing, specificity issues, and incomplete sensitivity to detect proteins in the lower range of the abundance spectrum (below picograms per milliliter). Emerging technologies to address these issues include nucleotide-labeled immunoassays and aptamer reagents that can be automated for efficient multiplexing of thousands of proteins at high sample throughput, coupling of affinity capture methods to mass spectrometry for improved specificity, and ultrasensitive detection systems to measure low-abundance proteins. In addition, proteomics can now be integrated with modern genomics tools to comprehensively relate proteomic profiles to genetic variants, which may both influence binding of affinity reagents and serve to validate the target specificity of affinity assays. The application of deep quantitative proteomic profiling to large cohorts has thus become increasingly feasible with emerging affinity methods. The aims of this article are to provide the broad readership of Circulation with a timely overview of emerging methods for affinity proteomics and recent progress in cardiovascular medicine based on such methods.

Project description:BackgroundSarcopenia, the gradual and generalized loss of muscle mass and function with ageing, is one of the major health problems in older adults, given its high prevalence and substantial socioeconomic implications. Despite the extensive efforts to reach consensus on definition and diagnostic tests and cut-offs for sarcopenia, there is an urgent and unmet need for non-invasive, specific and sensitive biomarkers for the disease. Extracellular vesicles (EVs) are present in different biofluids including plasma, whose cargo reflects cellular physiology. This work analysed EV proteome in sarcopenia and robust patients in the search for differentially contained proteins that can be used to diagnose the disease.MethodsPlasma small EVs (sEVs) from a total of 29 robust controls (aged 73.4 ± 5.6 years; 11 men and 18 women) and 49 sarcopenic patients (aged 82.3 ± 5.4 years; 15 men and 34 women) aged 65 years and older were isolated and their cargo was analysed by proteomics. Proteins whose concentration in sEVs was different between sarcopenic and robust patients were further validated using ELISA. The concentration of these candidates was correlated to the EWGSOP2 sarcopenia tests for low muscle strength and low physical performance, and receiver operating characteristic (ROC) curve analyses were carried out to evaluate their diagnostic power, sensitivity and specificity.ResultsProteomic analysis identified 157 sEVs proteins in both sarcopenic and robust samples. Among them, 48 proteins had never been reported in the ExoCarta nor Vesiclepedia databases. Statistical analysis revealed eight proteins whose concentration was significantly different between groups: PF4 (log2 FC = 4.806), OIT3 (log2 FC = -1.161), MMRN1 (log2 FC = -1.982), MASP1 (log2 FC = -0.627), C1R (log2 FC = 1.830), SVEP1 (log2 FC = 1.295), VCAN (FC = 0.937) and SPTB (log2 FC = 1.243). Among them, platelet factor 4 (PF4) showed the lowest concentration while Complement C1r subcomponent (C1R) increased the most in sarcopenic patients, being these results confirmed by ELISA (P = 1.07E-09 and P = 0.001287, respectively). The concentrations of candidate proteins significantly correlated with EWGSOP2 tests currently used. ROC curve analysis showed an area under the curve of 0.8921 and 0.7476 for PF4 and C1R, respectively. Choosing the optimal for PF4, 80% sensitivity and 85.71% specificity was reached while the optimal cut-off value of C1R would allow sarcopenia diagnosis with 75% sensitivity and 66.67% specificity.ConclusionsOur results support the determination of EV PF4 and C1R as plasma diagnostic biomarkers in sarcopenia and open the door to investigate the role of the content of these vesicles in the pathogeny of the disease.

Dataset Information

The development of a novel zeolite-based assay for efficient and deep plasma proteomic profiling.

Publications

The development of a novel zeolite-based assay for efficient and deep plasma proteomic profiling.

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