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Isomer Separation and Structural Differentiation of Glycans and Glycopeptides by Nano-LC/MS
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Dissertation
Isomer Separation and Structural Differentiation of Glycans and Glycopeptides by Nano-LC/MS
2012
Overview
The glycome, i.e. the glycan components of a biological source, has been widely reported to change with disease states. However, mining the glycome for biomarkers is complicated by glycan structural heterogeneity. Nanoflow liquid chromatography, or nano-LC, addresses the problem by providing a sensitive and quantitative method of separating and profiling glycans and glycopeptides. The first chapter of this thesis provides an overview of glycomic analysis by nanoflow liquid chromatography. Recent advances in analytical technology and methodology are presented that enhance and augment the advantages offered by nano-LC, especially when combined with mass spectrometry. Particular emphasis is placed on methods and technologies that allow structure-specific glycan profiling. The second chapter describes the development of a method for isomer-specific profiling of native N-glycans from human serum based on porous graphitized carbon nano-LC combined with mass spectrometry. The inclusion of isomer-specific characterization is expected to uncover more robust glycan biomarkers with higher specificity than compositional (MS-only) profiling. The N-glycan separation capabilities of chip-based porous graphitized carbon nano-LC are characterized in detail. The utility of this method for structure-specific biomarker discovery is demonstrated with a small pilot study on prostate cancer patients (n = 8) with good and bad prognoses. The third chapter describes the streamlining and optimization of the isomer-specific N-glycan profiling method to increase throughput and reproducibility, thereby enabling the discovery of sensitive and specific biomarkers for cancer. To demonstrate the utility of this method, serum samples from epithelial ovarian cancer cases (n = 46) and healthy control individuals (n = 48) were analyzed and compared. The N-glycan profiling results were used to create an optimized model for robust discrimination between epithelial ovarian cancer cases and controls, demonstrating the effectiveness of this platform for structure-specific biomarker discovery. The fourth chapter moves beyond profiling of released N-glycans to examine site-specific glycosylation analysis. This goal was accomplished via nano-LC separation and MS characterization of glycopeptides. Isomer-specific glycan profiles were thus obtained in the context of their location and relative abundance on a glycoprotein. The method was validated using well-characterized glycoprotein standards and then applied to the isomer-specific, site-specific characterization and quantitation of both N- and O-glycosylation on selected glycoproteins.
Publisher
ProQuest Dissertations & Theses
Subject
ISBN
9781267758040, 126775804X
