Tuesday, April 29, 2025
4/29/2025
Mass Spectrometric Tissue Imaging of Sugars, Glycans, and Glycoconjugates - PROJECT SUMMARY/ABSTRACT The glycome describes the complete repertoire of cell carbohydrates that are either free or covalently linked to lipid or protein molecules, having the span of biological roles from those that are subtle to those that are crucial for an organism's development, function, or survival. Because those molecules are not encoded directly in the genome, one cannot accurately predict the precise structures of glycans elaborated by a given cell type. Furthermore, small changes in environmental cues can cause dramatic changes in glycans produced by a given cell, which can often lead to pathology, and as such, developing capabilities for identifying those changes at the cell-specific level is necessary. Historically, nuclear magnetic resonance (NMR) and mass spectrometry (MS) have been used for glycome structural elucidation, but those techniques have limited capability to capture chemical differences at the spatial level, while lectins and other glycan-labeling imaging approaches provide only limited information on carbohydrates structures. Over the last decade, mass spectrometry imaging (MSI) evolved as a powerful tool to link chemical structures with tissue localization, and it has been successfully used to reveal differences in metabolites, lipids, and xenobiotics across numerous human tissues, cell types, and cell states. However, MSI still hasn’t shown its full potential in glycome imaging due to carbohydrates' poor ionizability, complex chemistry, and ambiguous molecular annotation. I have successfully solved some of those issues throughout my career, enabling a better understanding of the glycome-phenotype relationship. Herein, I propose to develop and advance MSI tools that will enable more accurate and comprehensive chemical characterization of the glycome at tissue functional unit and cellular resolutions. I will develop various workflows, modify and optimize existing MSI approaches, and, in combination with auxiliary tools, map soluble sugars, glycolipids, proteoglycans, polysaccharides, and glycoproteins from the human tissues. More specifically, in combination with high-resolving mass spectrometers, I will utilize various ionization and post-ionization sources, orthogonal analyses, on-tissue chemical derivatization, in-tissue digestion, and glycan enrichment strategies to overcome current limitations in glycome imaging. Successful completion of this research will create a robust, high- throughput capability for glycome imaging that will enable an understanding of how, at the cell-specific level, glycome processing and glycome redistribution mediate physiological and pathological processes, thus addressing a critical gap in the Glycosciences area of the Biochemistry and Bio-related Chemistry Branch of NIGMS.
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