Development of Biochemical Tools and Approaches for Studying Siglecs

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Four major types of biomolecules make up living cells: proteins, nucleic acids, lipids, and oligosaccharides. Of these, oligosaccharides – also known as glycans – are the only type in which there is no self-assembly (lipids) or template-driven biosynthesis (protein and DNA/RNA). Instead, the assembly of glycans is controlled by the successive actions of enzymes in a spatially- and temporally-controlled manner. For this reason, and others, glycans are chemically and biochemically complex, making their study inherently challenging. Consequently, tools that manipulate glycans lag behind the comparatively well-establish methodologies of manipulating the genetic code. Accordingly, there is considerable opportunity for developing innovative strategies to analyze and manipulate cellular glycans; indeed, new tools would benefit a broad range of scientists studying the biological roles for glycans. One key role of glycans is within the immune system as they are recognized as ligands by a plethora of glycan-binding proteins (GBPs) expressed on white blood cells. While many functions for GBP-glycan interactions have been described on immune cells, there is still much to be learned about the underlying mechanisms through which these interactions control immune cell function. My lab studies the Siglec (sialic acid-binding immunoglobulin-type lectin) family of GBPs which contains glycan ligands that are highly complex. Siglecs have immunomodulatory properties, which are regulated by interactions with their glycan ligands. Understanding the mechanisms by which Siglecs control immune cell function can only be fully realized by developing new approaches to analyze and modulate their glycan ligands. In this program of research, we will advance a variety of complementary approaches for dissecting glycan ligands for Siglec (e.g. mass spectrometry, flow cytometry, and liposomal nanoparticles) and, in turn, develop chemical tools to manipulate these glycans. Using a synergistic combination of chemical biology approaches and cutting-edge genome editing, the overall objective is to develop strategies that can be used for interrogating the function of Siglecs regulating immune cell function, which can be applied to the wider community of research scientists studying the roles of GBPs.