Research

The building blocks of life fall into four broad categories: polynucleotides, proteins, lipids, and glycans. Each of these exhibits a useful set of characteristics (with some overlap). DNA/RNA base pairing enables data storage, transport, and amplification. Strings of amino acids adopt exquisite three dimensional folds, creating pockets for catalysis and shapes that bind one another. Lipids self-organize into droplets which are the basis for cellular compartmentalization. What about glycans? Why is it that all cells studied to date, from archaea to neurons, synthesize complex glycans and use them to decorate their cell surfaces?

Electron micrograph of cell surface glycans, collectively termed the glycocalyx (G), of a starfish, British Library.

In humans, glycans are biosynthesized from 9 monomeric carbohydrate units, but are not done so based on sequence templates encoded in the genome. Rather, glycans are highly dynamic products of combinatorial enzymatic pathways that react nimbly to cell state and external stimuli. In addition, monosaccharide units are linked together in a multitude of branching arrangements, resulting in extraordinary structural heterogeneity, which is elaborated further by post-synthetic modifications.

Overview of glycan biosynthesis, highlighting one of the best understood types, N-linked protein glycosylation.

We are interested in developing tools rooted in chemical biology, protein engineering, and microscopy that leverage the unique characteristics of glycans to deepen our understanding of cellular functioning and pathology. As glycans exert their key influence at cellular interfaces, we aim our technologies at the study of multicellular systems, and are especially curious about the roles glycans play in modulating ultrastructure and signaling in the brain. For example, we and others have observed microheterogeneity in the distributions of glycans on cell surfaces— what is the precise organization of these structured, densely-glycosylated cell surface domains and how do they influence neuronal/glial function? How does the tissue-level distribution of glycans in the brain influence communication among cell populations? How are these processes regulated over the course of development?

Chemical structure of a biantennary N-glycan. Red text highlights the regio- and stereochemistry of glycosidic linkages. Blue text highlights examples of post-synthetic modifications.

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