Research Goals:

Cell surface molecular recognition occurs when complementary molecules on apposing cell surface or on the same cell surface meet, initiating a cascade of events that regulate cell behaviors ranging from cell-cell adhesion to complex cellular regulation. GLYCANS (glycoproteins, glycolipids, proteoglycans) richly decorate all cell surfaces, and represent the most prominent class of cell surface molecules. Members of this large and varied family are ligands for complementary binding proteins, lectins, on the same or adjacent cell surfaces. Lectin-carbohydrate interactions mediate cell-cell interactions and cell physiology throughout the body. The study of cell surface glycans, lectins, and their roles in cell physiology are part of the rapidly expanding field of GLYCOBIOLOGY.

Glycans and lectins in human airway inflammation

The lectin SIGLEC-8 was discovered on human eosinophils, basophils, and mast cells - the cells that drive allergic inflammation including asthma. Engaging Siglec-8 on the surface of these cells results in apoptosis and inhibition of immune mediator release, inhibiting allergic inflammation. We identified a glycan structures that bind to Siglec-8 as lead compounds for glycan-based asthma therapy. We identify, purify, and study the endogenous glycan counter-receptors for Siglec-8 in human airways - glycans that control eosinophilic inflammation.

Glycans and lectins in human neurodegenerative diseases

Remarkably, SIGLEC-8 and its cousin SIGLEC-3 are expressed on the immune cells of the human brain - microglia. These cells are thought to play both positive and negative roles in neurodegenerative proteinopathies (like Alzheimer's disease) where they may clear and remove misfolded proteins or initiate destructive local immune responses. Knowledge of the roles of immune regulatory Siglecs in this process may provide previously unanticipated ways to modify disease progression.

The Ganglioside Interactome

Human nerve cells (and those of other vertebrates) are remarkable for the abundance of a particular class of glycans, gangliosides, on their surfaces. Gangliosides are sialic acid-bearing glycosphingolipids found on the outer leaflet of the plasma membrane of all vertebrate cells, where they modulate cell recognition, cell regulation, and cell signaling by interacting with proteins on their own cell surface (cis) or on adjacent cells (trans). We are building powerful chemical biology tools - based on major ganglioside structures - that will be used to tag, identify, and isolate the binding proteins that translate ganglioside recognition into cellular regulation.

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