NIH Reporter #1R35GM165545-01

Fucosyltransferases in Mucosal Immunity: Probing Function and Innovating Tools to Define Novel Substrates

Research project to study how fucosyltransferases regulate immunity and tolerance in mucosal epithelial tissues, aiming to understand their molecular function and develop new therapeutic strategies.

Description

The long-term goal of this research program is to define how fucosyltransferases (FUTs) regulate immunity and tolerance in mucosal epithelial tissues. The mucosal epithelium lines the body's canals and organs in the digestive, respiratory, and reproductive systems, and occupies an area approximately 200 times greater than skin, making it the body's largest protective barrier. Glycans are overlooked regulators of the mucosa that play an essential role in mucosal immunity. On the mucosal epithelial cell surface, glycolipids and glycoproteins display covalently linked carbohydrate modifications (glycans) that vary in composition, length, and degree of branching. Fucosylation, the addition of fucose to glycans, is a highly regulated terminal 'capping' reaction that influences glycan structure, length, and function. Nine fucosyltransferases, responsible for catalyzing the linkage-specific transfer of fucose to glycoproteins and glycolipids, have been described in humans. Individuals with FUT-inactivating polymorphisms exhibit unique patterns of susceptibility and resistance to viral infections, have distinct microbiomes, experience higher incidence of mucosal malignancies involving immune evasion, and have higher rates of inflammatory diseases including Crohn's, celiac, and inflammatory bowel disease, compared to those with wild type FUTs. Despite the critical role that FUTs play in normal physiology and disease, there is a significant gap in knowledge regarding their molecular function and regulation in mucosal epithelia. This research aims to elucidate the molecular mechanisms involved in the regulation of immunity/tolerance in mammalian cells by FUTs, leveraging strengths in biochemistry, functional glycoproteomics, and cell biology.

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