Intersection of glycosylation and metabolism during tissue development - protein and lipid glycosylation is one of the most complex post-translational modifications in biology, impacting countless…

The National Institute of General Medical Sciences awarded Greenwood Genetic Center Inc. $284,847 on September 3, 2026, under the Biomedical Research and Research Training program (CFDA 93.859) to investigate the intersection of glycosylation and metabolism during tissue development.

The research employs zebrafish models to explore how metabolic and glycosylation pathways converge to control tissue development and how disruption of that coordination causes disease. The work focuses on congenital disorders of glycosylation (CDG), a group of rare inherited genetic diseases affecting approximately 200 different human conditions. Current studies include zebrafish models of multiple CDG subtypes, including PMM2-CDG, the most common form. The research combines systems-based analyses with biochemical and molecular approaches to characterize CDG pathogenesis at cellular and molecular levels.

Performance takes place in Greenwood, South Carolina, with a period of performance extending from September 3, 2026 through June 30, 2031. The award is structured as a Project Grant, the standard assistance type for investigator-initiated biomedical research under NIGMS.

Intersection of glycosylation and metabolism during tissue development - protein and lipid glycosylation is one of the most complex post-translational modifications in biology, impacting countless processes across all kingdoms of life. Protein-bound glycans mediate polypeptide folding, trafficking, localization, processing, stability, enzymatic activity, and can promote or inhibit interactions among protein partners. Glycosylation is a non-template driven process, where the type and amount of glycans synthesized is determined by availability of sugar precursors and expression of specific biosynthetic enzymes. Cellular glucose levels and flux within sugar phosphate metabolic pathways dictate abundance of the nucleotide-sugar precursors. Multiple glycosylation enzymes utilize the same metabolic precursors. Thus, balancing glycan biosynthesis and sugar metabolism is critical for normal tissue development. The complete repertoire of mechanisms regulating this coordination remains poorly understood, but the need for proper glycosylation is evidenced by the ~200 different inherited human disorders caused by a primary defect in one or more glycosylation pathways. These rare inherited genetic diseases, termed the congenital disorders of glycosylation (CDG), have a diverse biochemical and genetic etiology. While the number of newly identified CDG continues to expand, our understanding of their pathogenesis and the availability of approved treatments remain very limited. This research program leverages a powerful suite of novel tools in zebrafish to explore how metabolic and glycosylation pathways converge and cooperate to control tissue development, and how impairing that coordination causes disease. Using zebrafish models of multiple CDG, including the most common form, PMM2-CDG, our studies combine systems-based analyses with biochemical and molecular approaches to unravel CDG pathogenesis at a cellular and molecular level. Our current research is focused in three general areas: 1) defining how alterations in the level of nucleotide sugar precursors broadly impact glycosylation - studies that aim to understand how underlying defects in PMM2 impact both N- and O-linked glycans to drive disease pathology; 2) delineate how defects in glycosylation of cadherins (and the proteases that process them) impair their function to disrupt tissue development; 3) uncover how O-glcnacylation of key proteins contributes to disease in multiple CDG - studies that are based on our discovery that increased O- glcnacylation in PMM2-CDG leads to modification of key rate-limiting enzymes in the early N-glycosylation pathway. By comparing multiple CDG in a single model system, we hope to identify the common metabolic- and glycosylation-mediated mechanisms driving disease in affected tissues, and use this information to uncover and test new therapies.