Project description
Decoding O-glycosylation to gain novel disease insights
O-glycosylation, a complex post-translational modification of cell surface carbohydrates, is linked to a range of diseases, including inflammatory bowel disease, cystic fibrosis, and cancer. Despite its significance, the mechanisms underlying O-glycosylation and its impact on disease remain poorly understood. Funded by the European Research Council, the GLYCO TOOLS project seeks to better understand the role of O-glycosylation, with the aim of identifying effective treatments and diagnostics. The project will utilise synthetic organic and inorganic chemistry, enzymology and glycobiology to study the parameters controlling the combinatorial diversity of O-glycans and their implications on receptor binding and intracellular signalling. This ground-breaking research will pave the way for the development of glycan-based diagnostic tools and therapies.
Objective
Cell surface carbohydrates play key roles in cell recognition mechanisms. O-glycosylation is a ubiquitous post-translational modification that is highly dynamic and responsive to cellular stimuli through the action of cycling enzymes. Expression of specific O-glycans is linked to changes in gene expression in, for example, inflammatory bowel disease, cystic fibrosis and several types of cancer.
Protein-carbohydrate interactions typically exhibit high specificity and weak affinities toward their carbohydrate ligand. This low affinity is compensated in nature by the architecture of the protein, the host presenting the carbohydrate ligands in a multivalent manner or as clusters on the cell or mucosal surface. This effect is known as the multivalency or “cluster–glycoside effect” and has been well documented for lectin–carbohydrate interactions as increasing ligand affinity and selectivity. The fundamental understanding of these glycosylation patterns at molecular and functional levels will allow mechanisms associated with bacterial-host interactions, bowel disease and several cancers to be defined, which will facilitate the identification of effective treatments and diagnostics for these conditions in due course.
This is a multidisciplinary project involving synthetic organic and inorganic chemistry, enzymology and glycobiology. The proposal centres on the development of expedient synthetic and chemo-enzymatic methodologies for the preparation of novel multivalent O-glycan probes that will be used in the screening of O-glycosylation-linked interactions in health and in disease. These studies will help us understand the parameters controlling the combinatorial diversity of O-glycans and the implications of such diversity on receptor binding and subsequent intracellular signalling, which in turn will lead us to the development of new glycan-based diagnostic tools and therapeutics.
Fields of science
- natural sciencesbiological sciencescell biologycell signaling
- natural sciencesbiological sciencesbiochemistrybiomoleculescarbohydrates
- medical and health sciencesclinical medicineoncology
- natural scienceschemical sciencesinorganic chemistry
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsenzymes
Programme(s)
Funding Scheme
ERC-COG - Consolidator GrantHost institution
BS8 1QU Bristol
United Kingdom