Description du projet
Décoder la O-glycosylation pour mieux comprendre les maladies
La O-glycosylation, une modification post-traductionnelle complexe des hydrates de carbone à la surface des cellules, est liée à une série de maladies, notamment la maladie inflammatoire chronique de l’intestin, la mucoviscidose et le cancer. Malgré son importance, les mécanismes qui sous-tendent la O-glycosylation et son impact sur la maladie restent mal compris. Financé par le Conseil européen de la recherche, le projet GLYCO TOOLS vise à mieux comprendre le rôle de la O-glycosylation, en vue d’identifier des traitements et des diagnostics efficaces. Le projet utilisera la chimie organique et inorganique synthétique, l’enzymologie et la glycobiologie pour étudier les paramètres qui contrôlent la diversité combinatoire des O-glycanes et leurs implications sur la liaison des récepteurs et la signalisation intracellulaire. Ces recherches innovantes ouvriront la voie au développement d’outils diagnostiques et thérapeutiques basés sur les glycanes.
Objectif
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.
Champ scientifique
- natural sciencesbiological sciencescell biologycell signaling
- natural sciencesbiological sciencesbiochemistrybiomoleculescarbohydrates
- medical and health sciencesclinical medicineoncology
- natural scienceschemical sciencesinorganic chemistry
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsenzymes
Programme(s)
Régime de financement
ERC-COG - Consolidator GrantInstitution d’accueil
BS8 1QU Bristol
Royaume-Uni