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Bio-Inspired Tools for Glycoscience

Descrizione del progetto

Decodificare la O-glicosilazione per ottenere nuove conoscenze sulle malattie

La O-glicosilazione, una complessa modificazione post-traduzionale dei carboidrati della superficie cellulare, è legata a una serie di malattie, tra cui malattie infiammatorie intestinali, fibrosi cistica e cancro. Nonostante la sua importanza, i meccanismi alla base della O-glicosilazione e l’impatto sulle malattie sono ancora poco conosciuti. Il progetto GLYCO TOOLS, finanziato dal Consiglio europeo della ricerca, intende comprendere meglio il ruolo della O-glicosilazione, con l’obiettivo di individuare trattamenti e diagnosi efficaci. Il progetto utilizzerà la chimica organica e inorganica di sintesi, l’enzimologia e la glicobiologia per studiare i parametri che controllano la diversità combinatoria degli O-glicani e le relative implicazioni sul legame con i recettori e la segnalazione intracellulare. Questa ricerca innovativa aprirà la strada allo sviluppo di strumenti diagnostici e terapie basati sui glicani.

Obiettivo

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.

Meccanismo di finanziamento

ERC-COG - Consolidator Grant

Istituzione ospitante

UNIVERSITY OF BRISTOL
Contribution nette de l'UE
€ 1 986 356,00
Indirizzo
BEACON HOUSE QUEENS ROAD
BS8 1QU Bristol
Regno Unito

Mostra sulla mappa

Regione
South West (England) Gloucestershire, Wiltshire and Bristol/Bath area Bristol, City of
Tipo di attività
Higher or Secondary Education Establishments
Collegamenti
Costo totale
€ 1 986 356,00

Beneficiari (1)