Descrizione del progetto
Nuove informazioni sulla fisiopatologia dei disturbi della glicosilazione
I disturbi congeniti della glicosilazione (CDG, congenital disorders of glycosylation) sono caratterizzati da difetti nella glicosilazione di proteine e lipidi. I fenotipi variabili e le presentazioni cliniche di pazienti con le stesse mutazioni genetiche hanno spinto gli scienziati del progetto OST-CDG-omics, finanziato dall’UE, a studiare più da vicino le associazioni genotipo-fenotipo. Utilizzando le tecnologie della trascrittomica e dell’epigenomica, i ricercatori analizzeranno l’impatto della mutazione sulla funzione enzimatica e studieranno anche le proteine più colpite da glicosilazione aberrante. Il lavoro si concentrerà principalmente sul MAGT1, un gene che codifica per una transmembrana trasportatrice di ioni di magnesio. I risultati offriranno informazioni di fondamentale importanza in merito ai geni implicati nella fisiopatologia del CDG, con importanti conseguenze cliniche.
Obiettivo
Congenital disorders of glycosylation (CDG) are a group of over 100 inherited disorders characterised by defective glycosylation of proteins and lipids. Although the phenotypic and genetic characteristics of CDG as a whole are well established, their pathophysiology is poorly understood. In addition, the phenotype of affected patients is extremely variable, with dramatically different clinical presentations often appearing in patients with mutations in the same gene. I plan to investigate the link between pathogenic mutation and phenotype using recent advances in omics technologies, with a focus on the regulation of genes implicated in the pathophysiology of CDG.
Firstly, using transcriptomics and epigenomics, I will identify the mechanism by which mutations in homologous genes encoding subunits of the oligosaccharyltransferase (OST) complex cause divergent phenotypes, thought to be due to differences in the regulation of tissue-specific transcription. The primary model for these studies will be the MAGT1 gene, mutations in which can lead to either a severe developmental disorder (MAGT1-CDG) or an isolated primary immune deficiency (XMEN). Secondly, using glycoproteomic techniques, I will study the proteins most affected by aberrant glycosylation in CDG affecting the OST, thereby characterising their pathophysiology in both patient-derived and modified cell lines. findings will be further investigated using targeted techniques such as LC-MS/MS. In summary, this study will simultaneously provide valuable insight into both the pathophysiology of CDG and the functional regulation of the OST complex, an understudied aspect of cell biology.
Campo scientifico
Parole chiave
Programma(i)
Argomento(i)
Meccanismo di finanziamento
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinatore
3000 Leuven
Belgio