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The Role of Protein N-Glycosylation in Bone and Energy Homeostasis

Obiettivo

Osteoporotic bone loss due to aging or disease is a major health issue that affects hundreds of millions of people worldwide and costs tens of billions of euros each year. Since current osteoporosis medication only reduces fracture risk by 25-50%, there is an urgent need to define new pathways that control bone remodelling and strength in order to identify new therapeutic targets. Via the ‘Mouse Genetics Project’ consortium, we identified a mutation in one of the enzymes involved in the N-linked protein glycosylation pathway that leads to profound osteoporosis and obesity in mice; this observation accorded with the outcome of comparable human pathologies (congenital disorders of glycosylation). Though bone contains a large amount of glycoproteins, the importance of protein N-glycosylation to skeletal homeostasis remains to be characterised. This project aims (1) to identify the role of protein N-glycosylation in bone homeostasis, (2) to assess mechanistically how bone cell functioning is regulated by this process, and (3) to characterise the metabolic abnormalities associated with defects in N-glycosylation and to address its linkage to bone. We hypothesise that defective N-glycosylation impairs bone formation by osteoblasts, leading to the observed osteoporosis, and, likely, reduced bone-derived osteocalcin levels, which will in turn result in hampered insulin release and insulin resistance, with the observed obesity as a consequence. By combining the applicant’s and host’s skills in mouse genetics, skeletal phenotyping and high-throughput techniques, with the expertise in energy homeostasis, mouse embryonic stem cell technologies and (glyco)proteomics at the Wellcome Trust Sanger Institute, we are confident to gain insight in a process that most possibly regulates osteoblast functioning and bone matrix production; this knowledge will contribute to the development of novel, urgently warranted anabolic medication to treat osteoporosis.

Campo scientifico (EuroSciVoc)

Argomento(i)

Invito a presentare proposte

FP7-PEOPLE-2013-IEF
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Meccanismo di finanziamento

MC-IEF - Intra-European Fellowships (IEF)

Coordinatore

GENOME RESEARCH LIMITED LBG
Contributo UE
€ 221 606,40
Indirizzo
WELLCOME SANGER INSTITUTE WELLCOME GENOME CAMPUS HINXTON
CB10 1SA SAFFRON WALDEN
Regno Unito
Regione
East of England East Anglia Cambridgeshire CC
Tipo di attività
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Costo totale
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