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

Objective

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.

Field of science

  • /medical and health sciences/basic medicine/pathology
  • /medical and health sciences/medical biotechnology/cells technologies/stem cells
  • /medical and health sciences/basic medicine/physiology/homeostasis
  • /medical and health sciences/basic medicine/pharmacology and pharmacy/pharmaceutical drug
  • /natural sciences/biological sciences/genetics and heredity/mutation
  • /natural sciences/biological sciences/genetics and heredity
  • /natural sciences/biological sciences/biochemistry/biomolecules/proteins/proteomics
  • /natural sciences/biological sciences/biochemistry/biomolecules/proteins/enzymes

Call for proposal

FP7-PEOPLE-2013-IEF
See other projects for this call

Funding Scheme

MC-IEF - Intra-European Fellowships (IEF)

Coordinator

GENOME RESEARCH LIMITED
Address
The Gibbs Building, Euston Road 215
NW1 2BE London
United Kingdom
Activity type
Research Organisations
EU contribution
€ 221 606,40
Administrative Contact
Martin Dougherty (Dr.)