Understanding mammalian biomineralisation in health and disease via a molecular dissection of the mechanisms underpinning amelogenesis imperfecta. (360G-Wellcome-093113_B_10_Z)

Biomineralisation the controlled deposition and regulated growth of minerals in biological systems - generates biomaterials with complex architecture and specific biological functions. Control of biomineralisation is thought to be mediated via extracellular organic matrices but the precise mechanisms remain obscure. Dental enamel is the most extreme example of mammalian biomineralisation and amelogenesis is an excellent paradigm for biomineralisation more generally. Inherited defects of enamel formation (Amelogenesis imperfecta; AI) have been described that provide the opportunity to simultaneously dissect the fundamental events underlying biomineralisation processes and the molecular pathogenesis of skeletal disease. Despite the identification of genetic mutations underlying nine forms of AI (four of these by our own group), the precise causal mechanisms of the resulting biomineralisation defects have yet to be determined and new insights from our own studies are revealing hitherto unidentified cellular pathways that are fundamental to the process. The overall aim of the proposed programme is to define enamel biomineralisation in health and disease via an integrated, multi-disciplinary approach involving human and mouse genetics, detailed tissue phenotyping and functionality studies. The results will not only increase our understanding of AI but will also be used to inform novel therapeutic strategies to target human skeletal pathologies.