Structural biology of proteins involved in bone diseases

Summary Remodelling of bone is critical for normal physiological function and becomes dysfunctional in diseases such as Osteoporosis (bone thinning and fragility) and Osteosarcoma (bone cancer), where a paucity of bone material causes debilitating illness that is currently irreversible. Alternatively, mutation of a specific membrane protein, ClC-7, causes a rare inherited disease (Osteopetrosis) in which too much bone material is deposited leading to abnormally increased bone mass. Our preliminary studies have suggested a molecular basis for aberrant function of ClC-7 mutants in Osteopetrosis. The aim of this project is to fully characterise the mechanism of ClC-7 mutations that cause Osteopetrosis in order to develop drugs that mimic the phenotype of these mutations.

Project Details

Remodelling of bone is critical for normal physiological function and becomes dysfunctional in diseases such as Osteoporosis (bone thinning and fragility) and Osteosarcoma (bone cancer), where a paucity of bone material causes debilitating illness that is currently irreversible. Alternatively, mutation of a specific membrane protein, ClC-7, causes a rare inherited disease (Osteopetrosis) in which too much bone material is deposited leading to abnormally increased bone mass. Our preliminary studies have suggested a molecular basis for aberrant function of ClC-7 mutants in Osteopetrosis. The aim of this project is to fully characterise the mechanism of ClC-7 mutations that cause Osteopetrosis in order to develop drugs that mimic the phenotype of these mutations. Uniquely, these drugs would be able to reverse the damage done by a number of debilitating bone diseases. The project will involve a diverse range of experimental approaches, from X-ray crystallography and in silico computational studies to binding studies and functional measurements using advanced electrophysiological techniques and optical assays.

This project is conducted in St Vincent’s Institute of Medical Research, Structural Biology Unit.