Project Objectives

The principal aim of the proposed STREP is to determine the molecular mechanisms that underpin the pathophysiology of a number of distinct chondrodysplasia phenotypes, which result from mutations in one of a group of different gene products that are important for normal bone development. To achieve this objective we have developed a series of mouse models of chondrodysplasia that closely mimic the relevant human phenotype. We will now study in-depth the growth plate of these mice to determine the molecular, cell and extracellular matrix pathology of these distinct phenotypes.

In this context the objectives of this project are:-

1. To comprehensively define the clinical and radiographic phenotype of the mouse models during skeletal development.
2. To generate a visual interpretation of the different changes in growth plate morphology resulting from a range of diverse disease-causing mutations.
3. To determine the changes in the spatio-temporal location of proteins within the ECM and the effect on cell phenotype and function of disease-causing mutations.
4. To determine how specific disease-causing mutations affect chondrocyte gene expression and the resulting protein composition (proteome) of the growth plate.
5. To compare molecular mechanisms between the different mouse models to identify common basic mechanisms and learn general principles about genotype-phenotype correlations.

By the end of the project this multidisciplinary systems biology approach will allow us to generate a virtual representation of a cartilage growth plate in health and disease and pave the way for developing therapeutic strategies that might be targeted to a range of individual phenotypes.