Project description
Muscular dystrophies: the role of the extracellular matrix
Muscular dystrophies (MD) are a group of genetic disorders associated with weakness and progressive loss of muscle. MDs are primarily caused by defects in the trans-membrane dystroglycan protein complex, a structural and functional bridge between the myofiber contractile apparatus and the extracellular matrix (ECM). The key objective of the EU-funded DYSTROPHIC-ECM project is to identify ECM alterations associated with MD. For this purpose, researchers will analyse ECM composition using proteomics in different mouse models of MD. The project will also explore how ECM alterations affect various processes paramount for MD pathophysiology such as myogenesis, angiogenesis and fibrosis.
Objective
Most of the muscular dystrophies (MDs) are due to defects the trans-membrane protein complex called Dystro-Glycan
Complex, which is a structural and functional bridge between myofiber contractile apparatus and extracellular matrix
(ECM).MD research is focused upon the cellular mechanisms of the pathology and there is a lack of information about how
ECM molecules can affect MDs, although alteration in ECM composition is acknowledged since fibrosis is an important bad
outcome in the patients.Our hypothesis is that alterations in dystrophic muscle ECM directly account for mechanisms which
negatively affect skeletal muscle homeostasis.The goal of the project is to identify alterations in ECM compromised by
muscular dystrophy and to investigate their effects on cell behavior.Mdx mouse (model for Duchenne Muscular Dystrophy)
and Sarcoglycan-β-null mouse (model for Limb Girdle Muscular Dystrophy 2E) will be used.To obtain the ECMs we will take
advantage of decellularization approach that removes the cellular components while maintaining the molecular and structural
features as closer as possible to the native ECM.In tissue engineering the use of ECM biomaterials demonstrated that ECM
plays a fundamental, active role in tissue remodeling by growth factors release and ECM degradation product
action.Molecular alterations in the ECM composition will be investigated by proteomics that assures an accurate and
exhaustive characterization.ECM will be used as 3D environment to study its functions in the behavior of primary cells
involved in the pathology: myogenic stem cells, endothelial cells, fibro-adipogenic precursors and macrophages.Discovering
how alterations in dystrophic muscle ECM affect myogenesis, angiogenesis, fibrosis and inflammatory response will be of
paramount importance for a better understanding of MDs.Changing the focus of the research from the cells to the ECM, this
study will provide a new point of view and could contribute to identify new therapeutic targets.
Fields of science
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsproteomics
- medical and health sciencesmedical biotechnologytissue engineering
- medical and health sciencesmedical biotechnologycells technologiesstem cells
- medical and health sciencesbasic medicineneurologymuscular dystrophiesduchenne muscular dystrophy
- medical and health sciencesbasic medicinepathology
Programme(s)
Funding Scheme
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinator
69622 Villeurbanne Cedex
France