MODULATION OF MEMBRANE PROTEINS EXPRESSION IN PATHOLOGICAL AND EXPERIMENTAL CONDITIONS IN MUSCULAR DYSTROPHIES

The main objective of this project is to go further inside the knowledge of the mechanisms leading to muscle degeneration in primary muscular dystrophies. In preliminary results we have demonstrated that, in mdx mice, treatment with inhibitors of proteasome, that is the major proteolytic system present in all eukaryotic cells, rescues the muscle membrane expression and localization of dystrophin and dystrophin related proteins. The final target of this study is to demonstrate that it is possible to rescue the membrane expression of affected proteins by using proteasome inhibithor drugs also in human Duchenne muscular dystrophy and in other muscular dystrophies. We will propose to study by immunochemical techniques the expression of membrane proteins in different pathological and experimental conditions. In particular we will test the possibility to modulate, by treatment with proteasome inhibitors, the cell surface expression of membrane proteins in cell models of muscular dystrophies and in human primary cultures from patient with Duchenne and limb girdle muscular dystrophies. The goal of this study is to increase our knowledge of protein interactions at the muscle membrane level in muscular dystrophies, particularly in dystrophin-related disorders and in caveolin-3 deficient LGMD, in order to verify the possibility to modulate the “in situ” expression of muscle proteins by pharmacological treatment in pathological and experimental conditions. Thus, this study may open new and important avenues in our understanding of the pathogenesis of muscular dystrophies. Most importantly, these new findings may have clinical implications for the treatment of patients with Duchenne muscular dystrophy.