Francesco Muntoni & Carsten G. Bonnemann Collaboration
Title: Genetic, cellular and translational research in the muscular dystrophies: Imaging, regeneration, and the extracellular matrix
Mutations in a number of proteins located in the extracellular matrix (ECM) or in glycosyltransferases that in turn modify ECM proteins or their cellular receptors are a common cause of muscular dystrophies. They may present with childhood or even congenital onset, suggesting that the mutant ECM affects muscle maintenance and probably muscle formation already during development. In addition, most muscular dystrophies result in prominent and progressive changes in the ECM of muscle, along with the ongoing muscle damage and death.
This ECM reaction is accompanied by inflammatory infiltrates and eventually followed by replacement of muscle by fibrous and adipose tissues. It is likely that the buildup of this abnormal ECM further impairs muscle maintenance and regeneration, making it an important target for therapeutic intervention.
- Imaging techniques as biomarkers of ECM disease progression in animal models of muscular dystrophies. In this project, we aim to assess the efficacy of novel muscle imaging using magnetic resonance and magnetic resonance spectroscopy as well a molecular imaging techniques to assess the pattern of muscle degeneration and of matrix reactions in various mouse models of muscular dystrophy (including laminin2, dystrophin, and collagen VI deficient mice). In particular, we will aim to develop quantitative tools to assess the amount of fibrosis, fat replacement, inflammation, and regeneration in order to monitor their evolution and to follow the effect of therapeutic interventions such as genetic, molecular and pharmacological therapies.
- The role of pathological extracellular matrix in muscle regeneration in muscular dystrophies. The precise role that abnormal ECM has on the function of satellite cells and other muscle resident and transplanted stem cells is presently unknown, but of potentially great importance. This question will be further explored in this project using both relevant animal and cellular models and a variety of experimental paradigms and genetic manipulations.
- Discovery of novel ECM related muscular dystrophies. Many muscular dystrophies for which an ECM etiology can be assumed have not been clarified with respect to their genetic cause. We are using state of the art genetic and genomic technologies to discover the genetic cause in selected patients and families. We will the use available resources to generate the corresponding animal models allowing in-depth analysis of novel conditions along the lines outlined in the previous projects.