We aim at defining the role of macrophages in muscular dystrophy pathogenesis, using mdx mice as the best model for Duchenne Muscular Dystrophy (DMD). We will focus on the crosstalk between macrophages and muscle resident cells. To this end, we will take advantage of a mouse model recently generated in our laboratory, by crossing CD11bDTR mice with mdx mice in order to generate dystrophic mice (CD11bDTR-mdx) where we can transiently remove macrophages from muscles in an inducible manner, by serial intramuscular diphtheria toxin injections.
Specifically, we will investigate muscle regeneration process in CD11bDTR-mdx both treated with Givinostat and injected with diphtheria toxin, in order to dissect the role of macrophages in mediating Givinostat activity.
Muscular dystrophies are characterized by muscle fragility, contraction-induced damage, necrosis, and chronic inflammation. Considering that macrophages are the main cell populations involved in inflammation, both acute and chronic, dissecting the role of these cells in muscular dystrophies may represent a crucial point for therapeutic approaches. Indeed, macrophages could represent the key cell population able to mediate the action of anti-inflammatory drugs. For instance, corticosteroids have anti-inflammatory properties and have been used to treat DMD with some success; however, the side effects of these drugs often outweigh their benefits. Recently, Histone deacetylates inhibitors (HDACi, i.e. ITF2357, also referred to as Givinostat) have been considered as valid candidate drugs for pharmacological interventions in muscular dystrophies. Indeed, Histone deacetylases (HDACs) control the transcriptional networks underlying both muscle differentiation and progression of dystrophy, together with factors involved in inflammation. A more clear study of mechanisms and cell (or cells) that mediates the effects of HDAC inhibitors on dystrophic muscles will provide powerful clues to future combinatorial therapeutic approaches in treatment of DMD. One of the hurdles for the translation into clinical trials of experimental drugs endowed with therapeutic potential in animal models of muscular dystrophy is the absence of information on critical pharmacological parameters in children, an issue that often complicates the use of these drugs in DMD boys. A notable exception is represented by ITF2357, which is being tested currently in a phase I safety study in children affected by Systemic Onset Juvenile Arthritis (SOJIA, Vojinovic et al., 2011).
Moreover, the mouse model (CD11bDTR-mdx) generated in our laboratory represents the first transgenic model in which is possible to eliminate efficiently macrophages from dystrophic muscles in an inducible and transient manner. It would represent a valuable system to investigate particular hallmarks of dystrophy, for instance chronic inflammation, as well as fibrosis and fat deposition.
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