Protein kinase C Theta as a novel molecular target to counteract inflammation in Muscular Dystrophy

Duchenne muscular dystrophy (DMD) is a genetic disease characterized by muscular tissues degeneration and progressive weakness and reduction of motor capabilities. The primary defect in DMD is the lack of dystrophin, an important structural protein, however, inflammatory response plays a crucial role in the progression of the disease. Numerous anti-inflammatory therapies have been reported to improve healing, and are presently used in the treatment of DMD. However, the side effects of these drugs often outweigh their benefit. We recently observed that lack of Protein Kinase C ? (PKC?) in the bi-genetic mdx/?-/- mutant mice improves healing, regeneration and strength of skeletal muscle, preventing massive inflammation, revealing an unexpected anti-inflammatory role of PKC? in the progression of the disease. Many recent studies showed that lack or inhibition of PKC? in mice prevents immune disorders. Of note, mice lacking PKC? may still mount a normal protective immune response to clear viral infections, making it a particularly attractive target to selectively manipulate immune response that are relevant to pathogenesis of different diseases. Indeed, a large effort is now devoted to the synthesis of pharmacological PKC? inhibitors, to be used for anti-inflammatory therapies. In this context, our findings suggest that it can be targeted within a therapeutic approach for dystrophy. The goal of this project is to validate, using mdx mice as a model of DMD, that targeting (PKC?), an enzyme highly expressed in both immune cells and muscle, can be proposed as a valuable anti-inflammatory approach for the therapy of muscular dystrophy. We will deeply characterize the immune response in the dystrophic mice lacking PKC?, with the final goal of developing a pharmacologically-based therapeutic approach, as the basis for the eventual clinical studies in humans.