FRZDMD · Contribution of calcium-independent isoforms of phospholipase A2 in the pathogenesis of Duchenne muscular dystrophy

The applicant proposes a 2-year project to be performed under the supervision of Prof Bernheim, a neuromuscular disease expert at the University of Geneva. The goal of this project is to determine the role of isoforms of calcium-independent isoform phospholipase A2 (iPLA2) in cytosolic calcium entry and muscle cell death during Duchenne muscular dystrophy (DMD).DMD is the most severe case of muscle-wasting diseases of the muscular dystrophies family. It affects 1 in 3500 children, and is caused by mutations in dystrophin mRNA leading to the absence of the protein in skeletal muscles from affected patients. As dystrophin is an important player in muscle maintenance, its absence leads to skeletal muscle degeneration. To date, this is an incurable disease with 100% of fatality. Affected boys first lose the ability to walk, then breath, and finally die before being 30 years old. Although many mutations have been characterized, more research is needed to understand the molecular and signaling mechanisms underlying DMD, and increase the opportunities to find new therapeutic targets. Recent experiments have highlighted the importance of calcium entry in muscle fibers death. iPLA2 appears to have a role in this elevated cytosolic calcium, and has been shown to be upregulated both in DMD patients and dystrophic mdx mice. The applicant will 1) establish the implication and roles of the different iPLA2 isoforms in DMD by comparing calcium responses and muscle cell-death in wild-type (wt) and mdx muscle fibers, and 2) determine the effects of specific inhibitors on muscle cell survival.This project could have beneficial issues towards developing new strategies to counteract cytosolic calcium imbalance in muscle fibers from DMD patients, and thus potentially alleviate their symptoms.The applicant will benefit from the expertise of Prof Bernheim and the knowledge she previously acquired abroad to conduct this research project, and later pursue a research and teaching career in Europe.""