PAK1 Activation Reduces Muscular Dystrophy-Mediated Fibrosis

University Of Illinois At Chicago, Chicago IL

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Abstract

Fibrosis is a pathogenic occurrence in many diseases. In the chronic disease muscular dystrophy, fibrosis is particularly devastating as it impedes; function, recovery and treatment delivery. Fibrosis impedes function because it is non-contractile but more importantly for diaphragm and cardiac tissue fibrosis slows relaxation, a key component of optimal muscle function and for cardiac tissue cannot transmit a contraction impulse. Recovery is hampered by fibrosis because muscle stem cells ? satellite cells ? are exquisitely sensitive to their niche and fibrosis destroys the niche. Fibrosis also decreases treatments which cannot progress to their sites of action due to excessive fibrosis. We have statistically significant preliminary data that 3 week treatment with the PAK1 activator FTY-720 drastically inhibits fibrosis in all three muscle tissues tested. We now plan to identify the best dose and treatment regime to inhibit murine muscular dystrophy. We will also investigate if the treatment alleviates other muscular dystrophy phenotypes; membrane permeability, aberrant calcium signaling, and excessive immune infiltration. Finally the mechanisms of action will be investigated. These results will greatly aid patients with muscular dystrophy as FTY-720 is already FDA approved for multiple sclerosis.