PAK1 Activation Reduces Muscular Dystrophy-Mediated Fibrosis

纤维化是许多疾病的致病因素。慢性病中的肌肉 营养不良，纤维化尤其具有破坏性，因为它阻碍；功能、恢复和治疗 送货。纤维化阻碍功能，因为它是非收缩的，但更重要的是 横隔膜和心肌组织纤维化减缓松弛，这是最佳肌肉的关键组成部分 心脏功能和心脏组织不能传递收缩冲动。经济复苏受到以下因素的阻碍 纤维化是因为肌肉干细胞--卫星细胞--对它们的利基和 纤维化症破坏了这个利基。纤维化还会减少不能进展到 由于过度纤维化而导致的作用部位。我们有统计上有意义的初步数据，3 使用PAK1激活剂FTY-720治疗一周可显著抑制所有三种肌肉的纤维化 测试了纸巾。我们现在计划确定抑制小鼠的最佳剂量和治疗方案 肌肉营养不良症。我们还将研究该疗法是否缓解了其他肌肉营养不良症。 表型：膜通透性、钙信号异常和过度免疫 渗透。最后，对其作用机制进行了探讨。这些结果将极大地帮助 作为FTY-720的肌营养不良患者已经被FDA批准用于多发性硬化症。

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.