PAK1 Activation Reduces Muscular Dystrophy-Mediated Fibrosis

纤维化是许多疾病中的致病性发生。在慢性疾病肌肉 营养不良，纤维化是特别具有破坏性的，因为它阻碍;功能，恢复和治疗 交付.纤维化阻碍功能，因为它是非收缩性的，但更重要的是， 隔膜和心脏组织纤维化减缓松弛，松弛是最佳肌肉的关键组成部分 心脏组织不能传递收缩脉冲。复苏受到以下因素的阻碍 纤维化，因为肌肉干细胞-卫星细胞-对它们的生态位非常敏感， 纤维化破坏了生态位。纤维化还减少了不能进展到它们的治疗。 由于过度纤维化的作用部位。我们有统计学上显著的初步数据， 用PAK 1激活剂FTY-720治疗一周，可显著抑制所有三种肌肉中的纤维化 测试组织。我们现在计划确定最佳剂量和治疗方案，以抑制鼠 肌肉萎缩症我们还将调查是否治疗其他肌营养不良症 表型;膜通透性，异常钙信号传导，和过度免疫 浸润最后将研究其作用机制。这些结果将大大有助于 FTY-720已经被FDA批准用于治疗多发性硬化症。

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.