Role of PPAR-delta in Duchenne Muscular Dystrophy

描述(申请人提供)：骨骼肌表达多种核受体。然而，它们在肌营养不良症中的作用尚不清楚。最近，我们发现在骨骼肌中过表达核受体PPAR-Delta的转基因小鼠在跑步机上跑的时间是非转基因小鼠的两倍多[转基因/非转基因；时间：140分钟/80分钟；距离：1800米/800米]。这种通过激活PPAR-Delta来改善骨骼肌性能的方法可能对以虚弱和疲劳为特征的营养不良肌肉有益。在这项建议中，我们将测试PPAR-Delta激活降低Duchenne肌营养不良症(DMD)病理的假设。所有与这一假设相关的实验都将在DMD的啮齿动物模型MDX小鼠身上进行。总之，我们将从肌肉形态、基因表达和收缩特性的水平上，检测PPAR-Delta激动剂(GW1516)治疗和肌肉特异性PPAR-Delta过表达对MDX小鼠DMD病理生物标志物的抑制作用。我们的研究结果将揭示PPAR-Delta是否是对抗DMD的合适靶点，以及口服活性PPAR-Delta激动剂是否可以减轻DMD的病理。

DESCRIPTION (provided by applicant): Skeletal muscles express multiple nuclear receptors. However, their role in muscular dystrophy is unknown. Recently, we found that transgenic mice over-expressing nuclear receptor PPAR-delta in skeletal muscles ran twice as long and as far as non-transgenic mice on a treadmill [Transgenic/non-transgenic; time: 140 min/80 min; distance: 1800 m/800 m]. Such an improvement in skeletal muscle performance on activating PPAR-delta may be beneficial in dystrophic muscles, which are characterized by weakness and fatigue. In this proposal we will test the hypothesis that activation of PPAR-delta decreases the pathology of Duchenne muscular dystrophy (DMD). All the experiments related to the hypothesis will be performed in mdx mice, a rodent model of DMD. In brief, we will measure the suppressive effect of both PPAR-delta agonist (GW1516) treatment and muscle specific PPAR-delta over-expression on the pathological biomarkers of DMD in mdx mice at the level of muscle morphology, gene expression and contractile properties. The results from our study will reveal whether PPAR-delta is an appropriate target to counteract DMD as well as whether an orally active PPAR-delta agonist can decrease the pathology of DMD.