Extraocular muscle stem cells for DMD therapy

杜氏肌营养不良症（DMD）是由DMD基因突变引起的致命疾病，其导致肌营养不良蛋白的缺失或严重减少。目前的治疗方法不能显著减缓，更不用说治愈这种疾病了。我们的建议源于基本的观察，即即使在DMD的晚期病例中，眼外肌在临床和病理上仍然幸免。这提出了一个有趣的难题，因为我们以前已经表明，正常的人眼外肌产生全长肌营养不良蛋白和肌营养不良蛋白是完全不存在的DMD患者的眼外肌。这种现象在物种之间延伸，因为EOM在犬中幸免于难。 （GRMD）和DMD的鼠（mdx）模型。没有令人满意的解释EOM备用存在，尽管已经提出了许多假设和测试。 三个关键的发现提出了一个新的假设，有关眼外肌干细胞来解释眼外肌保留DMD。首先，成人肌肉已被证明含有能够潜水，转分化和移植的干细胞。第二，表达谱和代谢标记实验表明，在成人眼外肌中看到的持续的肌生成可能与眼外肌中驻留的干细胞数量增加有关。第三，mdx表型已显示通过肌生成抑制素阻断剂介导的肌生成/再生增强而改善。 我们建议测试的假设，眼外肌干细胞有助于保存眼外肌在DMD。我们 将通过分析在一系列体外和体内实验中，与肢体肌肉相比，成人眼外肌中干细胞的a）数量和B）植入和治疗潜力来检验这一假设。这些研究对于促进我们对DMD病理生理学的基本理解至关重要。此外，进行这项研究将提供一个原则证明的策略，旨在利用成人眼外肌的肌源性md干细胞的潜力，作为一种可能的手段DMD治疗。

Duchenne's muscular dystrophy (DMD) is a fatal disorder caused by mutations in the DMD gene that results in an absence or severe reduction of dystrophin. Current therapies can not significantly slow down, let alone cure the disease. Our proposal stems from the basic observation that EOMs remain clinically and pathologically spared even in advanced cases of DMD. This presents an intriguing conundrum since we have previously shown that normal human EOM produce full-length dystrophin and that dystrophin is completely absent in the EOM of DMD patients. This phenomena extends across species as EOM are spared in the canine (GRMD) and murine (mdx) models of DMD. No satisfactory explanation for EOM sparing exists, despite many hypotheses having been proposed and tested. Three key findings suggest a novel hypothesis related to EOM stem cells to explain EOM sparing in DMD. First, adult muscle has been shown to contain stem cells that are capable of diving, transdifferentiation and engraftment. Second, expression profiling and metabolic labeling experiments suggest that the continual myogenesis seen in adult EOM may be related to increased numbers of stem cells resident in EOM. Third, the mdx phenotype has been shown to be ameliorated by myostatin blockade-mediated enhancement of myogenesis/regeneration. We propose to test the hypothesis that EOM stem cells contribute to sparing of EOM in DMD. We will test this hypothesis by analyzing a) the number and b) the engraftment and therapeutic potential of stem cells resident in adult EOM compared to limb muscle in a series of in vitro and in vivo experiments. The studies are critical for advancing our basic understanding of DMD pathophysiology. Additionally, undertaking this research would provide a proof-of-principle for a strategy designed to harness the myogenic md stem cell potential of adult EOM as a possible means of DMD-therapy.