Extraocular muscle stem cells for DMD therapy

眼外肌干细胞用于 DMD 治疗

• 批准号: 6953261
• 负责人: TEJVIR S KHURANA
• 金额: $ 7.93万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6953261
• 关键词: cell population study; disease /disorder model; dystrophin; extraocular muscle; fluorescent in situ hybridization; genetically modified animals; laboratory mouse; limbs; muscle satellite cell; muscular dystrophy; myoblasts; myogenesis; nonhuman therapy evaluation; regeneration; stem cell transplantation; tissue /cell culture

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.

杜氏肌营养不良症 (DMD) 是一种致命性疾病，由 DMD 基因突变导致肌营养不良蛋白缺失或严重减少。目前的疗法无法显着减缓疾病，更不用说治愈疾病了。我们的建议源于这样的基本观察：即使在 DMD 的晚期病例中，EOM 在临床和病理上仍能幸免。这是一个有趣的难题，因为我们之前已经证明，正常人 EOM 产生全长肌营养不良蛋白，而 DMD 患者的 EOM 中完全不存在肌营养不良蛋白。这种现象遍及各个物种，而犬科动物则幸免于难 (GRMD) 和小鼠 (mdx) DMD 模型。尽管已经提出并测试了许多假设，但对于 EOM 保留还没有令人满意的解释。 三个关键发现提出了一个与 EOM 干细胞相关的新假设，可以解释 DMD 中 EOM 的保留。首先，成人肌肉已被证明含有能够潜水、转分化和植入的干细胞。其次，表达谱和代谢标记实验表明，成人 EOM 中持续的肌生成可能与 EOM 中干细胞数量的增加有关。第三，mdx表型已被证明可以通过肌生长抑制素阻断介导的肌生成/再生增强得到改善。 我们建议检验 EOM 干细胞有助于避免 DMD 中 EOM 的假设。我们 通过在一系列体外和体内实验中与肢体肌肉相比，分析成人 EOM 中干细胞的 a) 数量和 b) 植入和治疗潜力，来检验这一假设。这些研究对于增进我们对 DMD 病理生理学的基本了解至关重要。此外，开展这项研究将为旨在利用成人 EOM 的肌源性 md 干细胞潜力作为 DMD 治疗的可能手段的策略提供原理验证。

项目成果

Transcriptional and functional differences in stem cell populations isolated from extraocular and limb muscles.

• DOI: 10.1152/physiolgenomics.00051.2008
• 发表时间: 2009-03
• 期刊: Physiological genomics
• 影响因子: 4.6
• 作者: E. C. Pacheco-Pinedo;M. Budak;U. Zeiger;L. Jørgensen;S. Bogdanovich;H. Schrøder;N. Rubinstein;T. Khurana