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.

Duchenne的肌肉营养不良（DMD）是由DMD基因突变引起的致命疾病，导致肌营养不良蛋白的缺失或严重降低。当前的疗法无法显着放慢，更不用说治愈该疾病了。我们的提议源于基本观察结果，即即使在DMD的晚期病例中，EOM在临床和病理上仍然保留下来。这是一个有趣的难题，因为我们以前已经表明，正常的人EOM会产生全长肌营养不良蛋白，并且DMD患者的EOM完全不存在肌营养不良蛋白。随着EOM幸免在犬类中，这种现象遍布物种 DMD的（GRMD）和鼠（MDX）模型。尽管提出和测试了许多假设，但对于EOM保留尚无令人满意的解释。 三个关键发现提出了与EOM干细胞有关的新假设，以解释DMD中的EOM保留。首先，已证明成年肌肉包含能够潜水，转变和植入的干细胞。其次，表达分析和代谢标记实验表明，成人EOM中看到的持续肌发生可能与驻留在EOM中的干细胞数量增加有关。第三，已证明MDX表型通过肌生成蛋白介导的肌发生/再生的增强可以改善。 我们建议检验以下假设：EOM干细胞有助于DMD中的EOM保留。我们 将通过分析a）数量和b）在一系列体外和体内实验中与肢体肌肉相比，将居住在成人EOM中的干细胞的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，进行这项研究将为旨在利用成人EOM的肌源性MD干细胞电位的策略提供原则证明，以此作为DMD疗法的可能手段。

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