Molecular Characterization of Extraocular Muscle

眼外肌的分子表征

• 批准号: 6888029
• 负责人: TEJVIR S KHURANA
• 金额: $ 39.63万
• 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: 2004-05-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6888029
• 关键词: cell cycle; electron microscopy; extraocular muscle; eye movements; functional /structural genomics; gene expression; gene expression profiling; genetically modified animals; growth inhibitors; immunogenetics; in situ hybridization; laboratory mouse; laboratory rabbit; laboratory rat; limbs; microarray technology; molecular biology information system; molecular genetics; muscle satellite cell; muscular dystrophy; myostatin; neuromuscular function; northern blottings; polymerase chain reaction; regeneration; striated muscles; transcription factor

DESCRIPTION (provided by applicant): The extraocular muscles (EOM) are highly specialized muscles that affect a wide range of motions from the slow vestibulo-ocular reflexes to the rapid saccadic movements. The demands on them are constant, and the responses must be precise. Because the demands on these muscles are distinct from those on other skeletal muscles, it is not surprising that the detailed properties of EOMs are different from those of other muscles. What is surprising - and most important - is that the EOMs have differential sensitivity to certain diseases. EOMs have an increased involvement in disorders such as myasthenia gravis, Grave's disease and mitochondrial myopathies. Enigmatically, they are spared in Duchenne muscular dystrophy, despite the widespread involvement of all other skeletal muscle groups. While it is currently unclear why EOM are selectively involved or spared in different diseases, it has been hypothesized that EOM are a unique set of skeletal muscles and that their 'group-specific' properties play a role in their unique patho-physiology. Consistent with this hypothesis, certain genes (e.g. EOM-specific myosin, certain ACHR subunits) are differentially expressed in EOM compared to other skeletal muscles. This has been confirmed in our laboratory by gene expression profiling comparing EOMs and limb muscles over a small part of the transcriptome. Our central thesis is that EOMs are fundamentally different from other skeletal muscles in their gene expression profile; and that we can trace their unique properties and disease susceptibilities to specific and unique patterns of gene expression. To test these hypotheses we propose: (a) to use gene expression profiling to extend the comparison between EOMs and limb muscles to the entire transcriptome; i.e. beyond the one-third that we have already finished; (b) to use a variety of immunological, molecular, and biochemical methods to validate results of expression profiling and resolve inadequacies and disparities among previous studies; (c) to examine the ability of satellite cells to maintain growth and regeneration in normal mice, in mdx mice, in mdx mice treated with anti myostatin, and in mdx/MyoD knockout mice. This latter set of experiments should validate a major discovery from our previous profiling: that increased regenerative potential is a source of EOM resistance to DMD.

描述（由申请人提供）：眼外肌（EOM）是高度专业化的肌肉，影响从缓慢的前庭眼反射到快速的眼跳运动的广泛运动。对他们的要求是恒定的，响应必须准确。由于这些肌肉的需求与其他骨骼肌的需求不同，因此 EOM 的详细特性与其他肌肉的不同也就不足为奇了。令人惊讶且最重要的是 EOM 对某些疾病具有不同的敏感性。 EOM 越来越多地参与重症肌无力、格雷夫氏病和线粒体肌病等疾病。令人费解的是，尽管所有其他骨骼肌群都广泛受累，但它们却幸免于杜氏肌营养不良症。虽然目前还不清楚为什么 EOM 选择性地参与或不参与不同的疾病，但有人假设 EOM 是一组独特的骨骼肌，并且它们的“群体特异性”特性在其独特的病理生理学中发挥着作用。与这一假设一致，某些基因（例如 EOM 特异性肌球蛋白、某些 ACHR 亚基）在 EOM 中与其他骨骼肌相比有差异表达。我们的实验室通过比较 EOM 和肢体肌肉一小部分转录组的基因表达谱证实了这一点。 我们的中心论点是，EOM 的基因表达谱与其他骨骼肌有根本的不同。我们可以根据特定且独特的基因表达模式追踪其独特的特性和疾病易感性。为了检验这些假设，我们建议：（a）使用基因表达谱将 EOM 和肢体肌肉之间的比较扩展到整个转录组；即超出我们已经完成的三分之一； (b) 使用各种免疫学、分子和生物化学方法来验证表达谱的结果并解决先前研究中的不足和差异； (c) 检查正常小鼠、mdx 小鼠、用抗肌生长抑制素治疗的 mdx 小鼠和 mdx/MyoD 敲除小鼠中卫星细胞维持生长和再生的能力。后一组实验应该验证我们之前分析的一个重大发现：再生潜力的增加是 EOM 对 DMD 的抵抗力的一个来源。