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）是高度特化的肌肉，影响从缓慢前庭眼反射到快速扫视运动的广泛运动。对他们的要求是不断的，他们的反应必须是精确的。由于对这些肌肉的要求与对其他骨骼肌的要求不同，因此EOM的详细特性与其他肌肉不同也就不足为奇了。令人惊讶的是--也是最重要的是--眼外肌对某些疾病的敏感性不同。EOM在诸如重症肌无力、格雷夫斯病和线粒体肌病的疾病中的参与增加。令人费解的是，他们幸免于杜氏肌营养不良症，尽管广泛参与所有其他骨骼肌群。虽然目前还不清楚为什么EOM选择性地参与或幸免于不同的疾病，它已被假设，EOM是一组独特的骨骼肌和他们的“组特异性”的属性在其独特的病理生理学中发挥作用。与这一假设相一致，某些基因（例如眼外肌特异性肌球蛋白，某些ACHR亚基）在眼外肌中的表达与其他骨骼肌相比存在差异。这已经在我们的实验室中通过基因表达谱比较EOM和肢体肌肉的一小部分转录组得到证实。 我们的中心论点是，眼外肌在基因表达谱上与其他骨骼肌有着根本的不同;我们可以将其独特的性质和疾病易感性追溯到特定和独特的基因表达模式。为了验证这些假设，我们提出：（a）使用基因表达谱将眼外肌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）检查卫星细胞在正常小鼠、mdx小鼠、用抗肌生长抑制素处理的mdx小鼠和mdx/MyoD敲除小鼠中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主要发现：增加的再生潜力是EOM对DMD抗性的来源。