Molecular Characterization of Extraocular Muscle

眼外肌的分子表征

• 批准号: 7059921
• 负责人: TEJVIR S KHURANA
• 金额: $ 38.69万
• 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/7059921
• 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(申请人提供)：眼外肌(EOM)是高度专门化的肌肉，影响从缓慢的前庭-眼睛反射到快速的眼跳运动的广泛运动。对他们的要求是持续不断的，回应必须是准确的。由于对这些肌肉的需求不同于对其他骨骼肌的需求，EOMS的详细特性不同于其他肌肉也就不足为奇了。令人惊讶的是--也是最重要的--EOMS对某些疾病具有不同的敏感性。EOMS在重症肌无力、格雷夫氏病和线粒体肌病等疾病中的参与程度增加。令人费解的是，它们在杜氏肌营养不良症中幸免于难，尽管所有其他骨骼肌群都广泛参与其中。虽然目前还不清楚为什么EOM在不同的疾病中选择性地参与或不参与，但已经假设EOM是一组独特的骨骼肌，它们的组特异性特性在其独特的病理生理中发挥了作用。与这一假设一致的是，某些基因(如EOM特异性肌球蛋白、某些ACHR亚基)在EOM中的表达与其他骨骼肌不同。我们实验室通过比较EOMS和肢体肌肉的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，EOMS在基因表达谱上与其他骨骼肌有根本的不同；我们可以将它们的独特属性和疾病易感性追溯到特定和独特的基因表达模式。为了检验这些假说，我们建议：(A)使用基因表达谱方法将EOMS和肢体肌肉之间的比较扩展到整个转录组；即超过我们已完成的三分之一的转录组；(B)使用各种免疫学、分子和生化方法来验证表达谱分析结果，并解决先前研究中的不足和差异；(C)检测正常小鼠、mdx小鼠、mdx小鼠和mdx/myoD基因敲除小鼠中卫星细胞维持生长和再生的能力。后一组实验应该会验证我们之前的一项重大发现：再生潜力的增加是EOM对DMD抗性的一个来源。