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）：外部肌肉（EOM）是高度专业的肌肉，会影响从缓慢的前庭 - 眼反射到快速囊泡运动的广泛运动。对它们的需求是恒定的，并且响应必须精确。由于对这些肌肉的需求与其他骨骼肌上的需求不同，因此EOM的详细特性与其他肌肉的详细特性毫不奇怪。令人惊讶的是，最重要的是EOM对某些疾病具有不同的敏感性。 EOM越来越多地参与肌无力，肌无力，坟墓病和线粒体肌病。尽管所有其他骨骼肌群都广泛参与，但它们神秘地在Duchenne肌肉营养不良中幸免。虽然目前尚不清楚为什么EOM选择性地参与或在不同的疾病中幸免，但已经假设EOM是一组独特的骨骼肌肉，并且其“群体特定”特性在其独特的病态生理学中起着作用。与该假设一致，与其他骨骼肌相比，某些基因（例如EOM特异性肌球蛋白，某些ACHR亚基）在EOM中差异表达。在我们的实验室中，通过比较转录组一小部分的EOM和肢体肌肉的基因表达谱图证实了这一点。 我们的中心论点是，EOM与其基因表达谱的其他骨骼肌根本不同。并且我们可以将其独特的特性和疾病的敏感性追溯到基因表达的特定和独特的模式。为了检验这些假设，我们提出：（a）使用基因表达分析将EOM和肢体肌肉之间的比较扩展到整个转录组；即，超出了我们已经完成的三分之一； （b）使用多种免疫，分子和生化方法来验证以前研究中表达分析和解决不足和差异的结果； （c）检查卫星细胞在用抗肌生抑素和MDX/Myod敲除小鼠中处理的正常小鼠，MDX小鼠，MDX小鼠中维持生长和再生的能力。后一组实验应该从我们以前的分析中验证一个重大发现：增加的再生潜力是EOM对DMD的抗性的来源。