Molecular Characterization of Extraocular Muscle

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-眼反射到快速的跳眼运动的广泛运动。对他们的要求是不变的，回应必须是精确的。由于对这些肌肉的需求不同于其他骨骼肌，因此EOMs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——eom对某些疾病的敏感度不同。eom在重症肌无力、格雷夫斯病和线粒体肌病等疾病中的作用越来越大。令人费解的是，它们在杜氏肌营养不良症中幸免，尽管所有其他骨骼肌群都广泛参与。虽然目前尚不清楚为什么EOM选择性地参与或不参与不同的疾病，但已经假设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作用。与这一假设相一致的是，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中表达差异。我们的实验室通过比较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。

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.