Temporal and Spatial patterns of structural proteins in extraocular muscles

描述（由申请人提供）：眼外肌（EOM）虽然被归类为骨骼肌，但其发育起源、肌球蛋白重链（MyHC）蛋白亚型表达的发育模式和神经支配模式是独特的。有趣的是，EOM在许多影响外周骨骼肌的破坏性肌营养不良症中幸免，例如杜氏肌营养不良症和肢带肌营养不良症，另一方面，EOM特异性靶向眼咽肌营养不良症和重症肌无力。驱动这一提议的假设是，EOM的肌发生、肌原纤维发生和成熟的独特性质提供了增强的可塑性和再生特性的机制。眼外肌与体节衍生的骨骼肌经历不同的发育路径，因此受到不同信号通路的影响。EOM的基因表达谱表明存在心肌和骨骼肌肌原纤维和细胞骨架mRNA的亚型;然而，除了MyHC和肌桥蛋白的显著例外，几乎没有生化数据来证实这些数据。如具体目标中所述，该探索性项目的主要目标是评价这些信号传导途径中的终产物，其形式为发育中和成人EOM中表达的细胞骨架、肌原纤维和ECM蛋白，并将这些蛋白分布与原型快肌（成人和发育中）如EDL进行比较。我们将使用生物化学和免疫学的工具来研究肌原纤维，细胞骨架和细胞外基质的EOMs的表达模式。这一新的信息的蛋白质，整合的结构支持和收缩元素的发展和成熟的EOMs将产生洞察这种新的成人表型是如何建立的，并应增加我们的理解，它是如何被破坏的斜视。 公共卫生救济：在杜氏肌营养不良症的眼外肌的选择性保留证明了眼外肌的独特性质，并表明通过研究这种肌肉可以了解到破坏性肌肉疾病的重要见解。本分析中获得的信息可能为眼肌疾病和外周骨骼肌疾病的新治疗方法的开发铺平道路。

DESCRIPTION (provided by applicant): Extraocular muscles (EOM), although classified as skeletal muscle, are unique in their developmental origin, developmental pattern of myosin heavy chain (MyHC) protein isoform expression and patterns of innervation. Interestingly, EOM are spared in many of the devastating muscular dystrophies that affect the peripheral skeletal muscle, such as Duchenne's and limb girdle muscular dystrophies and on the other hand are specifically targeted in oculopharyngeal muscular dystrophy and myasthenia gravis. The hypothesis driving this proposal is that the unique nature of the myogenesis, myofibrillogenesis and maturation of the EOM provide the mechanisms for enhanced plasticity and regenerative properties. The EOM undergo a different developmental path than the somite derived skeletal muscles and therefore are affected by different signaling pathsways. Gene expression profiling of EOM have implicated the presence of both cardiac and skeletal muscle isoforms of myofibrillar and cytoskeletal mRNAs; however, with the notable exceptions of MyHC and myomesin, there is little biochemical data to substantiate these data. A major goal of this exploratory project as outlined in the specific aims is to evaluate the end products in these signaling pathways in the form of the cytoskeletal, myofibrillar and ECM proteins expressed in the developing and adult EOM and compare these protein distributions to prototypic fast muscle (both adult and developing) such as the EDL. We will use biochemical and immunological tools to examine the expression patterns of the myofibrillar, cytoskeletal and extracellular matrix of EOMs. This new information on the proteins that integrate the structural support and contractile elements of the developing and mature EOMs will yield insights into how this novel adult phenotype is established and should add to our understanding of how it is disrupted in strabismus. PUBLIC HEALTH RELEVENCE: The selective sparing of the extraocular muscle in Duchenne's muscular dystrophy demonstrates the unique nature of the extraocular muscle and suggests that important insights into devastating muscular disease can be learned by studying this muscle. Information gained in this analysis may pave the road for the development of new therapeutic treatments for both eye muscle diseases and peripheral skeletal muscle diseases.