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都是独特的。有趣的是，EOM在许多影响周围骨骼肌的破坏性肌肉萎缩症中都没有发生，例如杜氏肌萎缩症和肢带肌萎缩症，另一方面，EOM是专门针对眼咽肌萎缩症和重症肌无力的。推动这一提议的假设是，肌生成、肌纤维形成和EOM成熟的独特性质为增强可塑性和再生特性提供了机制。EOM经历了与体肌衍生的骨骼肌不同的发育路径，因此受到不同信号通路的影响。EOM的基因表达谱暗示心肌和骨骼肌肌原纤维和细胞骨架mrna的同种异构体的存在；然而，除了MyHC和myomesin的显著例外，很少有生化数据来证实这些数据。这个探索性项目的一个主要目标是评估这些信号通路中以细胞骨架、肌纤维和ECM蛋白的形式表达的最终产物，并将这些蛋白质分布与原型快速肌肉（包括成人和发育中）如EDL进行比较。我们将使用生化和免疫学工具来检查EOMs的肌原纤维、细胞骨架和细胞外基质的表达模式。关于整合发育和成熟EOMs的结构支持和收缩元素的蛋白质的新信息将有助于了解这种新的成人表型是如何建立的，并有助于我们了解它是如何在斜视中被破坏的。公共卫生相关性：杜氏肌营养不良症选择性保留眼外肌表明了眼外肌的独特性质，并表明通过研究眼外肌可以了解毁灭性肌肉疾病的重要见解。在这一分析中获得的信息可能为眼肌疾病和周围骨骼肌疾病的新治疗方法的发展铺平道路。

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.