Temporal and Spatial patterns of structural proteins in extraocular muscles

眼外肌结构蛋白的时空模式

• 批准号: 7470388
• 负责人: Carole L. Moncman
• 金额: $ 21.98万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-30 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7470388
• 关键词: Adult; Affect; Age; Automobile Driving; Biochemical; Cardiac; Cardiac Myosins; Characteristics; Child; Class; Collagen; Correlative Study; Cues; Cytoskeletal Proteins; Data; Development; Distal; Duchenne muscular dystrophy; Dystrophin; Elements; Embryo; Event; Exhibits; Extracellular Matrix; Eye; Fibronectins; Gene Expression Profile; Gene Expression Profiling; Goals; Hand; Immunologic Techniques; Integrins; Laminin; Learning; Light; Limb-Girdle Muscular Dystrophies; Metabolic; Microfilaments; Molecular; Molecular Profiling; Muscle; Muscular Dystrophies; Myasthenia Gravis; Myofibrillogenesis; Myopathy; Myosin Heavy Chains; Natural regeneration; Nature; Neuromuscular Diseases; Oculopharyngeal Muscular Dystrophy; Operative Surgical Procedures; Pathway interactions; Pattern; Peripheral; Phenotype; Physiological; Property; Protein Isoforms; Proteins; Proteomics; Public Health; Signal Pathway; Signal Transduction; Skeletal Muscle; Skeletal system; Somites; Strabismus; Structural Protein; System; Tissues; Tropomyosin; Troponin; Utrophin; concept; connectin; coping; embryo tissue; extracellular; fetal; insight; member; myogenesis; myomesin; nebulin; nerve supply; novel; novel therapeutics; oculomotor; orbit muscle; postnatal; protein distribution; research study; response; response to injury; scaffold; tool; trait

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.

描述(申请人提供)：眼外肌(EOM)，虽然被归类为骨骼肌，但在其发育起源、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方面是独特的。有趣的是，EOM在许多影响周围骨骼肌的破坏性肌营养不良中幸免于难，例如杜氏肌营养不良和四肢带状肌营养不良，另一方面专门针对眼咽肌营养不良和重症肌无力。支持这一建议的假设是，EOM的肌发生、肌原纤维形成和成熟的独特性质为增强可塑性和再生特性提供了机制。EOM经历了与体节源性骨骼肌不同的发育路径，因此受到不同信号通路的影响。EOM的基因表达谱表明存在心肌和骨骼肌肌原纤维和细胞骨架的亚型mRNAs；然而，除了MyHC和myomesin的显著例外，几乎没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的最终产物，以细胞骨架、肌原纤维和ECM蛋白的形式在发育中的和成年的EOM中表达，并将这些蛋白质的分布与典型的快速肌肉(包括成人和发育中的肌肉)，如EDL进行比较。我们将使用生化和免疫学工具来检测EOMS的肌原纤维、细胞骨架和细胞外基质的表达模式。这些关于整合发育和成熟的EOMS的结构支持和收缩元件的蛋白质的新信息将有助于我们深入了解这种新的成人表型是如何建立的，并应该增加我们对它在斜视中是如何被破坏的理解。公共卫生报道：Duchenne‘s肌营养不良症患者选择性保留眼外肌表明了眼外肌的独特性质，并表明通过研究这块肌肉可以获得对毁灭性肌肉疾病的重要见解。从这一分析中获得的信息可能为开发治疗眼肌疾病和外周骨骼肌疾病的新疗法铺平道路。