Determinants of extraocular muscle function

描述（由申请人提供）：先天性斜视或眼睛错位影响约4%的儿童。然而，现有的治疗方法还不是最理想的，复发率显著或功能结果不理想。眼外肌是眼球运动系统的最终效应臂，是斜视手术和药物治疗的目标。尽管我们对眼外肌生物学和功能的了解仍然不完整。虽然眼外肌属于骨骼肌类，但越来越多的证据表明，这些小肌肉的基本代谢和功能特征与典型骨骼肌有显著不同。首先，线粒体在眼外肌中作为新的快速钙汇，这一机制是眼外肌功能特征的重要决定因素。其次，出生后关键时期的异常视觉体验会显著改变眼外肌，使其变得更弱、更慢、更疲劳。第三，眼外肌的基因表达谱与其他骨骼肌有很大的不同。这些数据表明，眼外肌的不同功能特性必须通过替代的能量供应策略来满足。因此，该项目的目的是了解代谢途径如何适应眼外肌以应对其极端的功能需求。利用完善的功能、分子生物学和生化分析，该项目将确定(1)替代能量供应途径在大鼠眼外肌中的作用；(2)大鼠眼外肌线粒体的差异程度；(3)正常视觉经验在大鼠眼外肌代谢特性建立中的作用。这些实验有望获得眼外肌整体代谢特征的重要新信息，并为这些肌肉的功能和代谢特性提供一个综合的观点。通过了解是什么将眼外肌与其他骨骼肌区分开来，可以设想直接针对这些肌肉的干预措施。

DESCRIPTION (provided by applicant): Congenital strabismus, or eye misalignment, affects about 4% of children. However, available therapies are not yet optimal, with significance incidence of recurrence or unsatisfactory functional results. The extraocular muscles, the final effector arm of the oculomotor system, are the target of surgical and pharmacological treatments for strabismus. This is despite the fact that our understanding of extraocular muscle biology and function remains incomplete. Although the extraocular muscles are included in the skeletal muscle class, there is emerging evidence that basic metabolic and functional characteristics of these small muscles are significantly different from those seen in typical skeletal muscles. First, mitochondria serve as novel fast calcium sinks in extraocular muscles, and this mechanism is an important determinant of the functional characteristics of these muscles. Second, abnormal visual experience during a postnatal critical period significantly alters the extraocular muscles, and renders them weaker, slower and more fatigable. Third, the gene expression profile of the extraocular muscles is greatly different from that of other skeletal muscles. These data suggest that the divergent functional properties of the extraocular muscles must be met by alternative strategies for energy supply. In consequence, the objective of this project is to understand how metabolic pathways have adapted in the extraocular muscles to cope with their extreme functional requirements. Using well-established functional, molecular biological and biochemical assays, this project will determine (1) the role of alternative energy supply pathways in rat extraocular muscles; (2) the extent to which rat extraocular muscle mitochondria are different; and (3) the role of normal visual experience in establishing these metabolic properties in rat extraocular muscles. It is expected that these experiments will obtain significant new information the overall metabolic characteristics of the extraocular muscles, and provide an integrative view of functional and metabolic properties of these muscles. By understanding what sets the extraocular muscles apart from other skeletal muscles, interventions that directly target these muscles can be envisioned.