DETERMINANTS OF EXTRAOCULAR MUSCLE FUNCTION

描述（改编自申请人摘要）：眼外肌（EOM） 不是典型的骨骼肌它们的解剖排列和纤维类型 异质性提示了功能多样性， 特性呈现出在其他骨骼肌中不常见的特征。 EOM的一个特征是存在两个纤维层：轨道层，更靠近 而全球性的，更接近眼球。每一层都有一个特定的 纤维类型的群体，并可能在眼球运动中具有特定的作用。在 此外，在所有哺乳动物骨骼中， 肌肉，可能是由于他们几乎不断的活动。然而，在这方面， 我们对EOMS的结构特征的了解， 转化为这个肌肉群的功能特性。功能 轨道层和全球层之间的差异，以及线粒体的作用 在EOMs的游离胞浆Ca ~（2+）的瞬时调节中， 被探索。该项目的中心假设提出，EOM 功能取决于不同Ca 2+处理的区室化 分离肌肉层的特性以及线粒体作为新的 胞浆Ca 2+下沉。这一假设将通过实验进行验证， 体外生理学和药理学研究， Ca 2+特异性荧光光谱。确定的功能限制 EOM和那些决定它们的细胞元素，我们将（1）检查 （2）分析了EOM的Ca ~（2+）转运能力 确定的EOM纤维的动力学;和（3）确定功能性 EOM异常发展的后果。拟议的实验是一个 建立确定细胞成分的初步方法， EOM的功能特性。首先，现有证据表明， 两个EOM层的功能特性不同。第二，快速Ca 2 + 由EOM处理可能包括线粒体作为替代的新用途， Ca 2+下沉。第三，视觉发育异常和眼外膜特异性破坏 肌球蛋白的表达可能会改变心肌细胞的Ca ~（2+）处理特性， EOM。该项目的结果将增加我们对 眼外肌的生理学，并提供对这一肌肉群的行为的见解 在诸如斜视的疾病中，以及它们对治疗性药物的反应， 干预措施。

DESCRIPTION (Adapted from Applicant's abstract): The extraocular muscles (EOMs) are not typical skeletal muscles. Their anatomical arrangement and fiber type heterogeneity are suggestive of functional versatility, and their contractile properties present characteristics not commonly seen in other skeletal muscles. A feature of EOMs is the presence of two fiber layers: orbital, closer to the orbit; and global, closer to the eyeball. Each layer has a particular population of fiber types and may have a specific role in eye movement. In addition, EOMs have the highest mitochondrial content of all mammalian skeletal muscles, probably as a consequence of their almost constant activity. However, we know more about the structural traits of the EOMS than we do about how these translate into the functional properties of this muscle group. The functional differences between the orbital and global layers, and the role of mitochondria in the instantaneous regulation of free cystolic Ca 2+ of EOMs have not yet been explored. The central hypothesis of this project proposes that EOM function depends on the compartmentalization of distinct Ca2+handling properties to discrete muscle layers and the use of mitochondria as novel cytosolic Ca2+ sinks. This hypothesis will be tested with experiments combining in vitro physiological and pharmacological studies with the use of Ca2+-specific fluorescence spectroscopy. To establish the functional limits of EOMs and those cellular elements that determine them, we will (1) examining the Ca2+ handling ability of global and orbital layers of EOM; (2) analyze the Ca2+ kinetics of identified EOM fibers; and (3) determine the functional consequences of abnormal EOM development. The proposed experiments are an initial approach to establishing the cellular elements that determine the functional properties of EOMs. First, available evidence suggests that the functional properties of the two EOM layers are different. Second, rapid Ca2+ handling by the EOMs may include the novel use of mitochondria as alternative Ca2+ sinks. Third, abnormal visual development and disrupted EOM-specific myosin expression may alter the contractile of Ca2+ handling characteristics of EOMs. The results from this project will increase our understanding of the physiology of EOMs, and provide insights into the behavior of this muscle group in disorders such as strabismus, and their response to therapeutic interventions.