Impact of EOM specific myosin loss on extraocular muscle structure and function

描述(由申请人提供)：斜视是儿童的一种常见情况，经常导致永久性视力障碍。当眼外肌发育不完全时，可用的治疗方案针对的是眼外肌。眼外肌与其他肌肉不同；它们甚至有自己的组织特异性肌球蛋白亚型，即EOM特异性肌球蛋白，这种肌球蛋白在出生后不久就出现在与视觉体验有关的出生后眼外肌发育期间：在这段时间里，视觉的缺失扰乱了EOM特异性肌球蛋白的表达，并可能永久性地改变了眼外肌的收缩特性。同样的变化也发生在斜视患者身上，这可能解释了为什么他们中的许多人需要进行多次手术来恢复正常的眼位。这个项目将回答两个问题：EOM特异性肌球蛋白在多大程度上定义了正常的眼外肌功能，以及当这种组织特异性肌球蛋白的表达发生变化时，眼睛肌肉功能如何变化。为了解决这些问题，我们将去除或恢复EOM特异的肌球蛋白基因，以测试该肌球蛋白亚型与眼外肌功能和完整性的相关性。该实验方法依赖于我们最近开发的允许控制EOM特异性肌球蛋白基因表达的小鼠品系，并将检验EOM特异性肌球蛋白是眼外肌结构和功能正常发育所必需的假设，并且其在正常出生后窗口出现并不能恢复肌肉功能。具体目标2将确定EOM特异性肌球蛋白基因消融对小鼠眼外肌结构和功能出生后发育的影响。特定目标2将测试成年小鼠EOM特异性肌球蛋白表达的恢复是否恢复眼外肌功能。这个项目完成后的答案将为先天性斜视手术和治疗的时机提供信息。

DESCRIPTION (provided by applicant): Strabismus is a common condition in children that frequently leads to permanent visual impairment. Available treatment options target the extraocular muscles when they are not fully developed. The extraocular muscles are different from other muscles; they even have their own tissue-specific myosin isoform, EOM-specific myosin, which appears soon after birth during a period of postnatal extraocular muscle development linked to visual experience: absence of vision during this time disrupts EOM-specific myosin expression and alters the contractile properties of the extraocular muscles, perhaps permanently. The same changes occur in strabismus patients, and may explain the need for multiple surgeries to restore normal eye position in many of them. This project will answer two questions: to what extent EOM-specific myosin defines normal extraocular muscle function, and how eye muscle function changes when the expression of this tissue-specific myosin is altered. To address these issues, we will ablate or restore the EOM-specific myosin gene to test the relevance of this myosin isoform to extraocular muscle function and integrity. The experimental approach relies on our recently developed mouse strains that permit control of the expression of the EOM-specific myosin gene, and will test the hypothesis that EOM-specific myosin is necessary for normal development of extraocular muscle structure and function, and its appearance after its normal postnatal window does not restore muscle function. Specific Aim 2 will determine the consequences of EOM-specific myosin gene ablation on the postnatal development of mouse extraocular muscle structure and function. Specific Aim 2 will test whether the recovery of EOM-specific myosin expression in the adult mouse restores extraocular muscle function. The answers that will result from the completion of this project will inform the timing of surgical and medical treatment for congenital strabismus.