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疾病，经常导致永久性视力损害。当眼外肌尚未完全发育时，可用的治疗方案针对眼外肌。眼外肌不同于其他肌肉；他们甚至有自己的组织特异性肌球蛋白异构体，eom特异性肌球蛋白，在出生后不久就出现在与视觉经验相关的出生后眼外肌发育期间：在此期间视力缺失会破坏eom特异性肌球蛋白的表达并改变眼外肌的收缩特性，可能是永久性的。斜视患者也有同样的变化，这可能解释了许多斜视患者需要多次手术才能恢复正常眼位的原因。该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改变时，眼肌功能如何改变。为了解决这些问题，我们将切除或恢复eom特异性肌球蛋白基因，以测试这种肌球蛋白异构体与眼外肌功能和完整性的相关性。实验方法依赖于我们最近开发的小鼠菌株，该菌株允许控制eom特异性肌球蛋白基因的表达，并将验证eom特异性肌球蛋白对于眼外肌结构和功能的正常发育是必要的，并且它在正常的出生后窗口后出现并不能恢复肌肉功能的假设。特异性目的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。特异性Aim 2将测试eom特异性肌球蛋白表达的恢复是否能恢复成年小鼠眼外肌功能。完成这一项目所得到的答案将为先天性斜视手术和药物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.