A Zebrafish model of extraocular muscle regeneration.

描述（由申请人提供）：双眼视觉需要通过6对眼外肌（EOM）对眼球运动进行复杂的控制。先天性和后天性斜视会导致双眼输入不对准，这分别会导致弱视或复视。斜视手术是目前的标准治疗，但手术通常会导致纤维化和肌肉功能受损。这项研究计划的中心概念是，肌肉再生，结合手术，将提供更好的功能结果比肌肉手术单独。因此，PI研究的长期目标是确定控制眼外肌再生的分子基础，并利用它们开发治疗斜视的新治疗方法。哺乳动物修复受损眼外膜的能力有限，而斑马鱼在再生包括眼外膜在内的复杂组织方面特别有效。我们的策略是利用斑马鱼来识别和表征可以驱动EOM再生的生物机制。我们最近确定了一个子集的EOM再生的遗传调节。我们的数据显示，斑马鱼的眼外肌再生依赖于现存肌细胞的调节重编程，而不是内在的干细胞（卫星细胞），这表明了斑马鱼如此擅长眼外肌再生的生物学基础。拟议的项目旨在利用斑马鱼开发肌肉再生的机制理解，并专注于可作为潜在治疗靶点的过程，如细胞凋亡，自噬和细胞外基质重塑的调节。

DESCRIPTION (provided by applicant): Binocular vision requires intricate control of eye movement by 6 pairs of extraocular muscles (EOMs). Congenital and acquired strabismus cause misaligned binocular input, which can lead to amblyopia or diplopia, respectively. Strabismus surgery is the current standard of care, but surgery commonly results in fibrosis and compromise in muscle function. The central concept of this research program is that muscle regeneration, in conjunction with surgery, will provide better functional outcomes than muscle surgery alone. Therefore, the long-term goal of the PI's research is to identify the molecular underpinnings that govern EOM regeneration and use them to develop novel therapeutic approaches for treating strabismic conditions. Mammals have only a limited ability to repair damaged EOMs, whereas zebrafish are particularly effective at regenerating complex tissues, including EOMs. Our strategy is to utilize zebrafish to identify and characterize the biological mechanisms that can drive EOM regeneration. We recently identified a subset of the genetic regulators of EOM regeneration. Our data reveal that EOM regeneration in zebrafish relies upon regulated reprogramming of extant myocytes rather than on intrinsic stem (satellite) cells, suggesting a biological foundation for the reason why zebrafish are so adept at EOM regeneration. The proposed project is designed to develop a mechanistic understanding of muscle regeneration using zebrafish, and focusing on processes that can serve as potential therapeutic targets, such as regulation of apoptosis, autophagy and extracellular matrix remodeling.