A Zebrafish model of extraocular muscle regeneration.

描述(申请人提供)：双眼视觉需要6对眼外肌(EOMS)复杂地控制眼球运动。先天性和获得性斜视导致双眼输入错位，分别导致弱视或复视。斜视手术是目前的治疗标准，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，肌肉再生与手术相结合，将提供比单独肌肉手术更好的功能结果。因此，PI研究的长期目标是确定支配EOM再生的分子基础，并利用它们开发治疗斜视疾病的新治疗方法。哺乳动物修复受损的EOMS的能力有限，而斑马鱼在再生包括EOMS在内的复杂组织方面尤其有效。我们的策略是利用斑马鱼来识别和表征能够驱动EOM再生的生物学机制。我们最近发现了EOM再生的一个基因调控子集。我们的数据显示，斑马鱼的EOM再生依赖于现存肌细胞的调节重新编程，而不是内在的干细胞(卫星)细胞，这表明斑马鱼如此擅长EOM再生的原因是一个生物学基础。这个拟议的项目旨在从机制上理解斑马鱼肌肉再生的机制，并专注于可以作为潜在治疗靶点的过程，如调节细胞凋亡、自噬和细胞外基质重塑。

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.