A Zebrafish model of extraocular muscle regeneration.

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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.