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.

Public Health Relevance

The proposed research will identify the biological mechanisms that underlie repair and regeneration of the specialized muscles that control eye movement. The findings will help improve treatments for strabismus and amblyopia, which are leading causes of visual dysfunction in children and adults. Our long-term goal is to utilize regenerative medicine to treat blinding conditions.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Special Emphasis Panel (BVS)
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Araj, Houmam H
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University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
United States
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Saera-Vila, Alfonso; Louie, Ke'ale W; Sha, Cuilee et al. (2018) Extraocular muscle regeneration in zebrafish requires late signals from Insulin-like growth factors. PLoS One 13:e0192214
Louie, Ke'ale W; Saera-Vila, Alfonso; Kish, Phillip E et al. (2017) Temporally distinct transcriptional regulation of myocyte dedifferentiation and Myofiber growth during muscle regeneration. BMC Genomics 18:854
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