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.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY022633-02
Application #
8616762
Study Section
Special Emphasis Panel (BVS)
Program Officer
Araj, Houmam H
Project Start
2013-04-01
Project End
2017-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
2
Fiscal Year
2014
Total Cost
$372,273
Indirect Cost
$127,273
Name
University of Michigan Ann Arbor
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Grzegorski, Steven J; Chiari, Estelle F; Robbins, Amy et al. (2014) Natural variability of Kozak sequences correlates with function in a zebrafish model. PLoS One 9:e108475
Kahana, Alon; Elner, Victor M (2013) The meaning of diagnoses in orbital disease. Ophthal Plast Reconstr Surg 29:347-8