Retinal degenerative diseases often lead to blindness due to lost neurons. A major goal of vision scientists is to restore these lost neurons. Due to their remarkable regenerative powers, zebrafish provide an ideal system for identifying strategies for restoring lost neurons in the retina. Although the zebrafish and mammalian retina are composed of similar cell types that are organized and function in a similar manner, they respond very differently to injury. Zebrafish respond to retinal damage by mounting a regenerative response that restores lost sight, while mammals do not. Key to the success of retina regeneration in zebrafish are Muller glia (MG) that respond to retinal damage by undergoing a reprogramming event that allows them to acquire properties of a stem cell. These reprogrammed MG are responsible for generating a multipotent proliferating population of retinal progenitors that regenerate all major retinal cell types. We propose that an understanding of the mechanisms by which MG reprogram to a retinal stem cell will help identify strategies for stimulating mammalian MG to undergo a similar transformation and repair a damaged retina. This proposal focuses on identifying these mechanisms with an emphasis on secreted factors regulating MG reprogramming and the gene expression programs that drive multipotency. It is anticipated that these studies will lead to novel strategies for inducing MG dedifferentiation and retina regeneration in mammals which may facilitate repairing a damaged or diseased human retina.

Public Health Relevance

Human retinal diseases and injury often lead to irreparable blindness due to lost neurons. Muller glia represents a potential source of retinal stem cells for repair of the damaged and diseased human retina. Our research takes advantage of the robust regenerative powers of zebrafish Muller glia to help identify strategies for stimulating mammalian Muller glia to reprogram to a retinal stem cell so it can contribute to repair of the diseased human retina.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY018132-12
Application #
9608018
Study Section
Biology of the Visual System Study Section (BVS)
Program Officer
Greenwell, Thomas
Project Start
2007-04-01
Project End
2020-12-31
Budget Start
2019-01-01
Budget End
2020-12-31
Support Year
12
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Biochemistry
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Elsaeidi, Fairouz; Macpherson, Peter; Mills, Elizabeth A et al. (2018) Notch Suppression Collaborates with Ascl1 and Lin28 to Unleash a Regenerative Response in Fish Retina, But Not in Mice. J Neurosci 38:2246-2261
Mills, Elizabeth A; Goldman, Daniel (2017) The Regulation of Notch Signaling in Retinal Development and Regeneration. Curr Pathobiol Rep 5:323-331
Wan, Jin; Goldman, Daniel (2017) Opposing Actions of Fgf8a on Notch Signaling Distinguish Two Muller Glial Cell Populations that Contribute to Retina Growth and Regeneration. Cell Rep 19:849-862
Zhang, Shuqiang; Mu, Zhaoxia; He, Chunjiao et al. (2016) Antiviral Drug Ganciclovir Is a Potent Inhibitor of the Proliferation of Müller Glia-Derived Progenitors During Zebrafish Retinal Regeneration. Invest Ophthalmol Vis Sci 57:1991-2000
Powell, Curtis; Cornblath, Eli; Elsaeidi, Fairouz et al. (2016) Zebrafish Müller glia-derived progenitors are multipotent, exhibit proliferative biases and regenerate excess neurons. Sci Rep 6:24851
Wan, Jin; Goldman, Daniel (2016) Retina regeneration in zebrafish. Curr Opin Genet Dev 40:41-47
Wan, Jin; Zhao, Xiao-Feng; Vojtek, Anne et al. (2014) Retinal injury, growth factors, and cytokines converge on ?-catenin and pStat3 signaling to stimulate retina regeneration. Cell Rep 9:285-297
Goldman, Daniel (2014) Regeneration, morphogenesis and self-organization. Development 141:2745-9
Zhao, Xiao-Feng; Goldman, Daniel (2014) A new transgenic line reporting pStat3 signaling in glia. Zebrafish 11:588-9
Elsaeidi, Fairouz; Bemben, Michael A; Zhao, Xiao-Feng et al. (2014) Jak/Stat signaling stimulates zebrafish optic nerve regeneration and overcomes the inhibitory actions of Socs3 and Sfpq. J Neurosci 34:2632-44

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