Retinal degenerations are the most common cause of blindness in the Western world. Over 5% of the population will, at some point in their lives, suffer from retinal degeneration. Although we have made great strides in identifying genes responsible for much retinal degeneration, strategies for repairing the diseased retina have remained elusive. Recent studies suggest that the mammalian retina harbors progenitors that can restore lost neurons, albeit with very low efficiency. One goal of neurobiologists studying the retina is to identify strategies for inducing a regenerative response that would facilitate repair of the diseased or damaged retina. Model systems, like zebrafish, offer an exceptional advantage when studying retinal regeneration, in part because of their robust regenerative powers. The mechanism by which fish successfully regenerate a damaged retina is not known, although we recently provided evidence suggesting Muller glia are involved. The long term goal of our research is to ascertain the role Muller glia play in zebrafish retinal regeneration and identify the mechanisms by which these cells contribute to retinal repair. Ultimately it is hoped that this information can be applied to the mammalian retina to improve its regenerative ability. We propose to use a combination of cell and molecular biological approaches to investigate the role Muller glia play in retinal regeneration. Specifically we propose to: 1) Determine if Muller glia mediate regeneration of all major retinal cell types in the regenerating retina;2) Determine if Muller glia are necessary for successful retina regeneration;3) Identify the genetic changes that impart a progenitor status to Muller glia following retinal injury;and 4) Identify mechanisms underlying a1T gene expression and Muller glia dedifferentiation during retinal regeneration. These studies will form the foundation for future investigations of Muller glia as a source of cells for retinal repair in fish and mammals. Unlike mammals, injury to the fish retina initiates a regenerative response that can restore lost visual function.
Our research aims to identify the mechanisms underlying successful retina regeneration in fish. We propose that these mechanisms may suggest new strategies for improving repair of the damaged or diseased mammalian retina.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY018132-04
Application #
7768404
Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Greenwell, Thomas
Project Start
2007-04-01
Project End
2011-07-31
Budget Start
2010-03-01
Budget End
2011-07-31
Support Year
4
Fiscal Year
2010
Total Cost
$367,850
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
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
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
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
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
Zhao, Xiao-Feng; Wan, Jin; Powell, Curtis et al. (2014) Leptin and IL-6 family cytokines synergize to stimulate Müller glia reprogramming and retina regeneration. Cell Rep 9:272-84
Skaggs, Kaia; Goldman, Daniel; Parent, Jack M (2014) Excitotoxic brain injury in adult zebrafish stimulates neurogenesis and long-distance neuronal integration. Glia 62:2061-79
Goldman, Daniel (2014) Müller glial cell reprogramming and retina regeneration. Nat Rev Neurosci 15:431-42

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