The possibility of neural regeneration from glial cells has recently gained credibility and popularity. We have previously shown that large numbers of Muller glia in the postnatal chicken retina can re-enter the cell cycle, de-differentiate, express transcription factors normally expressed by retinal progenitors, and produce a few new neurons (Fischer and Reh, 2001 a). We found that Muller glia can become retinal progenitor-like cells in response to acute damage (Fischer and Reh, 2001 a) or in response to the combination of insulin and FGF2 (fibroblast growth factor 2) in the absence of damage (Fischer et al., 2002b). Thus, Muller glia hold the potential to act as a cellular source of neural regeneration within the retina. However, the mechanisms that regulate the ability of Muller glia to re-enter the cell cycle, become progenitor cells, and differentiate as neurons remain unknown and unexplored. The specific hypothesis that underlies this proposal is that MAP kinase, Jak/STAT and Notch signaling pathways regulate the different responses of Muller glia to retinal damage. Based on preliminary data we will test the following hypotheses. (1) MAP kinase pathways promote glial de-differentiation and proliferation, and suppress aspects of reactive gliosis such as GFAP (glial fibrillary acidic protein) expression. (2) CNTF (ciliary neurotrophic factor)/Jak-STAT signaling promotes glial maturation, promotes GFAP expression, and suppresses glial proliferation. (3) Notch-mediated signaling prevents neuronal differentiation from Muller glia-derived progenitors in acutely damaged retinas. (4) Mature, damaged retinas lack the cues required for neuronal differentiation of progenitor cells. This proposal provides specific aims and describes experiments to test the above-listed hypotheses. Data produced by these experiments will provide valuable information regarding the possibility that Muller glia can be used as a source of neural regeneration within the retina. In addition, the data will provide new insights into the secreted factors and signaling pathways that control gliosis and the ability of glial cells to re-enter the cell cycle. This information could be applied to not only stimulate neural regeneration to treat sight-threatening diseases of the retina, but also to control gliosis that may be detrimental to the pathogenesis of retinal disorders.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY016043-04
Application #
7609035
Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Greenwell, Thomas
Project Start
2006-05-05
Project End
2011-04-30
Budget Start
2009-05-01
Budget End
2011-04-30
Support Year
4
Fiscal Year
2009
Total Cost
$290,329
Indirect Cost
Name
Ohio State University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
Zelinka, Christopher P; Scott, Melissa A; Volkov, Leo et al. (2012) The reactivity, distribution and abundance of Non-astrocytic Inner Retinal Glial (NIRG) cells are regulated by microglia, acute damage, and IGF1. PLoS One 7:e44477
Ritchey, Eric R; Zelinka, Christopher; Tang, Junhua et al. (2012) Vision-guided ocular growth in a mutant chicken model with diminished visual acuity. Exp Eye Res 102:59-69
Ritchey, Eric R; Zelinka, Christopher P; Tang, Junhua et al. (2012) The combination of IGF1 and FGF2 and the induction of excessive ocular growth and extreme myopia. Exp Eye Res 99:1-16
Fischer, A J; Bongini, R; Bastaki, N et al. (2011) The maturation of photoreceptors in the avian retina is stimulated by thyroid hormone. Neuroscience 178:250-60
Ritchey, Eric R; Code, Kimberly; Zelinka, Christopher P et al. (2011) The chicken cornea as a model of wound healing and neuronal re-innervation. Mol Vis 17:2440-54
Fischer, Andy J (2011) Muller glia, vision-guided ocular growth, retinal stem cells, and a little serendipity: the Cogan lecture. Invest Ophthalmol Vis Sci 52:7705-10, 7704
Stanke, Jennifer; Moose, Holly E; El-Hodiri, Heithem M et al. (2010) Comparative study of Pax2 expression in glial cells in the retina and optic nerve of birds and mammals. J Comp Neurol 518:2316-33
Ghai, Kanika; Zelinka, Christopher; Fischer, Andy J (2010) Notch signaling influences neuroprotective and proliferative properties of mature Müller glia. J Neurosci 30:3101-12
Fischer, Andy J; Scott, Melissa A; Zelinka, Christopher et al. (2010) A novel type of glial cell in the retina is stimulated by insulin-like growth factor 1 and may exacerbate damage to neurons and Müller glia. Glia 58:633-49
Fischer, Andy J; Zelinka, Christopher; Scott, Melissa A (2010) Heterogeneity of glia in the retina and optic nerve of birds and mammals. PLoS One 5:e10774

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