There is a rapidly growing body of evidence that Mller glia can are a source of retinal progenitors to promote neural regeneration. Many studies have demonstrated that Mller glia can become proliferating progenitor cells in the retinas of different vertebrate species. Most reports have studied Mller glia-derived progenitors in acutely damaged retinas. However, little is known about the mechanisms that stimulate neurogenesis from Mller glia-derived progenitors in undamaged retinas or retinas undergoing slow, progressive degeneration. Furthermore, the regeneration of retinal neurons in warm-blooded vertebrates is limited compared to that seen in cold-blooded vertebrates. Therefore, the identification of the secreted factors and signaling pathways that permit and/or stimulate neural regeneration from Mller glia-derived progenitors is crucially important to developing new therapies to treat degenerative diseases of the human retina. We have obtained compelling novel preliminary data indicating that signaling through the glucocorticoid receptor (GCR) and the mTor-pathway significantly impacts the plasticity of Mller glia and neurogenic potential of Mller glia-derived progenitors. We will investigate how the phenotype and plasticity of the Mller glia are regulated by GCR- and mTor-signaling in normal, damaged and growth factor-treated retinas. We will use a combination of pharmacological and genetic approaches to selectively activate or inhibit GCR- or mTor-pathways in Mller glia. We will compare and contrast how GCR- and mTor-pathways impact the formation of Mller glia-derived progenitors in chick and rodent model systems with different inherent capacities for retinal regeneration. We expect that the completion of the experiments described in this proposal will provide significant new information regarding how GCR and mTor-signaling influences the formation of Mller glia-derived progenitors and regeneration of retinal neurons. Identification and understanding of the mechanisms that enhance the neurogenic potential of Mller glia is required to develop new therapies for sight-threatening diseases, such as glaucoma and macular degeneration that involve the loss of retinal neurons.

Public Health Relevance

A thorough understanding of the mechanisms that regulate the functions of glial cells is crucially important to the development of new therapies to treat sight-threatening diseases of the retina. A primary function of retinal glia is to support neuronal function and survival. In addition, retinal Mller glia is known to have the potential to become neurogenic progenitor cells. Identification and understanding the mechanisms that regulate the neuron-supporting actions and neurogenic potential of Mller glia-derived progenitors is key to developing new therapies to treat degenerative disease of the retina. This proposal seeks to identify important signaling pathways that enhance the ability of Mller glia to become proliferating progenitors and produce new functional neurons. A goal of this project is to study the molecular mechanisms and signaling pathways that regulate glial functions related to reactivity, proliferation, and neuronal regeneration. Another goal of this project is to investigat how to enhance the ability of retinal glia to support the survival or retinal neurons by regulating cell signaling pathways. The findings produced by the proposed studies will provide valuable new insights into the factors and signaling mechanisms that regulate inter-glial communication, glia-mediated neuronal regeneration, and survival-supporting actions of retinal glia.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Biology of the Visual System Study Section (BVS)
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Greenwell, Thomas
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Ohio State University
Schools of Medicine
United States
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Todd, Levi; Suarez, Lilianna; Quinn, Colin et al. (2018) Retinoic Acid-Signaling Regulates the Proliferative and Neurogenic Capacity of Müller Glia-Derived Progenitor Cells in the Avian Retina. Stem Cells 36:392-405
Wisely, C Ellis; Sayed, Javed A; Tamez, Heather et al. (2017) The chick eye in vision research: An excellent model for the study of ocular disease. Prog Retin Eye Res 61:72-97
Todd, Levi; Palazzo, Isabella; Squires, Natalie et al. (2017) BMP- and TGF?-signaling regulate the formation of Müller glia-derived progenitor cells in the avian retina. Glia 65:1640-1655
Todd, Levi; Squires, Natalie; Suarez, Lilianna et al. (2016) Jak/Stat signaling regulates the proliferation and neurogenic potential of Müller glia-derived progenitor cells in the avian retina. Sci Rep 6:35703
Zelinka, Christopher P; Volkov, Leo; Goodman, Zachary A et al. (2016) mTor signaling is required for the formation of proliferating Müller glia-derived progenitor cells in the chick retina. Development 143:1859-73
Todd, Levi; Suarez, Lilianna; Squires, Natalie et al. (2016) Comparative analysis of glucagonergic cells, glia, and the circumferential marginal zone in the reptilian retina. J Comp Neurol 524:74-89
Gallina, Donika; Palazzo, Isabella; Steffenson, Lillia et al. (2016) Wnt/?-catenin-signaling and the formation of Müller glia-derived progenitors in the chick retina. Dev Neurobiol 76:983-1002
Todd, Levi; Fischer, Andy J (2015) Hedgehog signaling stimulates the formation of proliferating Müller glia-derived progenitor cells in the chick retina. Development 142:2610-22
Fischer, Andy J; Zelinka, Christopher; Milani-Nejad, Nima (2015) Reactive retinal microglia, neuronal survival, and the formation of retinal folds and detachments. Glia 63:313-27
Gallina, Donika; Zelinka, Christopher Paul; Cebulla, Colleen M et al. (2015) Activation of glucocorticoid receptors in Müller glia is protective to retinal neurons and suppresses microglial reactivity. Exp Neurol 273:114-25

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