Novel Activators of Regeneration in Mller Glia Mller glia are the predominant source of regenerative repair in the fish retina, but this is not the case in humans, where Mller glia respond to injury, pathology, or degeneration by becoming reactive, and, in many cases, gliotic. Recent research in non-regenerative mammalian model systems, such as the mouse, suggests that Mller glia could be pushed down a regenerative pathway, but bona-fide regeneration and repair will involve factors and protocols that are not yet identified. To address this gap in knowledge, we propose three projects that focus on the proliferative and neurogenic properties needed for regeneration. In the first project, we will develop a regeneration-priming protocol for mouse Mller glia through modulation of neurotransmitter uptake and inhibition of p27Kip1, a cell cycle protein that prevents properties associated with reactivity and regeneration in Mller glia. In the second project, we will perform a screen using exosomes to discover candidate exosomes and their constituent proteins and/or RNAs that stimulate regenerative properties in zebrafish and mouse Mller glia. In the third project, we will develop thiouracil tagging combined with RNA sequencing to capture the transcriptomes of Mller glia in selected states of regeneration based on our work from the first two projects. The culmination of this work will yield new factors for promoting regeneration and provide proof-of-concept for exosome-based delivery of factors as a therapeutic strategy.

Public Health Relevance

Novel Activators of Regeneration in Mller Glia Zebrafish spontaneously repair damaged retinas by activating an adult stem cell population (Mller glia) to dedifferentiate, divide, and replace lost cell types. Mammalian Mller glia, including in humans, are incapable of spontaneous regeneration. We seek to use complementary expertise between zebrafish and mouse model systems to discover novel factors that can initiate a robust regenerative response in mammalian Mller glia with the ultimate goal of developing regeneration-based treatments for retinal injuries and diseases.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01EY027265-02
Application #
9340183
Study Section
Special Emphasis Panel (ZEY1)
Program Officer
Greenwell, Thomas
Project Start
2016-09-01
Project End
2019-08-31
Budget Start
2017-09-01
Budget End
2018-08-31
Support Year
2
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Type
DUNS #
079917897
City
Nashville
State
TN
Country
United States
Zip Code
37232
Rao, Mahesh B; Didiano, Dominic; Patton, James G (2017) Neurotransmitter-Regulated Regeneration in the Zebrafish Retina. Stem Cell Reports 8:831-842