The leading causes of blindness and low vision in the US include AMD, diabetic retinopathy and glaucoma. Current therapies offer few options to those suffering from late stages of these diseases. In order to explore possible therapies, it is important to use animal models with regenerative capabilities such as the chick embryo. Embryonic chicks regenerate their retina, following retinectomy, by reprogramming the remaining retinal pigmented epithelium (RPE) as long as an inducing factor is present. This reprogramming process allows the RPE to dedifferentiate, proliferate and form a neuro-epithelium that eventually differentiates generating retina. The process of dedifferentiation is ke to understanding how RPE reprogramming works. RPE reprogramming utilizes a two-step dedifferentiation process where injury (retinectomy) stimulates the RPE to become competent to respond to inducing factors. We have identified several inducing factors that are able to reprogram the RPE to neural retina, however, the role for these molecules in RPE reprogramming remains unknown. In this proposal we will dissect the mechanisms by which inducing factors such complement components C3a, C5a and inflammation associated molecules including IL-6 and antioxidant N-acetyl cysteine (NAC) reprogram the RPE. Specifically, we will explore if these factors/molecules exhibit interdependence, if they require common signaling pathways or if they regulate common target genes using similar or distinct epigenetic strategies. We will test the following hypothesis: Inducing factors direct RPE reprogramming and retina regeneration by initiating downstream signaling cascades such as MAPK, PI3K, Wnt and/or Jak/Stat pathways commonly activated by growth factor and G-coupled receptors. Through these pathways, the inducing factors epigenetically control common genes that regulate RPE reprogramming. The urgency for restoring vision lead the NEI to announce an audacious goal to restore vision through regeneration of neurons and neural connections in the eye and visual system. This study provides a model system where to test small molecules such as C3a, C5a, IL-6 and NAC to evaluate induction of retina regeneration and a platform where to dissect the cellular and molecular mechanisms involved in this process. This work will have a significant impact on the field of regenerative medicine since the information obtained can be extrapolated to the process of retina repair in mammals including humans, and specifically on the potential reprogramming of human RPE to generate new neurons.

Public Health Relevance

Age-related macular degeneration (AMD), diabetic retinopathy and glaucoma can lead to loss of neurons and permanent vision loss. There are no current therapies for neural replacement, however studying animal models that can regenerate damaged retinas, such as the chick embryo, provide a venue to explore possible treatments. The embryonic chick can reprogram the retinal pigmented epithelium (RPE) located in the back of the eye to give rise to a new retina. This research could provide strategies that can be extrapolated to the process of retina repair in humans, and specifically on the potential reprogramming of human RPE to generate new neurons.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY026816-02
Application #
9246537
Study Section
Special Emphasis Panel (ZRG1-CB-G (02)M)
Program Officer
Neuhold, Lisa
Project Start
2016-04-01
Project End
2021-03-31
Budget Start
2017-04-01
Budget End
2018-03-31
Support Year
2
Fiscal Year
2017
Total Cost
$325,125
Indirect Cost
$100,125
Name
Miami University Oxford
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
041065129
City
Oxford
State
OH
Country
United States
Zip Code
45056
Grajales-Esquivel, Erika; Luz-Madrigal, Agustin; Bierly, Jeffrey et al. (2017) Complement component C3aR constitutes a novel regulator for chick eye morphogenesis. Dev Biol 428:88-100