One potentially important approach to restore vision is the regeneration of lost retinal neurons from an endogenous population of retinal cells, the Mller glia. To explore the potential of ultimately stimulating the resident Mller glia in the damaged human retina, we will take a comparative approach using zebrafish (regeneration competent), chick (regeneration limited), and mouse (regeneration refractory). We will conduct a comprehensive and unbiased, comparative analysis of gene expression and chromatin conformation in isolated retinal progenitor cells and Mller glia in developing zebrafish, chick, and mouse retinas. We will also study changes Mller glia from all three model organisms as they are activated/reprogrammed in response to retinal injury (light damage, NMDA) or exposure to extrinsic factors that are capable of inducing their activation in the absence of retinal damage.
Aims 1 and 2 will generate transcriptome and chromatin data of genes and chromatin structures that are associated with formation of Mller glia progenitor cells.
In Aim 3, we will integrate this data using newly developed bioinformatic analysis to identify transcription factors and transcriptional networks that control neurogenic competence in Mller glia from each organism.
In Aim 4, we will validate and test candidate genes in regulating the dedifferentiation of Mller glia in zebrafish, chick, and mice, using a combination of gain- and loss-of-function approaches. This work will begin to identify the transcription factors and miRNAs that regulate the extent of retinal regeneration in the three different model organisms. Understanding how to restore Mller glia to a youthful status will enable targeted regenerative retinal therapies.
Vision loss is among the top ten disabilities in the United States, with an estimated burden on society of over $35 billion with approximately 285 million people worldwide are visually impaired and 39 million are blind. We propose to carry out a comprehensive and unbiased analysis of the gene expression and chromatin differences in the retinal Muller glia among zebrafish (capable of regenerating damaged retinas), chick (which show limited regeneration of damaged retinas), and mice (which cannot regenerate damaged retinas). Identifying the molecular pathways that permit zebrafish to regenerate, but prevent mouse from regenerating, may result in the development of novel therapies that will restore vision to the visually impaired and blind.