Rod photoreceptor regeneration in a zebrafish model of Retinitis Pigmentosa.

Abstract: A cellular hallmark of inherited retinal degenerative diseases, such as Retinitis Pigmentosa (RP), is progressive loss of photoreceptors until the individual is completely blind. With degeneration starting at an early age, many patients with RP become blind early on in their adulthood. Affecting 100,000 people annually in the US alone and being the second most prominent genetic retinal degenerative disease worldwide, research is necessary in order to identify therapies that can improve the quality of life for these patients. Unlike mammalian models, Zebrafish (Zf) have a remarkable capacity to regenerate neurons following retinal injury or disease, making them a suitable model organism for regenerative studies. Current studies in Zf have indicated that upon detection of retinal insult, Mϋller glial cells (MGCs) are reprogrammed to re-enter the cell cycle, asymmetrically divide, and produce multi-potent progenitor cells. These newly formed progenitor cells rapidly proliferate and re-differentiate to replace lost retinal cells. Several genes, pathways, and transcriptional factors have been shown to play a role in reprogramming MGCs, inducing progenitor cell proliferation, and differentiating these cells into functional inner retinal neurons; however, the mechanisms by which genes work together spatially and temporally to regenerate rods in a model with chronic retinal degeneration remain unknown. The purpose of this study is to understand the regeneration mechanisms of rod photoreceptors in Zf and to identify the master regulatory genes crucial for their lineage trajectory. Our preliminary analyses have identified a group of retinal progenitor cells believed to be responsible for rod photoreceptor regeneration. Aim 1 of this proposal will assess the roles of candidate regulatory genes and transcription factors in the differentiation of these progenitor cells into rod photoreceptors. Aim 2 will assess the lineage trajectory of progenitor cells to form rod photoreceptors and identify when and how the progenitor cells are formed. Upon successful completion of this project, I will have identified the set of transcription factors needed to induce rod photoreceptor regeneration in adult Zf. The ultimate goal of this project is to provide the targets necessary to restore vision in blind patients with retinal degenerative diseases such as RP so that they may have an improved quality of life.