Department of Ophthalmic Research

Cleveland Clinic
Cleveland, OH

BASIC RESEARCH PROJECT

Effects of Oxidative Stress on Retinal Regeneration in a Zebrafish model of Age-related Macular Degeneration

Research Interests

A key goal of regenerative medicine is to replace neurons lost to disease. Age-related macular degeneration (AMD) is the leading cause of visual impairment in adults in the developed world. Retinitis Pigmentosa (RP) is an inherited retinal dystrophy leading to loss of photoreceptors. In both AMD and RP, light-induced oxidative damage and inflammation are drivers of disease pathology. The retina has a high metabolic demand and generates considerable amounts of reactive oxygen species (ROS). Over time, ROS production can exceed the antioxidant systems that remove ROS, thus leading to oxidative stress. This creates a feedback loop, whereby increasing oxidative stress triggers inflammation and enhances photoreceptor degeneration. Mammals do not have the capability to regenerate retinal tissues, and photoreceptor degeneration is irreversible in mammals. However, zebrafish can regenerate photoreceptors.  Over the past 25 years, several groups, including Dr. Perkin’s lab, have demonstrated the ability of zebrafish to regenerate lost neurons following acute retinal injury.

Plans for 2026

The central goal of Dr. Perkin’s project is to determine the impact of elevated oxidative stress on regeneration in the zebrafish retina. To develop strategies that regenerate photoreceptors in humans with retinal disease, study of animal models that do regenerate retinas under diseased conditions, such as elevated oxidative stress must be studied.  Through this research, the effects of oxidative stress on retinal regeneration in vivo, which remains unexplored will be studied. The experiments will identify the signaling and metabolic pathways that are altered by chronic oxidative stress, and provide understanding of how oxidative stress impacts regeneration of cone photoreceptors to provide the foundation for approaches to restore cones in the retina’s macula.

Dr. Perkins will define the cellular impacts of oxidative stress on MG-driver regeneration and the gene expression changes that occur in the retina. These data can then be leveraged to target specific signaling pathways and/or gene regulatory networks to maximize regeneration within the contest of a diseased retina. Dr. Perkin’s research will research whether elevated oxidative stress restricts or enhances the regenerative response following acute injury in a  Tg(SOD-GFP)-model zebrafish.  He will also determine how oxidative stress alters gene expression in the zebrafish retina to impact retinal regeneration.