Macular Degeneration Research
David R. Hyde, Ph.D.
University of Notre Dame
Notre Dame, IN, United States
Title: Generating a Zebrafish Model to Study AMD
Non-Technical Title: New Model of Macular Degeneration
Duration: July 1, 2011 - June 30, 2013
Award Type: Standard
Award Amount: $100,000
This project will address if the loss of retinal pigmented epithelial (RPE) cells is the primary or secondary cause of cone cell loss in macular degeneration. Using zebrafish, which possesses the ability to regenerate photoreceptor cells in the eye, we will also examine if the damaged RPE cells can be regenerated and the subsequent consequences on cone photoreceptor cell regeneration.
In age‐related macular degeneration (AMD), the retinal pigment epithelium (RPE) cells, which are located behind the retina and are essential to keep the light‐detecting rod and cone photoreceptor cells alive, are damaged and die. However, it is unclear if the RPE cell death is the primary cause of AMD or a secondary effect. To address this question, Dr. David Hyde and collaborators will generate a zebrafish model of AMD, where a number of the retinal RPE cells die. They will then test whether the death of RPE cells is sufficient to cause two hallmarks of advanced AMD—the death of the adjacent photoreceptor cells and the appearance of tears in the blood‐retina barrier (called Bruch's membrane). Since zebrafish have a natural ability to regenerate a number of body parts, including retinal neurons, these researchers will also determine if the RPE cell layer can spontaneously repair itself and, if so, determine the origin of these new RPE cells. Studying how the zebrafish eye can repair its RPE and retina will give clues for future RPE cell replacement therapies for people with AMD.
Age-related macular degeneration (AMD) causes the death of retinal pigment epithelium (RPE) cells and the death of light-detecting cone photoreceptors in the central part of the retina, called the macula. It remains unknown if the death of the RPE cells is the initial cause of the cone cell death or simply another point in the progression of the disease. Dr. Hyde’s team intends to determine the effect of RPE cell death on cone cell survival and if the RPE cells can regenerate. The team is using zebrafish, which spontaneously regenerate the retinal neurons that die in a variety of human-like retinal degenerative diseases. As the first step in this AMD research, the team successfully created two specific lines of zebrafish (called Tg[[fTYP:nfsB-EGFP] and Tg[[fTYRP1:nfsB-EGFP]) that express a protein called nitroreductase in their RPE cells. When the fish are exposed to the chemical, called metronidazole, in their water, the nitroreductase will convert the chemical into a toxin in only the RPE cells and kill those cells. This will allow for selective death of the RPE cells at any age in the life of the fish to determine if RPE cell death affects older fish differently than younger fish. So far, Dr. Hyde’s team confirmed that both Tg[[fTYP:nfsB-EGFP] and Tg[[fTYRP1:nfsB-EGFP] fish express the nitroreductase protein in the RPE cells and have raised large numbers of these fish to perform the desired experiments. They are currently working to optimize the death of these cells by exposing the fish to metronidazole for different lengths of time.
Dr. David Russell Hyde is a Professor of Biology and the Rev. Howard J. Kenna, C.S.C Memorial Director of the Center for Zebrafish Research at the University of Notre Dame. He completed his doctoral studies at the Pennsylvania State University and was a postdoctoral researcher at the California Institute of Technology with Dr. Seymour Benzer. His laboratory develops neurodegenerative models in zebrafish to mimic human diseases and then studies how the fish rapidly and spontaneously regenerate neurons from an endogenous population of adult stem cells. While humans possess the same adult stem cell population as do the zebrafish, we lack this regenerative ability. Hyde's research team is focusing on how this neuronal regeneration process works in fish so they may develop therapies to induce neuronal regeneration therapies to correct human diseases, such as age-related macular degeneration and Alzheimer's disease. In addition to his BrightFocus award, Hyde is funded by the National Eye Institute of NIH.