Progress Updates
Dr. Goldman’s team has generated transgenic zebrafish models that allow them to conditionally ablate (destroy) retinal ganglion cells in adult animals and may serve as models of glaucoma. The team has also discovered that they can use the growth factor protein, called HB-EGF, to stimulate Müller glia to change into a retinal stem cell that can regenerate all types of retina cells. These studies provide novel models and approaches for understanding the mechanisms by which diseased or damaged retinal neurons can be restored. These studies may suggest novel strategies for stimulating retinal repair in humans following injury or disease.
One aim in the team’s proposal was to generate transgenic fish harboring the bacterial nitroreductase gene under control of the retinal ganglion cell-specific promoter, Pou4f3. The expression of nitroreductase causes a toxin to be created that conditionally ablates the retinal ganglion cells in which the protein is present. Nitroreductase on its own has no effect on cells, however, when the cells are exposed to metronidazole, the nitroreductase is converted into a cytotoxic product. Dr. Goldman’s team has successfully generated these fish, which are anticipated to serve as a model for glaucoma-induced retinal ganglion cell death.
In addition, the team has generated another type of fish with a gene that has the tuba1a promoter driving expression of bacterial nitroreductase. Unlike the Pou4f3 fish that constitutively (continually) express nitroreductase in retinal ganglion cells, the tuba1a fish only express this protein after their optic nerve has been damaged. Both lines of fish are now being raised to adults to examine if adult Müller glia can regenerate ablated retinal ganglion cells. If successful, this team could provide a new treatment option for glaucoma.
