Grant: Project Grant

Retinal degenerative diseases such as glaucoma and diabetic retinopathy exhibit devastating vision loss, each as a result of the death over time of specific types of eye cell. Each disease needs the affected cell types to be replaced, and for the new cells to integrate into functional vision circuits. Thus, we need to explore how different types of eye cell are made and in the right proportions. Importantly, we need to understand these events in the adult eye, because the blueprints likely differ from those for eye cell production in the fetus, from where most of our knowledge comes. The problem is that the mammalian eye is incapable of replacing new eye cells when they degenerate. This is not true in the eyes of adult fish, which retain two subpopulation of cells that allow the eye and retinal circuits to grow throughout life, and that in response to retinal injury are activated and replace lost cells. Importantly, these two classes of cells are also present in the mammalian adult retina, but do not respond to retinal damage by making new cells. The fish eye has the same main classes of eye cells, and with similar functions, as those in humans. Thus, we want to understand how new cells are generated in the fish adult eye, and how these pathways can be harnessed in repair programs after retinal cell loss. We have identified related proteins in the zebrafish eye, Semaphorin3fa and Semaphorin3fb, that our data indicate act on the two key cell populations, both as these cells continue to provide new cells for the ever-expanding eye visual circuits, and as they ramp up their activities in response to eye damage. We will explore their roles in both contexts with the hope of understanding how to transform the dormant cells of the human adult eye into progenitors like their fish counterparts, so that they too can replace specific eye cell types that get lost in each of the degenerative retinal diseases.