Grant: Project Grant

Dominant retinitis pigmentosa (RP) is a genetic disorder of the retina. The most common cause is mutations in the Rhodopsin gene, which causes death of rod photoreceptors. A subset of patients have a form called "Sector RP" in which the lower portion of the retina is more severely affected, which is likely due to an effect of light exacerbating the disease. The phenotype suggests that this form of RP should be preventable, as the disease has already been prevented or delayed in a significant fraction of these patients' retinas. We have modeled disease caused by several different sector RP-associated mutations in transgenic frogs (X. laevis), and determined that there are multiple mechanisms by which light promotes retinal degeneration including promoting biosynthetic defects, phototoxicity, and abnormal aggregation of rhodopsin. We have also demonstrated that animal models of these disease mechanisms respond very differently to therapeutic interventions, demonstrating how critical it is to understand which disease mechanisms exist, and which patients they affect. Here we propose further investigations of each of these mechanisms underlying sector RP. Our results may suggest therapeutic or lifestyle interventions for these patients, and inform future clinical trials. Our results will also provide new information on the in-vivo properties of rhodopsin, and the mechanisms by which light can injure the retina.