Our research is driven by the prospect that the progressive nature of photoreceptor degeneration leaves open an opportunity for treatments that delay the time-course of cellular damage and forestall vision loss. Humans are largely dependent upon cone-mediated central vision. However, in a significant number of people, death or dysfunction of rods results in the secondary loss of cones, remodeling of retinal circuitry and blindness. The heterogeneous nature of the molecular defects underlying retinitis pigmentosa (RP) has made identifying the specific mechanisms leading to degeneration difficult. Even less understood, are the principal causes of the secondary death of photoreceptors not expressing the mutated gene. There exists a critical need for robust models that recapitulate the pathological sequence leading to disease and to rapidly and reliably screen for agents to lessen the impact of the disease. My laboratory has taken advantage of the genetic manipulations available in zebrafish to identify genes regulating photoreceptor development and survival. In this proposal, we will directly address two common features observed in people affected by a wide range of photoreceptor disease; the cellular alterations that precipitating initial photoreceptor death, and secondary alterations leading to blindness. We propose a two prong approach: 1) Apply innovative genetic manipulations to introduce analogous mutations in zebrafish rhodopsin as precisely defined models of human retinal disease; 2) Use these and our existing degeneration models to screen for small molecules that modify disease progression. Completion of the specific aims will significantly advance the field's understanding of alterations underlying photoreceptor death, and identify potential novel targets or therapeutic agents as lead compounds to confer protection from the secondary consequences of photoreceptor degeneration.
Photoreceptor cell degeneration as a result of genetic mutations, environmental insults, or aging is a critical health issue for which there is currently o cure. In retinitis pigmentosa and related hereditary disorders most debilitating is that following the initial loss of the rods and night blindness, is the secondary death of cones and loss of central vision. Tools are now available to recapitulate in zebrafish precise models of human retinal diseases, and accelerate the identification of lead compounds or novel targets as the basis for novel therapeutic approaches to diminish the progressive loss of vision in photoreceptor dystrophies.
| Zelinka, Christopher P; Sotolongo-Lopez, Mailin; Fadool, James M (2018) Targeted disruption of the endogenous zebrafish rhodopsin locus as models of rapid rod photoreceptor degeneration. Mol Vis 24:587-602 |
