The long-term goal of our study is to decipher the mechanisms controlling the morphogenesis of the photoreceptor outer segment (OS), a cellular compartment vital for our vision. This proposal will specifically investigate the role of ?Progressive Rod Cone Degeneration? (PRCD), in photoreceptor function and OS biogenesis. PRCD is exclusively present in photoreceptor OS disc membranes and associates with rhodopsin. The proposed studies are also clinically relevant as mutations in PRCD cause retinitis pigmentosa (RP) in humans and dogs. Our recent study showed that PRCD is post-translationally lipid modified by ?palmitoylation? in a sole cysteine (Cys2), which is linked with RP in humans and dogs (Cys2Tyr). Despite the importance of PRCD in retinal function, the role for PRCD in photoreceptors is not known and is the main focus of this application.
The first aim of this study will investigate the role of PRCD in photoreceptors using a novel PRCD-KO animal model generated by CRISP-Cas9 genome editing.
The second aim will determine how the common patient mutation (C2Y) in PRCD leads to retinitis pigmentosa (RP) using multiple transgenic animal models. Our proposed studies are aligned with the Retinal Diseases Program of the NEI to ?Identify the genes involved in both inherited and retinal degenerative diseases (including RP), determine the pathophysiological mechanisms underlying PRCD mutations, and determine new potential therapeutic strategies for treatment such as gene transfer, tissue and cell transplantation, growth factor therapy, and pharmacological intervention.
The studies proposed in this application will address the mechanism(s) behind photoreceptor cell outer segment biogenesis. This research study will significantly advance our understanding of the maintenance of OS, and how the discs are shaped, stacked and organized. We strongly believe that these studies have a strong potential to reveal an important ?missing link? where the photoreceptor outer segment architecture is maintained, and which will significantly advance the knowledge in the field of photoreceptor cell biology.