The long term goals of our research are to study the role of post-translational protein modifications and their role in phototransduction protein synthesis and maturation. The purpose of this proposal is to investigate the importance of the isoprenylation of phosphodiesterase-6 (PDE6) in retinal photoreceptor neurons. PDE6 is an enzyme that is essential for vision, and its absence or mutations in humans lead to retinitis pigmentosa (RP) and color blindness. Interestingly, changes in Aryl hydrocarbon receptor protein-like-1 (AIPL1), a co- chaperone for PDE6 leads to more severe childhood blindness. Despite the clear link to several blinding diseases, our knowledge on assembly and maturation of this essential enzyme in photoreceptor neurons is not known. Our study will specifically focus on the interplay between AIPL1, HSP90, and lipid modification in PDE6 assembly, maturation, and trafficking to the photoreceptor outer segments. We will also study the importance of differential isoprenylation in mediating light-dependent signaling in the photoreceptor cells. We will use a combination of unique animal models, in vivo electrophysiological measurements, ex vivo retinal culture models and in vitro biochemical analyses to comprehensively address this question. 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 these mutations, and determine new potential therapeutic strategies for treatment such as gene transfer, tissue and cell transplantation, growth factor therapy, and pharmacological intervention.? Our proposed studies have clinical implications, such as therapy for mutations in PDE6 and AIPL1 that lead to blindness in humans.
The focus of the proposed study is to decipher the mechanism behind the synthesis and maturation of phosphodiesterase (PDE6), an enzyme essential for our vision. We hope to use the knowledge gained from this study to design novel therapies for PDE6 related blindness.