Synthetic Retinal Pigments and Binding Proteins

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DESCRIPTION (provided by applicant): Our long-term goal is to define the roles of retinoids in the visual transduction process and to explore the potential of retinal analogs in treating disorders resulting from improper retinoid processing, such as in Leber's amaurosis. Our working premise is that the retinal chromophore (11-cis retinal) controls the biochemical and physiological properties of visual pigments. Our first aim is to investigate the structural determinants in opsins that modulate retinal interactions. Studies will determine: 1) if the unique red cone opsin properties are due to the absence of a palmitate group anchoring the C-terminus of the protein, 2) if a putative secondary retinoid binding site on opsins exists and if its integrity is dependent on the presence of a palmitate, and 3) if all-trans retinol formation and clearance from the outer segment are controlled by structural features of opsins, the opsin/retinoid interactions and photoreceptor morphology. Our second aim is to investigate the role of retinoid cycling in rod and cone degeneration. Studies will determine: 1) if rod opsin phosphorylation slows the degeneration arising from opsin activity in models that lack 11-cis retinal, 2) if improper vitamin A processing leads to cone opsin mislocalization and eventual cone degeneration, and 3) if light-stable, analogues of 11-cis retinal can correct this cone opsin mislocalization and prevent cone degeneration. We anticipate that these studies will form a rational basis for using retinoid-like compounds to treat the blinding diseases that result from improper vitamin A processing. The retinoid, vitamin A, is known to be essential for vision. Lack of adequate vitamin A for the visual process can arise from dietary deficiency or through a failure of processing this compound properly. We are studying the processing of vitamin A in the eye and exploring the pharmaceutical potential of using retinoid-like compounds to treat diseases resulting from improper processing of vitamin A.