The long-term goal of this research program is to elucidate the molecular mechanisms of the function and regulation of rod and cone cGMP-phosphodiesterases (PDE6). PDE6s serve as key effectors enzymes in the vertebrate visual transduction cascade. The phototransduction cascades in rods and cones are principally similar, and the main rod and cone signaling molecules are highly homologous. In contrast, the physiology of rods and cones is markedly dissimilar, most notably with respect to sensitivity, response kinetics, and adaptation range. These differences are fundamental to the ability of the dual photoreceptor visual system to operate within a wide range of light intensities, yet they are poorly understood. Elucidating the molecular origins of the differences in physiology of rods and cones is a major current task in the phototransduction field. We hypothesize that distinct rod and cone PDE6 provide an important contribution into dissimilar physiology of rods and cones. The first main goal of the proposed research is to test this hypothesis with the use of a novel and robust transgenic mouse model expressing cone PDE6C instead of functional PDEAB in rods. These studies will establish the significance of different PDE6 isozymes in rods and cones. Furthermore, we expect to significantly advance understanding of cone PDE6 signaling, which at present is underdeveloped. The second major focus of this proposal is the study of PDE6 transport in photoreceptor cells and mistrafficking of PDE6 mutants as a mechanism of PDE6-linked retinal diseases. Mutations in PDE6 are known to cause retinitis pigmentosa (RP) and achromatopsia in humans. We hypothesize that PDE6 mistrafficking is a primary underlying mechanism of certain missense PDE6 mutations associated with the retinal diseases. The structural requirements for proper transport of PDE6, the mechanisms of mutant PDE6 enzymes, and their trafficking in photoreceptor cells will be examined using transgenic X. laevis. The ultimate goal is to generate important insights into the mechanisms of PDE6-linked RP and achromatopsia that will impact development of therapeutical interventions for these retinal dysfunctions.
Rod and cone cGMP phosphodiesterases (PDE6 family) are the key effector enzymes in vision. Mutations in rod and cone PDE6 lead to human retinal diseases, such as retinitis pigmentosa and achromatopsia. The goals are to elucidate the differences between rod and cone PDE6 in relation to the distinct physiology of rods and cones and to achieve a new level of understanding of the mechanisms of PDE6 mutations in diseased retina. Mechanistic insights are sought that may aid development of therapeutical interventions for the PDE6-linked diseases.
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