Leber congenital amaurosis (LCA), the most severe form of inherited retinal dystrophy, causes blindness or impaired vision at birth. In agreement with the severity of LCA caused by mutations in Aryl hydrocarbon receptor interacting protein like-1 (Aipl1), a mouse model for this disease shows rapid degeneration of rod and cone photoreceptor cells. Although photoreceptor cells form normally in Aipl1-/- mice, neither rods nor cones are functional. Rapid rod degeneration in Aipl1-/- mice is caused by loss of functional rod phosphodiesterase (PDE), an enzyme essential for phototransduction and photoreceptor viability. However, the relationship between AIPL1 and PDE stability is not yet known. Rapid degeneration of cones in Aipl1-/- mice suggests that AIPL1 is also important for cone function and viability. But, the function of AIPL1 in cone photoreceptors is not yet known. We propose to use a combination of ex vivo biochemical analyses together with tissue culture expression analysis and transgenic rescue to reveal the essential role of AIPL1 in PDE stability and photoreceptor viability.
The specific aims of this study are to: 1. Determine the role of AIPL1 in post-translational regulation of PDE in rods. 2. Investigate the requirement of AIPL1 for the function and survival of cone photoreceptors. The long-term goals of this study are to elucidate the role of AIPL1 in retina, understand the mechanisms by which defects in AIPL1 contribute to rapid retinal degeneration, and to lay the groundwork for the development of therapeutic approaches to the disease.
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