Role of AIPL1 in inherited retinal degenerative disease

描述（由申请人提供）：Leber先天性黑朦（LCA）是遗传性视网膜营养不良的最严重形式，在出生时导致失明或视力受损。与芳烃受体相互作用蛋白样-1 （Aipl1）突变引起的LCA的严重程度一致，该疾病的小鼠模型显示杆状和锥状光感受器细胞快速变性。虽然Aipl1-/-小鼠的感光细胞形成正常，但视杆细胞和视锥细胞都没有功能。Aipl1-/-小鼠的杆状细胞快速变性是由杆状细胞磷酸二酯酶（PDE）的丧失引起的，PDE是一种光传导和光受体活力所必需的酶。然而，AIPL1与PDE稳定性之间的关系尚不清楚。Aipl1-/-小鼠视锥细胞的快速退化表明Aipl1对视锥细胞的功能和活力也很重要。但是，AIPL1在视锥光感受器中的作用尚不清楚。我们建议采用离体生化分析、组织培养表达分析和转基因救援相结合的方法来揭示AIPL1在PDE稳定性和光感受器活力中的重要作用。

DESCRIPTION (provided by applicant): 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.