Role of AIPL1 in inherited retinal degenerative disease

描述（由申请人提供）：莱伯先天性黑蒙（LCA），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。与由芳香烃受体相互作用蛋白样-1（Aipl 1）突变引起的LCA的严重性一致，这种疾病的小鼠模型显示出视杆和视锥光感受器细胞的快速变性。虽然感光细胞在Aipl 1-/-小鼠中正常形成，但视杆细胞和视锥细胞都不起作用。Aipl 1-/-小鼠的视杆快速变性是由功能性视杆磷酸二酯酶（PDE）的丧失引起的，磷酸二酯酶是一种对光传导和光感受器活力至关重要的酶。然而，AIPL 1和PDE稳定性之间的关系尚不清楚。Aipl 1-/-小鼠中视锥细胞的快速变性表明Aipl 1对视锥细胞功能和生存能力也很重要。但是，AIPL 1在视锥光感受器中的功能尚不清楚。我们建议使用离体生物化学分析与组织培养表达分析和转基因拯救的组合，以揭示AIPL 1在PDE稳定性和感光细胞活力中的重要作用。 这项研究的具体目标是： 1.确定AIPL 1在视杆细胞PDE翻译后调节中的作用。 2.研究AIPL 1对视锥细胞功能和存活的需求。 本研究的长期目标是阐明AIPL 1在视网膜中的作用，了解AIPL 1缺陷导致快速视网膜变性的机制，并为开发治疗方法奠定基础。

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.