Role of AIPL1 in Inherited Retinal Degenerative Disease

描述（由申请人提供）：本研究计划的长期目标是了解光转导机制是如何组装，运输和维持在外部段（OS），作为预防和/或修复当这个过程出错时出现的缺陷的先决条件。我们认为蛋白质脂质修饰在这一过程中起作用。我们假设蛋白质的脂质化是一个动态过程，并且在组织和促进椎间盘膜光转导途径中蛋白质之间的串扰中是必不可少的。我们将使用磷酸二酯酶-6（PDE 6）作为模型蛋白来验证这一假设。PDE 6是视杆细胞和视锥细胞中光信号传导所需的关键效应酶。光感受器细胞中纤毛OS中PDE 6的缺失导致视力丧失，伴随着快速变性。在人类中，OS中PDE 6的缺乏导致各种致盲性疾病，如视网膜色素变性、莱伯先天性黑蒙和色盲。尽管我们知道PDE 6在光转导中作为效应酶的作用，但这种关键酶如何在内部片段中组装，运输然后锚定在外部片段膜中尚不清楚。该项目中提出的实验旨在破译蛋白质脂化和PDE 6在视杆细胞和视锥细胞的存活和功能中的进一步加工的需要背后的机制。我们计划通过在表达PDE 6突变形式的动物模型或缺乏负责这些修饰的特定酶的模型中研究脂化蛋白（包括PDE 6）的功能、稳定性、组装和转运来实现这些目标。最后，我们将使用这些动物模型研究视锥细胞中的蛋白质转运机制。我们提出的研究与NEI的视网膜疾病计划一致，以“确定导致视网膜退行性疾病的突变的病理生理机制”。我们提出的研究奠定了一个框架，通过这个框架，我们可以理解各种致盲疾病背后的基础，并设计新的疗法来治疗它们。

DESCRIPTION (provided by applicant): The long term goal of this research program is to understand how the phototransduction machinery is assembled, transported and maintained in outer segment (OS), as a prerequisite for preventing and/or repairing defects that arise when this process goes awry. We believe protein lipid modification plays a role in this process. We hypothesize that lipidation of proteins is a dynamic process and is essential in organizing and facilitating cross-talk between proteins in the phototransduction pathway at disc membranes. We will use phosophodiesterase-6 (PDE6) as a model protein to test this hypothesis. PDE6 is the crucial effectors enzyme needed for light signaling in rod and cone photoreceptor cells. Absence of PDE6 in ciliated OS in photoreceptor cells leads to vision loss accompanied by rapid degeneration. In humans, lack of PDE6 in OS leads to various blinding diseases such as retinitis pigmentosa, leber congenital amaurosis and achromatopsia. Despite our knowledge about the role of PDE6 as an effectors enzyme in phototransduction, how this crucial enzyme is assembled in inner segments, transported and then anchored in outer segment membranes is not known. The experiments proposed in this project are aimed at deciphering the mechanism behind the need for protein lipidation and further processing of PDE6 in survival and function of rods and cones. We plan to accomplish these goals by investigating the function, stability, assembly and transport of lipidated proteins including PDE6, in animal models that either expresses mutant forms of PDE6 or in models that lack specific enzymes that are responsible for these modifications. Finally, we will investigate the protein transport mechanisms in cone cells using these animal models. Our proposed studies are aligned with Retinal Diseases Program of the NEI to "determine the pathophysiological mechanisms underlying mutations" that cause retinal degenerative diseases. Our proposed studies lay a framework by which we can understand the basis behind various blinding diseases and design novel therapies to treat them.