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换机械是如何在外段(OS)组装、运输和维护的，作为防止和/或修复当该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发挥了作用。我们假设蛋白质的脂化是一个动态的过程，在组织和促进盘膜上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(PDE6)作为模型蛋白来验证这一假说。PDE6是视杆细胞和视锥细胞光信号传递所需的关键效应酶。光感受器细胞纤毛化OS中缺乏PDE6会导致视力丧失，并伴有快速变性。在人类中，OS中缺乏PDE6会导致各种致盲疾病，如视网膜色素变性、Leber先天性黑色素和色盲。尽管我们知道PDE6作为效应酶在光转导中的作用，但这个关键的酶是如何在内节段组装、运输然后固定在外节段膜上的尚不清楚。本项目中提出的实验旨在破译PDE6在杆状和圆锥体的生存和功能中需要蛋白质脂化和进一步加工的机制。我们计划通过研究包括PDE6在内的脂化蛋白的功能、稳定性、组装和运输来实现这些目标，在表达PDE6突变形式的动物模型中，或者在缺乏负责这些修饰的特定酶的模型中。最后，我们将利用这些动物模型研究蛋白质在锥体细胞中的转运机制。我们建议的研究与NEI的视网膜疾病计划保持一致，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，通过它我们可以了解各种致盲疾病背后的基础，并设计新的治疗方法来治疗它们。 与公共健康相关：视杆细胞和视锥细胞在视网膜中的生存和功能依赖于蛋白质机械的有效合成和从内节到纤毛外节的运输。这一过程中的缺陷会导致人类患上致残致盲疾病。这一建议将阐明蛋白质脂质修饰在视杆细胞和视锥细胞中关键蛋白质的运输和功能中的作用，并为我们理解致盲疾病的基础和设计治疗这些疾病的新方法奠定基础。

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. PUBLIC HEALTH RELEVANCE: Survival and function of rod and cone cells in retina depends on efficient synthesis and transport of protein machinery from inner segments to ciliated outer segment. Defects in this process lead to debilitating blinding diseases in humans. This proposal will elucidate the role of protein lipid modification in trafficking and function of crucial proteis in rods and cones and lay a framework by which we can understand the basis behind blinding diseases and design novel treatments for these diseases.