Role of AIPL1 in Inherited Retinal Degenerative Disease

AIPL1 在遗传性视网膜退行性疾病中的作用

基本信息

批准号：
8518329
负责人：
Visvanathan Ramamurthy
金额：
$ 35.15万
依托单位：
WEST VIRGINIA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-01 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8518329
关键词：
ARA9 protein Affect Animal Model Blindness Carrier Proteins Catalytic Domain Complement Complex Coupled Defect Degenerative Disorder Disease Electroporation Enzymes Esterification Exhibits Functional disorder Goals Human Inherited Knock-out Knowledge Lead Leber&apos s amaurosis Light Lipids Mediating Membrane Modeling Modification Molecular Morphology Mus Mutant Strains Mice Mutation Pathway interactions Phase Photoreceptors Phototransduction Play Process Proteins Proteolysis Research Retina Retinal Cone Retinal Degeneration Retinal Diseases Retinitis Pigmentosa Rhodopsin Role Signal Transduction System Testing Transducin Transferase Transgenic Organisms Vertebrate Photoreceptors Vesicle achromatopsia base cone-rod degeneration design in vivo mecysteine mouse model mutant novel phosphodiesterase 6 prevent programs protein transport public health relevance repaired research study response retinal rods rhodopsin kinase trafficking

项目摘要

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.

描述（由申请人提供）：该研究计划的长期目标是了解光转导机械如何在外段（OS）中组装、运输和维护，作为预防和/或修复此过程中出现的缺陷的先决条件出了差错。我们相信蛋白质脂质修饰在此过程中发挥了作用。我们假设蛋白质的脂化是一个动态过程，对于组织和促进椎间盘膜光转导途径中蛋白质之间的串扰至关重要。我们将使用磷酸二酯酶 6 (PDE6) 作为模型蛋白来检验这一假设。 PDE6 是视杆细胞和视锥细胞感光细胞中光信号传递所需的关键效应酶。感光细胞纤毛 OS 中缺乏 PDE6 会导致视力丧失并伴有快速退化。在人类中，OS中缺乏PDE6会导致各种致盲疾病，例如色素性视网膜炎、莱伯先天性黑蒙和全色盲。尽管我们了解 PDE6 作为光转导效应酶的作用，但这种关键酶如何在内节中组装、运输然后锚定在外节膜中尚不清楚。该项目提出的实验旨在破译视杆细胞和视锥细胞的存活和功能中蛋白质脂化和 PDE6 进一步加工的需要背后的机制。我们计划通过在表达 PDE6 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。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，旨在“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，通过该框架我们可以了解各种致盲疾病背后的基础并设计新的疗法来治疗它们。