Fibulin-Associated Age-Related Macular Degeneration

纤维蛋白相关的年龄相关性黄斑变性

• 批准号: 7122350
• 负责人: EDWIN M STONE
• 金额: $ 36.14万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-15 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7122350
• 关键词: aging; animal tissue; clinical research; disease /disorder etiology; extracellular matrix proteins; eye fundus photography; family genetics; gene expression; gene mutation; genetic polymorphism; genetic screening; histology; human genetic material tag; human subject; immunocytochemistry; laboratory rat; macular degeneration; macular drusen; pathologic process; patient oriented research; phenotype; retinal pigment epithelium

DESCRIPTION (provided by applicant): Age-related macular degeneration - the most common cause of severe visual loss in the developed world has a significant genetic component. This fact raises the possibility that the expanding knowledge of the human genome can be used to improve our ability to diagnose and treat this disorder. Recently, we demonstrated that mutations in the gene encoding an extracellular matrix protein known as fibulin 5 are responsible for a statistically significant subset of age-related macular degeneration. In this proposal, we will pursue this discovery at four different levels. First we will screen portions of three fibulin genes (2, 5, and 6) in the cohort of AMD patients and controls that were gathered as part of the Age-Related Eye Disease Study (AREDS) to determine whether our previous results can be confirmed in this well characterized group of individuals. We will also use a novel, focused screening approach to evaluate a minimum of 25 other genes whose proteins are functionally related to the fibulins to determine whether any of these are also involved in the pathogenesis of AMD. In addition, we will explore the pathophysiology of fibulin associated AMD at the tissue level by carefully evaluating the eyes of mice with abnormalities in fibulins 2, 3 and 5 as well as by crossing these mice to ABCA4 deficient mice in an attempt to augment their phenotype. Finally, we will carefully study 37 human kindreds already known to harbor mutations in fibulin genes to test the hypothesis that the phenotype we observed in the fibulin 5 patients in our previous study is characteristic of fibulin associated AMD as a whole. This part of the study will also assess the age-dependent penetrance of fibulin mutations in these kindreds, which will be a critical factor in determining whether large scale molecular testing for fibulin variations will someday be of value.

描述（由申请人提供）：与年龄相关的黄斑变性 - 发达国家严重视觉丧失的最常见原因具有重要的遗传成分。这一事实提高了人们对人类基因组的不断扩展知识可用于提高我们诊断和治疗这种疾病的能力的可能性。最近，我们证明了编码被称为斐库蛋白5的细胞外基质蛋白的基因中的突变负责与年龄相关的黄斑变性的统计学显着子集。在此提案中，我们将在四个不同的层面上追求这一发现。首先，我们将在AMD患者和对照组中筛选三个纤维蛋白基因（2、5和6）的部分，这些患者和对照组是与年龄相关的眼病研究（AREDS）的一部分，以确定在这个表征良好的个体组中是否可以确认我们的先前结果。我们还将使用一种新颖的，集中的筛选方法来评估其蛋白质在功能上与斐bul蛋白在功能上相关的其他25种基因，以确定这些基因是否也参与AMD的发病机理。此外，我们将通过仔细评估腓蛋白2、3和5中异常的小鼠的眼睛，以及将这些小鼠与ABCA4缺乏小鼠跨越，试图增强其表型，从而探讨组织水平上相关AMD的病理生理学。最后，我们将仔细研究37种已知的菌素基因突变的人类亲属，以检验以下假设：我们先前研究中我们在fibulin 5患者中观察到的表型是整个相关AMD的特征。研究的这一部分还将评估这些属性中腓蛋白突变的年龄依赖性渗透率，这将是确定腓骨蛋白变异的大规模分子测试是否有价值的关键因素。