Model for dominant Stargardt-like macular dystrophy

显性 Stargardt 样黄斑营养不良模型

• 批准号: 6877022
• 负责人: WOJCIECH KEDZIERSKI
• 金额: $ 15.6万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6877022
• 关键词: autosomal dominant trait; biotechnology; disease /disorder model; electrophysiology; electroporation; electroretinography; gene deletion mutation; genetic disorder; genetic models; genetically modified animals; immunocytochemistry; laboratory mouse; macular degeneration; model design /development; nucleic acid amplification techniques; pathologic process; polymerase chain reaction

DESCRIPTION (provided by applicant): Macular dystrophies are an important group of diseases leading to loss of central vision and blindness. Recent genetic studies of a group of patients with autosomal dominant Stargardt-like macular dystrophies identified a 5-bp deletion in ELOVL4 gene. Its predicted protein has a high degree of homology to mammalian and yeast enzymes involved in the membrane-bound fatty acid chain elongation system. The human pathogenic deletion leads to a truncated protein with a net loss of 44 amino acids, including a di-lysine endoplasmic reticulum (ER) retention motif. The deletion can lead to perturbation of biosynthesis of very long chain fatty acids, resulting in their reduced synthesis in the ER and/or abnormal, ectopic synthesis outside the ER. Besides these two pathogenic mechanisms, there is also a possibility that the truncated ELOVL4 protein is toxic. To achieve our long-term goal of understanding pathophysiology of macular dystrophies and subsequently preventing vision loss, we propose the generation of Stgd3 knockin mice carrying human ELOVL4 deletion as well as Elovl4 knockout mice. These mice will be characterized by structural, functional, and biochemical studies of the retina, using microscopy, immunocytochemistry, electroretinography, as well as lipid and protein analysis. Our research will address the following specific aims: (i) understanding of the function of the ELOVL4 gene in physiology and pathology of the retina, and (ii) elucidation of the mechanism of disease for the STGD3 mutation.

描述（由申请人提供）：黄斑营养不良是一群重要的疾病，导致中央视力和失明的丧失。一组常染色体显性星状黄斑样性障碍患者的遗传研究确定了ELOVL4基因的5 bp缺失。它的预测蛋白质与参与膜结合的脂肪酸链延伸系统的哺乳动物和酵母酶具有高度同源性。人类的致病缺失导致截短的蛋白质，净损失为44个氨基酸，包括二烯丙胺内质网（ER）保留基序。缺失可能导致非常长的链脂肪酸的生物合成扰动，从而导致其在ER以外的ER中的合成和/或异常的异位合成。除了这两种致病机制外，截断的Elovl4蛋白也有毒。为了实现我们的长期目标，即了解黄斑营养不良的病理生理学并随后预防视力丧失，我们提出了携带人Elovl4缺失以及Elovl4敲除小鼠的STGD3敲击蛋白小鼠的产生。这些小鼠的特征将以视网膜的结构，功能和生化研究为特征，使用显微镜，免疫细胞化学，电视图以及脂质和蛋白质分析。我们的研究将解决以下具体目的：（i）理解Elovl4基因在视网膜生理和病理学中的功能，以及（ii）阐明STGD3突变的疾病机制。