Large Animal Model of Macular Degeneration

黄斑变性大型动物模型

• 批准号: 6611739
• 负责人: Robert M Petters
• 金额: $ 14.65万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-01 至 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6611739
• 关键词: autosomal dominant trait; disease /disorder model; gene expression; genetically modified animals; genotype; immunocytochemistry; light microscopy; macular degeneration; microinjections; model design /development; molecular cloning; molecular pathology; ophthalmoscopy; pathologic process; polymerase chain reaction; retinoid binding proteins; southern blotting; swine; visual photoreceptor

DESCRIPTION (provided by applicant): The prime objective of this proposal is to produce a large animal model of macular degeneration using the gene ELOVL4. Transgenic pigs may be useful for the elucidation of the molecular mechanisms responsible for macular degeneration and for the development of therapeutic interventions. The pig's similarity to humans in size and retinal anatomy and physiology make it a logical choice for these experiments. Further, the production of transgenic pigs is a virtual surety. Only transgenic primates would provide a more accurate model, however, both the low supply of primates and low efficiency of these procedures will likely prevent gone transfer being a routine procedure in primates. Using a positional cloning approach, one of us (Zhang) has identified a disease gene called ELOVL4, which is responsible for an autosomal dominant form of Stargardt's-like macular dystrophy (STGD3) and autosomal dominant macular dystrophy (adMD). STGD3 and adMD are two related forms of inherited macular degeneration characterized by decreased visual acuity, macular atrophy, and fundus flecks. A single five base-pair deletion in the coding region of ELOVL4 is found in all affected members of four independent STGD3 families and one adMD family. The deletion generates a frame-shift mutation and results in loss of 51 amino acids at the C-terminus including a putative di-lysine ER targeting signal. ELOVL4 demonstrated cone and rod photoreceptor specific expression in the eye and encoded a putative transmembrane protein with similarities to the ELO family of proteins involved in elongation of very long chain fatty acids. Stargardt's macular dystrophy is the most common juvenile macular degeneration and shares many important clinical and histopathological similarities with AMD including an abnormal accumulation of lipofuscin in the RPE, atrophy of the RPE and overlying photoreceptor cells, and loss of central vision. ELOVL4 is the first gene involved in the biosynthesis of long chain fatty acids implicated in any form of photoreceptor degeneration. Studies of pigs transgenic for ELOVL4 should lead to new insights into lipid metabolism in photoreceptor cells and may reveal a novel pathway in the pathogenesis of macular degeneration.

描述（由申请人提供）：该提案的主要目标是使用基因 ELOVL4 产生黄斑变性的大型动物模型。转基因猪可能有助于阐明黄斑变性的分子机制和开发治疗干预措施。猪在体型、视网膜解剖学和生理学方面与人类相似，使其成为这些实验的合理选择。此外，转基因猪的生产实际上是有保证的。只有转基因灵长类动物才能提供更准确的模型，然而，灵长类动物供应量少和这些程序的低效率可能会阻止消失转移成为灵长类动物的常规程序。 我们中的一个人（张）利用定位克隆方法，鉴定出了一种名为 ELOVL4 的疾病基因，该基因负责常染色体显性遗传的斯塔加特样黄斑营养不良 (STGD3) 和常染色体显性黄斑营养不良 (adMD)。 STGD3 和 adMD 是遗传性黄斑变性的两种相关形式，其特征是视力下降、黄斑萎缩和眼底斑点。在四个独立 STGD3 家族和一个 adMD 家族的所有受影响成员中都发现 ELOVL4 编码区中存在单个 5 个碱基对缺失。该缺失会产生移码突变，并导致 C 末端丢失 51 个氨基酸，其中包括假定的二赖氨酸 ER 靶向信号。 ELOVL4在眼睛中表现出视锥细胞和视杆细胞光感受器的特异性表达，并编码一种假定的跨膜蛋白，该跨膜蛋白与涉及极长链脂肪酸延伸的ELO蛋白家族相似。 Stargardt 黄斑营养不良是最常见的青少年黄斑变性，与 AMD 有许多重要的临床和组织病理学相似之处，包括 RPE 中脂褐素的异常积累、RPE 和覆盖的感光细胞萎缩以及中央视力丧失。 ELOVL4 是第一个参与长链脂肪酸生物合成的基因，该生物合成与任何形式的光感受器变性有关。对 ELOVL4 转基因猪的研究应该会对感光细胞中的脂质代谢产生新的认识，并可能揭示黄斑变性发病机制的新途径。