ELOVL4 and Retinal Disease

Stargardt样黄斑营养不良(STGD3，MIM 600110)是一种常染色体显性遗传性青少年型 黄斑变性以视力下降、黄斑萎缩和广泛斑点为特征的黄斑变性。 利用定位克隆的方法，我们确定了ELOVL4是与致病相关的基因 Stargardt样黄斑营养不良(STGD3，MiM 600110)。ELOVL4编码一种蛋白质，其序列和 与ELO蛋白家族的结构相似。ELO家族的蛋白质与伸长有关 长链脂肪酸(LCFA)，这表明ELOVL4可能具有类似的功能。从长远来看 这项建议的目的是表征ELOVL4的生化特性并阐明 ELOVL4基因突变导致人类黄斑变性的分子机制ELOVL4 蛋白质在脊椎动物物种中是高度保守的。ELOVL4和ELOVL4的确切酶功能 突变的ELOVL4导致黄斑变性的致病机制尚不清楚。我们的 中心假设是ELOVL4是生物合成途径中的一个关键酶，该途径产生非常长的链 脂肪酸对视网膜的发育和功能起着至关重要的作用。在这个假设的指导下，我们 建议在体外通过对脂肪酸组成的综合分析来确定ELOVL4的功能 在体内，并在ELOVL4转基因、敲除和敲除中检测视网膜发育和发病机制 老鼠。进一步了解ELOVL4的功能和黄斑的发病机制 我们将解决以下具体目标： 特异目的1：测定ELOVL4的酶功能 具体目的2：确定ELOVL4在视网膜发育和病理中的作用。 特定目标3：检测ELOVL4突变转基因小鼠的RPE功能障碍 Stargardt黄斑营养不良是最常见的青少年黄斑变性，与 AMD的重要临床和组织病理学相似之处包括异常堆积的 RPE中的脂褐素，RPE和覆盖的光感受器细胞的萎缩，以及中心视力的丧失。 ELOVL4是第一个参与长链脂肪酸生物合成的基因，与任何形式的 黄斑变性。这项拟议的研究应该会为人类的脂代谢带来新的见解。 光感受器细胞，揭示了黄斑变性发病机制的新途径。我们的研究 也应该为脂褐素的形成提供洞察力，并为治疗 Stargardt黄斑营养不良和AMD。

Stargardt-like macular dystrophy (STGD3, MIM 600110) is an autosomal dominant form of juvenile macular degeneration characterized by decreased visual acuity, macular atrophy, and extensive flecks. Using a positional cloning approach, we identified ELOVL4 as the causal disease gene responsible for Stargardt-like macular dystrophy (STGD3, MIM 600110). ELOVL4 encodes a protein with sequence and structural similarities to the ELO family of proteins. The ELO family of proteins is involved in the elongation of long chain fatty acids (LCFA), suggesting that ELOVL4 may have a similar function. The long term objectives of this proposal are to characterize the biochemical properties of ELOVL4 and to elucidate molecular mechanism leading to macular degeneration due to ELOVL4 mutations in humans. ELOVL4 proteins are strongly conserved throughout vertebrate species. The exact enzymatic function of ELOVL4 and the pathogenic mechanisms by which mutant ELOVL4 causes macular degeneration are unclear. Our central hypothesis is that ELOVL4 is a key enzyme in a biosynthetic pathway that produces very long chain fatty acids which play an essential rolejn retina development and function. Guided by this hypothesis, we propose to define ELOVL4 function through a comprehensive analysis of fatty acid composition in vitro and in vivo, and to examine retinal development and pathogenesis in ELOVL4 transgenic, knockin, and knockout mice. To further understand ELOVL4 functions and pathogenic mechanisms giving rise to macular degeneration we will address the following specific aims: Specific Aim 1: To determine the enzymatic function of ELOVL4 Specific Aim 2: To determine the role of ELOVL4 in retinal development and pathology . Specific Aim 3: To examine RPE dysfunction in ELOVL4 mutant transgenic mice Stargardt 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 macular degeneration. The proposed study should lead to new insights into lipid metabolism in photoreceptor cells and reveal a novel pathway in the pathogenesis of macular degeneration. Our study should also provide insights into the formation of lipofuscin and provide new avenues for treatments for Stargardt macular dystrophy and AMD.