ELOVL4 and Retinal Disease

Stargardt样黄斑营养不良（STGD 3，MIM 600110）是一种常染色体显性形式的青少年黄斑营养不良， 以视力下降、黄斑萎缩和广泛的视网膜震颤为特征的黄斑变性。 使用定位克隆方法，我们鉴定了HPVL4作为致病基因， Stargardt样黄斑营养不良（STGD 3，MIM 600110）。HPVL4编码具有序列的蛋白质， 与ELO蛋白家族的结构相似。蛋白质的ELO家族参与延伸 长链脂肪酸（LCFA），这表明LIFVL4可能具有类似的功能。长期 该提案的目的是表征BCLVL4的生化特性，并阐明 导致人类黄斑变性的分子机制是由于MAPKVL4突变。ELOVL4 蛋白质在整个脊椎动物物种中高度保守。BMPVL4的确切酶功能和 突变体VL4V14引起黄斑变性的致病机制尚不清楚。我们 一个中心假设是，HPVL4是生物合成途径中的一个关键酶， 在视网膜发育和功能中起重要作用的脂肪酸。根据这一假设，我们 建议通过体外脂肪酸组成的综合分析来定义HPVL4功能， 在体内，并检查视网膜发育和发病机制在ESTVL4转基因，敲入，和敲除 小鼠为了进一步了解MAPKVL4的功能和引起黄斑变性的致病机制， 我们将致力于实现以下具体目标： 具体目的1：确定p53 VL4的酶功能 具体目的2：确定CD34 VL4在视网膜发育和病理学中的作用。 具体目的3：检查RPVL4突变转基因小鼠中的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性，包括 RPE中的脂褐质、RPE和覆盖的感光细胞的萎缩以及中心视力的丧失。 HPVL4是参与长链脂肪酸生物合成的第一个基因，其涉及任何形式的 黄斑变性这项拟议中的研究将导致对脂质代谢的新见解， 光感受器细胞，揭示了黄斑变性发病机制中的新途径。我们的研究 还应该提供对脂褐素形成的见解，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.