FATTY ALCOHOL METABOLISM IN SJOGREN-LARSSON SYNDROME

干燥-拉尔森综合征(SLS)是一种遗传性疾病 以先天性鱼鳞病、智力低下和 痉挛。初步研究表明，培养的皮肤 系统性红斑狼疮患者成纤维细胞脂肪醇代谢改变 由于酶的缺乏，脂肪醇：NAD-氧化还原酶 (粮农组织)。人们对正常的脂肪酒精代谢知之甚少， 目前尚不清楚脂肪改变的临床效果。 酒精新陈代谢。此外，人类的粮农组织还没有 特色化的。这项提议的一个长期目标是 了解正常的脂肪酒精代谢和粮农组织缺乏症 可能导致SLS的临床表型。 我们建议研究培养皮肤中的脂肪酒精代谢。 了解正常人和系统性红斑狼疮患者的成纤维细胞 系统性红斑狼疮患者的脂肪醇代谢。气液结合使用技术 结合放射化学示踪研究的层析， 我们将研究脂肪酒精水平的调节 正常和SLS成纤维细胞。粮农组织的活动将被描述为 在正常人成纤维细胞中，并与残留的粮农组织进行比较 在SLS细胞中的活性来确定FAO酶是否 运动学上或结构上改变的。我们将搜索基因 基因互补分析在SLS中的异质性 体细胞CLL融合技术。理解脂肪醇 粮农组织活动差异很大的组织中的代谢， 代谢研究将在大鼠肝细胞和大脑中进行 使用放射化学和酶技术的组织切片。这个 脂肪醇代谢相关酶的亚细胞定位 路径的确定将使用差分法和 密度梯度离心法。SLS的发病机制将是 在老鼠喂养研究中进行调查，以确定组织是否 脂肪酒精蓄积导致生化和临床 改变了SLS的特征。这些研究将提供 关于正常脂肪酒精代谢和 系统性红斑狼疮患者脂肪醇代谢紊乱。

Sjogren-Larsson syndrome (SLS) is an inherited disorder characterized by congential ichthyosis, mental retardation and spasticity. Preliminary studies show that cultured skin fibroblasts from SLS patients have altered fatty alcohol metabolism due to deficiency of the enzyme, fatty alcohol: NAD- oxidoreductase (FAO). Normal fatty alcohol metabolism is poorly understood and no information is known about the clinical effects of altered fatty alcohol metabolism. Furthermore, human FAO has not been characterized. A long-term objective of this proposal is to understand normal fatty alcohol metabolism and how FAO deficiency may lead to the clinical phenotype of SLS. We propose to investigate fatty alcohol metabolism in cultured skin fibroblasts from normal and SLS subjects to understand the deranged fatty alcohol metabolism in SLS. Using techniques of gas-liquid chromatography in combination with radiochemical tracer studies, we will investigate the regulation of fatty alcohol levels in normal and SLS fibroblasts. FAO acitivity will be characterized in normal human fibroblasts and compared to the residual FAO activity in SLS cells to determine whether the FAO enzyme is kinetically or structurally altered. We will search for genetic heterogeneity in SLS by gene complementation analysis using the techniques of somatic cll fusion. To uderstand fatty alcohol metabolism in tissues with quite different FAO activities, metabolic studies will be performed in rat hepatocytes and brain tissue slices using radiochemnical and enzymatic techniques. The subcellualr location of enzymes involved in fatty alcohol metabolic pathways will be determined using methods of differential and density-gradient centrifugation. The pathogenesis of SLS will be investigate in rat feeding studies to establish whether tissue fatty alcohol accumulation leads to biochemical and clinical changes characteristic of SLS. These studies will provide fundamental information about normal fatty alcohol metabolism and the deranged fatty alcohol metabolism in SLS.