FATTY ALCOHOL METABOLISM IN SJOGREN-LARSSON SYNDROME

干燥-拉尔森综合征中的脂肪醇代谢

• 批准号: 3242761
• 负责人: WILLIAM B. RIZZO
• 金额: $ 17.77万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-02-01 至 1992-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3242761
• 关键词: Sjogren's syndrome; alcohols; aldehydes; autosomal recessive trait; brain metabolism; congenital ichthyosis; enzyme mechanism; enzyme substrate; fatty acid analog; fibroblasts; gas chromatography; gene complementation; human tissue; laboratory rat; liver cells; mental retardation; palmitates; Sjogren's syndrome; alcohols; aldehydes; autosomal recessive trait; brain metabolism; congenital ichthyosis; enzyme mechanism; enzyme substrate; fatty acid analog; fibroblasts; gas chromatography; gene complementation; human tissue; laboratory rat; liver cells; mental retardation; palmitates

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.

Sjogren-Larsson综合征（SLS）是一种遗传疾病 以聚集的鱼质病，智力低下和 痉挛。 初步研究表明培养的皮肤 SLS患者的成纤维细胞改变了脂肪酒精代谢 由于酶的不足，脂肪醇：氧化还原酶 （粮农组织）。 正常的脂肪酒精代谢知之甚少，并且 尚无有关改变脂肪的临床影响的信息 酒精代谢。 此外，人群还没有 特征。 该提议的长期目标是 了解正常的脂肪酒精代谢以及粮农 可能导致SLS的临床表型。 我们建议研究培养的皮肤中的脂肪酒精代谢 来自正常和SLS受试者的成纤维细胞以理解失调的 SLS中的脂肪酒精代谢。 使用气体液体技术 色谱法与放射化学示踪剂研究， 我们将调查脂肪酒精水平的调节 正常和SLS成纤维细胞。 粮农组织activitive将被描述 在正常的人成纤维细胞中，与残留的粮农 SLS细胞中的活性以确定FAO酶是否为 动力学或结构改变。 我们将搜索遗传 SLS中通过基因互补分析的异质性使用 体细胞融合的技术。 给udstand脂肪酒精 具有完全不同的粮农组织的组织中的代谢， 代谢研究将在大鼠肝细胞和大脑中进行 使用放射性和酶促技术的组织切片。 这 涉及脂肪酒精代谢的酶的子细胞位置 将使用差分方法和 密度梯度离心。 SL的发病机理将是 在大鼠喂养研究中调查以确定组织是否 脂肪酒精积累会导致生化和临床 改变SLS的特征。 这些研究将提供 有关正常脂肪酒精代谢和的基本信息 SLS中的脂肪酒精代谢发狂。