Ichthyosis in Sjogren-Larsson syndrome

干燥-拉尔森综合征中的鱼鳞病

• 批准号: 7196136
• 负责人: WILLIAM B. RIZZO
• 金额: $ 33.51万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-04-10 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7196136
• 关键词: adduct; aldehyde dehydrogenases; biopsy; clinical research; congenital ichthyosis; crosslink; dietary lipid; disease /disorder etiology; enzyme activity; enzyme deficiency; gene mutation; genetic disorder; human subject; keratinocyte; laboratory mouse; lipid metabolism; mental retardation; molecular pathology; nutrition related tag; skin; spastic paralysis; tissue /cell culture

DESCRIPTION (provided by applicant): Sjogren-Larsson syndrome (SLS) is an inherited neurocutaneous disorder caused by mutations in the ALDH3A2 gene that encodes fatty aldehyde dehydrogenase (FALDH). The symptoms of SLS include ichthyosis, mental retardation and spasticity, and are hypothesized to arise from the deranged metabolism of fatty aldehydes and precursor lipids such as fatty alcohols, which cannot be metabolized by FALDH. However, little is known about the underlying biochemical pathogenesis of SLS and effective therapy for the disease is lacking. The long-term goal of our research is to understand the pathogenic mechanisms causing the symptoms of SLS in order to develop specific therapy for affected patients. To gain insight into the biochemical and pathologic abnormalities in SLS, we will extensively characterize the biochemical and phenotypic features of a new FALDH-deficient gene knockout mouse model for SLS, and examine the role of genetic background on its phenotypic expression. Cultured keratinocytes, oligodendrocytes and mixed neuronal cells from FALDH-deficient mice will be investigated to reveal cell- specific lipid abnormalities. Using FALDH-deficient mice and cultured cells from SLS patients, we will determine whether FALDH is implicated in the metabolism of fatty aldehydes and fatty alcohols generated from farnesol, w-hydroxy fatty acids and (R)-trioxilin A3. These pathways are potentially amenable to therapeutic intervention with dietary modification and pharmacologic agents. Using immunologic and chemical methods together with mass spectrometry, we will identify the proteins that are covalently modified by fatty aldehyde in SLS cells to gain insight into the pathogenic mechanisms responsible for the cutaneous and neurologic symptoms. In summary, these studies will define the aberrant metabolism in SLS cells arising from FALDH deficiency and take advantage of the first animal model for SLS to uncover new pathogenic mechanisms responsible for cutaneous and neurologic symptoms. This research is directed at investigating Sjogren-Larsson syndrome (SLS), an inherited metabolic disease affecting the skin and brain of children and adults. We will study the abnormal fat metabolism that occurs in skin cells from patients to discover the cause of the symptoms, and characterize a newly developed mouse that has the same metabolic problem as people with SLS in hopes of developing an effective treatment.

描述（由申请人提供）：干燥-拉尔森综合征（SLS）是一种遗传性神经皮肤疾病，由编码脂肪醛脱氢酶（FALDH）的 ALDH3A2 基因突变引起。 SLS的症状包括鱼鳞病、智力低下和痉挛，推测是由于脂肪醛和脂肪醇等前体脂质的代谢紊乱引起的，而FALDH不能代谢这些物质。然而，人们对 SLS 的潜在生化发病机制知之甚少，也缺乏有效的治疗方法。我们研究的长期目标是了解导致 SLS 症状的致病机制，以便为受影响的患者开发特异性治疗方法。为了深入了解 SLS 的生化和病理异常，我们将广泛表征新的 FALDH 缺陷基因敲除 SLS 小鼠模型的生化和表型特征，并检查遗传背景对其表型表达的作用。将研究来自 FALDH 缺陷小鼠的培养角质形成细胞、少突胶质细胞和混合神经元细胞，以揭示细胞特异性脂质异常。使用 FALDH 缺陷小鼠和来自 SLS 患者的培养细胞，我们将确定 FALDH 是否参与由金合欢醇、w-羟基脂肪酸和 (R)-trioxilin A3 生成的脂肪醛和脂肪醇的代谢。这些途径可能适合饮食调整和药物制剂的治疗干预。利用免疫学和化学方法以及质谱分析法，我们将鉴定 SLS 细胞中被脂肪醛共价修饰的蛋白质，以深入了解导致皮肤和神经系统症状的致病机制。总之，这些研究将定义 FALDH 缺陷引起的 SLS 细胞中的异常代谢，并利用第一个 SLS 动物模型来揭示导致皮肤和神经系统症状的新致病机制。这项研究旨在调查干燥-拉尔森综合征 (SLS)，这是一种影响儿童和成人皮肤和大脑的遗传性代谢疾病。我们将研究患者皮肤细胞中发生的脂肪代谢异常，以找出症状的原因，并鉴定出与 SLS 患者具有相同代谢问题的新开发小鼠的特征，以期开发出有效的治疗方法。