Ichthyosis in Sjogren-Larsson Syndrome

描述：(逐字)干燥-拉尔森综合征(SLS)是一种遗传性疾病 以鱼鳞病、智力低下和痉挛的双或四肢瘫痪为特征。 这种疾病是由脂肪醛脱氢酶基因突变引起的。 (FALDH)，导致该酶活性不足。FALDH缺乏是 与脂肪醛和其他脂质的组织积聚有关，这 是导致系统性红斑狼疮症状的假说，但致病机制 都是未知的。我们研究的长期目标是了解 FALDH基因突变会导致SLS症状，并利用这一知识 开发有效的治疗方法。 为了了解导致FALDH活性缺陷的遗传机制 ，我们将鉴定SLS患者的某些突变，并调查 基因交替剪接的功能作用。我们将调查 系统性红斑狼疮皮肤病的病机探讨 培养的皮肤角质形成细胞和系统性红斑狼疮皮肤的脂质代谢 病人。了解脂肪醛是如何干扰正常表皮的 功能，我们将在SLS中鉴定脂肪醛-脂肪和-蛋白质加合物 角质形成细胞。为了检验这一新的假设，异常的交联剂 角质细胞蛋白参与了鱼鳞病，我们将确定其程度 系统性红斑狼疮角膜细胞包膜中交联蛋白的性质 病人。最后，建立一种实验动物模型，用于研究脑缺血再灌注损伤 系统性红斑狼疮的生化发病机制和治疗，我们将从基因工程的角度 FALDH基因敲除小鼠，并用其表征生化反应 饮食脂肪修饰和药物治疗。这些研究将 提供有关FALDH在表皮脂质中的作用的基本信息 新陈代谢和揭示脂肪醛毒性的新机制 SLS。

DESCRIPTION: (Verbatim) Sjogren-Larsson syndrome (SLS) is an inherited disorder characterized by ichthyosis, mental retardation and spastic di- or tetraplegia. The disease is caused by mutations in the gene for fatty aldehyde dehydrogenase (FALDH) which result in deficient activity of this enzyme. FALDH deficiency is associated with tissue accumulation of fatty aldehyde and other lipids, which are hypothesized to cause the symptoms of SLS, but the pathogenic mechanisms are unknown. The long-term goals of our research are to understand how mutations in the FALDH gene lead to symptoms of SLS and use this knowledge to develop effective therapy. To understand the genetic mechanisms leading to deficient FALDH activity in SLS, we will characterize certain mutations in SLS patients and investigate the functional role of alternate splicing of the gene. We will investigate the pathogenesis of the cutaneous disease in SLS by characterizing the abnormal lipid metabolism in cultured skin keratinocytes and in the skin of SLS patients. To understand how fatty aldehyde interferes with normal epidermal function, we will identify fatty aldehyde-lipid and -protein adducts in SLS keratinocytes. To test the novel hypothesis that abnormal crosslinking of corneocyte proteins contributes to the ichthyosis, we will determine the extent and nature of crosslinked proteins in corneocyte cell envelopes from SLS patients. Finally, to develop an experimental animal model for studies of the biochemical pathogenesis and therapy of SLS, we will genetically engineer a FALDH gene knockout mouse and use it to characterize the biochemical response to dietary fat modification and pharmacologic therapy. These studies will provide fundamental information about the role of FALDH in epidermal lipid metabolism and promise to reveal new mechanisms for fatty aldehyde toxicity in SLS.