Ichthyosis in Sjogren-Larsson Syndrome

描述（由申请人提供）：Sjogren-Larsson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、智力迟钝和痉挛，据推测是由于脂肪醛和前体脂质（如脂肪醇）代谢紊乱引起的，而脂肪醇不能被FALDH代谢。然而，对SLS的潜在生化发病机制知之甚少，缺乏有效的治疗方法。我们研究的长期目标是了解引起SLS症状的致病机制，以便为受影响的患者开发特异性治疗。为了深入了解SLS的生化和病理异常，我们将广泛表征一种新的faldh缺陷基因敲除小鼠SLS模型的生化和表型特征，并研究遗传背景对其表型表达的作用。我们将研究faldh缺陷小鼠培养的角质形成细胞、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SLS患者培养的细胞，我们将确定FALDH是否与由法尼醇、w-羟基脂肪酸和(R)-三oxilin A3生成的脂肪醛和脂肪醇的代谢有关。这些途径可能适用于饮食调整和药物治疗干预。利用免疫学和化学方法以及质谱法，我们将鉴定SLS细胞中被脂肪醛共价修饰的蛋白质，以深入了解引起皮肤和神经症状的致病机制。综上所述，这些研究将明确由FALDH缺乏引起的SLS细胞代谢异常，并利用首个SLS动物模型揭示皮肤和神经系统症状的新致病机制。这项研究旨在调查Sjogren-Larsson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异常脂肪代谢，以发现症状的原因，并对新开发的具有与SLS患者相同代谢问题的小鼠进行表征，以期开发出有效的治疗方法。

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.