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Studies of pathogenesis in Farber disease-cloning of the DNA and study of signal transduction system

法伯病发病机制研究——DNA克隆及信号转导系统研究

基本信息

批准号：
09670805
负责人：
INUI Koji
金额：
$ 2.05万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1998
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09670805/
关键词：
Farber disease ceramidase mutation analysis apoptosis cytokins 遺伝子異常フポトーシス

项目摘要

Farber disease is a rare autosomal recessive sphingolipidosis caused by a deficiency of acid ceramidase, a lysosomal enzyme that normally catalyzes the hydrolysis of ceramide to sphingosine and free fatty acids.The disease is clinically characterized by swollen joints with limitation of movements, disseminated subcutaneous nodules, particularly in the joints and over pressured points, hoarseness, and progressive cachexia.Recently the mode of ceramide action and the regulation of its production have attracted great attention impart due to the emerging role of ceramide as an intracellular effector molecule in apoptosis.It is possible that at least some of the pathologic events in Farber disease are related to second messenger functions.We have recently diagnosed two patients with type II Farber disease due to the reduced enzymatic activity of ceramidase and accumulation of ceramide after feeding of radiolabelled serin.cDNA analysis of these patients disclosed V369I/V97E and homogygous mutation of V96 del, respectively.These mutations were confirmed in expression studies in COS I cells.Increased secreations of cytokins including IL-2, -6, and TNF- alpha, not detected in skin fibroblasts from control and Farber disease, and ceramide did not induced cytokin productions.The removed nodules showed increased level of ceramide and macrophage infiltrations.However, immunostainig of Fas, bcl-2, and IL-6 showed negative.Tunel method did not show significant positive staining and no DNA ladder was not detected in extracted DNA from nodules.These evidence suggest that apoptosis did not occur in the nodules.

法伯病是一种罕见的常染色体隐性鞘脂病，由酸性神经酰胺酶缺乏引起，这种酶通常催化神经酰胺水解为鞘氨醇和游离脂肪酸。该疾病的临床特征是关节肿胀，活动受限，弥散性皮下结节，特别是在关节和压力过大的部位，声音嘶哑和进行性恶病质。近年来，神经酰胺作为细胞内效应分子在细胞凋亡中的作用日益突出，神经酰胺的作用模式及其产生调控受到广泛关注。至少有一些法伯氏病的病理事件可能与第二信使功能有关。我们最近诊断了两例II型法伯病，由于神经酰胺酶活性降低和神经酰胺在喂食放射性标记丝氨酸后的积累。对这些患者进行cDNA分析，分别发现V369I/V97E和V96 del同源突变。这些突变在COS I细胞的表达研究中得到证实。细胞因子包括IL-2、-6和TNF- α的分泌增加，在对照组和法伯病的皮肤成纤维细胞中未检测到，神经酰胺没有诱导细胞因子的产生。切除的结节显示神经酰胺和巨噬细胞浸润水平升高。Fas、bcl-2、IL-6免疫染色均为阴性。Tunel法未见明显阳性染色，提取的结节DNA未见DNA阶梯。这些证据表明，在结节中没有发生细胞凋亡。