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Role of Rab38G protein expressed in specifically in the lower respiratory epithelium in the interstitial lung disease

下呼吸道上皮特异性表达的 Rab38G 蛋白在间质性肺疾病中的作用

基本信息

批准号：
15590833
负责人：
OSANAI Kazuhiro
金额：
$ 2.11万
依托单位：
Kanazawa Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2006
项目状态：
已结题

项目摘要

Ruby rats including Fawn-Hooded and Long Evans Cinnamon/Crj (LEC/Crj) are known as animal model of Hermansky-Pudlak syndrome. We extracted genome DNA from tails of these rats, performed DNA sequence, and found a point mutation in the translation initiation codon in the exon 1 of Rab38 gene, resulting in ATG to ATA that indicates no translation of nucleic acids to amino acids. Western blot analysis on the lung tissue lysates from these rats confirmed no existence of Rab38 protein. These rats had ruby-like dark red eyes and cinnamon-like coat hairs, and showed elongation of bleeding time to more than 15 minutes. Thus, these rats have oculocutaneous albinism. The lungs of LEC/Crj showed emphysema-like appearance, and alveolar type II cells were swelled with cytoplasmic lammelar bodies increased in number and in size. Western blot analysis of bronchoalveolar lavage fluid, lamellar body fraction, and total lung homogenate showed that surfactant protein B was increased in the lung tissue but decreased in the alveolar lumen. Isolated alveolar type II cells from LEC/Crj showed decreased basal secretion of [3H]-rabeled surfactant phosphatidylcholine but remarkably increased agonist-induced secretion. These results indicate that Rab38 deficiency in the rat causes oculocutaneous albinism, bleeding diathesis, and lung disease. As these phenotypes correspond to those of human Hermansky-Pudlak syndrome, it is suggested that genetic abnormality of Rab38 may cause the disease in humans.

Ruby大鼠包括Fawn-hooded和Long Evans Cinnamon/CRJ(LEC/CRJ)，被称为Hermansky-Pudlak综合征的动物模型。我们从这些大鼠的尾巴中提取基因组DNA，进行DNA测序，发现Rab38基因外显子1的翻译起始密码子存在点突变，导致ATG到ATA，这表明核酸没有翻译成氨基酸。对这些大鼠肺组织裂解产物进行Western印迹分析，证实不存在Rab38蛋白。这些老鼠有红宝石般的深红眼睛和肉桂般的毛发，出血时间延长到15分钟以上。因此，这些大鼠患有眼皮肤白化病。LEC/CRJ组大鼠肺组织呈肺气肿样变，肺泡II型细胞肿胀，胞浆板层小体增多，体积增大。支气管肺泡灌洗液、肺板层体积分数和总肺匀浆的Western印迹分析表明，肺组织中表面活性蛋白B增加，而肺泡腔中表面活性蛋白B减少。从LEC/CRJ分离的肺泡II型细胞基础分泌量减少，但激动剂诱导的分泌量显著增加。这些结果表明，Rab38缺乏会导致大鼠眼皮肤白化、出血素质和肺部疾病。由于这些表型与人类Hermansky-Pudlak综合征的表型一致，因此认为Rab38的基因异常可能导致了人类的疾病。