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The factor analysis causing hereditary awarfism of the rdw rat and evaluatio as an animal model

rdw大鼠遗传性侏儒症的影响因素分析及动物模型评价

基本信息

批准号：
08680911
负责人：
FURUDATE Sen-ichi
金额：
$ 1.54万
依托单位：
KITASATO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1996
资助国家：
日本
起止时间：
1996 至 1997
项目状态：
已结题

项目摘要

The rdw rat was initially reported as an animal model for fereditary dwarfism, but the rat has been shown as primary hypothyroidism by much accumulated evidence. We examined the thyroid gland of the rdw rat morphologically and proteins of the gland related to the hereditary dwarfism and/or primary hypothyroidism. The thyroid gland of rdw seems very poor in the general development. The average size of the follicle was very small. The follicle lumen was not stained with hematoxylin and eosin. In electron microscope observation, a huge vacuole was seen in the infra-nuclear region and the nucleus was shifted to the lamina side in the follicular epithelial cells of rdw. Secretory granules could not be detected in follicular epithelial cells. The cytoplasm of follicular cells had markedly distended rough endoplasmic reticulum. Proteins having relations to hereditary dwarfism of the rdw rat were searched for in various tissues of the rat with an improved two-dimensional gel electrophoresis technique followed by immunoblotting and microsequencing. Only pituitary and thyroid glands among those tissues showed abnormalities in protein contents. GH and PRL contents in the rdw pituitary were much less than in the normal one, but the abnormalities in the rdw thyroid were far more serious than in the pituitary. At least 18 protein levels in the rdw thyroid were above, and 17 were below the normal. Those identified among the increased proteins were endoplasmin, immunoglobulin heavy chain binding protein (Bip), and heat shock protein 70 (hsp70), the contents of which respectively were a40 times, 10 times and more than 50 times as much in the rdw thyroid as in the normal tissue. Because Bip and endoplasmin are known to be ER resident proteins, and because all three belong to a chaperone protein family, accumulation of these proteins in the rdw, thyroid suggests that protein folding and secreting disorders underlie the hypothyroidism of the rdw rat.

rdw大鼠最初被报道为遗传性侏儒症的动物模型，但大量积累的证据表明该大鼠为原发性甲状腺功能减退症。我们检查了 rdw 大鼠的甲状腺形态以及与遗传性侏儒症和/或原发性甲状腺功能减退症相关的腺体蛋白质。 rdw的甲状腺整体发育似乎很差。卵泡的平均尺寸非常小。卵泡管腔未用苏木精和曙红染色。电镜观察，rdw的滤泡上皮细胞核下区可见巨大空泡，细胞核移至膜层侧。滤泡上皮细胞中未检测到分泌颗粒。滤泡细胞胞浆内粗面内质网明显扩张。采用改进的二维凝胶电泳技术，随后进行免疫印迹和微测序，在大鼠的各个组织中寻找与 rdw 大鼠遗传性侏儒症相关的蛋白质。这些组织中只有垂体和甲状腺的蛋白质含量出现异常。 rdw垂体中GH和PRL的含量远低于正常垂体，但rdw甲状腺的异常情况却远比垂体严重。 rdw 甲状腺中至少有 18 种蛋白质水平高于正常水平，17 种蛋白质水平低于正常水平。增加的蛋白质中有内质蛋白、免疫球蛋白重链结合蛋白（Bip）和热休克蛋白70（hsp70），其含量在rdw甲状腺中分别是正常组织的40倍、10倍和50倍以上。因为已知 Bip 和内质蛋白是 ER 驻留蛋白，并且因为这三种蛋白都属于伴侣蛋白家族，所以这些蛋白在 rdw、甲状腺中的积累表明蛋白质折叠和分泌障碍是 rdw 大鼠甲状腺功能减退的基础。