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

RDW大鼠最初被报道为生殖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。我们观察了RDW大鼠甲状腺的形态和与遗传性侏儒症和/或原发性甲状腺功能减退症相关的蛋白质。RDW的甲状腺在一般发育中似乎很差。卵泡的平均大小很小。滤泡腔未见苏木精-伊红染色。在电子显微镜下，RDW的滤泡上皮细胞核下区可见一个巨大的空泡，核移至板层一侧。滤泡上皮细胞内未检测到分泌颗粒。滤泡细胞胞浆内粗面内质网明显扩张。用改进的双向凝胶电泳法，结合免疫印迹和微测序技术，在RDW大鼠的不同组织中寻找与遗传性侏儒症有关的蛋白质。在这些组织中，只有垂体腺和甲状腺的蛋白质含量出现异常。RDW组的GH和PRL含量明显低于正常组，但RDW组甲状腺的异常程度远大于垂体组。RDW患者甲状腺中至少有18个蛋白质水平高于正常，17个低于正常水平。在这些增加的蛋白质中，内纤溶酶、免疫球蛋白重链结合蛋白(BiP)和热休克蛋白70(HSP70)在RDW甲状腺中的含量分别是正常组织的40倍、10倍和50多倍。由于Bip和内纤溶酶是已知的内质网驻留蛋白，而且这三种蛋白都属于伴侣蛋白家族，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。

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.