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Expression cloning of the cDNA encoding intracellular transporters of thyroid hormones.

编码甲状腺激素细胞内转运蛋白的 cDNA 的表达克隆。

基本信息

批准号：
09671039
负责人：
ICHIKAWA Kazuo
金额：
$ 2.05万
依托单位：
Shinshu 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 2000
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09671039/
关键词：
Thryoid hormone Sick euthyroid syndrome Cellular T3 transport Tumor necrosis factor Interleukin 1 Interleukin 6 Tetraiodothyroacetic acid Nuclear T3 receptor Sick eathyroid syndrome 細胞内輸送担体レチノイン酸ビタミンD HL-60 cell 脂質低下薬レチノイドX受

项目摘要

1) TNF, IL-1, and IL-6 enhanced nuclear uptake of tetrac and thyroxine (T4). The effects were more notable in pituitary cells than in hepatic cells. Tetrac may be responsible for the reduced serum TSH level despite reduced levels of serum triiodothyronine (T3) and T4 in sick euthyroid syndrome in which elevated production of these cytokines enhances pituitary nuclear transport of tetrac. These data also indicate the different nuclear uptake mechanisms between T3 and tetrac or T4.2) SK＆F L-949Ol shows more potent thyromimetic activity in liver than in pituitary gland or heart when administered to rats. Using cultured rat hepatoma cells (dRLH-84) and rat pituitary tumor cells (GH3), we found that SK＆F L-94901 is more effectively transported to nuclear thyroid hormone receptors in hepatic cells than in pituitary cells and therefore shows liver-selective thyromimetic activity. Other than SK＆F L-94901, we also found various new compounds that show liver-selective thyromimetic activities. These compounds, when administered to rats, showed hypolipidemic effects without cardiac or pituitary action.3) cDNA encoding the cytosolic thyroid hormone binding protenis that regulate transport of T3 from cytosol to nuclei were isolated from human fetal brain cDNA library. This protein resides in cytosol and modifies thyroid hormone action. We will continue isolation of cellular transporters of thyroid hormones from other tissues, in order to design drugs that discriminate differences in structures of the transporters among various cell types.

1)肿瘤坏死因子、白介素1和白介素6促进T4和T4的核摄取。这种作用在脑垂体细胞中比在肝细胞中更为显著。尽管病态甲状腺功能正常综合征患者血清三碘甲腺原氨酸(T3)和T4水平降低，但Tetrac可能是导致血清TSH水平下降的原因，在这种综合征中，这些细胞因子的产生增加了TRARC的脑垂体核转运。这些数据还表明，T3和TURC或T4.2)SK&F L-9491在大鼠肝脏中表现出比在脑下垂体和心脏中更强的拟甲状腺活性。用培养的大鼠肝癌细胞(DRLH84)和大鼠垂体肿瘤细胞(GH3)，我们发现SK&F L-94901在肝细胞中比在脑垂体细胞中更有效地转运到核甲状腺激素受体，从而显示出肝脏选择性类甲状腺激素活性。除SK&F L-94901外，我们还发现了多种具有肝脏选择性类甲状腺活性的新化合物。3)从人胎脑c DNA文库中克隆了编码甲状腺激素结合蛋白的胞浆c DNA，它调节T 3从胞浆到胞核的转运。这种蛋白质存在于细胞质中，可以改变甲状腺激素的作用。我们将继续从其他组织中分离甲状腺激素的细胞转运体，以便设计出区分不同细胞类型之间转运体结构差异的药物。