MULTIHORMONAL REGULATION OF GROWTH HORMONE SYNTHESIS

拟议的研究涉及定义详细的机制， 糖皮质激素和其他激素与甲状腺激素相互作用， 哺乳动物细胞中的生物过程。 细胞培养系统 研究了GH 1细胞，大鼠垂体细胞系的两种克隆细胞， 合成生长激素。 这些细胞的生理浓度 甲状腺激素增加生长激素的合成， 糖皮质激素对生长激素合成的调节高度依赖于 甲状腺激素作用。 这些细胞含有核受体， 甲状腺激素也含有糖皮质激素受体和调节 甲状腺激素和糖皮质激素合成生长激素似乎 由它们各自的常规受体调节。 此外，GH 1细胞和 GC细胞含有胰岛素受体，其估计Kd为2-5 × 10 - 6至-10 - 6。 10次幂M，每个细胞约有8，000个胰岛素结合位点。 在胃癌 细胞甲状腺激素和糖皮质激素诱导胰岛素受体增加 糖皮质激素的水平和影响是相加的，但不是协同的， 与生长激素调节不同的甲状腺激素调节 反应 此外，甲状腺激素和糖皮质激素独立地抑制 这些细胞的胰岛素降解过程似乎涉及 细胞对胰岛素的摄取减少，从而抑制胰岛素 降解似乎受到甲状腺激素和/或 糖皮质激素抑制胰岛素内化。 的机理 将通过评估GH 1细胞中胰岛素代谢的抑制来研究 胰岛素内化的动力学和内化的动力学 膜胰岛素受体。 这将由一个 生物化学的观点，以及通过使用荧光直接可视化 通过视频增强显微镜监测胰岛素衍生物的动力学 的内在化。 胰岛素作用的影响和这些内在化 将根据胰岛素对控制细胞的影响来评估细胞。 生长激素反应与甲状腺和糖皮质激素一致。

The proposed research involves defining the detailed mechanisms by which glucocorticoids and other hormones interact with thyroid hormone to control biological processes in mammalian cells. The cell culture systems to be investigated are GH1 cells, two clonal cells of rat pituitary cell lines which synthesize growth hormone. With these cells physiological concentrations of thyroid hormones increase growth hormone synthesis and the effect of glucocorticoids on regulating growth hormone synthesis is highly dependent on the action of thyroid hormone. These cells contain nuclear receptors for thyroid hormone and also contain glucocorticoid receptors and the regulation of the synthesis of growth hormone by thyroid hormone and glucocorticoid appears to be modulated by their respective regular receptors. In addition, GH1 cells and GC cells contain insulin receptors with an estimated Kd of 2-5 x 10 to the minus 10th power M with approximately 8,000 insulin binding sites per cell. In GC cells thyroid hormone and glucocorticoid induce increases in insulin receptor levels and the influence of glucocorticoid is additive but not synergistic with that of thyroid hormone differing from the regulation of the growth hormone response. Furthermore, thyroid hormone and glucocorticoid independently inhibit insulin degradation by these cells by a process which appears to involve a decrease in cell uptake of insulin and therefore the inhibition of insulin degradation appears to be modulated by the influence of thyroid hormone and or glucocorticoid on inhibiting insulin internalization. The mechanism of inhibition of insulin metabolism in GH1 cells will be investigated by assessing the kinetics of internalization of insulin and the kinetics of internalization of surface membrane insulin receptors. This will be determined from a biochemical point of view as well as by direct visualization using fluorescent insulin derivitives by Video Intensification Microscopy to monitor the kinetics of internalization. The influence of insuin action and internalization of these cells will be assessed in terms of the influence of insulin on controlling the growth hormone response in concert with thyroid and glucocorticoid hormones.