Role of Conformational Change in Activation of the Growth Hormone Receptor

生长激素是治疗侏儒症的重要激素。近年来，生长激素的许多新的治疗应用已被发现，特别是其作为合成代谢剂的作用。这些包括术后恢复、骨折愈合、克罗恩病、扩张性心肌病、不孕症，当然还有衰老。该项目旨在找出生长激素如何通过其表面受体将其信号传递到目标细胞。据信，信号传导的主要事件是激素将两个受体聚集在一起的能力（受体二聚化）。然而，也有可能受体已经是二聚体，激素的作用是诱导受体形状的特定变化，将激素结合的信号传递到细胞中，从而启动向基因组的信号传递。我们有充分的证据表明，生长激素激活一条重要的信号通路需要特定的形状变化，并且在激素结合之前，结构上密切相关的促红细胞生成素受体已经二聚体化。我们想弄清楚形状变化是如何发生的，以及受体是否被预聚了。这一信息对于设计小型口服活性生长激素模拟物至关重要，这种模拟物可能是体弱老年人的合成代谢补充剂。

Growth hormone is an important hormone therapeutic for treating dwarfism. Recently, many new therapeutic applications for growth hormone have been discovered, particularly in relation to its role as an anabolic agent. These include post surgery recovery, enhanced bone fracture healing, Crohns disease, dilated cardiomyopathy, infertility and of course, ageing. This project seeks to find out how growth hormone sends its signal into the target cell through its surface receptor. It is believed that the primary event in signalling is the ability of the hormone to bring two receptors together (receptor dimerization). However, it may be that the receptor already is dimerized, and the role of the hormone is to induce a specific change in shape of the receptor, which transfers the signal of hormone binding into the cell to initiate signalling to the genome. We have good evidence that a specific shape change is required for activation of an important signalling pathway by growth hormone, and the closely structurally related receptor for erythropoietin is already dimerized before hormone binds. We want to find out exactly how the shape change acts, and whether the receptor is predimerized. This information is vital for designing small orally active mimics of growth hormone which could be of great value as an anabolic supplement for the frail elderly.