A transgenic analysis of the physiologic roles of signalling domains in the growth hormone receptor

促进出生后生长的关键激素是生长激素(GH)，它通过生长激素受体启动多种信号，调节基因表达。除了在生长中的作用外，生长激素在饥饿中也是一种重要的代谢调节剂。它似乎也在衰老过程中发挥着重要作用，因为缺乏生长激素受体的小鼠比正常小鼠活得长50%。尽管生长激素受体使用的信号系统在体外得到了合理的定义，但我们不知道哪些信号用于控制活动物出生后的生长、新陈代谢和衰老。在NHMRC的支持下，我们一直在创造GH受体的单个信号域被删除的小鼠。这项建议旨在利用这些小鼠来确定生长激素受体如何实现其促进出生后生长、调节新陈代谢和改变寿命的作用。特别是，通过使用基因阵列，我们打算定义在这些过程中调节的关键基因。这将为药物开发提供潜在的治疗靶点，以单独改变这些关键过程。

The key hormone promoting growth postnatally is growth hormone (GH), and it acts through the growth hormone receptor to initiate a variety of signals which regulate gene expression. In addition to its role in growth, GH is an importnat metabolic regulator in starvation. It also appears to play a significant role in the ageing process, since mice lacking the GH receptor live 50% longer than normal mice. Although the signalling systems used by the GH receptor are reasonably well defined in vitro, we have no idea which signals are used to control postnatal growth, metabolism and ageing in the live animal. With NHMRC support, we have been creating mice with individual signalling domains of the GH receptor deleted. This proposal aims to use these mice to determine how the GH receptor brings about its actions of promoting postnatal growth, regulating metabolism and altering lifespan. In particular, through the use of gene arrays, we intend to define the key genes regulated in these processes. This would provide potential therapeutic targets for drug development to individually alter these key processes.