A Transgenic Analysis Of The Physiologic Roles Of Signalling Domains In The Growth Hormone Receptor
Funder
National Health and Medical Research Council
Funding Amount
$262,500.00
Summary
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, ....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.Read moreRead less
Growth hormone is responsible for normal postnatal growth, is an important metabolic regulator in starvation, and has many useful therapeutic applications, including forms of cardiac insufficiency, Crohns disease and, it is thought, amelioration of ageing. The means whereby GH brings about these changes are not known, although we do know a considerable amount about how the individual domains within the GH receptor signal. What we do not know is which genes are regulated by GH in these processes, ....Growth hormone is responsible for normal postnatal growth, is an important metabolic regulator in starvation, and has many useful therapeutic applications, including forms of cardiac insufficiency, Crohns disease and, it is thought, amelioration of ageing. The means whereby GH brings about these changes are not known, although we do know a considerable amount about how the individual domains within the GH receptor signal. What we do not know is which genes are regulated by GH in these processes, and how this will change the state of the cell. We propose here to use the new technique of gene arrays to uncover the programs, or groups of genes, which GH regulates to change important cellular processes. When used in conjunction with cells expressing GH receptor mutants which are unable to signal to defined pathways, we will be able to know which functional families genes are regulated, and how they are regulated. This information will enable us to know how GH regulates cell growth and metabolism, and therfore to understand what goes wrong when GH or its mediator, IGF-1 , are abnormal. We can also use this information to validate small molecules designed to mimic GH through activating its receptor, to be certain that they are acting in the same way as GH.Read moreRead less