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
Endocrine And Autocrine Regulation Of Breast Cancer Cell Growth By IGF Binding Protein-3 (IGFBP-3).
Funder
National Health and Medical Research Council
Funding Amount
$497,250.00
Summary
The insulin-like growth factor (IGF) system of growth factors and their regulatory proteins is essential for normal growth, but is also involved in a number of overgrowth disorders. Some clinical studies have shown that a high level of IGF-I in the blood increases the risk of breast cancer in some women, but if the protein which carries it in the circulation, IGFBP-3, is also high, the risk is reduced. It has therefore been suggested that IGFBP-3 may be useful in the treatment of breast cancer. ....The insulin-like growth factor (IGF) system of growth factors and their regulatory proteins is essential for normal growth, but is also involved in a number of overgrowth disorders. Some clinical studies have shown that a high level of IGF-I in the blood increases the risk of breast cancer in some women, but if the protein which carries it in the circulation, IGFBP-3, is also high, the risk is reduced. It has therefore been suggested that IGFBP-3 may be useful in the treatment of breast cancer. This is supported by laboratory studies showing that IGFBP-3 can inhibit cell division and stimulate cell death in many cell types, including breast cells. However, some cells are resistant to IGFBP-3 s inhibitory effects, and in some cases IGFBP-3 may stimulate cells to grow and divide. In fact, the amount of IGFBP-3 present in breast tumours is highest in the fastest growing, most malignant tumours, suggesting that IGFBP-3 may be stimulating their growth. Our laboratory data indicates that breast cancer cells which produce a high level of IGFBP-3 grow faster as tumours than cells which produce little or no IGFBP-3. We believe that this is because IGFBP-3 interacts with another hormone system which is involved in rapid tissue growth, the EGF system, and increases its ability to stimulate breast cells to divide. These observations raise a number of important questions: how does IGFBP-3 interact with the EGF system to stimulate tumour growth; does IGFBP-3 from the blood promote the growth of EGF-sensitive tumours; and can the interaction between IGFBP-3 and the EGF system be abolished, or switched from growth stimulatory to growth inhibitory, thus inhibiting tumour growth. Answering these questions will provide important new information regarding IGFBP-3 s stimulatory and inhibitory actions, and the role of endocrine IGFBP-3 in tumour growth, and have the potential to lead to the development of novel therapies involving IGFBP-3 for the treatment of overgrowth disorders.Read moreRead less