Insulin-like Growth Factor (IGF)-II Binding Specificity Of IGF Binding Protein-6: Structural And Functional Studies.
Funder
National Health and Medical Research Council
Funding Amount
$265,630.00
Summary
Insulin-like growth factor II (IGF-II) is a protein which is involved in normal growth. However, in some circumstances it may also stimulate cancer growth. IGF binding protein-6 (IGFBP-6) binds to IGF-II and stops its activity. One of the major challenges of modern biology is understanding why some proteins bind to other proteins. Proteins fold in various ways and have specific three-dimensional structures. Two proteins which bind strongly to each other have structures which fit each other like ....Insulin-like growth factor II (IGF-II) is a protein which is involved in normal growth. However, in some circumstances it may also stimulate cancer growth. IGF binding protein-6 (IGFBP-6) binds to IGF-II and stops its activity. One of the major challenges of modern biology is understanding why some proteins bind to other proteins. Proteins fold in various ways and have specific three-dimensional structures. Two proteins which bind strongly to each other have structures which fit each other like a 'lock and key'. The aim of this project is to understand how IGFBP-6 binds to IGF-II by looking at its three-dimensional structure. Using this information, it may be possible to develop new treatments which can inhibit IGF-II activity and therefore may be useful in the treatment of some cancers.Read moreRead less
Role Of The Growth Hormone Binding Protein As A Transcriptional Activator
Funder
National Health and Medical Research Council
Funding Amount
$387,226.00
Summary
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 proposal examines a novel way that GH could work, that is by sending the extracellular part of its receptor (GHBP) to the nucleus, wh ....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 proposal examines a novel way that GH could work, that is by sending the extracellular part of its receptor (GHBP) to the nucleus, where it can directly activate gene readout. This would have the effect of augmenting the normal action of GH to regulate gene readout. We have exciting preliminary data which makes us think this may be a new mechanism for hormone activation of genes. The level of GHBP in the nucleus is regulated, and if a defect in export of the GHBP occurred, this would lead to accumulation of nuclear GHBP and stimulate cell proliferation. This may be important in cancer cell proliferation, since we find nuclear GHBP in cancers.Read moreRead less
Role Of IGF Binding Protein-3 (IGFBP-3) And IGFBP-5 As Modulators Of Nuclear Hormone Signalling
Funder
National Health and Medical Research Council
Funding Amount
$465,750.00
Summary
The insulin-like growth factors are small proteins involved in the growth of most tissues. Their actions are regulated by binding to larger proteins (known as IGFBPs) in the bloodstream and outside the cell. However, some IGFBPs are also found inside cells, where they seem to carry out other functions. We believe that two of these binding proteins, IGFBP-3 and IGFBP-5, change the way cells respond to vitamin A and vitamin D. These two vitamins are important in cell growth and in the way certain ....The insulin-like growth factors are small proteins involved in the growth of most tissues. Their actions are regulated by binding to larger proteins (known as IGFBPs) in the bloodstream and outside the cell. However, some IGFBPs are also found inside cells, where they seem to carry out other functions. We believe that two of these binding proteins, IGFBP-3 and IGFBP-5, change the way cells respond to vitamin A and vitamin D. These two vitamins are important in cell growth and in the way certain cells perform specialised functions. In test-tube experiments, IGFBP-3 and IGFBP-5 interact directly with the receptors that regulate the effects of these hormones. If the same thing happens inside the cell, IGFBP-3 and IGFBP-5 could change the way these receptors respond to signals from outside the cell. We will investigate what effect these IGFBPs have in living cells and in whole animals and how this may relate to human disease. If we are able to understand how IGFBP-3 and IGFBP-5 affect the way cells respond to vitamin A and D, then we may be able to develop new ways to treat certain human diseases.Read moreRead less
Pathways Involved In The Insulin-like Growth Factor (IGF)-independent Actions Of IGF Binding Protein-6
Funder
National Health and Medical Research Council
Funding Amount
$550,725.00
Summary
Insulin-like growth factors (IGFs) are important proteins that regulate growth. When not regulated properly, diseases such as cancer can occur. A family of IGF binding proteins regulates IGFs. IGFBPs may inhibit IGFs and we have shown that one of them, IGFBP-6, decreases growth of some experimental cancers. As well as regulating IGFs, some IGFBPs alter cell behaviour independently of IGFs, and we found that IGFBP-6 stimulates cell movement in this way. We will now determine how this happens.
The Role Of Ezrin-radixin-moesin Proteins, Novel Binding Proteins For Advanced Glycation Endproducts, In Kidney Cells
Funder
National Health and Medical Research Council
Funding Amount
$493,220.00
Summary
High glucose levels in diabetes react with proteins to form AGEs and it is thought that this reaction may lead to kidney damage, which is one of the complications of diabetes. However, how this damage occurs is not completely understood. Cells need to maintain their shape and position for an organ to stay healthy. We have shown that AGEs affect kidney cells by interacting with and disturbing the function of proteins that maintain cell shape. We now want to study how this occurs.
Molecular Regulation Of Metabolism And Body Composition By Ski Via Crosstalk With Nuclear Hormone Receptor Signalling.
Funder
National Health and Medical Research Council
Funding Amount
$558,441.00
Summary
Obesity is a common and burdensome health problem in the community which leads to diabetes and heart disease. A number of factors, including hormones play important roles in determing risk of obesity. This study proposes to investigate whether the Ski gene which is a regulatory factor for many hormones affects metabolism in transgenic mouse models of altered Ski function. The proposed studies may identify Ski as a target for therapy for obesity and improvement in sketal muscle metabolism.
Evaluation Of Functional Protein Molecules In Treating Obesity
Funder
National Health and Medical Research Council
Funding Amount
$349,407.00
Summary
This project aims to reduce excessive food consumption by controlling the satisfaction that people get from eating. This will be achieved through varying protein supplements (whey, leucine and beta-conglycinin) and their combinations. The idea is that people will feel satisfied despite eating less, leading to weight loss and the correction of related metabolic disorders.
Regulation And Functional Roles Of ADAM 10 Protease In Prostate Cancer.
Funder
National Health and Medical Research Council
Funding Amount
$465,750.00
Summary
Prostate cancer is the second most common cause of cancer death among western males. Most deaths from prostate cancer are due to the development of secondary tumours (metastases) in other body organs. Metastasis involves actions of enzymes, (called metalloproteinases) which can break down the tissue structure surrounding tumour cells, and actions of a family of proteins (called integrins)that control how cells stick to each other or to other tissue components. Both these actions allow tumour cel ....Prostate cancer is the second most common cause of cancer death among western males. Most deaths from prostate cancer are due to the development of secondary tumours (metastases) in other body organs. Metastasis involves actions of enzymes, (called metalloproteinases) which can break down the tissue structure surrounding tumour cells, and actions of a family of proteins (called integrins)that control how cells stick to each other or to other tissue components. Both these actions allow tumour cells to break free from their original tissue positions, walk through surrounding tissue and deposit themselves at distant sites to form a secondary tumour. In this research we are looking at a protein, called ADAM-10, which belongs to a family of proteases, the ADAMs, which contain both A Disintegrin And Metalloprotease activity, hence their name. Our data suggest ADAM-10 is produced in large quantities by prostate cancer cells but can be differently located within these cells it sits on the outer membrane of normal or benign prostate glands but re-locates to the cell nucleus in high grade prostate cancer cells. We have also identified ADAM-10 protein in small membrane fragments that are commonly shed from prostate cancer cells. Preliminary evidence suggests that levels of ADAM-10 in each of these locations is regulated by growth factors and-or the male sex hormone, androgen, key hormones involved in prostate cancer growth and progression. We do not yet know what actions ADAM-10 has when it occurs in these different locations but believe the membrane form will be involved in metastasis, with the nuclear form being involved in regulating events within the nucleus, the control centre for the cell. This grant application aims to build on our novel observations and investigate the underlying mechanisms of ADAM-10 hormonal regulation and function. If proven, these issues may be important for the development, progression and future treatment of prostate cancer.Read moreRead less