A Solution To The Parathyroid Gland Secretion Problem
Funder
National Health and Medical Research Council
Funding Amount
$508,003.00
Summary
Parathyroid hormone is the master hormone regulator of whole body calcium metabolism and a powerful new treatment for osteoporosis but the mechanism by which its natural secretion is controlled has never been solved. In this project we will apply new insights and advanced technical approaches to resolve this most fundamental question of calcium homeostasis, namely how parathyroid hormone secretion is controlled.
Interaction Between PTH And Y2 Bone Anabolic Pathways
Funder
National Health and Medical Research Council
Funding Amount
$731,311.00
Summary
Osteoporosis is a costly condition that affects more than 150 million people worldwide and fills more hospital beds than any other disease*. People who have osteoporotic fractures experience a diminished quality of life and a reduced life expectancy. Although there are currently a number of therapies in use to reduce further loss of bone in osteoporotic patients, there is only one to replace lost bone, parathyroid hormone. For clinical and economic reasons, there is a need for additional bone-bu ....Osteoporosis is a costly condition that affects more than 150 million people worldwide and fills more hospital beds than any other disease*. People who have osteoporotic fractures experience a diminished quality of life and a reduced life expectancy. Although there are currently a number of therapies in use to reduce further loss of bone in osteoporotic patients, there is only one to replace lost bone, parathyroid hormone. For clinical and economic reasons, there is a need for additional bone-building therapies. Like all tissues, the nervous system affects skeletal function. We recently discovered a powerful control pathway by which the nervous system regulates bone formation. This project will test whether altering the function of this neural pathway can increase bone formation and whether it can work together with parathyroid hormone therapy to produce an enhanced bone formation response greater than either therapy alone. This research is important because of the need for new osteoporosis therapies to repair weakened bones. The knowledge gained from this study has the potential to provide a very important and useful contribution to skeletal health and thus aged health worldwide. *The Burden of Brittle Bones: Costing Osteoporosis in Australia. A report prepared by Access Economics Pty. Ltd. September 2001Read moreRead less
Molecular Determinants Of Amino Acid-dependent Signalling By The Calcium-sensing Receptor
Funder
National Health and Medical Research Council
Funding Amount
$566,035.00
Summary
Amino acids are the building blocks of proteins and an alternative energy source to carbohydrate and fat. Proteins are major structural components of our bodies. They also fulfil an amazing diversity of cellular and bodily functions acting, for example, as enzymes (biological catalysts), receptors, molecular chaperones and biological machines. Thus, amino acids are key nutrients and the human body has developed mechanisms for tightly regulating cellular responses depending upon their levels in b ....Amino acids are the building blocks of proteins and an alternative energy source to carbohydrate and fat. Proteins are major structural components of our bodies. They also fulfil an amazing diversity of cellular and bodily functions acting, for example, as enzymes (biological catalysts), receptors, molecular chaperones and biological machines. Thus, amino acids are key nutrients and the human body has developed mechanisms for tightly regulating cellular responses depending upon their levels in blood. Identifying amino acid sensing molecules and identifying the mechanisms they use to control cellular responses is thus a key issue in human biology. The applicant identified the calcium-sensing receptor as an amino acid sensor and has shown that this receptor provides a means by which fluctuations in amino acid levels regulate the secretion of the key calcium-regulating hormone, PTH. In the current proposal, the mechanisms that link amino acid activation of the calcium-sensing receptor to its key cellular responses will be determined.Read moreRead less
Impact Of Progesterone Receptor Subnuclear Localisation On Progesterone Action In Endocrine Target Cells
Funder
National Health and Medical Research Council
Funding Amount
$459,514.00
Summary
Breast cancer affects 10,000 Australian women annually and is a major cause of cancer death. The hormone progesterone, which is produced by the ovaries in women, is responsible for some aspects of the development of the normal breast in women and is also implicated in the development and response of breast and endometrial cancers. In normal cells progesterone acts via a specific protein (or receptor) in the nucleus, and we have shown that this protein accumulates into foci when it is active. We ....Breast cancer affects 10,000 Australian women annually and is a major cause of cancer death. The hormone progesterone, which is produced by the ovaries in women, is responsible for some aspects of the development of the normal breast in women and is also implicated in the development and response of breast and endometrial cancers. In normal cells progesterone acts via a specific protein (or receptor) in the nucleus, and we have shown that this protein accumulates into foci when it is active. We have noticed that in cancers, this accumulation is disrupted, and this is a bad sign for the cancer. As breast cancer develops, it causes many dramatic changes in the structure of cells of the breast, and particularly in the nucleus, which carries the genetic information that programs cancer cell behaviour. The nucleus normally is highly organised into compartments, which carry out different functions of the cell, such as duplication of the DNA, repair of DNA after damage, and switching on and off of particular genes important to the function of the cell. This organisation is altered dramatically in cancer cells, and it seems that this altered organisation is responsible for altered function. In this project we aim to work out what makes the receptor for progesterone form foci, how these foci are involved in the action of progesterone, and how the changed structure of the nucleus changes this process. This project will link the structure of the cell nucleus with the ability of progesterone to switch on or off particular genes, and this will provide the first signposts of how changes seen in cancer cell nuclei are reflected in changed hormonal signalling. Healthy women are regularly exposed to progestins in oral contraceptives and hormone replacement therapy. The known increased risk of breast cancer as a result of exposure to progestins creates an imperative to understand how progesterone may have aberrant effects. This project will address this important health issue.Read moreRead less
Alpha-2-Macroglobulin And The Transport And Uptake Of The Hormone, Hepcidin
Funder
National Health and Medical Research Council
Funding Amount
$533,541.00
Summary
Hepcidin is a peptide hormone that is a major regulator of iron metabolism. It has been suggested that hepcidin is free in the blood. However, we recently identified that hepcidin binds with alpha-2-macroglobulin (a2-M) in the plasma and this increases the efficacy of this peptide. The demonstration that a2-M plays a role in hepcidin biology will lead to a better understanding of hepcidin physiology, the development of methods for its measurement and improved treatment of iron related diseases.
Validating A New Model For Growth Hormone Receptor Activation
Funder
National Health and Medical Research Council
Funding Amount
$472,500.00
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 anabolic actions. These include post surgery recovery, enhanced bone fracture healing, Crohns disease, dilated cardiomyopathy, infertility and ageing. The hormone exerts these actions through its receptor, which is a class1 cytokine receptor, similar to many receptors important in regulating immunity, inflam ....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 anabolic actions. These include post surgery recovery, enhanced bone fracture healing, Crohns disease, dilated cardiomyopathy, infertility and ageing. The hormone exerts these actions through its receptor, which is a class1 cytokine receptor, similar to many receptors important in regulating immunity, inflammation, metabolism and cancers. In principle, if we can find out how the GH receptor works, this information would help in designing drugs to treat many immune and inflammatory disorders. With current NHMRC support we have developed a model which describes how GH activates the receptor at a molecular level. The model involves two pre-associated receptors at the cell surface binding to the hormone, with the result that the receptors are rotated relative to each other, and this brings the two JAK2 signalling units attached tothe receptor inside the cell into alignment, so they can activate each other. We can activate the receptor without hormone by artificially rotating it. This model is a prediction based on several techniques, but lacks proof of rotation. There are also a number of issues relating to the need for rigidity in the receptors, so the torque can be transmitted into the cell, since many believe there is no rigidity just above the membrane. We predict there is , but need to prove this. This information is vital for designing small orally active mimics of growth hormone, and for developing GH antagonists, likely to be useful for breast and colon cancer. Finally, we have evidence that the specificity of receptor signalling can be changed by mutating the outer part of the receptor (novel). We believe this can be used to change the activity spectrum of GH, hence decrease side effects, by developing analogs which activate one pathway or the other.Read moreRead less
Steroid hormones, such as estrogen and androgens, act in the body by locking onto a family of proteins (nuclear receptors) that bind directly to the DNA to regulate genes. The mechanisms underlying this process are complex and involve recruitment of additional molecules or coactivators to improve efficiency. Recently a novel coactivator was identified, termed SRA, which exerts its effects as an RNA, rather than as a protein. SRA is aberrantly expressed in breast cancer, raising the possibility t ....Steroid hormones, such as estrogen and androgens, act in the body by locking onto a family of proteins (nuclear receptors) that bind directly to the DNA to regulate genes. The mechanisms underlying this process are complex and involve recruitment of additional molecules or coactivators to improve efficiency. Recently a novel coactivator was identified, termed SRA, which exerts its effects as an RNA, rather than as a protein. SRA is aberrantly expressed in breast cancer, raising the possibility that it plays an important role in breast cancer cell proliferation. To better understand how estrogen signals in breast cancer and identify proteins that bind to SRA in cancer cells, we established a collaboration with the O'Malley group at Baylor College of Medicine in Texas (who discovered SRA). We have identified several novel SRA-binding proteins, each of which plays an important role to regulate estrogen and androgen action. Up to this point, we have used a model that has enabled proof of principle studies in the same cancer cells from which SRA was discovered (non-breast or prostate cancer). However, we now need to carefully study the role of these proteins in cancer cells relevant to breast and prostate cancer. Thus, we plan to investigate how these proteins interact with SRA, how they influence nuclear receptor activity and breast and prostate cancer cell proliferation, examine their role in activating other pathways of cell growth in cancer cells, assay the levels of each protein in a series of human breast cancer specimens and solve the physcial 3-D structure of these proteins complexed to the SRA RNA. This work will provide novel insight into several key areas of hormone action in breast and prostate cancer. We hope to identify new markers that can be used for improved diagnosis and for prognosis, and provide structural information for the development of novel therapeutics.Read moreRead less