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Mechanisms Of Negative Feedback Regulation Of GnRH By Testosterone In Males
Funder
National Health and Medical Research Council
Funding Amount
$243,336.00
Summary
This project will improve our knowledge of the hormonal control of reproduction in males. The hormone testosterone, produced by the testes, acts on the brain to control the secretion of a substance called gonadotrophin releasing hormone (GnRH). GnRH acts on a small gland at the base of the brain to cause the production of hormones called gonadotrophins, that are essential for reproduction. These gonadotrophins act on the testes to ensure the production of sperm and other hormones, including test ....This project will improve our knowledge of the hormonal control of reproduction in males. The hormone testosterone, produced by the testes, acts on the brain to control the secretion of a substance called gonadotrophin releasing hormone (GnRH). GnRH acts on a small gland at the base of the brain to cause the production of hormones called gonadotrophins, that are essential for reproduction. These gonadotrophins act on the testes to ensure the production of sperm and other hormones, including testosterone. We plan to determine how testosterone acts on the brain to control GnRH secretion. To do this we will use male sheep and conduct a series of experiments designed to show where in the brain testosterone acts to ultimately affect the nerve cells that produce GnRH. Testosterone and similar compounds are increasingly being used as treatments for infertility, as a male contraception and misused as anabolic steroids. A thorough knowledge of how testosterone acts in the brain is necessary to improve treatments for reproductive disorders and ultimately to improve reproductive health in men.Read moreRead less
Progesterone Signalling In Normal And Malignant Breast Relies On Chromosomal Positioning Of Progesterone Receptor
Funder
National Health and Medical Research Council
Funding Amount
$569,346.00
Summary
The cell nucleus carries genetic information that directs cell function. The nucleus is organised into compartments, which are altered in breast cancer, leading to altered function. The ovarian hormone progesterone acts via a receptor, which clumps into foci in the nucleus when active. In cancers, this clumping is disrupted. In this project we will work out how these foci control cell function, and how this leads to the specific functions of progesterone in normal breast and breast cancers.
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
Steroid hormones, such as oestrogen and cortisol, act in the body by binding 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 remarkably is never made into protein in cells, rather exerting its effects as a RNA. We have identified a novel family of proteins t ....Steroid hormones, such as oestrogen and cortisol, act in the body by binding 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 remarkably is never made into protein in cells, rather exerting its effects as a RNA. We have identified a novel family of proteins that bind to SRA in cancer cells, and may well play a critical role in regulating how SRA modulates genes. This project seeks to understand how this family interacts with SRA, the functional effects on breast cancer cells, and the detailed 3-dimensional structure of the family members coupled with SRA. This work will provide novel insight into how SRA regulates steroid hormone action, and may create new potential avenues for developing therapeutics in breast cancer.Read moreRead less
Osteoporosis is a major health burden resulting from bone fractures in older men and women due to progressive loss of bone and weakening of the skeleton. Although there are currently therapies to reduce bone loss, no current treatment effectively reconstructs lost bone. In this project, which is designed to identify new genes that may in the future be targeted by drugs to reverse osteoporosis, we have identified specific sets of genes that appear to work together to increase bone formation. This ....Osteoporosis is a major health burden resulting from bone fractures in older men and women due to progressive loss of bone and weakening of the skeleton. Although there are currently therapies to reduce bone loss, no current treatment effectively reconstructs lost bone. In this project, which is designed to identify new genes that may in the future be targeted by drugs to reverse osteoporosis, we have identified specific sets of genes that appear to work together to increase bone formation. This proposal is aimed at characterising these genes and the ways in which they work to determine whether they may be good targets for new osteoporosis treatments. We will examine the patterns of these genes in bone. We will also use cell cultures in which bone forming cells develop and function, to determine when the genes are expressed and how they function. We will test the ability of the candidate genes to cause an increase in the amount of bone forming activity in these cell cultures. An increase in bone formation may be caused by an increase in the number bone-forming cells, an increase in the activity of the cells, a decrease in cell death, or a combination of these changes. Each possibility will be tested. This research is important because of the need for new osteoporosis therapies to repair weakened bones. The knowledge resulting from this proposal has the potential to provide an important contribution to skeletal health and thus aged health worldwide.Read moreRead less