ATR-X Syndrome: Role Of ATRX In Testicular Growth And Spermatogenesis
Funder
National Health and Medical Research Council
Funding Amount
$650,881.00
Summary
Infertility is surprisingly common and affects 1 in 20 Australian men. Testosterone and its receptor, the androgen receptor, are well known to be essential for spermatogenesis and fertility. We have identified an important regulator protein (ATRX) of androgen receptor activity and show that loss of function of ATRX in testes of mice leads to spermatogenesis defects. Identifying the molecular action of ATRX will lead to a better understanding of the underlying causes of infertility in men.
Sex Steroids Modulate The Neuronal Control Of Bone Formation
Funder
National Health and Medical Research Council
Funding Amount
$620,647.00
Summary
It is well recognised that changes in sex hormones are pivotal to the development of osteoporosis in both men and women. Our group has been instrumental in identifying a novel and powerful system regualting bone mass and strength by neural activity. Recent findings indicate critical interactions between these two pathways in the control of bone formation. Greater understanding of these interactions could lead to therapies capable of controlling this extremely common disease.
The Metabolic Effects Of Oestrogens And SERMs: Regulatory Interactions With The GH-IGF-system In Health And Disease
Funder
National Health and Medical Research Council
Funding Amount
$379,142.00
Summary
This project extends work aimed at understanding how GH and sex hormones work together to optimise physical health in women and men. It addresses the benefits and safety of oestrogen compounds in relation to their effects on body fat and muscle (body composition). Oestrogen compounds are among the most widely used medicines and include tradition oestrogens (female hormone) and synthetic oestrogens called SERMs. Oestrogens are used in young women as oral contraception and in the postmenopause for ....This project extends work aimed at understanding how GH and sex hormones work together to optimise physical health in women and men. It addresses the benefits and safety of oestrogen compounds in relation to their effects on body fat and muscle (body composition). Oestrogen compounds are among the most widely used medicines and include tradition oestrogens (female hormone) and synthetic oestrogens called SERMs. Oestrogens are used in young women as oral contraception and in the postmenopause for replacement therapy. Body composition is an important determinant of fitness and health. Obesity reduces fitness and increases the risk of diabetes and heart attacks while muscle loss causes weakness and frailty. GH is a major regulator of body composition; it acts by breaking down fat and building muscle mass. We discovered that oestrogens, when taken as a tablet interferes with the action of GH and causes detrimental changes in body composition. On the positive side, we have exploited the GH blocking action to treat acromegaly. This is a debilitating disease of excessive GH production from a pituitary tumour and for which available drug treatments are very expensive and require injection. The effects of SERMs on body composition are unknown. SERMs are interesting compounds because they act like oestrogens in some but as oestrogen blockers in other tissues. These are widely used in the treatment of breast cancer and osteoporosis. The extent to which they interfere with the action of GH has not been studied. They may exert additional effects because they act on the pituitary gland to reduce the secretion of GH. They may also prove to be effective in acromegaly which could extend their usefulness to men. In summary, the work will provide important information on the long-term benefits of SERMs in patient groups that tend to be frail. It may also prove to be a simple and inexpensive treatment for acromegaly.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
Kallikrein Gene Variants In Prostate Cancer: Analysis Of Gene Regulation And Diagnostic/Prognostic Use
Funder
National Health and Medical Research Council
Funding Amount
$486,801.00
Summary
Prostate cancer is the most common male cancer in Australia. However, early detection through screening programs has proven challenging, and about 30% of the 10,000 new cases diagnosed annually already have advanced disease. Hence, there is a fundamental need for increased basic research in prostate cancer etiology (cause) and tumour biology, and a critical requirement for methods that will assist in earlier detection of the disease and predict progression. A family of proteins called kallikrein ....Prostate cancer is the most common male cancer in Australia. However, early detection through screening programs has proven challenging, and about 30% of the 10,000 new cases diagnosed annually already have advanced disease. Hence, there is a fundamental need for increased basic research in prostate cancer etiology (cause) and tumour biology, and a critical requirement for methods that will assist in earlier detection of the disease and predict progression. A family of proteins called kallikreins (including prostate specific antigen, PSA) are often associated with clinical features of prostate cancer. We will characterise genetic variants (polymorphisms) in kallikrein genes that are consistently over-produced in prostate cancer, and determine whether they cause more protein to be produced in cells grown in the laboratory and in tumour tissue, and-or give rise to different expression products or splice variants. We will use bioinformatics (computer programs) to characterise published kallikrein gene sequences and to examine them for genetic variants that might be related to changes in gene expression or to splice variants. We will then use a case-control study, involving 1200 men with prostate cancer and 1200 healthy men, to determine whether these gene variants are associated with an increased risk of prostate cancer or with clinical aspects of the disease. Finally, we will examine the functional significance of the gene variants. This project represents an important and novel combination of molecular biology with the study of clinical disease at the population level, in the relatively new field of molecular epidemiology. It will clarify the role of kallikrein gene variants in prostate cancer risk and progression. The technologies may ultimately prove useful clinically for diagnosis of prostate cancer or for monitoring of treatment and prognosis, and hopefully will assist in clinical decision-making.Read moreRead less
How Does Disruption Of Circadian Rhythms Induce Diabetes?
Funder
National Health and Medical Research Council
Funding Amount
$631,782.00
Summary
Increasing evidence suggests that disturbed circadian rhythms initiate and amplify metabolic and cardiovascular disease. The increasing and already high proportion of workers engaged in shiftwork, and increased frequency of disruption of these rhythms in the population more generally, implicate this body system as contributing to the growing epidemic of obesity and diabetes and related disorders in our community and world-wide. While we are now beginning to understand how our rhythms are synchro ....Increasing evidence suggests that disturbed circadian rhythms initiate and amplify metabolic and cardiovascular disease. The increasing and already high proportion of workers engaged in shiftwork, and increased frequency of disruption of these rhythms in the population more generally, implicate this body system as contributing to the growing epidemic of obesity and diabetes and related disorders in our community and world-wide. While we are now beginning to understand how our rhythms are synchronised to night and day, how this rhythmicity is linked to our organs in the normal and common disease states such as diabetes is poorly understood. The discovery of a special set of genes, called clock genes that function in all of the cells in our bodies and strongly influence the function of our organs such as the liver, pancreas and heart has been particularly important. We hypothesise that both environmentally (exogenous) and genetically (endogenous) induced disruption of circadian rhythms causes metabolic dysfunction. This is due to altered central and peripheral clock gene expression rhythms, which in turn alter metabolic rhythms and impair glucose homeostasis. This project aims to determine the impact of disrupted rhythmicity on metabolism with a particular emphasis on the possibility that the disrupted rhythmicity may be a predisposing factor for the development of diabetes.Read moreRead less