Progesterone Receptor Action In The Normal Human Breast
Funder
National Health and Medical Research Council
Funding Amount
$360,500.00
Summary
Breast cancer affects 10000 Australian women annually and is a major cause of cancer-related death. The hormone progesterone, which is produced by the ovaries in women, is responsible for many aspects of normal breast development and function. Progesterone is also a major component of hormone replacement therapy (HRT) and oral contraceptives (OCP), which are taken by millions of women worldwide. It has been established that the use of HRT and OCP containing progesterone-like hormones leads to in ....Breast cancer affects 10000 Australian women annually and is a major cause of cancer-related death. The hormone progesterone, which is produced by the ovaries in women, is responsible for many aspects of normal breast development and function. Progesterone is also a major component of hormone replacement therapy (HRT) and oral contraceptives (OCP), which are taken by millions of women worldwide. It has been established that the use of HRT and OCP containing progesterone-like hormones leads to increased breast cancer risk, yet the ways in which this happens are not known. Breast cancer is thought to begin early in a woman's life, with a number of genetic changes that accumulate over a period of many years; the majority of breast malignancies are not diagnosed until after the age of 50. However, there are recent indications that some areas of apparently normal breast have undergone a few genetic changes, even in women with no evidence of malignancy, but there is nothing known about how progesterone may affect these areas and possibly encourage breast cancer development. This project will firstly explore the influence of progesterone on the normal breast, to clarify how this hormone acts in normal cells. We will then investigate the involvement of progesterone in areas of normal breast that have undergone genetic alterations. This will determine whether one way in which progesterone may increase breast cancer risk is by affecting the behaviour of cells with genetic changes to make them more likely to develop further changes and subsequently progress to full cancer development. If women are to continue to derive the benefits of progesterone exposure, there is a compelling need to appreciate how progesterone acts in the normal breast and how it increases breast cancer risk. Achievement of the aims of this project will provide invaluable knowledge and greatly increase our understanding in this area.Read moreRead less
Identification And Characterisation Of A Gene Causing Insulin Hypersecretion In A Mouse Model Of Diabetes Susceptibility
Funder
National Health and Medical Research Council
Funding Amount
$430,320.00
Summary
Diabetes is a disorder primarily characterised by the inability to produce and secrete the pancreatic hormone insulin, which regulates plasma sugar levels. This results in increased sugar levels which cause diabetic complications such as retinopathy and nephropathy. The inability to produce and secrete insulin is due to both defects in function as well as a reduction in pancreatic beta cells. Paradoxically it has been shown that some patients who are at risk of develping diabetes actually secret ....Diabetes is a disorder primarily characterised by the inability to produce and secrete the pancreatic hormone insulin, which regulates plasma sugar levels. This results in increased sugar levels which cause diabetic complications such as retinopathy and nephropathy. The inability to produce and secrete insulin is due to both defects in function as well as a reduction in pancreatic beta cells. Paradoxically it has been shown that some patients who are at risk of develping diabetes actually secrete more insulin than normal. Furthermore it has been suggested that this increase in insulin secretion actually may be associated with the decreased production and secretion of insulin characteristic of diabetes. The DBA-2 mouse is a model of reduced insulin production and secretion when exposed to high sugar levels or diabetes. However we have shown that in the normal non-stressed state DBA-2 mice actually secrete more insulin than normal and that this occurs from a very early age, suggesting that this trait is inherited. We have subsequently performed genetic studies and have identified a segment of DNA containing 10 genes associated with increased insulin secretion in DBA-2 mice. The level of one of these genes we have called Hip1 is increased 5-fold in DBA-2 mice, providing a candidate gene for increased insulin secretion in this model of diabetes susceptibility. However, whether Hip1 is also responsible for reduced insulin production and secretion in the DBA-2 mouse is not known. Therefore the overall hypothesis of this project is that the gene Hip1 which is associated with increased insulin secretion is also responsible for reduced insulin production and secretion when DBA-2 mice are exposed to high sugar or obesity. Determining why Hip1 is increased and whether it results in diabetes in DBA-2 mice may provide a reasonable candidate for the development of therapeutic interventions which may prevent the progression of diabetes in some patients.Read moreRead less
Reversal Of Diabetes In A Humanised Mouse Using A Clinically Applicable Vector System
Funder
National Health and Medical Research Council
Funding Amount
$842,173.00
Summary
Somatic gene therapy is one of the strategies that is being considered to cure Type I diabetes. Specifically, we wish to engineer liver cells to replace beta cell function. The aim of this project is to design a clinically-applicable protocol for the reversal of diabetes using a recombinant adeno-associated vector that delivers genes to human livers with high efficiency showing long term expression without pathogenicity and immunogenicity following a simple intra-peritoneal injection.
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