Reproduction is dependent upon the secretion of gonadotropin releasing hormone (GnRH) from the brain, that stimulates gonadotropin synthesis and release from the pituitary gland. In turn, GnRH and gonadotropin secretion is controlled by feedback effects of gonadal steroids such as estrogen. Various neural systems regulate GnRH cells. Kisspeptin is a recently discovered neuropeptide that appears to play a major role in the regulation of GnRH cells. Because it is newly recognized, the significance ....Reproduction is dependent upon the secretion of gonadotropin releasing hormone (GnRH) from the brain, that stimulates gonadotropin synthesis and release from the pituitary gland. In turn, GnRH and gonadotropin secretion is controlled by feedback effects of gonadal steroids such as estrogen. Various neural systems regulate GnRH cells. Kisspeptin is a recently discovered neuropeptide that appears to play a major role in the regulation of GnRH cells. Because it is newly recognized, the significance of kisspeptin and the relevant receptor, GPR54, is not well defined. This project aims to use our unique combination of abilities to determine the significance of kisspeptin in the regulation of GnRH and gonadotropin secretion. We will study both sheep and monkey brains, measuring gene expression for kisspeptin and GPR54 in a range of physiological states and we will determine how kisspeptin acts on GnRH cells. We will determine whether kisspeptin plays a role in the feedback effects to GnRH cells. Effects on the pituitary gland will also be studied. We will use sheep models to measure kisspeptin effects on GnRH secretion, because this cannot be done in the monkey or the rodent. We will examine the function of kisspeptin and GPR54 in relation to puberty. We will also use a model of puberty (seasonal breeding in the sheep) to determine whether activation and quiescence of the reproductive system is related to the function of kisspeptin and GPR54. This work will define the role of kisspeptin in the regulation of reproduction.Read moreRead less
Endocrine And Molecular Regulation Of Placental CRH Expression
Funder
National Health and Medical Research Council
Funding Amount
$466,980.00
Summary
Approximately 70% of infant death is associated with premature birth. Preterm birth occurs in 6-10% of pregnancies, and there has been no reduction in the rates of premature birth in the last 30 years. This is largely because we remain ignorant of how normal and abnormal birth is controlled. Understanding the physiology of human pregnancy is a critical step in the development of ways to detect and prevent preterm birth. Our group has demonstrated a link between production of a hormone (corticotr ....Approximately 70% of infant death is associated with premature birth. Preterm birth occurs in 6-10% of pregnancies, and there has been no reduction in the rates of premature birth in the last 30 years. This is largely because we remain ignorant of how normal and abnormal birth is controlled. Understanding the physiology of human pregnancy is a critical step in the development of ways to detect and prevent preterm birth. Our group has demonstrated a link between production of a hormone (corticotrophin releasing hormone, CRH) in the placenta and the length of time the baby is carried in the mother. In women who will deliver prematurely a rise in CRH occurs earlier in the pregnancy and more rapidly, while in women who deliver late the rise occurs more slowly. This work has given rise to the concept of a biological clock that determines the length of time the fetus will be carried by the mother before birth, and in which production of CRH in the placenta plays a central role. We have been studying how the CRH gene is controlled in placental cells. We have discovered some regions in the DNA of the CRH gene which have important roles in controlling how much CRH is made by the placenta. The experiments described in this research project will determine the molecular mechanisms that control the production of CRH in the human placenta. This will be done in two ways: (1) by examining the DNA sequences involved in controlling expression of the CRH gene and (2) by identifying the proteins that actually perform the regulating functions that result in either increased or decreased amounts of CRH being produced by the placenta. This important information will help us better understand how normal and abnormal birth is controlled, and from that knowledge new ways to detect and prevent premature birth can be invented.Read moreRead less
Secretion is an essential step in memory and learning, control of metabolism and reproduction and the functioning of most organs. Secretory dysfunction also underlies many diseases including type 2 diabetes. We plan experiments to test for a new model of control of insulin secretion.
In the last decade there has been a substantial increase in the number of overweight and obese individuals. Obesity is now a major public health issue in Australia and, along with its associated disorders of type 2 diabetes and heart disease, incurs significant health care costs. There is a widespread awareness of the problem, but it has proved difficult to bring this obesity epidemic under control, and unless we can understand the underlying causes, the trend seems set to continue. This researc ....In the last decade there has been a substantial increase in the number of overweight and obese individuals. Obesity is now a major public health issue in Australia and, along with its associated disorders of type 2 diabetes and heart disease, incurs significant health care costs. There is a widespread awareness of the problem, but it has proved difficult to bring this obesity epidemic under control, and unless we can understand the underlying causes, the trend seems set to continue. This research proposal seeks to define the mechanisms which lead to the development of obesity. Evidence from a large range of clinical and population-based studies has shown that infants who are exposed to an increased supply of nutrients before birth have an increased risk of being overweight or obese as children and adults. It is not however, fully understood why this occurs. In normal adults, factors released by fat cells play an important role in the maintenance of energy balance, and changes in the levels of these factors in the fat cell or in the circulation can lead to increased weight gain and the development of poor sensitivity of the body's tissues to the actions of hormones, such as insulin. Fat cells develop before birth, and therefore changes in nutrient supply to the fetus have the potential to alter the functional properties of fat cells for life. In this proposal, we will investigate the effect of being exposed to an increased supply of nutrients in fetal life on the properties of fat cells after birth and define how such changes explain the development of obesity in these individuals. Understanding the mechanisms which link the risk of obesity to events before birth will allow clinicians of the future to provide children who are born to overweight, glucose-intolerant or diabetic mothers with a healthy start to life.Read moreRead less
LKB1 - The Link Between Obesity And Breast Cancer In Postmenopausal Women
Funder
National Health and Medical Research Council
Funding Amount
$292,216.00
Summary
Obesity is a worldwide epidemic affecting 60% of Australians and is linked to many diseases including breast cancer. Changes in sex hormone levels during menopause may cause these diseases. The focus of this proposal is to determine the role of the sex hormones to regulate a protein (LKB1) involved in both fat metabolism and cancer. This research will benefit the ageing population by making a contribution toward generating therapeutics to combat obesity and breast cancer.
Aromatase Regulation By P53 And HIF-1alpha In Obesity And Post-menopausal Breast Cancer.
Funder
National Health and Medical Research Council
Funding Amount
$607,523.00
Summary
Current hormone therapy for breast cancer using inhibitors of oestrogen production results in serious side-effects including bone loss, joint pain and possibly cognitive issues. Our current work is aimed at understanding how oestrogen production is regulated with the goal of developing breast-specific inhibitors of oestrogen production to obviate these problems. In addition, this work is aimed at devising therapeutic intervention to break the linkage between obesity and breast cancer.
The Effects Of Testosterone And A Nutritional Supplement On Hospital Admissions In Under-nourished, Older People.
Funder
National Health and Medical Research Council
Funding Amount
$1,054,231.00
Summary
Weight loss and undernutrition in older people are assocated with poor outcomes including increased rates of hospital admissions and death. In a pilot study of 49 undernourished older, community dwelling people we found that daily treatment for one year with a combination of testosterone tablets and a nutritional supplement produced a significant reduction in hospitalisations. We propose a larger, multicentre study to explore and hopefully confirm this exciting, potentiallly important finding.
Role Of The Podocyte In Diabetic Nephropathy: Structural, Functional, Molecular And Interventional Studies
Funder
National Health and Medical Research Council
Funding Amount
$227,036.00
Summary
Kidney disease is a major cause of disability and premature death in the Australian population. In disease the kidney's ability to filter out impurities and toxins in blood is impaired as a consequence of excessive cell growth and scar tissue formation. Studies from our group indicate that a highly specialised cell within the kidney's filtering apparatus becomes altered early in the course of diabetes. In the setting of diabetes, this cell, called the podocyte, stretches and begins forming scar ....Kidney disease is a major cause of disability and premature death in the Australian population. In disease the kidney's ability to filter out impurities and toxins in blood is impaired as a consequence of excessive cell growth and scar tissue formation. Studies from our group indicate that a highly specialised cell within the kidney's filtering apparatus becomes altered early in the course of diabetes. In the setting of diabetes, this cell, called the podocyte, stretches and begins forming scar tissue. In addition, it no longer maintains its barrier function and starts to leak protein. The proposed studies will explore the mechanisms that lead to these diabetes-induced changes in the podocyte. In addition, strategies for reversing these changes will also be explored in detail with the aim of providing new treatments for diabetic kidney disease.Read moreRead less
Common Pathways Influencing Osteoporosis And Atherosclerosis Clinical Risk
Funder
National Health and Medical Research Council
Funding Amount
$443,090.00
Summary
It is recognised there are strong inherited effects on bone density and bone turnover as well as cardiovascular markers like serum cholesterol and arterial function. The study will examine the relationship between osteoporosis and atherosclerosis risk using the powerful twin model and two established large twin cohorts in Sydney and Melbourne. The work may lead to better prediction of common risk factors for these two important conditions.