Glucocorticoid-progesterone Interactions In The Control Of Fetal And Placental Growth
Funder
National Health and Medical Research Council
Funding Amount
$227,036.00
Summary
The growth and function of the placenta is of critical importance to the successful maintenance and completion of human pregnancy. The placenta is effectively the lifeline of the growing fetus through its supply of nutrients, removal of wastes, and coordination of homone signals that regulate fetal growth and development. If the placenta does not perform these functions adequately, the growth rate of the fetus is compromised and can lead to difficulties before and after birth. This project exami ....The growth and function of the placenta is of critical importance to the successful maintenance and completion of human pregnancy. The placenta is effectively the lifeline of the growing fetus through its supply of nutrients, removal of wastes, and coordination of homone signals that regulate fetal growth and development. If the placenta does not perform these functions adequately, the growth rate of the fetus is compromised and can lead to difficulties before and after birth. This project examines how two important steroid hormones, progesterone and glucocorticoids, interact with growth factors in the placenta to control its growth and function. Progesterone is recognized as 'the hormone of pregnancy' as it helps the mother adapt to pregnancy. Progesterone may also affect the placenta by regulating its synthesis and breakdown of other hormones, and the balance between placental cell proliferation and death. These effects of progesterone will be studied in this project. We will also examine how glucocorticoid hormones regulate the growth and function of the placenta. Glucocorticoids are structurally very similar to progesterone, and are secreted by the adrenal gland in increased quantities during pregnancy. Glucocorticoids exert a wide range of effects on the mother, placenta and fetus; indeed, glucocorticoids are recognized clinically as the single-most importnat signal for fetal maturation in late pregnancy. However, too much glucocorticoid retards fetal and placental growth, and in this project we will study how this occurs in the placenta, and how the placenta may protect itself from detrimental effects of glucocorticoids. We will test whether placental growth is restricted by glucocorticoids through their effects on placental growth factor hormones. Overall, these studies could have important implications for the clinical management of pregnancy, particularly in relation to fetal and placental growth.Read moreRead less
GLUCOCORTICOID EFFECTS ON BONE: THE ROLE OF THE OSTEOBLAST
Funder
National Health and Medical Research Council
Funding Amount
$464,520.00
Summary
Glucocorticoids (usually referred to as cortisone) are used as therapeutic agents in almost all fields of medicine, where they have been proven to be of great benefit to countless patients suffering from diseases such as rheumatoid arthritis, asthma, inflammatory bowel disease and malignancies. Glucocorticoids are also of live saving benefit to patients who have undergone organ transplantation. It is, however, well known that glucocorticoids may also exert deleterious effects on bone, muscle, ca ....Glucocorticoids (usually referred to as cortisone) are used as therapeutic agents in almost all fields of medicine, where they have been proven to be of great benefit to countless patients suffering from diseases such as rheumatoid arthritis, asthma, inflammatory bowel disease and malignancies. Glucocorticoids are also of live saving benefit to patients who have undergone organ transplantation. It is, however, well known that glucocorticoids may also exert deleterious effects on bone, muscle, cartilage and skin, causing osteoporosis, muscle wasting and skin damage. As a matter of fact, cortisone-induced muscle and bone disease is one of the most frequent and serious side effects associated with glucocorticoid treatment, and substantially affects quality of life and co-morbidity in many patients. In the present project, we aim to develop new strategies for the understanding and prevention of costisone-induced bone disease. The first step is to investigate the mechanisms of actions of glucocorticoids in bone. To this aim, we have generated a model in which a cortisone- inactivating enzyme is produced in excess in the bone forming cells (osteoblasts). Previous studies have shown that these cells are protected against the effects on cortisone, while other cells not producing this enzyme remained vulnerable. We now intend to use this model to study the mechanisms of glucocorticoid action on bone and muscle under normal and diseased conditions (e.g. in a model of glucocorticoid excess and in a model of rheumatoid arthritis). We also intend to study how internal glucocorticoids affect the development of bone forming cells. Our long-term aim is to uncover new ways to target drug action to the desired tissues and cells, while protecting other tissues and cells from deleterious side effects.Read moreRead less
Aldosterone Mediated Cardiac Pathophysiology:The Role Of Corticosteroid Receptors And 11 HSD Isoforms
Funder
National Health and Medical Research Council
Funding Amount
$481,500.00
Summary
Aldosterone a hormone that circulates in blood and is associated with cardiovascular disease. Recently, two clinical trials (RALES, EPHUSUS) demonstrate that if you stop this hormone from acting by giving drugs that inhibit it from binding to the receptor that mediates its response, there is an improvement in the health of heart failure patients. How aldosterone mediates its detrimental effects on heart is largely unknown. Glucocorticoids are another hormone that circulates in blood and can bind ....Aldosterone a hormone that circulates in blood and is associated with cardiovascular disease. Recently, two clinical trials (RALES, EPHUSUS) demonstrate that if you stop this hormone from acting by giving drugs that inhibit it from binding to the receptor that mediates its response, there is an improvement in the health of heart failure patients. How aldosterone mediates its detrimental effects on heart is largely unknown. Glucocorticoids are another hormone that circulates in blood and can bind to the same receptor as aldosterone. In contrast to aldosterone glucocorticoids appear to play a basic maintenance role in heart. Our central hypothesis is that in the healthy heart aldosterone has minimal effects , however, in the diseased heart aldosterone associated pathophysiology is a result of both an increase in the ability of aldosterone to signal to cells and disruption of glucocorticoid signalling. This grant proposal will address how aldosterone and glucocorticoids may directly signal within cardiac cells and how this signalling changes in the diseased heart. In addition, we investigate if enzymes that metabolize glucocortioids and thus render them non-functional play a role in cardiac disease, and if we can reverse the detrimental effects of aldosterone by artificially increasing the production of glucocorticoids in heart. By understanding the mechanisms by which aldosterone promotes cardiac disease, and the role of glucocorticoids and their metabolism in this process will lead to a better understanding of aldosterone induced pathology and thus lead to novel therapeutic targets.Read moreRead less