Cellular Localisation Of Mineralocorticoid Receptor-mediated Vascular Inflammation And Cardiac Fibrosis.
Funder
National Health and Medical Research Council
Funding Amount
$476,264.00
Summary
Cardiovascular disease is a major health and economic burden throughout the world, especially in developed countries and is the leading cause of death and disability in Australia, claiming the lives of over 50,000 Australians each year. Heart failure accounts for many of these deaths and the incidence continues to increase. Two recent large scale clinical trials have shown a 30-35% improvement in patient outcome when a blocker for the mineralocorticoid receptor (MR) is included in current best p ....Cardiovascular disease is a major health and economic burden throughout the world, especially in developed countries and is the leading cause of death and disability in Australia, claiming the lives of over 50,000 Australians each year. Heart failure accounts for many of these deaths and the incidence continues to increase. Two recent large scale clinical trials have shown a 30-35% improvement in patient outcome when a blocker for the mineralocorticoid receptor (MR) is included in current best practice therapy for either heart failure or after a heart attack. The mechanisms underlying these benefits remain to be identified. We have shown that the hormone aldosterone and its receptor, the MR, not only play an important role in the development of high blood pressure but also the progression of cardiac disease. Our most recent studies have shown that blocking the MR not only prevents cardiac fibrosis and vascular damage, but also reverses this process. To understand the mechanisms that translate MR signalling into blood vessel damage and cardiac fibrosis we wish to use mice who have the MR gene inactivated in specific cells only. In this way we can identify those cells critical to the disease process and focus our investigations to these cell types. Understanding the cell specific regulatory mechanisms for the MR may enable the development of heart-specfic blockers of the MR that have minimal, if any side effects.Read moreRead less
Osteocytes (OY) are the most abundant cell type in bone whose high density and viability are essential for healthy bone. We have found that vitamin K, vitamin D and strontium, promote human OY differentiation. We will test these in novel models of human OY differentiation and survival, and in animal models of bone loss associated with vitamin D deficiency, menopause and glucocorticoid treatment. Our work will lead to a better understanding of human OY and give a new approach to treat osteoporosi ....Osteocytes (OY) are the most abundant cell type in bone whose high density and viability are essential for healthy bone. We have found that vitamin K, vitamin D and strontium, promote human OY differentiation. We will test these in novel models of human OY differentiation and survival, and in animal models of bone loss associated with vitamin D deficiency, menopause and glucocorticoid treatment. Our work will lead to a better understanding of human OY and give a new approach to treat osteoporosis.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