Molecular Characterisation Of The Ligand-binding Domain Of The Mineralocorticoid Receptor
Funder
National Health and Medical Research Council
Funding Amount
$215,183.00
Summary
The steroid hormone aldosterone regulates blood pressure by controlling sodium retention. The important role of this hormone in blood pressure control is underlined by the fact that all known monogenetic hypertensive conditions involve aldosterone or sodium reabsorption. Aldosterone works by activating an intracellular 'receptor' protein that in turn switches on specific genes. The products of these genes act to produce sodium retention. Antagonists (blockers) of this receptor are used in the tr ....The steroid hormone aldosterone regulates blood pressure by controlling sodium retention. The important role of this hormone in blood pressure control is underlined by the fact that all known monogenetic hypertensive conditions involve aldosterone or sodium reabsorption. Aldosterone works by activating an intracellular 'receptor' protein that in turn switches on specific genes. The products of these genes act to produce sodium retention. Antagonists (blockers) of this receptor are used in the treatment of hypertension but have undesirable side effects. The design of new, more specific, antagonists has been slow because we do not understand how these drugs bind to the receptor and what effect they have on the protein. How the aldosterone receptor functions is poorly understood. This project aims to investigate the receptor in detail. We are in the process of determining regions of the receptor structure important for hormone binding. This information is vital for the design of new antagonists. The aldosterone receptor is unusual in that it is also activated by cortisol, a steroid hormone involved in stress and inflammation. By examining hormone binding it may be possible to determine if the two steroids activate the receptor in the same way. An understanding of how both natural hormones and synthetic antagonists function is impossible without thorough study of the receptor itself. We intend to examine fundamental aspects of aldosterone receptor function. In particular we wish to identify proteins that interact with the receptor. These proteins either enhance or inhibit the ability of the receptor to switch on genes and are vital to explaining the actions of both natural hormones and synthetic antagonists. Results from these experiments should advance our understanding of the basic biology of aldosterone action and its role in cardiovascular biology, and lead to the design of better receptor antagonists for use in the treatment of hypertension and cardiac fibrosis.Read moreRead less
Aldosterone Inhibition And Diabetic Retinopathy: Treatments And Mechanisms Of Action
Funder
National Health and Medical Research Council
Funding Amount
$511,294.00
Summary
The World Health Organization predicts that by 2030, more than 360 million people will have diabetes. Despite almost all patients developing retinopathy, current treatments do not prevent disease progression. One strategy being evaluated is blockade of a hormone called angiotensin II. We have new evidence that a related system called aldosterone exists in retina and contributes to damage. This project will determine if aldosterone blockade is a potential treatment for diabetic retinopathy.
The Cardiomyocyte Mineralocorticoid Receptor Plays A Critical Role In Cardiac Disease.
Funder
National Health and Medical Research Council
Funding Amount
$613,477.00
Summary
Drugs that block the mineralocorticoid receptor (MR), which responds to adrenal hormones, protect against heart disease and hypertension. We have shown that this effect is in part due to MR blockade in heart muscle cells. This novel finding is being explored further to understand the precise role of the MR in heart muscle cells in normal physiology and in disease. An understanding of the role of the MR in different tissues will enable development of tissue specific treatments for heart disease.
Drugs that block the mineralocorticoid receptor (MR), which responds to adrenal hormones, protect against heart disease and hypertension. We have shown that this effect is in part due to MR blockade in inflammatory cells. This novel finding is being explored further to understand the precise role of the MR in inflammatory cells in normal physiology and in disease. An understanding of the role of the MR in different tissues will enable development of tissue specific treatments for heart disease.
Mineralocorticoid Receptor Blockade: Mechanisms Of Selectivity
Funder
National Health and Medical Research Council
Funding Amount
$540,270.00
Summary
The steroid hormone aldosterone controls salt balance and hence, blood pressure. It also has been shown to have a significant role in cardiac failure. Although drugs that block the aldosterone receptor are beneficial in the treatment of heart failure, they are limited by potassium retention in the kidney. In order to develop tissue-specific blockers of the aldosterone receptor, it is necessary to identify mechanisms by which the receptor can be activated and/or blocked in specific tissues.
Mineralocorticoid Receptor Co-regulator Recruitment Determines Ligand Specific Signalling.
Funder
National Health and Medical Research Council
Funding Amount
$491,530.00
Summary
Heart disease is a major cause of death and economic burden in Australia and throughout the world. The steroid hormone aldosterone controls salt and water balance,blood pressure and hasa significant role in heart failure. Although drugs that block the aldosterone receptor significantly help patients with heart failure, their use is limited by side effects. This work will identify the profile of proteins that promote aldosterone effects and enable the development of heart-specific blockers.
Characterisation Of The Molecular Mechanisms Mediating Aldosterone-induced Epithelial Electrolyte Transport
Funder
National Health and Medical Research Council
Funding Amount
$488,386.00
Summary
The steroid hormone aldosterone regulates blood pressure by controlling sodium retention. The importance of this role is underlined by the fact that all known mongenetic hypertensive conditions involve aldosterone or sodium retention. Aldosterone mediates this effect by activating an intracellular receptor protein that in turn switches on specific genes. This study seeks to identify the genes that are switched on (or off) by aldosterone and to characterise the region of the gene that interacts w ....The steroid hormone aldosterone regulates blood pressure by controlling sodium retention. The importance of this role is underlined by the fact that all known mongenetic hypertensive conditions involve aldosterone or sodium retention. Aldosterone mediates this effect by activating an intracellular receptor protein that in turn switches on specific genes. This study seeks to identify the genes that are switched on (or off) by aldosterone and to characterise the region of the gene that interacts with the receptor. Both cell and gene specific factors are thought to be important in defining the nature of this interaction; these factors will also be sought. This information will enhance our understanding of the basic biology of sodium transport in the colon and the kidney which in turn will clarify the role of aldosterone in high blood pressure, cardiac disease and perhaps even stress.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