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
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