Grant: Project Grant

Glucocorticoids, colloquially known as steroids, are naturally occurring substances made by the human body that regulate many physiological processes including metabolism, cognition, arousal and development. In addition, drug companies have made synthetic glucocorticoids to treat a wide variety of diseases with asthma, rhinitis, inflammatory bowel disease, ulcerative colitis, rheumatoid arthritis, lupus and cancer being typical examples. Glucocorticoids work by increasing and decreasing the expression of hundreds of genes in most, if not all, cell types and tissues of the body. They do this through their ability to bind and activate a specific protein known as the glucocorticoid receptor (GR). It has been assumed that all glucocorticoids are equivalent in this respect; that is, the same population of genes in a given tissue is modulated to approximately the same extent irrespective of the glucocorticoid. However, new evidence suggests that this does not have to be the case. Changes in the size and shape of glucocorticoids have been shown to differentially alter the 3-dimensional structure of GR. Moreover, evidence from the study of other physiological systems predict that this will give rise to distinct, non-identical gene expression "signatures". This idea has huge implications because different patterns of gene expression will lead to different functional outcomes that could be exploited therapeutically. This application for funding is designed to gain evidence that glucocorticoids and other molecules of different size and shape that activate GR behave uniquely in their ability to "switch on" and "switch off" genes.