Grant: Project Grant

Asthma is a chronic inflammatory disease, characterised by intermittent airways constriction and occurs in up to 10% of individuals. Regular inhaled glucocorticoids are clinically referred to as inhaled corticosteroid (ICS) and dampen lung inflammation to control mild to moderate asthma. However, more severe disease and asthma exacerbations are poorly controlled by ICS and clinical guidelines recommend the addition of a long-acting beta2-adrenoceptor agonist (LABA). These drugs enhance the effectiveness of the ICS to a level that is not achieved by increasing the glucocorticoid dose. The glucocorticoid receptor (GR), the protein target by which glucocorticoids act, is responsible for modulating gene expression to mediate beneficial effects in asthma. In the context of LABA, combinatorial effects between glucocorticoid and LABA-activated pathways result in enhanced clinical effectiveness of ICS/LABA therapies. However, the mechanistic basis, and the genes modulated, are not established and therefore cannot be selectively targeted. The current proposal will elucidate mechanisms underlying this clinically important effect. In this context, it is salient that the pharmaceutical sector is currently testing novel drugs that activate GR in ways that are different to conventional glucocorticoids. These compounds enhance some aspects of GR function relative to other activities. While, the objective is to improve the clinical efficacy of GR-based therapies, it is important to stress that we do not know which aspects of GR function are most important for synergy with LABA. There is therefore a risk of failing to identify novel GR ligands that most effectively synergise with LABAs. This will preclude maximising benefit from future combination therapies. The current project addresses this key knowledge gap by identifying mechanisms of GR action that are important for synergy with LABA. Such data will help guide the discovery of improved combination treatments for asthma.