My research aims to discover how circadian timing mechanisms affect inflammation, and immunity and the role of nuclear receptors to mediating this communication.
I came to this from studying how glucocorticoid signalling regulates immunity and inflammation. I worked on glucocorticoid sensitivity in human small cell lung cancer, and discovered the underlying mechanism explaining ectopic ACTH secretion. This led to analysis of immune system cross-talk with the hypothalamic-pituitary-adrenal axis, which identified the role of intrapituitary cytokine expression, and action.
I returned to Manchester as a clinical lecturer, and moved to define structure-activity relations for synthetic glucocorticoid. This led to the first publication of a model for the ligand binding domain of the glucocorticoid receptor, which was later validated by crystallography. I reported on the GRgamma isoform, as a constitutive splice variant, with distinct properties. I went on to discover the mechanism explaining production of the isoform, and to show that this is conserved through mammalian evolution.
I extended my interest to include circadian timing mechanisms as it became clear that glucocorticoids serve as a major timing signal, by regulating PER1 expression. Moreover, working with Andrew Loudon, we discovered that timing cells in the lung were enriched for glucocorticoid receptor expression.
Variation in glucocortiocid sensitivity is a major issue in human healthcare, with huge annual usage of glucocorticoid drugs to treat lung disease. I have led a discovery programme to find mechanisms explaining such variation in sensitivity. This programme of work has identified cave-in (highly enriched in the lung), MERM1 (a methyltransferase with very high expression in bronchial epithelium), PIN1 (an isomerase with selective action of GR transactivation), and BMPRII (a transmembrane receptor genetically linked to primary pulmonary hypertension).
My interest in glucocortiocid action, and expertise in structure:activity modelling and experimental validation led to a drug discovery programme which has resulted in world-wide patent protection for a series of synthetic steroids with selective glucocorticoid action, SEGRA molecules. This programme was funded by a Wellcome Trust SDDI award.
My interests in nuclear receptor function naturally led to a programme identifying synthetic ligands for NR1D1 (REVERBa). We published the first such molecules, and have gone on to find both agonist and antagonist ligands. We are pursuing the mechanisms of action now, with a view to obtaining appropriate probes for in-vivo testing in lung inflammation (current molecules lack potency, and have undesirable PK properties).
With Andrew Loudon I have led a programme studying circadian control of macrophage function, and more recently circadian regulation of pulmonary immunity. In this latter programme we have discovered the key timing cells in the lung, and shown that the circadian clock regulates inflammation in part through epigenetic regulation of glucocorticoid receptor function in the lung.