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Endocrine Abstracts (2014) 34 PL8 | DOI: 10.1530/endoabs.34.PL8

SFEBES2014 Plenary Lecturers’ Biographical Notes Clinical Endocrinology Trust Lecture (2 abstracts)

Understanding glucocorticoid action, and the role of the glucocorticoid receptor

David Ray


University of Manchester, Manchester, UK.


The glucocorticoid receptor (GR) is a ligand activated transcription factor, serving to regulate both energy metabolic and immune functions. The natural endogenous glucocorticoid in humans is cortisol, but a variety of synthetic molecules have been developed to treat inflammatory disease. These synthetic ligands offer new insights into how the GR works, and how it can be manipulated. Novel, non-steroidal GR agonists specifically alter the GR LBD structure at the HSP90 binding site. Despite their high affinity the non-steroidal ligands induce surprisingly slow GR nuclear translocation, followed by prolonged duration of action. These non-steroidal ligands predict new anti-inflammatory drugs with prolonged duration of action due to altered pharmacodynamics rather than altered pharmacokinetics.

Downstream of ligand activation the cellular response to GR varies greatly by time of day, between tissues and within populations. We adopted a systems biology approach to understand the basis for variation in glucocorticoid response. In this way we stratified a healthy human cohort by glucocorticoid response, and profiled the genes expressed in isolated T lymphoblasts, thereby discovering genes whose expression associated with in-vivo glucocorticoid sensitivity. This approach revealed two proteins, BMPRII, and IFI16, as novel regulators of the glucocorticoid signalling cascade.

In further studies we employed proteomics to identify novel proteins bound to the glucocorticoid receptor. These studies identified a different spectrum of protein partners under basal, and glucocorticoid treated conditions, with a shift from cytoplasmic and membrane partners under the former, and nuclear and chromatin components in the latter. We used these insights to determine how the membrane protein caveolin binds to, and regulates the glucocorticoid receptor, and how this regulation may play a role in the regulation of inflammation.

Taken together we have discovered new controls regulating glucocorticoid action in cells, and also found new mechanisms explaining glucocorticoid regulation of inflammation.

Generously supported by Clinical Endocrinology Trust

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