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Personal profile

Overview

Professor of medicine and endocrinology

Honorary consultant in endocrinology at Manchester Royal Infirmary

 

Biography

Graduated in medicine, University of Manchester, in 1987.

Trained in general internal medicine and endocrinology in the North West of England.

PhD University of Manchester in 1994

Post doctoral work at UCLA 1994-1996

GSK fellow University of Manchester, then lecturer, senior lecturer and professor in 2005

 

Research interests

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.

Teaching

My collaborations

Memberships of committees and professional bodies

Society for Endocrinology

Endocrine Society

British Medical Association

Royal College of Physicians of London

Qualifications

MB ChB Manchester

PhD Manchester

FRCP Royal College of Physicians

Expertise related to UN Sustainable Development Goals

In 2015, UN member states agreed to 17 global Sustainable Development Goals (SDGs) to end poverty, protect the planet and ensure prosperity for all. This person’s work contributes towards the following SDG(s):

  • SDG 3 - Good Health and Well-being

Education/Academic qualification

Doctor of Philosophy, Glucocorticoid resistance in human small cell lung cancer, The University of Manchester

30 Sep 200130 Aug 2004

Award Date: 1 Sep 1994

External positions

Panel member, The Wellcome Trust

1 Mar 2017 → …

Chair, Bioscientifica Trust

1 Jun 201630 May 2024

Senior Editor, Journal of Endocrinology

1 Jan 2005 → …

Areas of expertise

  • R Medicine (General)

Research Beacons, Institutes and Platforms

  • Manchester Institute for Collaborative Research on Ageing

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