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- Professor of Vascular Physiology
- Metabolism & Experi Therapeutics
- Div of Medicine
- Faculty of Medical Sciences
In 1988, I went back to the UK and worked in the Pharmacology Department at St Thomas' Hospital investigating ion channel regulation in the pulmonary circulation. In 1992, I was awarded a Wellcome Trust Career Development Fellowship and continued studies in the Cardiovascular Research Department on the vascular ATP-sensitive potassium (KATP) channels, demonstrating not only its presence but different biophysical properties to the channel descrbed in the heart and pancreas. At the same as being awarded a 5 year MRC Senior Fellowship to elucidate the role of potassium channels in septic shock, I moved to the Centre for Clinical Pharmacology, Department of, Medicine,UCL as a Senior Lecturer in 1996. My Fellowship was renewed in 2001, where the focus switched to calcineurin regulation of inwardly rectifying potassium channels, identifying this calcium-dependent phosphatase as a critical regulator of the KATP channel. In recognition of my research contribution, I was elected fellow of the AHA in 2001, appointed a Reader in Clinical Pharmacology in 2002 and subsequently awarded a personal chair as Professor of Vascular Physiology in 2005. I was elected Fellow of the Pulmonary Vascular Research Institute in 2010 for my work on prostacyclin pharmacology and cell signalling in the context of pulmonary hypertension, and a Fellow of the Society of Biology in 2011.
My international standing is recognised by publications in top peer-reviewed journals, including PNAS, Circulation Research, Lancet and Am J Respir Crit Care Med, editorials in Circulation Research and invitations to speak at symposia organised by the AHA, American College of Chest Physicians, European Respiratory Society, International Society for Heart and Lung Transplant, Intensive Care and Emergency Medicine and European Society of Cardiology. I am currently an editor for the British Journal of Pharmacology and peer review for numerous journals and also grant awarding bodies (Action Research, BBRSC, British Heart Foundation, Diabetes Foundation, Medical Research Council, Ireland Health Research Board, Dr Hadwen Trust, Wellcome Trust).
Experimental Medicine is at the forefront of my activities, and I have active links with hospital-based clinicians and scientists at the Royal Free (Prof Abraham and Dr Gerry Coghlan), GOSH (Prof Klein, Dr Schulze-Neick and Dr Moldina) and UCLH (Prof Singer and Dr Williams) as well as with Prof Morrell at Addenbrooke’s, Hospital Cambridge. I have been involved in the first clinical use of terlipressin in sepsis, the identification of a new clinical syndrome associated with drug-induced hyperkalemia and proof of concept of novel treatments for pulmonary arterial hypertension for which clinical trials are being set-up or are on-going. I have productive relationships (Consultancies, Research Grants) with several Pharma companies, including United Therapeutics, Pfizer, Cytokinetics, Bayer and GSK, and regularly provide information to market research companies (e.g. Adelphi Communications, Health Science Communications, Biopharm Insight).
Overall summary of research
In the last decade, our group has principally been involved in elucidating the biophysical and functional properties of vascular potassium channels with a strong emphasis on their roles in sepsis, vascular remodelling and pulmonary hypertension. Work has specifically focused on in vitro and in vivo models of septic shock in rodents and humans, the biochemistry and confocal imaging of calcineurin and its role in mediating smooth muscle proliferation as well as the mechanistic basis underlying the therapeutic effects of prostacyclins in pulmonary arterial hypertension (PAH). Complimenting these are studies in patients to establish biomarkers of early disease (smooth muscle hypertrophy) and the impact of prostacyclin therapy on a broader range of markers of endothelial dysfunction and inflammation in PAH.
Prostacyclin signalling through membrane and nuclear receptors
In collaboration with Prof Howarth and Dr Hall (ICH/GOSH) and Prof Morrell (Cambridge) we are exploring cellular mechanisms underlying abnormal cell growth in lung cells derived from patients with PAH in addition to the impact of prostacyclin therapy on this process. Interestingly, we have found in PAH that prostacyclin signalling is disrupted in pulmonary smooth muscle cells, switching away from the classical IP receptor and cyclic AMP driven pathway, to one involving the nuclear transcription factor, PPARy. The mechanism of PPARy activation by prostacyclin is unknown but we are exploring whether it inhibits growth through an impact on the NFAT/calcineurin pathway. In biochemical studies funded in partnership with United Therapeutics (USA) and Prof Whittle (William Harvey, Barts), we have very recently established that the prostacyclin analogue treprostinil has a novel pharmacology compared with other agents in its class like iloprost, activating both DP1 and EP2 receptors in the nanomolar range. These receptors therefore represent previously unrecognised targets for this agent, and suggest that the overall beneficial pulmonary vasorelaxant profile and other pharmacological actions of treprostinil, especially in diseases where the IP receptor is down-regulated, may contribute to its therapeutic efficacy. It remains to be determined how these findings impact on selexipag, a selective non prostanoid IP receptor agonist, currently in phase III clinical trials in PAH.
Calcineurin interaction with KATP channels
Our lab has been instrumental in showing that the calcium-dependent phosphatase, calcineurin is a key regulator of the ATP-sensitive potassium (KATP) channel. In collaboration with Prof Tinker (UCL and Barts and the London) we have shown that the molecular basis for this regulation involves dephosphorylation of channel subunits, and that such a mechanism, is likely to directly oppose the action of vasodilators which open this channel through phosphorylation. We and others have demonstrated that excessive opening of the vascular KATP channel is implicated in the vasodilation and vascular hyporeactivity that underlies septic shock, though despite this, therapeutic channel inhibition using sulfonylurea agents like glibenclamide has proved disappointing in humans. Our recent observations that sympathetic activity, which is often high in septic patients, may actually be helping maintain blood pressure by keeping the channel closed, could therefore explain lack of efficacy of channel inhibitors in sepsis. Studies in the future are planned to more fully understand the influence of sympathetic tone on in vivo KATP channel function and blood pressure, where the regulation may ultimately be determined by calcineurin activity.
I teach across 3 different Faculties at UCL, including on BSc and MSc/MRes courses run in the Division of Medicine, in the Department of Neuroscience, Physiology & Pharmacology, in Biochemistry and in the Institute of Cardiovascular Science. I am part of the organising committee for the newly created MSc in Cardiovascular science and for the 4 Year BHF PhD programme for which I am a co-applicant on the successful renewal of this PhD scheme in July 2012. As Deputy Postgraduate Tutor, I am responsible for overseeing postgraduate students within the research department of Metabolism & Experimental Therapeutics (currently ~40 PhD/MD students). Duties of various teaching activities can be briefly summarised:
1. 3rd Year BSc students & intercalating medics (PHOL3902 & PHOL3904). This involves supervising laboratory research and library projects based around sepsis & pulmonary hypertension as well as examining oral presentations and marking dissertations.
2. Heart & Circulation (PHOL3002) for 3rd year BSc and MSc students
I am director of this 30 credit Module which I co-organise with Dr Nephtali Marina-Gonzalez. The course is a series of lectures, tutorials & lab-based practicals and covers the physiology and pathophysiology with special reference to the human heart and circulation.
3. Biochemistry of Cardiovascular Disease (BIOC3011)
I lecture on vascular remodelling in cardiovascular diseases in which the students learn about how remodelling in diseases such systemic hypertension and atherosclerosis is caused by endothelial dysfunction, overproduction of vasoconstrictors and growth factors and extracellular matrix degradation. Setting of in-course exam questions.
4. MSc in Clinical and Experimental Medicine - Drug Discovery (MEDCG004)
Includes lecturing on animal models of cardiovascular disease, the pathobiology of pulmonary hypertension and the molecular targets for potential future novel treatments, the setting, providing of a model answer and the marking of exam questions. In addition, I host MRes students for 6 month laboratory-based research projects and mark their dissertations.
5.MSc in Cardiovascular Science (MEDGC012)
I give two lectures on this course. The first is on "Ion Channels in Cardiovascular disease" which covers topics around the genetic basis of various diseases linked to mutations in ion channels, including pathogenic mutations in ATP-sensitive potassium channels involved in insulin secretion disorders and sudden cardiac death. The second is on in vitro and in-vivo animal models of pulmonary hypertension. I set in course essays, am part of the committee which oversees the course and have been appointed chair of the exam board.
6. BHF 4 Year PhD programme.
5 students will be appointed each year for the next 4 years to engage in research in any area of cardiovascular biomedicine at UCL. I am involved in interviewing, tutoring, helping students to network to choose appropriate rotation projects, meeting with them in 1st year assessments of rotation projects.
7. International teaching
Teaching in symposia with CME (Continuing Medical Education) credits, including at the 2011 International Society for Heart and Lung Transplantation held in San Diego which also included providing online materials to AKH Inc, an accredited provider of continuing education for licensed health care specialists in the USA.
|1985||PhD||Doctor of Philosophy – Pharmacology||University of London|
|1981||BSc||Bachelor of Science – Pharmacology||University of London|