Margaret MacLeanFaculty of Biomedical and Life Science, University of Glasgow, Glasgow, Scotland, UK F1000 Section Head (since 16 March 2009)
Professor of Pulmonary Pharmacology
Professor Margaret (Mandy) R MacLean directs a research group studying the pharmacology of pulmonary hypertension. The group has a particular interest in the role of serotonin in the pathobiology of pulmonary hypertension.
The MacLean laboratory is studying the pharmacological and molecular mechanisms underlying pulmonary arterial hypertension (PAH). In particular our research is focussed on how the serotonin system is involved in PAH. There is evidence that there is increased activity of the rate limiting enzyme in the synthesis of serotonin (tryptophan hydroxylase1), the serotonin transporter and the 5HT1B receptor. Our research is also revealing important interactions of serotonin with the downstream signalling of the bone morphogenetic protein type II receptor (BMPR-II). Mutations in this receptor member of the transforming growth factor-beta superfamily, cause familial pulmonary arterial hypertension (PAH) and our collaborator in this is Prof N Morrell at Cambridge University. PAH is more frequent in females than males and we are also unravelling possible cellular mechanisms behind this. Achievements to date include:
1. Direct evidence for the serotonin hypothesis of dexfenfluramine-induced pulmonary hypertension. (Circulation 2008)
2. Direct evidence that peripheral serotonin is required for the development of hypoxia-induced pulmonary hypertension. (Hypertension, 2007)
3. Evidence that serotonin increases susceptibility to pulmonary hypertension in BMPR2-deficient mice (Circ Res, 2006)
4. 5HT1B receptors and SERT interact to mediate pulmonary vasoconstriction and proliferation (Circ Res, JPET, 2005)
5. Over-expression of SERT predisposes to PAH and hypoxia-induced PAH (Circulation, 2004)
6. The 5HT1B receptor plays a pivotal role in the development of experimental PAH (13 publications)
Our group has collaborative links with many groups world wide. Locally, we currently collaborate with Prof Andy Baker at GCRC looking into 1. potential in vivo gene transfer approaches to PAH 2. characterisation of changes in miRNA profile in models of PAH. 3. using novel knockout models of TPH1, further characterisation of its role on PAH.
Additional research themes in the MacLean laboratory are determining how serotonin interacts with KCNQ channels (collaboration with A Gurney, Manchester University), how it interacts with S100A4/Mts 1, a gene associated with cancer and vascular disease (collaborations with M Rabinovitch (USA) and RAGE pathways (collaboration with S Kennedy (Glasgow).
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