Dr. Allan Lawrie BSc PhD
BHF Senior Basic Science Research Fellow
Head of Pulmonary Vascular Research Group
Department of Infection, Immunity & Cardiovascular Disease
University of Sheffield
Beech Hill Road
Tel: +44 (0)114 215 9536
Fax: +44 (0)114 271 1863
I completed my PhD “The effects of ultrasound on vascular gene delivery” (Supervisor”: Prof Chris Newman) in the Department of Cardiovascular Science at the University of Sheffield at the end of 2001. I followed this with a post-doctoral position with Prof Marlene Rabinovitch at Stanford University, California where I developed my interested in Pulmonary Hypertension. I gained my first independent Fellowship to return to Sheffield at the end of 2004 (Russell Fellowship) and started to build a basic science research group focused understanding the molecular mechanisms underlying pulmonary hypertension. I obtained a Medical Research Council Career Development Award in 2008 and now hold a British Heart Foundation Senior Basic Science Research Fellowship (since 2012). Within the newly formed Donald Heath programme I lead a talented group of scientists and maintain strong translational links through the Sheffield Pulmonary Vascular Disease Unit at the Royal Hallamshire Hospital working towards my core research interests of drug target identification, novel therapies and early disease diagnosis.
My group has a strong interest in understanding the molecular mechanisms underlying pulmonary arterial hypertension (or PAH). We have a strong translational and collaborative focus working with the Sheffield Pulmonary Vascular Disease Unit, nationally with all UK PH Centres through the UK Idiopathic and Heritable Pulmonary Arterial Hypertension Cohort, and multiple international collaborations.
Drug target identification / development: Work in my lab identified the Osteoprotegerin (OPG) / Tumor necrosis factor (TNF)-Related Apoptosis-Inducing Ligand (TRAIL) axis as both key regulators of disease pathogenesis and therapeutic targets (Lawrie et al Am J Pathol 2008, Hameed et al JEM 2012). Working though MRC:MICA Developmental Pathway Funding Scheme, in partnership with Kymab Ltd we have identified and patented a human therapeutic antibody targeting OPG.
I also have a strong interest in the role of inflammation, specifically IL-1 (Lawrie et al Am J Path 2011) in PAH, and on the regulation of BMPR2 signalling (Pickworth et al Pulm Circ 2017) in the lung and in miRNA and non-coding RNA biology. We have identified a number of key miRNA that offer diagnostic, prognostic and therapeutic potential. Once such example under further study is miR-140-5p which we have recently shown to be a regulator of BMP signalling, a potential explanation for reduced BMPR2 expression independent of mutation, and identified SMURF1 as a potential drug target (Rothman et al JCI 2016). Several other individual miRNA are currently under investigation including miR-34a.
Biomarkers and Precision Medicine for Pulmonary Arterial Hypertension: Through developing the Sheffield Pulmonary Hypertension Biobank (blood derived DNA/RNA/Plasma/Serum from patients with all major forms of PH) I have a strong interest in biomarkers (proteomic, miRNA and epigenetic). I have developed a number of national and international collaborations to maximise the utilisation of this valuable and rare resource (e.g. Nick Morrell (Cambridge) / Martin Wilkins (Imperial) / Roham Zamanian (Stanford)). The combination of clinical phenotype with biological data from multi-omic studies including whole genome sequencing (Gräf et al Nat. Comms 2018), RNA expression, miRNA (Rhodes et al AMRCCM 2013, Rothman et al JCI 2016), proteomics (Rhodes et al Lancet Resp Med 2017) and metabolomics (Rhodes et al Circulation 2017) offers great potential to identify novel drug targets, and develop tools for Precision Medicine.
Early detection: Working with our partner IQVIA and GSK we are currently exploring the potential for harnessing real-world healthcare resource utilisation data in the form of NHS Hospital Episode Statistics to develop an algorithm to aid early detection of IPAH – Sheffield Pulmonary Hypertension IndeX project (Bergemann et al Pulm Circ 2018.). We are currently in the process of validating such an algorithm.
I currently provide lectures on the molecular and cellular mechanism of pulmonary hypertension, the use of pre-clinical models and pharmacogenomics on the following courses:
- MSc in Molecular Medicine (Cardiovascular Pathway).
- MSc in Genomic Medicine.
- BSc Pharmacology (Cardiovascular Pharmacology Pathway).
- British Heart Foundation Project Grant Committee 2016-present
- Scleroderma & Raynaud’s UK Research Committee, 2017-present
- Editorial Board Member of Pulmonary Circulation, 2017-present
- Grant Reviewer for MRC, Wellcome Trust, BBSRC, Heart Research UK
- Manuscript Reviewer for the leading journals in the field including Nature, Journal of Clinical Investigation, Circulation, Circulations Research, ATVB, American Journal of Respiratory and Critical Care Medicine, European Respiratory Journal and Thorax.
- Fellow of the Pulmonary Vascular Research Institute (PVRI).
- British Heart Foundation Senior Basic Science Research Fellow – Dec 2013 to Nov 2018. Defining cellular and molecular interactions in the OPG/TRAIL pathway in pulmonary arterial hypertension - £1,010,100. Allan Lawrie (PI).
- British Heart Foundation Project Grant - Jul 2018 to Jun 2020. Investigating the sex-dependent role of macrophage subtypes in the pathogenesis of pulmonary arterial hypertension - £158,377. Allan Lawrie (PI), G. Millar, A.A.R. Thompson.
- British Heart Foundation Project Grant - Dec 2017 to Nov 2019. The role of H3K27 methylation in vascular endothelial cell proliferation and function: Implications for pulmonary arterial hypertension - £193,282. S. John Wort (PI), Ian Adcock, Dongmin Shao, Allan Lawrie.
- Wellcome Trust Clinical Research Career Development Fellowship to Dr Alexander Rothman - Nov 2017 to Feb 2020. Determining Novel SMURF1 Signalling Pathways and Precision Medicine Strategies in Patients with Pulmonary Arterial Hypertension - £460,409. (Research Supervisors: Sheila Francis, Allan Lawrie).
- British Heart Foundation Intermediate Clinical Research Fellowship to Dr A. A. Roger Thompson – Sep 2018 to Aug 2022. The role of double-stranded RNA in pulmonary vascular remodelling - £722,505. (Research Supervisors: Ian Sabroe, Allan Lawrie).
- British Heart Foundation Project Grant – Jun 2016 to May 2019. The disrupted hepcidin/ferroportin axis and proliferative responses in pulmonary arterial hypertension - £294,534. Gregory Quinlan (PI), S. John Wort, Allan Lawrie.
For key publications see below. For a full list of publications click here.
- Hickey PM, Lawrie A & Condliffe R (2018) Circulating Protein Biomarkers in Systemic Sclerosis Related Pulmonary Arterial Hypertension: A Review of Published Data.. Frontiers in Medicine, 5. View this article in WRRO
- Gräf S, Haimel M, Bleda M, Hadinnapola C, Southgate L, Li W, Hodgson J, Liu B, Salmon RM, Southwood M, Machado RD, Martin JM, Treacy CM, Yates K, Daugherty LC, Shamardina O, Whitehorn D, Holden S, Aldred M, Bogaard HJ, Church C, Coghlan G, Condliffe R, Corris PA, Danesino C, Eyries M, Gall H, Ghio S, Ghofrani HA, Gibbs JSR, Girerd B, Houweling AC, Howard L, Humbert M, Kiely DG, Kovacs G, MacKenzie Ross RV, Moledina S, Montani D, Newnham M, Olschewski A, Olschewski H, Peacock AJ, Pepke-Zaba J, Prokopenko I, Rhodes CJ, Scelsi L, Seeger W, Soubrier F, Stein DF, Suntharalingam J, Swietlik EM, Toshner MR, Van Heel DA, Vonk Noordegraaf A, Waisfisz Q, Wharton J, Wort SJ, Ouwehand WH, Soranzo N, Lawrie A, Upton PD, Wilkins MR, Trembath RC & Morrell NW (2018) Identification of rare sequence variation underlying heritable pulmonary arterial hypertension. Nature Communications, 9(1). View this article in WRRO
- Chen K-H, Dasgupta A, Lin J, Potus F, Bonnet S, Iremonger J, Fu J, Mewburn J, Wu D, Dunham-Snary K, Theilmann AL, Jing Z-C, Hindmarch C, Ormiston ML, Lawrie A & Archer SL (2018) Epigenetic Dysregulation of the Drp1 Binding Partners MiD49 and MiD51 Increases Mitotic Mitochondrial Fission and Promotes Pulmonary Arterial Hypertension: Mechanistic and Therapeutic Implications.. Circulation. View this article in WRRO
- Renshall L, Arnold N, West L, Braithwaite A, Pickworth J, Walker R, Alfaidi M, Chamberlain J, Casbolt H, Thompson AAR, Holt C, Iglarz M, Francis S & Lawrie A (2017) Selective improvement of pulmonary arterial hypertension with a dual ET A /ET B receptors antagonist in the apolipoprotein E −/− model of PAH and atherosclerosis. Pulmonary Circulation, 8(1). View this article in WRRO
- Pickworth JA, Rothman A, Iremonger J, Casbolt H, Hopkinson K, Hickey P, Gladson S, Shay S, Morrell N, Francis S, West JD & Lawrie A (2017) Differential IL-1 signaling induced by BMPR2 deficiency drives pulmonary vascular remodeling. Pulmonary Circulation. View this article in WRRO
- Rhodes CJ, Wharton J, Ghataorhe P, Watson G, Girerd B, Howard LS, Gibbs JSR, Condliffe R, Elliot CA, Kiely DG, Simonneau G, Montani D, Sitbon O, Gall H, Schermuly RT, Ghofrani HA, Lawrie A, Humbert M & Wilkins MR (2017) Plasma proteome analysis in patients with pulmonary arterial hypertension: an observational cohort study. The Lancet Respiratory Medicine, 5(9), 717-726. View this article in WRRO
- Thompson AAR & Lawrie A (2017) Targeting Vascular Remodeling to Treat Pulmonary Arterial Hypertension. Trends in Molecular Medicine, 23(1), 31-45. View this article in WRRO
- Rothman AM, Rowlands DJ & Lawrie A (2016) miRNA-140-5p: new avenue for pulmonary arterial hypertension drug development?. Epigenomics. View this article in WRRO
- Rothman AM, Arnold N, Pickworth J, Iremonger J, Ciuclan L, Allan R, Guth-Gundel S, Southwood M, Morrell N, Thomas M, Francis S, Rowlands D & Lawrie A (2016) MicroRNA-140-5p and SMURF1 regulate pulmonary arterial hypertension. Journal of Clinical Investigation, 126(7), 2495-2508. View this article in WRRO
- Lawrie A (2014) The role of the osteoprotegerin/tumor necrosis factor related apoptosis-inducing ligand axis in the pathogenesis of pulmonary arterial hypertension. Vascular Pharmacology, 63(3), 114-117.
- Rothman AMK, Chico TJA & Lawrie A (2014) MicroRNA in pulmonary vascular disease.. Prog Mol Biol Transl Sci, 124, 43-63.
- Hameed AG, Arnold ND, Chamberlain J, Pickworth JA, Paiva C, Dawson S, Cross S, Long L, Zhao L, Morrell NW, Crossman DC, Newman CMH, Kiely DG, Francis SE & Lawrie A (2012) Inhibition of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) reverses experimental pulmonary hypertension.. J Exp Med, 209(11), 1919-1935. View this article in WRRO
- Condliffe R, Pickworth JA, Hopkinson K, Walker SJ, Hameed AG, Suntharaligam J, Soon E, Treacy C, Pepke-Zaba J, Francis SE, Crossman DC, Newman CMH, Elliot CA, Morton AC, Morrell NW, Kiely DG & Lawrie A (2012) Serum osteoprotegerin is increased and predicts survival in idiopathic pulmonary arterial hypertension.. Pulm Circ, 2(1), 21-27. View this article in WRRO
- Lawrie A, Hameed AG, Chamberlain J, Arnold N, Kennerley A, Hopkinson K, Pickworth J, Kiely DG, Crossman DC & Francis SE (2011) Paigen diet-fed apolipoprotein e knockout mice develop severe pulmonary hypertension in an interleukin-1-Dependent Manner. American Journal of Pathology, 179(4), 1693-1705. View this article in WRRO
- Lawrie A, Waterman E, Southwood M, Evans D, Suntharalingam J, Francis S, Crossman D, Croucher P, Morrell N & Newman C (2008) Evidence of a role for osteoprotegerin in the pathogenesis of pulmonary arterial hypertension.. Am J Pathol, 172(1), 256-264.
- Lawrie A, Spiekerkoetter E, Martinez EC, Ambartsumian N, Sheward WJ, MacLean MR, Harmar AJ, Schmidt AM, Lukanidin E & Rabinovitch M (2005) Interdependent serotonin transporter and receptor pathways regulate S100A4/Mts1, a gene associated with pulmonary vascular disease. Circulation Research, 97(3), 227-235.
- Newman CM, Lawrie A, Brisken AF & Cumberland DC (2001) Ultrasound gene therapy: on the road from concept to reality.. Echocardiography, 18(4), 339-347.
- Lawrie A, Brisken AF, Francis SE, Cumberland DC, Crossman DC & Newman CM (2000) Microbubble-enhanced ultrasound for vascular gene delivery.. Gene Ther, 7(23), 2023-2027.
- Lawrie A, Brisken AF, Francis SE, Tayler DI, Chamberlain J, Crossman DC, Cumberland DC & Newman CM (1999) Ultrasound enhances reporter gene expression after transfection of vascular cells in vitro.. Circulation, 99(20), 2617-2620.