BHF Professor of Cardiopulmonary Medicine
Research Director, National Pulmonary Hypertension Service, Papworth Hospital
Departments and Institutes
Genetics, epidemiology and cell biology of pulmonary hypertension
We study the molecular mechanisms underlying pulmonary arterial hypertension (PAH). In particular, our research focuses on how mutations in the bone morphogenetic protein type II receptor (BMPR-II), a receptor member of the transforming growth factor-beta superfamily, cause familial PAH.
Our research is revealing how BMPR-II mutation leads to dysfunctional signalling, gene transcription and vascular cell biology. This work has also revealed a broader role for BMPR-II in angiogenesis, inflammation, iron metabolism and innate immunity.
Our research has suggested new approaches to the rescue of BMPR-II deficiency. These include gene therapy, enhanced BMPR-II transcription and the demonstration that BMPR-II is rapidly degraded by the lysosome. Inhibition of the lysosomal turnover of BMPR-II with agents such as chloroquine increase cell surface BMPR-II and are effective in experimental models of pulmonary hypertension.
Using structural biology approaches (Dr Wei Li) we are defining the molecular interaction between bone morphogenetic protein ligands and receptors. The BMP9/BMPR-II/ALK-1 complex is the focus of these studies. The aim is to develop designer peptides or small molecules that enhance BMPR-II signalling specifically in the vasculature.
We are using induced pluripotent stem cells derived from patients with gain and loss of function in BMP pathways (Dr Amer Rana) to understand the impact of BMPs on heart and blood vessel development and function.
Our research is demonstrating the broader role of the BMP pathway in vascular disease and providing new insights into the pathogenesis of other conditions, including atherosclerosis.
National Pulmonary Hypertension Service
Our group has close links with the National Pulmonary Hypertension Service at Papworth Hospital, where Professor Morrell is the Research Director. We are employing next generation sequencing in our cohort of patients to define the genetic architecture of PAH, which may reveal further tractable targets for therapy. Our clinical research team has identified novel biomarkers for predicting survival in PAH patients and we are assessing better ways to measure response to therapy in patients using imaging techniques (MRI/CT) and physiological measurements of exercise and gas exchange. We have an active translational research programme at Papworth where new targets identified from basic science studies can be trialed for the first time in patients with severe PAH.
genetics ; cell biology ; molecular biology ; pulmonary hypertension ; stem cells ; right heart failure
Most recent publications are listed on PubMed.
Endothelial Apoptosis in Pulmonary Hypertension Is Controlled by a microRNA/Programmed Cell Death 4/Caspase-3 Axis. White K, Dempsie Y, Caruso P, Wallace E, McDonald RA, Stevens H, Hatley ME, Van Rooij E, Morrell NW, Maclean MR, Baker AH. Hypertension. 2014 Apr 14. PMID: 24732886
Proteomic Analysis Implicates Translationally Controlled Tumor Protein as a Novel Mediator of Occlusive Vascular Remodeling in Pulmonary Arterial Hypertension. Lavoie JR, Ormiston M, Perez-Iratxeta C, Courtman DW, Jiang B, Ferrer E, Caruso P, Southwood M, Foster WS, Morrell NW, Stewart DJ. Circulation. 2014 Mar 21. PMID: 24657995
Transcript analysis reveals a specific HOX signature associated with positional identity of human endothelial cells. Toshner M, Dunmore BJ, McKinney EF, Southwood M, Caruso P, Upton PD, Waters JP, Ormiston ML, Skepper JN, Nash G, Rana AA, Morrell NW. PLoS One. 2014 Mar 20;9(3):e91334. doi: 10.1371/journal.pone.0091334. eCollection 2014. PMID: 24651450 Free PMC Article
Future breakthroughs in the genetics of pulmonary arterial hypertension. Morrell NW. Pulm Circ. 2013 Sep;3(3):451-3. doi: 10.1086/674305. PMID: 24618532
An official American Thoracic Society Statement: pulmonary hypertension phenotypes. Dweik RA, Rounds S, Erzurum SC, Archer S, Fagan K, Hassoun PM, Hill NS, Humbert M, Kawut SM, Krowka M, Michelakis E, Morrell NW, Stenmark K, Tuder RM, Newman J; ATS Committee on Pulmonary Hypertension Phenotypes. Am J Respir Crit Care Med. 2014 Feb 1;189(3):345-55. doi: 10.1164/rccm.201311-1954ST. PMID: 24484330
Relevant issues in the pathology and pathobiology of pulmonary hypertension. Tuder RM, Archer SL, Dorfmüller P, Erzurum SC, Guignabert C, Michelakis E, Rabinovitch M, Schermuly R, Stenmark KR, Morrell NW. J Am Coll Cardiol. 2013 Dec 24;62(25 Suppl):D4-12. doi: 10.1016/j.jacc.2013.10.025. Review. PMID: 24355640
Evidence for the involvement of type I interferon in pulmonary arterial hypertension. George PM, Oliver E, Dorfmuller P, Dubois OD, Reed DM, Kirkby NS, Mohamed NA, Perros F, Antigny F, Fadel E, Schreiber BE, Holmes AM, Southwood M, Hagan G, Wort SJ, Bartlett N, Morrell NW, Coghlan JG, Humbert M, Zhao L, Mitchell JA. Circ Res. 2014 Feb 14;114(4):677-88. doi: 10.1161/CIRCRESAHA.114.302221. PMID: 24334027 Free PMC Article
Treatment with anti-gremlin 1 antibody ameliorates chronic hypoxia/SU5416-induced pulmonary arterial hypertension in mice. Ciuclan L, Sheppard K, Dong L, Sutton D, Duggan N, Hussey M, Simmons J, Morrell NW, Jarai G, Edwards M, Dubois G, Thomas M, Van Heeke G, England K. Am J Pathol. 2013 Nov;183(5):1461-73. doi: 10.1016/j.ajpath.2013.07.017. PMID: 24160323
MicroRNA-124 controls the proliferative, migratory, and inflammatory phenotype of pulmonary vascular fibroblasts. Wang D, Zhang H, Li M, Frid MG, Flockton AR, McKeon BA, Yeager ME, Fini MA, Morrell NW, Pullamsetti SS, Velegala S, Seeger W, McKinsey TA, Sucharov CC, Stenmark KR. Circ Res. 2014 Jan 3;114(1):67-78. doi: 10.1161/CIRCRESAHA.114.301633. PMID: 24122720
BMP9 mutations cause a vascular-anomaly syndrome with phenotypic overlap with hereditary hemorrhagic telangiectasia. Wooderchak-Donahue WL, McDonald J, O'Fallon B, Upton PD, Li W, Roman BL, Young S, Plant P, Fülöp GT, Langa C, Morrell NW, Botella LM, Bernabeu C, Stevenson DA, Runo JR, Bayrak-Toydemir P. Am J Hum Genet. 2013 Sep 5;93(3):530-7. doi: 10.1016/j.ajhg.2013.07.004. PMID: 23972370 Free PMC Article