The Morrell laboratory is studying the molecular mechanisms underlying pulmonary arterial hypertension. In particular our research is focussed 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 pulmonary arterial hypertension (PAH). In addition we are leading large national and international studies to identify novel genetic drivers of PAH (www.ipahcohort.com) and chronic thromboembolic pulmonary hypertension.
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. Loss of BMPR-II is associated with increased activity of other important growth factor pathways including platelet-derived growth factor (PDGF) and transforming growth factor-beta (TGF-beta) signalling. We have confirmed that inhibitors of these pathways are effective in experimental models of PAH. Recently, we discovered that bone morphogenetic protein 9 (BMP9) can reverse and prevent pulmonary arterial hypertension in preclinical models by targeting the endothelial BMPR-II/ALK1 receptor complex, suggesting a promising new treatment for patients. This research has led to a university spin-out company, MORPHOGEN-IX (www.morphogen-ix.com), to take this new treatment into the clinic.
Nick Morrell is one of the founding board members of the Pulmonary Vascular Research Institute (PVRI), the only global medical research charity fighting pulmonary vascular disease (PVD). The PVRI’s vision is to reduce the global burden of PVD within the next two decades, through global collaboration, striving for excellence in clinical care, research and education in PVD (www.pvrinstitute.org).
Evans JD, Girerd B, Montani D, Wang XJ, Galiè N, Austin ED, Elliott G, Asano K, Grünig E, Yan Y, Jing ZC, Manes A, Palazzini M, Wheeler LA, Nakayama I, Satoh T, Eichstaedt C, Hinderhofer K, Wolf M, Rosenzweig EB, Chung WK, Soubrier F, Simonneau G, Sitbon O, Gräf S, Kaptoge S, Di Angelantonio E, Humbert M, Morrell NW. BMPR2 mutations and survival in pulmonary arterial hypertension: an individual participant data meta-analysis. Lancet Respir Med. 2016;4:129-37.
Hurst LA, Dunmore BJ, Long L, Crosby A, Al-Lamki R, Deighton J, Southwood M, Yang X, Nikolic MZ, Herera B, Inman CJ, Bradley JR, Rana AA, Upton PD, Morrell NW. TNFα drives pulmonary arterial hypertension by suppressing the BMP type-II receptor and altering NOTCH signaling. Nat Commun 2017;Jan 13;8:14079 PMID 28084316
Long L, Ormiston ML, Yang X, Southwood M, Graf S, Machado RD, Mueller M, Kinzel B, Yung LM, Wilkinson JM, Moore JD, Drake KM, Aldred MA, Yu PB, Upton PB, Morrell NW. Selective enhancement of endothelial BMPR-II with BMP9 reserves pulmonary arterial hypertension. Nat Med 2015;21:777-85.
Soon E, Crosby A, Southwood M, Yang P, Tajsic T, Toshner M, Appleby S, Shanahan CM, Bloch KD, Pepke-Zaba J, Upton P, Morrell NW. Bone morphogenetic protein receptor type II deficiency and increased inflammatory cytokine production. Am J Respir Crit Care Med. 2015;192:859-72.
Mair KM, Yang XD, Long L, White K, Wallace E, Ewart MA, Docherty CK, Morrell NW*, MacLean MR*. Sex Affects BMPR-II Signalling in Pulmonary Artery Smooth Muscle Cells. Am J Respir Crit Care Med. 2015;191:693-703. *joint senior authors
Lavoie JR, Ormiston ML, Perez-Iratxeta C, Courtman DW, Jiang B, Ferrer E, Caruso P, Southwood M, Foster WS, Morrell NW*, Stewart DJ*. Proteomic analysis implicates translationally controlled tumor protein as a novel mediator of occlusive vascular remodeling in pulmonary arterial hypertension. Circulation 2014;129:2125-35. *joint senior authors
Long L, Yang X, Southwood M, Lu J, Marciniak SJ, Dunmore BJ, Morrell NW. Chloroquine prevents progression of experimental pulmonary hypertension via inhibition of autophagy and lysosomal bone morphogenetic protein type II receptor degradation. Circ Res. 2013;112:1159-70.
Yang J, Li X, Al-Lamki RS, Wu C, Weiss A, Berk J, Schermuly RT, Morrell NW. Sildenafil potentiates bone morphogenetic protein signaling in pulmonary arterial smooth muscle cells and in experimental pulmonary hypertension. Arterioscler Thromb Vasc Biol. 2013;33:34-42.
Dunmore BJ, Drake KM, Upton PD, Toshner MR, Aldred MA, Morrell NW. The lysosomal inhibitor, chloroquine, increases cell surface BMPR-II levels and restores BMP9 signalling in endothelial cells harbouring BMPR-II mutations. Hum Mol Genet. 2013;22:3667-79.