Welcome
Research
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).
Selected References
Hodgson J, Swietlik EM, Salmon RM, Hadinnapola C, Nikolic I, Wharton J, Guo J, Liley J, Haimel M, Bleda M, Southgate L, Machado RD, Martin JM, Treacy CM, Yates K, Daugherty LC, Shamardina O, Whitehorn D, Holden S, 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, Lawrie A, MacKenzie Ross RV, Moledina S, Montani D, Olschewski A, Olschewski H, Ouwehand WH, Peacock AJ, Pepke-Zaba J, Prokopenko I, Rhodes CJ, Scelsi L, Seeger W, Soubrier F, Suntharalingam J, Toshner MR, Trembath RC, Vonk Noordegraaf A, Wort SJ, Wilkins MR, Yu PB, Li W, Gräf S, Upton PD, Morrell NW. Characterization of GDF2 Mutations and Levels of BMP9 and BMP10 in Pulmonary Arterial Hypertension. Am J Respir Crit Care Med. 2019 Oct 29. doi: 10.1164/rccm.201906-1141OC. PMID: 31661308
Rhodes CJ, Batai K, Bleda M, Haimel M, Southgate L, Germain M, Pauciulo MW, Hadinnapola C, Aman J, Girerd B, Arora A, Knight J, Hanscombe KB, Karnes JH, Kaakinen M, Gall H, Ulrich A, Harbaum L, Cebola I, Ferrer J, Lutz K, Swietlik EM, Ahmad F, Amouyel P, Archer SL, Argula R, Austin ED, Badesch D, Bakshi S, Barnett C, Benza R, Bhatt N, Bogaard HJ, Burger CD, Chakinala M, Church C, Coghlan JG, Condliffe R, Corris PA, Danesino C, Debette S, Elliott CG, Elwing J, Eyries M, Fortin T, Franke A, Frantz RP, Frost A, Garcia JGN, Ghio S, Ghofrani HA, Gibbs JSR, Harley J, He H, Hill NS, Hirsch R, Houweling AC, Howard LS, Ivy D, Kiely DG, Klinger J, Kovacs G, Lahm T, Laudes M, Machado RD, MacKenzie Ross RV, Marsolo K, Martin LJ, Moledina S, Montani D, Nathan SD, Newnham M, Olschewski A, Olschewski H, Oudiz RJ, Ouwehand WH, Peacock AJ, Pepke-Zaba J, Rehman Z, Robbins I, Roden DM, Rosenzweig EB, Saydain G, Scelsi L, Schilz R, Seeger W, Shaffer CM, Simms RW, Simon M, Sitbon O, Suntharalingam J, Tang H, Tchourbanov AY, Thenappan T, Torres F, Toshner MR, Treacy CM, Vonk Noordegraaf A, Waisfisz Q, Walsworth AK, Walter RE, Wharton J, White RJ, Wilt J, Wort SJ, Yung D, Lawrie A, Humbert M, Soubrier F, Trégouët DA, Prokopenko I, Kittles R, Gräf S, Nichols WC, Trembath RC, Desai AA,Morrell NW, Wilkins MR; UK NIHR BioResource Rare Diseases Consortium; UK PAH Cohort Study Consortium; US PAH Biobank Consortium. Genetic determinants of risk in pulmonary arterial hypertension: international genome-wide association studies and meta-analysis. Lancet Respir Med. 2019 Mar;7(3):227-238. (joint senior and corresponding author). PMID: 30527956
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. Identification of rare sequence variation underlying heritable pulmonary arterial hypertension. Nat Commun. 2018;9(1):1416.PMID: 29650961
Kiskin FN, Chang CH, Huang CJZ, Kwieder B, Cheung C, Dunmore BJ, Sinha S, Morrell NW, Rana AA. Contributions of BMPR2 mutations and extrinsic factors to cellular phenotypes of pulmonary arterial hypertension revealed by iPSC modelling. Am J Respir Crit Care Med 2018;198(2):271-275. PMID: 29547009
Hadinnapola C, Bleda M, Haimel M, Screaton N, Swift A, Dorfmüller P, Preston SD, Southwood M, Hernandez-Sanchez J, Martin J, Treacy C, Yates K, Bogaard H, Church C, Coghlan G, Condliffe R, Corris PA, Gibbs S, Girerd B, Holden S, Humbert M, Kiely DG, Lawrie A, Machado R, MacKenzie Ross R, Moledina S, Montani D, Newnham M, Peacock A, Pepke-Zaba J, Rayner-Matthews P, Shamardina O, Soubrier F, Southgate L, Suntharalingam J, Toshner M, Trembath R, Vonk Noordegraaf A, Wilkins MR, Wort SJ, Wharton J; NIHR BioResource–Rare Diseases Consortium; UK National Cohort Study of Idiopathic and Heritable PAH, Gräf S,Morrell NW. Phenotypic characterization of EIF2AK4 mutation carriers in a large cohort of patients diagnosed clinically with Pulmonary Arterial Hypertension. Circulation 2017;136:2022-2033. PMID: 28972005
Caruso P, Dunmore BJ, Schlosser K, Schoors S, Dos Santos C, Perez-Iratxeta C, Lavoie JR, Zhang H, Long L, Flockton AR, Frid MG, Upton PD, D'Alessandro A, Hadinnapola C, Kiskin FN, Taha M, Hurst LA, Ormiston ML, Hata A, Stenmark KR, Carmeliet P, Stewart DJ, Morrell NW. Identification of MicroRNA-124 as a Major Regulator of Enhanced Endothelial Cell Glycolysis in Pulmonary Arterial Hypertension via PTBP1 (polypyrimidine Tract Binding Protein) and Pyruvate Kinase M2. Circulation 2017;136:2451-2467. PMID: 28971999
Dean A, Gegorc T, Docherty CK, Harvey KY, Nilsen M, Morrell NW, MacLean MR. Role of the Aryl Hydrocarbon Receptor in Sugen 5416-induced Experimental Hypertension. Am J Respir Cell Mol Biol 2018;58(3):320-330. PMID: 28956952
Mitrofan CG, Appleby SL, Nash GB, Mallat Z, Chilvers ER, Upton PD, Morrell NW. Bone morphogenetic protein 9 (BMP9) and BMP10 enhance tumor necrosis factor-α-induced monocyte recruitment to the vascular endothelium mainly via activing receptor-like kinase 2. J Biol Chem2017;292:13714-13726. PMID: 28646109
Yang, P, Read, C, Kuc RE, Buonincontri G, Southwood M, Torella R, Upton PD, Crosby A, Sawiak SJ, Carpenter TA, Glen RC, Morrell NW, Maguire JJ, Davenport AP. Elabela/Toddler is an Endogenous Agonist of the Apelin APJ receptor in the adult cardiovascular system, and exogenous administration of the peptide compensates for the downregulation of its expression in pulmonary arterial hypertension. Circulation 2017:135(12):1160-1173. PMID: 28137936
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;13;8:14079. PMID: 28084316
2016
Evans JD, Girerd B, Montani D, Wang XJ, Galie N, Austin ED, Elliott G, Asano K, Grunig 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, Graf S, Kaptoge S, Di Angelantonio E, Humber M, Morrell NW. BMPR2 mutations and survival in pulmonary arterial hypertension: an individual participant data meta-analysis. Lancet Respir Med2016;4(2):129-37. PMID: 26795434
Jiang H, Salmon RM, Upton PD, Wei Z, Lawera A, Daenport AP, Morrell NW, Li W. The prodomain-bound form of bone morphogenetic protein 10 is biologically active on endothelial cells. J Biol Chem 2016;291(6):2954-66. PMID: 26631724
Morrell NW, Bloch DB, ten Dijke P, Goumans MJ, Hata A, Smith J, Yu PB, Bloch KD. Targeting BMP signalling in cardiovascular disease and anaemia. Nat Rev Cardiol. 2016;13(2):106-20.PMID: 26461965
2015
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. PMID: 26076038
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. BMPR-II deficiency promotes pulmonary hypertension via increased inflammatory cytokine production. Am J Respir Crit Care Med2015;192(7):859-72. PMID: 26073741