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).
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, and PDGF inhibition has now proven beneficial in patients with PAH.
Ormiston ML, Chang C, Long LL, Soon E, Jones D, Machado R, Treacy C, Toshner MR, Campbell K, Riding A, Southwood M, Pepke-Zaba J, Exley A, Trembath RC, Colucci F, Wills M, Trowsdale J, Morrell NW. Impaired natural killer cell phenotype and function in idiopathic and heritable pulmonary arterial hypertension. Circulation. 2012;126(9):1099-109.
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 Jan;33(1):34-42.
Geti I, Ormiston ML, Rouhani F, Toshner M, Movassagh M, Nichols J, Mansfield W, Southwood M, Bradley A, Rana AA, Vallier L, Morrell NW. A practical and efficient cellular substrate for the generation of induced pluripotent stem cells from adults: blood-derived endothelial progenitor cells. Stem Cells Transl Med. 2012 Dec;1(12):855-65. doi: 10.5966/sctm.2012-0093. Epub 2012 Nov 29.