The Respiratory Medicine Division has research interests in granulocyte cell biology and trafficking, the genetic and molecular basis of pulmonary hypertension, the structure and function of alph1-antitrypsin and related serpins, the immunopathology of allergic diseases, phagosome maturation and bacterial killing, and the molecular mechanisms of ER stress and ubiquitination.
Edwin Chilvers, Professor of Respiratory Medicine, interests relate to granulocyte cell biology, in particular, the mechanisms underlying neutrophil priming, activation and apoptosis. The group also has an interest in P13-kinase and hypoxia signalling, neutrophil and eosinophil trafficking in vivo and primary immunodeficiency.
Nick Morrell, BHF Professor of Cardiopulmonary Medicine, is studying novel approaches to the treatment of pulmonary arterial hypertension (PAH). In particular, his laboratory has elucidated the ways in which mutations in the bone morphogenetic protein type II receptor (BMPR-II), which underlie the majority (80%) of familial PAH and 20% of idiopathic PAH, cause disease. The lab is identifying further rare genetic variation underlying PAH.
Stefan Marciniak, Professor of Respiratory Science, is interested in the cell biology of protein folding within the endoplasmic reticulum and how failure of this process manifests as disease. This is relevant to malignancy, hypoxia and conformational diseases such as alpha1-antitrypsin.
Andres Floto, Professor of Respiratory Cell Biology, works on the molecular basis of phagocytosis and phagosomal function, how these processes influence the host responses to bacterial and mycobacterial infection, and how cell-autonomous immunity can be therapeutically enhanced. The group is also utilising population-level whole genome sequencing to understand the epidemiology and pathophysiology of non-tuberculous mycobacteria.
James Nathan, Wellcome Senior Clinical Research Fellow, studies mechanisms of ubiquitin-mediated protein degradation and their relevance to respiratory disease. In particular, his group is interested in how the hypoxia response is regulated and the interplay between oxygen and nutrient sensing pathways in cells.
Ekpenyong AE, Toepfner N, Fiddler C, Herbig M, Li W, Cojoc G, Summers C, Guck J, Chilvers ER. Mechanical deformation induces depolarization of neutrophils. Science Adv 2017; 3(6): e1602536.
Cowburn AS, Crosby A, Macias D, Branco C, Colaço R, Southwood M, Crotty Alexander LE, Morrell NW, Chilvers ER, Johnson RS. Pulmonary endothelial HIF2α-arginase axis plays an essential role in the development of hypoxia pulmonary hypertension. PNAS 2016; 113(31): 8801-8806. doi: 10.1073/pnas.1602978113.
Hurst LA, Dunmore BJ, Long L, Crosby A, Al-Lamki R, Deighton J, Southwood M, Yang X, Nikolic MZ, Herrera B, Inman GJ, Bradley JR, Rana AA, Upton PD, Morrell NW. TNF? drives pulmonary arterial hypertension by suppressing the BMP type-II receptor and altering NOTCH signalling. Nat Commun. 2017 Jan 13;8:14079
Long L, Ormiston ML, Yang X, Southwood M, Gräf S, Machado RD, Mueller M, Kinzel B, Yung LM, Wilkinson JM, Moore SD, Drake KM, Aldred MA, Yu PB, Upton PD, Morrell NW. Selective enhancement of endothelial BMPR-II with BMP9 reverses pulmonary arterial hypertension. Nat Med. 2015 Jul;21(7):777-85.
van ‘t Wout F.A., van Schadewijk A., van Boxtel R., Dalton L.E., Clarke H.J., Tommassen J., Marciniak S.J.*, Hiemstra P.S.* (2015). Virulence factors of Pseudomonas aeruginosa induce both the unfolded protein and integrated stress responses in airway epithelial cells. PLoS Pathogens 11(6): e1004946. doi:10.1371/journal.ppat.1004946 *Joint senior authors
Chambers, J.E., Dalton, L.E., Clarke, H.J., Malzer, E., Dominicus, C.S., Patel, V., Moorhead, G.B.G., Ron, D., and Marciniak, S.J. (2015). Actin dynamics tune the integrated stress response by regulating eukaryotic initiation factor 2α dephosphorylation. eLIFE org/10.7554/eLife.04872.
Bryant JM, Grogono DM, Greaves D, Foweraker J, Roddick I, Inns T, Reacher M, Haworth CS, Curran MD, Harris SR, Peacock SJ, Parkhill J, Floto RA. Whole-genome sequencing to identify transmission of Mycobacterium abscessus between patients with cystic fibrosis: a retrospective cohort study. Lancet 2013; 381:1551-60.
Renna M, Schaffner C, Brown K, Shang S, Tamayo MH, Hegyi K, Grimsey NJ, Cusens D, Coulter S, Cooper J, Bowden AR, Newton SM, Kampmann B, Helm J, Jones A, Haworth CS, Basaraba RJ, DeGroote MA, Ordway DK, Rubinsztein DC, Floto RA. Azithromycin blocks autophagy and may predispose cystic fibrosis patients to mycobacterial infection. J Clin Invest 2011; 121:3554-63.
Miles AL*, Burr SP*, Grice GL, and Nathan JA. The vacuolar-ATPase complex and assembly factors, TMEM199 and CCDC115, control HIF1α prolyl hydroxylation by regulating cellular iron levels. eLife http://dx.doi.org/10.7554/eLife.22693 (2017). *Equal contribution.
McGovern NN, Cowburn AS, Walmsley SR, Thompson R, Summers C, Willcocks LC, Whyte MKB, Condliffe AM, Chilvers ER. Hypoxia inhibits respiratory burst activity and killing of staphylococcus aureus in human neutrophils. J Immunol 2011; 186:453-63.
Walmsley SR, Chilvers ER, Vaughan K, Marriott H, Thompson R, McGrath E, Shaw G, Pugh CW, Ratcliffe PJ, Taylor C, Sabroe I, Dockrell D, Johnson RS, Maxwell PH, Carmeliet P, Whyte M. Prolyl hydroxylase PHD3 is essential for hypoxic regulation of neutrophilic inflammation. J Clin Invest 2011; 121:1053-63.
Yang J, Li X, Al-Lamki RS, Southwood M, Zhao J, Lever AM, Grimminger F, Schermuly RT, Morrell NW. Smad-dependent and smad-independent induction of id1 by prostacyclin analogues inhibits proliferation of pulmonary artery smooth muscle cells in vitro and in vivo. Circ Res 2010; 107:252-62.
Durrington HJ, Upton PD, Hoer S, Boname J, Dunmore BJ, Yang J, Crilley TK, Butler LM, Blackbourn DJ, Nash GB, Lehner PJ, Morrell NW. Identification of a lysosomal pathway regulating degradation of the bone morphogenetic protein receptor type II. J Biol Chem 2010; 285:37641-9.
Renna M, Schaffner C, Brown K, Shang S, Henao Tamayo M, Hegyi K, Grimsey N, Cusens D, Coulter S, Cooper J, Bowden A R, Newton S, Kampmannm B, Helm J, Jones A, Haworth H, Basaraba, RJ, DeGroote M, Ordway DJ, Rubinsztein DC, Floto RA. Azithromycin blocks autophagy and may predispose to mycobacterial infection. J Clin Invest 2011 121:3554-63.
Malzer E, Daly ML, Moloney A, Sendall TJ, Thomas SL, Ryder E, Ryoo HD, Crowther DC, Lomas DA, Marciniak SJ. Impaired tissue growth is mediated by checkpoint kinase 1 (CHK1) in the integrated stress response. J Cell Sci 2010; 123:2892-900.