Respiratory Medicine

Research

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 and Alison Condliffe’s, University Lecturer in 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, MRC Senior Clinical Fellow, 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 Trust Senior Clinical Fellow, studies the regulation of the ubiquitin proteasome system in disease and in particular, how different cellular proteins are efficiently targeted for degradation.  The group also has an interest in the regulation of hypoxic response by ubiquitination.

Angulo-Herrera I, Vadas O, Garson F, Banham-Hall E, Plagnol V, Leahy R, Baxendale H, Coulter T, Curtis J, Wu C, Perisic O, Smith D, Fiddler C, Juss J, Cilliers D, Markelj G, Farmer G, Stephens L, Hawkins P, Abinum M, Clatworthy M, Doffinger R, Chilvers ER, Cant AJ, Kumararatne D, Okkenhaug K, Williams RL, Condliffe AM*, Nejentsev S*.  Phosphoinositide 3-kinase delta activity mutation predisposes to infection and airway damage.  Science 2013; 342:866-71 (*joint senior authors)

Cowburn AS, Takeda N, Boutin AT, Kim JW, Sterling J, Nakasaki M, Southwood M, Goldrath AW, Jamora C, Nizet V, Chilvers ER*, Johnson RS*.  Differential regulatin of systemic arterial pressure by the skin: role of HIF isoforms.  PNAS 2013; 110:17570-5 (*joint corresponding authors).

Farahi N, Singh NR, Heard S, Loutsios C, Summers C, Simmonds RP, Solanki CK, Solanki K, Balan KK, Ruparelia P, Peters AM, Condliffe AM, Chilvers ER.  Use of III-Indium-labelled autologous eosinophils to establish the in vivo kinetics of human eosinophils in healthy subjects.  Blood 2012; 120:4068-71.

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; 122:1159-70.

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; 12:855-65 (*joint senior authors).

van ‘t Wout EFA, Dickens JA, van Schadewijk A, Haq I, Kwok HF, Ordóñez A, Murphy G, Stolk J, Lomas DA, Hiemstra PS, Marciniak SJ.  Increased ERK Signalling promotes inflammatory signalling in primary airway epithelial cells expressing Z α1-antitrypsin.  Hum Mol Gen 2014; 23:929-41.

Ordóñez A, Snapp EL, Tan L, Miranda E, Marciniak SJ*, Lomas DA*.  Endoplasmic reticulum ploymers impair liminal protein mobility and sensitise to cellular stress in α1-antitrypsin deficiency.  Hepatology 2013; 57:2049-60 (*joint senior authors).

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.

Nathan JA, Spinnenhirn V, Schmidtke G, Basler M, Groettrup M, Goldberg AL.  Immuno- and constitutive proteasomes do not differ in ability to degrade ubiquitinated proteins.  Cell 2013; 152:1184-94.

Nathan JA, Kim HT, Ting L, Gygi S , Goldberg AL.  Why do cell proteins linked to K63-polyubiquitin chains not associate with proteasomes? EMBO J 2013; 32:552-65.

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.

Clark AT, Islam S, King Y, Deighton J, Anagnostou K, Ewan PW.  Successful oral tolerance induction in severe peanut allergy.  Allergy 2009; 64:1218-20.

Renna M, Schaffner C, Winslow AR, Menzies FM, Peden AA, Floto RA, Rubinsztein DC.  Autophagic substrate clearance requires activity of the syntaxin-5 SNARE complex.  J Cell Sci 2011; 124:469-82.

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.

Hopkins TG, Maher E, Reid E, Marciniak SJ.  Recurrent pneumothorax. Lancet 2011; 377:1624.

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.