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Published: Oct 20, 2014 9:38:58 AM
Published: Oct 1, 2014 4:15:14 PM
Published: Oct 1, 2014 3:40:18 PM
Antitrypsin deficiency and the serpinopathies: disease mechanisms and therapeutic interventions
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My research group has worked for over 20 years on understanding the pathogenesis of a1-antitrypsin deficiency. We were the first to show that mutant Z a1-antitrypsin forms polymers within the liver and that these comprise the PAS positive inclusions that are associated with disease. We showed that the same process also underlies the deficiency of the Siiyama, Mmalton, S and I variants and more recently have described the a1-antitrypsin Kings mutant that also forms polymers in association with hepatic inclusions and profound plasma deficiency.
We have dissected the pathway of polymerisation using crystallography, biochemistry, biophysical analysis and have generated monoclonal antibodies to the pathological polymers associated with disease. We have also probed the formation of polymers by developing cell, fly and animals models of disease. Our understanding of the process of polymerisation has allowed us to advance new paradigms for both the liver and lung disease associated with a1-antitrypsin deficiency.
The lung disease results from a process that is more complex than solely plasma deficiency. Z a1-antitrypsin is present in the lungs from passive diffusion and is also produced locally by bronchial epithelial cells and macrophages.
We have shown that this protein can spontaneously form polymers within the lung and that these polymers are chemotactic for neutrophils in vitro and in animal models of disease. Thus the lung disease is a combination of deficiency of a major protease inhibitor, inactivation of this inhibitor by the process of polymerisation and the conversion to a conformation that acts as a pro-inflammatory stimulus to recruit and retain neutrophils within the interstitium.
We have shown that the process of polymerisation also occurs in mutants of other members of the serpin superfamily in association with disease. Specifically mutants of antithrombin, C1-inhibitor and a1-antichymotrypsin form polymers that result in plasma deficiency in association with thrombosis, angioedema and emphysema respectively. This process is most strikingly displayed in mutants of neuroserpin in association with the autosomal, inclusion body dementia that we have called familial encephalopathy with neuroserpin inclusion bodies or FENIB. We have grouped these conditions together as a new class of disease that we have called the serpinopathies.
My long-term aim is to develop strategies to block polymerisation in vitro and in vivo and so provide a cure for a1-antitrypsin deficiency and the serpinopathies.
- 2013 - Professor of Medicine and Dean of the Faculty of Medical Sciences. University College London
- 1998 - 2013 Professor of Respiratory Biology, University of Cambridge and Honorary Consultant Physician, Addenbrooke�s and Papworth Hospitals.
- 2007 - Fellow of the Higher Education Academy
- 2004 - ScD, Trinity College, University of Cambridge.
- 2001 - Fellow of the Academy of Medical Sciences
- 1995-1998 Lecturer in Medicine, University of Cambridge
- 1997 FRCP (London)
- 1993-1995 MRC Clinician Scientist/Honorary Senior Registrar in Respiratory Medicine, University of Cambridge
- 1990 - 1993 MRC Training Fellow, Department of Haematology, University of Cambridge
- 1993 PhD, Trinity College, University of Cambridge.
- 1988 PhD, MRCP (UK)
- 1985 Bachelor of Medicine, Bachelor of Surgery (Honours), University of Nottingham
- 1983 Bachelor of Medical Sciences (Honours), University of Nottingham
Excess ERK signalling promotes inflammatory signalling in primary airway epithelium expressing Z a1-antitrypsin. E.F.A. van 't Wout, J.A. Dickens, A. van Schadewijk, I. Haq , H-F. Kwok, A. Ordonez, G. Murphy, J. Stolk, D.A. Lomas*, P.S. Hiemstra* and S.J. Marciniak* (*joint senior authors). Hum. Mol. Genet. 2013; in press
Sterol metabolism regulates neuroserpin polymer degradation in the absence of the unfolded protein response inteh dementia FENIB. B.D Roussel, T.M Newton, E. Malzer, N. Simecek, I. Haq, S.E Thomas, M.L Burr, P.J Lehner, D.C. Crowther, S.J Marciniak and D.A Lomas. . Hum. Mol. Genet. 2013; In press.
Endoplasmic reticulum polymers impair luminal protein mobility and sensitise to cellular stress in a1-antitrypsin deficiency. A. Ordonez, E.L. Snapp, L. Tan, E. Miranda, S.J. Marciniak*, D.A. Lomas*. (*joint senior authors). Hepatology 2013; 57:2049-60.
Prevalence and risk factors for liver involvement in individuals with PiZZ-related lung disease. M.F. Dawwas, S.E. Davies, W.J.H. Griffiths, D.A. Lomas and G.J.M. Alexander. Am. J. Resp. Crit. Care Med. 2013; 187: 502-508.
Implications of endoplasmic reticulum dysfunction in neurological disease. B.D. Roussel, A.J. Kruppa, D.C. Crowther, D.A. Lomas, S.J. Marciniak. Lancet Neurology. 2013; 12: 105-118.
Blood fibrinogen as a biomarker of chronic obstructive pulmonary disease. A. Duvoix*, J.A. Dickens*, I. Haq, D. Mannino, B.E. Miller, R. Tal-Singer and D.A. Lomas (joint first* authors). Thorax 2013; 68: 670-676.
Determinants of presence and progression of emphysema in COPD. H.O Coxson, A. Dirksen, L.D. Edwards, J.C. Yates, A. Agusti, P. Bakke, P.M.A. Calverley, B. Celli, C. Crim, D.A. Lomas, W. MacNee, B.E. Miller, S.I. Rennard, E.K. Silverman, R. Tal-Singer, E. Wouters, J. Vestbo for the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) Investigators. Lancet Respiratory Medicine. 2013; 1: 129-136.
Further publication information can be viewed at https://iris.ucl.ac.uk/iris/browse/profile?upi=DALOM96