David A Lomas

Summary

Affiliation: University of Cambridge
Country: UK

Publications

  1. ncbi Hypersensitive mousetraps, alpha1-antitrypsin deficiency and dementia
    D A Lomas
    Respiratory Medicine Unit, Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust MRC Building, Hills Road, Cambridge CB2 2XY, U K
    Biochem Soc Trans 30:89-92. 2002
  2. ncbi Polymerisation underlies alpha1-antitrypsin deficiency, dementia and other serpinopathies
    David A Lomas
    Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust MRC Building, Hills Road, Cambridge CB2 2XY, United Kingdom
    Front Biosci 9:2873-91. 2004
  3. pmc Structural dynamics associated with intermediate formation in an archetypal conformational disease
    Mun Peak Nyon
    Institute of Structural and Molecular Biology, Department of Biological Sciences, Birkbeck College, London, WC1E 7HX, UK
    Structure 20:504-12. 2012
  4. pmc Stem cell-based therapy for α₁-antitrypsin deficiency
    S Tamir Rashid
    Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust MRC Building, Hills Road, Cambridge CB2 0XY, UK
    Stem Cell Res Ther 3:4. 2012
  5. doi An oral inhibitor of p38 MAP kinase reduces plasma fibrinogen in patients with chronic obstructive pulmonary disease
    David A Lomas
    Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust MRC Building, Hills Road, Cambridge, CB2 0XY, UK
    J Clin Pharmacol 52:416-24. 2012
  6. pmc Characterisation of COPD heterogeneity in the ECLIPSE cohort
    Alvar Agusti
    Thorax Institute, Hospital Clinic, IDIBAPS, Universitat de Barcelona, Spain
    Respir Res 11:122. 2010
  7. pmc Association between neuroserpin and molecular markers of brain damage in patients with acute ischemic stroke
    Raquel Rodríguez-González
    Clinical Neuroscience Research Laboratory, Department of Neurology, Hospital Clinico Universitario, University of Santiago de Compostela, Santiago de Compostela, Spain
    J Transl Med 9:58. 2011
  8. pmc Chronic obstructive pulmonary disease. Introduction
    D A Lomas
    Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, UK
    Thorax 57:735. 2002
  9. ncbi Serpinopathies and the conformational dementias
    David A Lomas
    Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust MRC Building, Hills Road, Cambridge CB2 2XY, UK
    Nat Rev Genet 3:759-68. 2002
  10. pmc Alpha1-antitrypsin polymerization and the serpinopathies: pathobiology and prospects for therapy
    David A Lomas
    Respiratory Medicine Unit, Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Cambridge, United Kingdom
    J Clin Invest 110:1585-90. 2002

Detail Information

Publications104 found, 100 shown here

  1. ncbi Hypersensitive mousetraps, alpha1-antitrypsin deficiency and dementia
    D A Lomas
    Respiratory Medicine Unit, Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust MRC Building, Hills Road, Cambridge CB2 2XY, U K
    Biochem Soc Trans 30:89-92. 2002
    ..This must now be achieved in vivo if we are to treat the associated clinical syndromes...
  2. ncbi Polymerisation underlies alpha1-antitrypsin deficiency, dementia and other serpinopathies
    David A Lomas
    Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust MRC Building, Hills Road, Cambridge CB2 2XY, United Kingdom
    Front Biosci 9:2873-91. 2004
    ..We have grouped these conditions together as the serpinopathies as recognition of their common pathophysiology provides a platform to develop strategies to treat the associated clinical syndromes...
  3. pmc Structural dynamics associated with intermediate formation in an archetypal conformational disease
    Mun Peak Nyon
    Institute of Structural and Molecular Biology, Department of Biological Sciences, Birkbeck College, London, WC1E 7HX, UK
    Structure 20:504-12. 2012
    ..Conformational disease intermediates may best be defined using powerful but minimally perturbing techniques, mild disease mutants, and physiological conditions...
  4. pmc Stem cell-based therapy for α₁-antitrypsin deficiency
    S Tamir Rashid
    Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust MRC Building, Hills Road, Cambridge CB2 0XY, UK
    Stem Cell Res Ther 3:4. 2012
    ..Several important safety concerns will need to be addressed before this can be translated into clinical practice...
  5. doi An oral inhibitor of p38 MAP kinase reduces plasma fibrinogen in patients with chronic obstructive pulmonary disease
    David A Lomas
    Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust MRC Building, Hills Road, Cambridge, CB2 0XY, UK
    J Clin Pharmacol 52:416-24. 2012
    ..87; 95% confidence interval, 0.82-0.93; P < .001). It was concluded that oral losmapimod significantly reduced plasma fibrinogen in patients with COPD...
  6. pmc Characterisation of COPD heterogeneity in the ECLIPSE cohort
    Alvar Agusti
    Thorax Institute, Hospital Clinic, IDIBAPS, Universitat de Barcelona, Spain
    Respir Res 11:122. 2010
    ..Chronic obstructive pulmonary disease (COPD) is a complex condition with pulmonary and extra-pulmonary manifestations. This study describes the heterogeneity of COPD in a large and well characterised and controlled COPD cohort (ECLIPSE)...
  7. pmc Association between neuroserpin and molecular markers of brain damage in patients with acute ischemic stroke
    Raquel Rodríguez-González
    Clinical Neuroscience Research Laboratory, Department of Neurology, Hospital Clinico Universitario, University of Santiago de Compostela, Santiago de Compostela, Spain
    J Transl Med 9:58. 2011
    ..Our aim was to study whether neuroserpin serum levels could be associated to biomarkers of excitotoxicity, inflammation and blood brain barrier disruption...
  8. pmc Chronic obstructive pulmonary disease. Introduction
    D A Lomas
    Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, UK
    Thorax 57:735. 2002
    ....
  9. ncbi Serpinopathies and the conformational dementias
    David A Lomas
    Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust MRC Building, Hills Road, Cambridge CB2 2XY, UK
    Nat Rev Genet 3:759-68. 2002
    ....
  10. pmc Alpha1-antitrypsin polymerization and the serpinopathies: pathobiology and prospects for therapy
    David A Lomas
    Respiratory Medicine Unit, Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Cambridge, United Kingdom
    J Clin Invest 110:1585-90. 2002
  11. pmc Alpha1-antitrypsin deficiency. 4: Molecular pathophysiology
    D A Lomas
    Respiratory Medicine Unit, Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Cambridge CB2 2XY, UK
    Thorax 59:529-35. 2004
    ..The current goals are to determine the cellular response to polymeric alpha(1)-antitrypsin and to develop therapeutic strategies to block polymerisation in vivo...
  12. ncbi Genetic predisposition to chronic obstructive pulmonary disease: advances in alpha1-antitrypsin deficiency and the serpinopathies
    David A Lomas
    University of Cambridge, Cambridge Institute for Medical Research
    Clin Med 7:446-7. 2007
  13. pmc Parker B. Francis lectureship. Antitrypsin deficiency, the serpinopathies, and chronic obstructive pulmonary disease
    David A Lomas
    Department of Medicine, Cambridge Institute for Medical Research, Wellcome Trust MRC Building, University of Cambridge, Hills Road, Cambridge CB2 2XY, UK
    Proc Am Thorac Soc 3:499-501. 2006
    ..This conformational transition may explain the excessive inflammation that underlies the progressive emphysema associated with Z alpha(1)-antitrypsin deficiency...
  14. doi Serum surfactant protein D is steroid sensitive and associated with exacerbations of COPD
    D A Lomas
    Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust MRC Building, Hills Road, Cambridge, CB2 0XY, UK
    Eur Respir J 34:95-102. 2009
    ..It may represent an intermediate measure for the development of novel anti-inflammatory agents...
  15. pmc The genetics of chronic obstructive pulmonary disease
    D A Lomas
    Department of Medicine, University of Cambridge, Cambridge, UK
    Respir Res 2:20-6. 2001
    ..Many candidate genes have been assessed, but the data are often conflicting. We review the genetic factors that predispose smokers to COPD and highlight the future role of genomic scans in identifying novel susceptibility genes...
  16. ncbi Loop-sheet polymerization: the mechanism of alpha1-antitrypsin deficiency
    D A Lomas
    Respiratory Medicine Unit, Department of Medicine, University of Cambridge, Wellcome Trust Centre for Molecular Mechanisms in Disease, Cambridge Institute for Medical Research, UK
    Respir Med 94:S3-6. 2000
    ..Understanding this mechanism of polymerization allows rational drug design to block the protein-protein linkage and so ameliorate the associated disease...
  17. ncbi The selective advantage of alpha1-antitrypsin deficiency
    David A Lomas
    Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust MRC Building, Hills Road, Cambridge, CB2 2XY UK
    Am J Respir Crit Care Med 173:1072-7. 2006
    ....
  18. doi Evaluation of serum CC-16 as a biomarker for COPD in the ECLIPSE cohort
    D A Lomas
    Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust MRC Building, Hills Road, Cambridge CB2 0XY, UK
    Thorax 63:1058-63. 2008
    ..Circulating levels of Clara cell secretory protein-16 (CC-16) have been linked to Clara cell toxicity. It has therefore been suggested that this protein may be a useful marker of chronic obstructive pulmonary disease (COPD)...
  19. ncbi Molecular mousetraps, alpha1-antitrypsin deficiency and the serpinopathies
    David A Lomas
    Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research
    Clin Med 5:249-57. 2005
    ..In view of the common mechanism underlying these conditions, we have grouped them together as the serpinopathies...
  20. ncbi Molecular mousetraps and the serpinopathies
    D A Lomas
    Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust MRC Building, Hills Road, Cambridge CB2 2XY, UK
    Biochem Soc Trans 33:321-30. 2005
    ..We review in this paper the molecular and structural basis of the serpinopathies and show how this has allowed the development of specific agents to block the polymerization that underlies disease...
  21. doi The serpinopathies studying serpin polymerization in vivo
    James A Irving
    Department of Medicine, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom
    Methods Enzymol 501:421-66. 2011
    ..We describe here the biochemical techniques, monoclonal antibodies, cell biology, animal models, and stem cell technology that are useful to characterize the serpin polymers that form in vivo...
  22. pmc The intracellular accumulation of polymeric neuroserpin explains the severity of the dementia FENIB
    Elena Miranda
    Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust MRC Building, Hills Road, Cambridge CB2 0XY, UK
    Hum Mol Genet 17:1527-39. 2008
    ..Moreover, mutant neuroserpin causes locomotor deficits in the fly allowing us to demonstrate a direct link between polymer accumulation and neuronal toxicity...
  23. ncbi Latent S49P neuroserpin forms polymers in the dementia familial encephalopathy with neuroserpin inclusion bodies
    Maki Onda
    Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust MRC Building, Hills Road, Cambridge CB2 2XY, United Kingdom
    J Biol Chem 280:13735-41. 2005
    ..These data provide an alternative method for the inactivation of mutant neuroserpin as a proteinase inhibitor in FENIB and demonstrate a second pathway for the formation of intracellular polymers in association with disease...
  24. pmc Endoplasmic reticulum-associated degradation (ERAD) and autophagy cooperate to degrade polymerogenic mutant serpins
    Heike Kroeger
    Department of Medicine, Cambridge Institute for Medical Research, Wellcome Trust MRC Building, University of Cambridge, Cambridge CB2 0XY, United Kingdom
    J Biol Chem 284:22793-802. 2009
    ..The significance of these findings to the treatment of serpinopathies is discussed...
  25. ncbi Sugar and alcohol molecules provide a therapeutic strategy for the serpinopathies that cause dementia and cirrhosis
    Lynda K Sharp
    Department of Medicine, University of Cambridge, UK
    FEBS J 273:2540-52. 2006
    ..These data demonstrate that sugar and alcohol molecules can reduce the polymerization of serpin mutants that cause disease, possibly by binding to and stabilizing beta-sheet A...
  26. pmc Iron promotes the toxicity of amyloid beta peptide by impeding its ordered aggregation
    Beinan Liu
    Department of Medicine, Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust Medical Research Council Building, Hills Road, Cambridge CB2 0XY, United Kingdom
    J Biol Chem 286:4248-56. 2011
    ..These data support the hypothesis that iron delays the formation of well ordered aggregates of Aβ and so promotes its toxicity in Alzheimer disease...
  27. ncbi Neuroserpin Portland (Ser52Arg) is trapped as an inactive intermediate that rapidly forms polymers: implications for the epilepsy seen in the dementia FENIB
    Didier Belorgey
    Cambridge Institute for Medical Research, Department of Medicine, University of Cambridge, UK
    Eur J Biochem 271:3360-7. 2004
    ..Moreover the inactivity of the mutant may result in uncontrolled activity of tissue plasminogen activator, and so explain the epileptic seizures seen in individuals with more severe forms of the disease...
  28. ncbi Neuroserpin binds Abeta and is a neuroprotective component of amyloid plaques in Alzheimer disease
    Kerri J Kinghorn
    Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust Medical Research Council Building, Hills Road, Cambridge CB2 2XY, United Kingdom
    J Biol Chem 281:29268-77. 2006
    ..Taken together, these data show that neuroserpin interacts with Abeta(1-42) to form off-pathway non-toxic oligomers and so protects neurons in Alzheimer disease...
  29. pmc Coordinate regulation of eIF2α phosphorylation by PPP1R15 and GCN2 is required during Drosophila development
    Elke Malzer
    Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research CIMR, Wellcome Trust MRC Building, Hills Road, Cambridge CB2 0XY, UK
    J Cell Sci 126:1406-15. 2013
    ..Moreover, we show that its expression is necessary for embryonic and larval development and that this is to oppose the inhibitory effects of GCN2 on anabolic growth...
  30. doi Targeted metabolomics identifies perturbations in amino acid metabolism that sub-classify patients with COPD
    Baljit K Ubhi
    Department of Biochemistry and the Cambridge Systems Biology Centre, University of Cambridge, UK
    Mol Biosyst 8:3125-33. 2012
    ..New methods were developed and validated to evaluate small molecules as potential diagnostic tools in patients with COPD, COPD related cachexia and cancer related cachexia...
  31. ncbi Targeting a surface cavity of alpha 1-antitrypsin to prevent conformational disease
    Helen Parfrey
    Respiratory Medicine Unit, Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust MRC Building, Hills Road, Cambridge CB2 2XY, United Kingdom
    J Biol Chem 278:33060-6. 2003
    ..These results demonstrate the importance of this cavity as a site for drug design to ameliorate polymerization and prevent the associated conformational disease...
  32. pmc p53 and translation attenuation regulate distinct cell cycle checkpoints during endoplasmic reticulum (ER) stress
    Sally E Thomas
    Department of Medicine and Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust Medical Research Council Building, Hills Road, Cambridge CB2 0XY, United Kingdom
    J Biol Chem 288:7606-17. 2013
    ..We propose that cell cycle regulation in response to ER stress comprises redundant pathways invoked sequentially first to impair G(2) progression prior to ultimate G(1) arrest...
  33. doi A novel monoclonal antibody to characterize pathogenic polymers in liver disease associated with alpha1-antitrypsin deficiency
    Elena Miranda
    Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust Medical Research Council Building, Cambridge, UK
    Hepatology 52:1078-88. 2010
    ..This antibody also recognized polymers formed by the Siiyama (Ser53Phe) and Brescia (Gly225Arg) mutants, which also mediate their effects on the shutter region of alpha(1)-antitrypsin...
  34. pmc Small molecules block the polymerization of Z alpha1-antitrypsin and increase the clearance of intracellular aggregates
    Meera Mallya
    Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust MRC Building, Cambridge CB2 2XY, UK
    J Med Chem 50:5357-63. 2007
    ..Identifying small molecules provides a novel therapy for the treatment of liver disease associated with the Z allele of alpha1-antitrypsin...
  35. pmc Expression in drosophila of tandem amyloid β peptides provides insights into links between aggregation and neurotoxicity
    Elena Speretta
    Department of Genetics, University of Cambridge, Downing Street, Cambridge CB2 3EH, United Kingdom
    J Biol Chem 287:20748-54. 2012
    ....
  36. pmc Neuroserpin polymers activate NF-kappaB by a calcium signaling pathway that is independent of the unfolded protein response
    Mark J Davies
    Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust Medical Research Council Building, Hills Road, Cambridge CB2 0XY, United Kingdom
    J Biol Chem 284:18202-9. 2009
    ..Our results provide strong support for the endoplasmic reticulum overload response being independent of the unfolded protein response...
  37. ncbi Inhibitory activity of the Drosophila melanogaster serpin Necrotic is dependent on lysine residues in the D-helix
    Andrew S Robertson
    Department of Genetics, University of Cambridge, Cambridge CB2 3EH, United Kingdom
    J Biol Chem 281:26437-43. 2006
    ..These data demonstrate a critical role for basic residues within the D-helix (and lysine 68 in particular) in the inhibitory mechanism of the serpin Necrotic...
  38. doi alpha1-Antitrypsin deficiency, chronic obstructive pulmonary disease and the serpinopathies
    Ugo I Ekeowa
    Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust MRC Building, Cambridge CB2 0XY, U K
    Clin Sci (Lond) 116:837-50. 2009
    ....
  39. doi Characterisation of serpin polymers in vitro and in vivo
    Didier Belorgey
    Dept of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust MRC Building, Hills Road, Cambridge CB2 0XY, UK
    Methods 53:255-66. 2011
    ..The characterisation of the pathological polymers requires heating of the folded protein or alternatively the assessment of ordered polymers from cell and animal models of disease or from the tissues of humans who carry the mutation...
  40. pmc Probing neuroserpin polymerization and interaction with amyloid-beta peptides using single molecule fluorescence
    Albert Chiou
    Department of Chemistry, University of Cambridge, Cambridge, United Kingdom
    Biophys J 97:2306-15. 2009
    ..The A beta(1-40) is displaced from the complex so that it acts as a catalyst and is not incorporated into neuroserpin polymers...
  41. ncbi Mutant Neuroserpin (S49P) that causes familial encephalopathy with neuroserpin inclusion bodies is a poor proteinase inhibitor and readily forms polymers in vitro
    Didier Belorgey
    Respiratory Medicine Unit and Neurology Unit, Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust Medical Research Council Building, United Kingdom
    J Biol Chem 277:17367-73. 2002
    ..These findings provide strong support for the role of neuroserpin polymerization in the formation of the intraneuronal inclusions that are characteristic of FENIB...
  42. ncbi Mutants of neuroserpin that cause dementia accumulate as polymers within the endoplasmic reticulum
    Elena Miranda
    Departments of Medicine and Clinical Biochemistry, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust Medical Research Council Building, Hills Road, Cambridge CB2 2XY, United Kingdom
    J Biol Chem 279:28283-91. 2004
    ....
  43. doi Suppression of Aβ toxicity by puromycin-sensitive aminopeptidase is independent of its proteolytic activity
    Antonina J Kruppa
    Cambridge Institute for Medical Research, Wellcome Trust MRC Building, Hills Road, Cambridge CB2 0XY, UK Department of Medicine, University of Cambridge, Box 157, Addenbrooke s Hospital, Hills Road, Cambridge CB2 2QQ, UK Department of Genetics, University of Cambridge, Downing Street, Cambridge CB2 3EH, UK
    Biochim Biophys Acta 1832:2115-26. 2013
    ..However PSA's promotion of autophagosome fusion with lysosomes required proteolytic activity and so its effect on autophagy is not identical to its protection against Aβ toxicity. ..
  44. pmc Defining the mechanism of polymerization in the serpinopathies
    Ugo I Ekeowa
    Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust Medical Research Council Building, Cambridge CB2 0XY, United Kingdom
    Proc Natl Acad Sci U S A 107:17146-51. 2010
    ..Understanding the structure of the serpin polymer is essential for rational drug design strategies that aim to block polymerization and so treat α(1)-antitrypsin deficiency and the serpinopathies...
  45. ncbi Inhibiting polymerization: new therapeutic strategies for Z alpha1-antitrypsin-related emphysema
    Helen Parfrey
    Division of Respiratory Medicine, Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, MRC Wellcome Trust Building, Hills Road, Cambridge CB2 2XY, UK
    Am J Respir Cell Mol Biol 31:133-9. 2004
    ..Thus, it raises the novel prospect of ameliorating both the cirrhosis and the emphysema associated with Z-AT...
  46. pmc Sequestration of the Abeta peptide prevents toxicity and promotes degradation in vivo
    Leila M Luheshi
    Department of Chemistry, University of Cambridge, Cambridge, United Kingdom
    PLoS Biol 8:e1000334. 2010
    ....
  47. ncbi Practical genetics: alpha-1-antitrypsin deficiency and the serpinopathies
    Damian C Crowther
    1Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust MRC Building, Hills Road, Cambridge CB2 2XY, UK
    Eur J Hum Genet 12:167-72. 2004
    ..We review here the genetic and molecular basis and clinical features of alpha(1)-antitrypsin deficiency, and show how this provides a platform to understand the other serpinopathies...
  48. pmc COPD association and repeatability of blood biomarkers in the ECLIPSE cohort
    Jennifer A Dickens
    Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Cambridge, UK
    Respir Res 12:146. 2011
    ..A panel of putative blood biomarkers was assessed in a subgroup of the Evaluation of COPD Longitudinally to Identify Surrogate Endpoints (ECLIPSE) cohort...
  49. pmc Detection of early locomotor abnormalities in a Drosophila model of Alzheimer's disease
    Thomas R Jahn
    Department of Genetics, University of Cambridge, UK Department of Chemistry, University of Cambridge, UK
    J Neurosci Methods 197:186-9. 2011
    ..The approach can be widely applied to different disease models in a number of model organisms...
  50. pmc Protein misfolding and the serpinopathies
    Didier Belorgey
    Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Cambridge, United Kingdom
    Prion 1:15-20. 2007
    ..The common mechanism of polymerization has allowed us to group these conditions together as a novel class of disease, the serpinopathies...
  51. pmc pH-dependent stability of neuroserpin is mediated by histidines 119 and 138; implications for the control of beta-sheet A and polymerization
    Didier Belorgey
    Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Cambridge CB2 0XY, United Kingdom
    Protein Sci 19:220-8. 2010
    ..This mechanism is likely to have evolved to protect neuroserpin from the acidic environment of the secretory granules...
  52. ncbi Nucleation of alpha 1-antichymotrypsin polymerization
    Damian C Crowther
    Neurology Unit, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust MRC Building, Hills Road, Cambridge, CB2 2XY, United Kingdom
    Biochemistry 42:2355-63. 2003
    ..This mechanism is analogous to the fibrillization of the Abeta(1-42) peptide and may be important in the deposition of alpha(1)-antichymotrypsin in the plaques of Alzheimer's disease...
  53. pmc Intrinsic determinants of neurotoxic aggregate formation by the amyloid beta peptide
    Ann Christin Brorsson
    Department of Chemistry, University of Cambridge, Cambridge, United Kingdom
    Biophys J 98:1677-84. 2010
    ....
  54. ncbi Characterization of the necrotic protein that regulates the Toll-mediated immune response in Drosophila
    Andrew S Robertson
    Department of Genetics, University of Cambridge, Downing Street, Cambridge CB2 3EH, United Kingdom
    J Biol Chem 278:6175-80. 2003
    ..These data show that Necrotic is likely to inhibit a wide range of proteases in Drosophila and that Nec has the specificity requirements to act as the physiological inhibitor of Persephone in vivo...
  55. doi Intracellular serpins, firewalls and tissue necrosis
    Stefan J Marciniak
    Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust MRC Building, Hills Road, Cambridge CB2 0XY, UK
    Trends Cell Biol 18:45-7. 2008
    ..We discuss how mutant serpins cause disease either through polymerization or now, perhaps, by unleashing necrosis...
  56. ncbi Alpha1-antitrypsin deficiency--a model for conformational diseases
    Robin W Carrell
    Department of Hematology, University of Cambridge, Cambridge Institute for Medical Research, Cambridge, United Kingdom
    N Engl J Med 346:45-53. 2002
  57. ncbi 6-mer peptide selectively anneals to a pathogenic serpin conformation and blocks polymerization. Implications for the prevention of Z alpha(1)-antitrypsin-related cirrhosis
    Ravi Mahadeva
    Respiratory Medicine Unit, Department of Medicine, University of Cambridge, Cambridge CB2 2XY, United Kingdom
    J Biol Chem 277:6771-4. 2002
    ..Furthermore they demonstrate how a conformational disease process can be selectively inhibited with a small peptide...
  58. pmc Blood fibrinogen as a biomarker of chronic obstructive pulmonary disease
    Annelyse Duvoix
    Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust MRC Building, Cambridge, UK
    Thorax 68:670-6. 2013
    ..Here we review the current clinical evidence linking fibrinogen with COPD and its associated co-morbidities and discuss its potential utility as a biomarker...
  59. doi Endoplasmic reticulum dysfunction in neurological disease
    Benoit D Roussel
    Department of Medicine, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK
    Lancet Neurol 12:105-18. 2013
    ..By targeting components of these signalling responses, amelioration of their toxic effects and so the treatment of a range of neurodegenerative disorders might become possible...
  60. pmc Polymers of Z alpha1-antitrypsin co-localize with neutrophils in emphysematous alveoli and are chemotactic in vivo
    Ravi Mahadeva
    Department of Medicine, Box 157, Level 5, Addenbrookes NHS Trust, Hills Road, Cambridge CB2 2QQ, UK
    Am J Pathol 166:377-86. 2005
    ..These findings may also explain the progression of emphysema in some individuals despite alpha(1)-antitrypsin replacement therapy...
  61. doi Unravelling the twists and turns of the serpinopathies
    Benoit D Roussel
    Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust MRC Building, Cambridge, UK
    FEBS J 278:3859-67. 2011
    ..These include the use of small molecules to block polymerization, stimulation of autophagy to clear inclusions and stem cell technology to correct the underlying molecular defect...
  62. pmc Impaired tissue growth is mediated by checkpoint kinase 1 (CHK1) in the integrated stress response
    Elke Malzer
    Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research CIMR, Wellcome Trust MRC Building, Hills Road, Cambridge, CB2 0XY, UK
    J Cell Sci 123:2892-900. 2010
    ..PERK was both necessary and sufficient for CHK1 activation. These findings indicate that non-genotoxic misfolded protein stress accesses DNA-damage-induced cell cycle checkpoints to couple the ISR to cell cycle arrest...
  63. doi The iFly tracking system for an automated locomotor and behavioural analysis of Drosophila melanogaster
    Kai J Kohlhoff
    Department of Chemistry, University of Cambridge, Cambridge, UK
    Integr Biol (Camb) 3:755-60. 2011
    ....
  64. pmc Endoplasmic reticulum polymers impair luminal protein mobility and sensitize to cellular stress in alpha1-antitrypsin deficiency
    Adriana Ordonez
    Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Cambridge, UK
    Hepatology 57:2049-60. 2013
    ..Conclusion: Changes in protein diffusion provide an explanation for the cellular consequences of ER protein overload in mutants that cause inclusion body formation and α1AT deficiency...
  65. pmc Modeling inherited metabolic disorders of the liver using human induced pluripotent stem cells
    S Tamir Rashid
    Laboratory for Regenerative Medicine, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK
    J Clin Invest 120:3127-36. 2010
    ..These patient-derived hepatocytes demonstrate that it is possible to model diseases whose phenotypes are caused by pathological dysregulation of key processes within adult cells...
  66. pmc Disease-related amyloidogenic variants of human lysozyme trigger the unfolded protein response and disturb eye development in Drosophila melanogaster
    Janet R Kumita
    Department of Chemistry, University of Cambridge, Cambridge, UK
    FASEB J 26:192-202. 2012
    ....
  67. ncbi Drosophila necrotic mutations mirror disease-associated variants of human serpins
    Clare Green
    Department of Genetics, University of Cambridge, Downing Street, Cambridge CB2 3EH, UK
    Development 130:1473-8. 2003
    ..Taken together, these data establish Drosophila as a powerful system to study serpin polymerization in vivo...
  68. ncbi Alpha(1)-antitrypsin deficiency, liver disease and emphysema
    Helen Parfrey
    Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust MRC Building, Hills Road, Cambridge CB2 2XY, UK
    Int J Biochem Cell Biol 35:1009-14. 2003
    ..We show how this knowledge has led to the development of novel therapeutic approaches to treat this condition...
  69. pmc Fenton chemistry and oxidative stress mediate the toxicity of the beta-amyloid peptide in a Drosophila model of Alzheimer's disease
    Thomas Rival
    Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust MRC Building, Cambridge, UK
    Eur J Neurosci 29:1335-47. 2009
    ....
  70. doi α(1)-antitrypsin deficiency and inflammation
    Ugo I Ekeowa
    Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust MRC Building, Cambridge, CB2 0XY, UK
    Expert Rev Clin Immunol 7:243-52. 2011
    ..Therapeutic strategies are now being developed to block the aberrant conformational transitions of mutant α(1)-antitrypsin and so treat the associated disease...
  71. ncbi How small peptides block and reverse serpin polymerisation
    Aiwu Zhou
    Departments of Haematology and Medicine, University of Cambridge, Cambridge Institute for Medical Research, Hills Road, Cambridge CB2 2XY, UK
    J Mol Biol 342:931-41. 2004
    ..This is demonstrated here with a tetrapeptide that preferentially blocks the polymerisation of a pathologically unstable serpin commonly present in people of European descent...
  72. doi Metabolic profiling detects biomarkers of protein degradation in COPD patients
    Baljit K Ubhi
    Dept of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, Cambridge, UK
    Eur Respir J 40:345-55. 2012
    ..Increased protein turnover occurred in all COPD patients with increased protein degradation in individuals with emphysema and cachexia...
  73. doi Evaluation of full-length, cleaved and nitrosylated serum surfactant protein D as biomarkers for COPD
    Annelyse Duvoix
    Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust MRC Building, Cambridge, UK
    COPD 8:79-95. 2011
    ..Moreover, levels of serum nitrosylated-SP-D did not correlate with serum level of SP-D or any clinical phenotype of COPD. The measurement of modified SP-D is of limited value in characterising individuals with COPD...
  74. ncbi Polymers of alpha(1)-antitrypsin are chemotactic for human neutrophils: a new paradigm for the pathogenesis of emphysema
    Jasvir S Parmar
    Respiratory Medicine Division, Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke s and Papworth Hospitals, United Kingdom
    Am J Respir Cell Mol Biol 26:723-30. 2002
    ....
  75. pmc Systematic in vivo analysis of the intrinsic determinants of amyloid Beta pathogenicity
    Leila M Luheshi
    Department of Chemistry, University of Cambridge, Cambridge, United Kingdom
    PLoS Biol 5:e290. 2007
    ....
  76. ncbi A Drosophila model of Alzheimer's disease
    Damian C Crowther
    Department of Medicine, University of Cambridge, CIMR Wellcome Trust, Cambridge, United Kingdom CB2 2XY
    Methods Enzymol 412:234-55. 2006
    ..Phenotypes may be modulated by changes in gene expression as part of a genetic screen or by potential therapeutic compounds...
  77. ncbi Therapeutic targets from a Drosophila model of Alzheimer's disease
    Damian C Crowther
    Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust MRC Building, Hills Road, Cambridge CB2 2XY, UK
    Curr Opin Pharmacol 4:513-6. 2004
    ..Several groups are now using the power and speed of genetic screens in the fly to accelerate the discovery of novel therapeutic agents...
  78. doi Airway wall thickening and emphysema show independent familial aggregation in chronic obstructive pulmonary disease
    Bipen D Patel
    Department of Medicine, University of Cambridge, Cambridge, UK
    Am J Respir Crit Care Med 178:500-5. 2008
    ..It is unclear whether airway wall thickening and emphysema make independent contributions to airflow limitation in chronic obstructive pulmonary disease (COPD) and whether these phenotypes cluster within families...
  79. doi The molecular aetiology of the serpinopathies
    Mark J Davies
    Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust MRC Building, Hills Road, Cambridge CB2 0XY, United Kingdom
    Int J Biochem Cell Biol 40:1273-86. 2008
    ..We review here the structural basis of the serpinopathies and discuss how the ordered accumulation of polymers causes cell death...
  80. ncbi Alpha-1-antitrypsin deficiency, the serpinopathies and conformational disease
    J S Parmar
    Cambridge Institute for Medical Research
    J R Coll Physicians Lond 34:295-300. 2000
    ..The interaction provides a useful paradigm for other 'conformational diseases' such as Huntington's disease, Creutzfeldt-Jakob disease and the amyloidoses...
  81. ncbi Intraneuronal Abeta, non-amyloid aggregates and neurodegeneration in a Drosophila model of Alzheimer's disease
    D C Crowther
    Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust MRC Building, Hills Road, Cambridge CB2 2XY, UK
    Neuroscience 132:123-35. 2005
    ..Moreover it provides a platform to dissect the pathways of neurodegeneration in Alzheimer's disease and to develop novel therapeutic interventions...
  82. ncbi Neuroserpin: a serpin to think about
    E Miranda
    Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust Medical Research Council Building, Hills Road, Cambridge CB2 2XY, United Kingdom
    Cell Mol Life Sci 63:709-22. 2006
    ..We review here the role of neuroserpin and other proteinase inhibitors in brain development, function and disease...
  83. ncbi A kinetic mechanism for the polymerization of alpha1-antitrypsin
    T R Dafforn
    Department of Haematology, Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust Medical Research Council Building, Hills Road, Cambridge CB2 2XY, United Kingdom
    J Biol Chem 274:9548-55. 1999
    ..Taken together, these data allow us to propose a kinetic mechanism for alpha1-antitrypsin polymer formation that involves the generation of an unstable intermediate, which can form polymers or generate latent protein...
  84. pmc Heteropolymerization of S, I, and Z alpha1-antitrypsin and liver cirrhosis
    R Mahadeva
    Respiratory Medicine Unit, Department of Medicine and Department of Haematology, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust MRC Building, Hills Road, Cambridge CB2 2XY, United Kingdom
    J Clin Invest 103:999-1006. 1999
    ..Taken together, these results indicate that not only may mixed variants form heteropolymers, but that this can causally lead to the development of cirrhosis...
  85. ncbi Wild-type alpha 1-antitrypsin is in the canonical inhibitory conformation
    P R Elliott
    Department of Medicine, University of Cambridge, UK
    J Mol Biol 275:419-25. 1998
    ..This pocket may provide a target for rational drug design to prevent the formation of polymers and the associated plasma deficiency, liver cirrhosis and emphysema...
  86. ncbi Polymerization of plasminogen activator inhibitor-1
    A Zhou
    Department of Haematology, University of Cambridge, Wellcome Trust Centre for Molecular Mechanisms in Disease, Cambridge Institute for Medical Research, Wellcome Trust MRC Building, Hills Road, Cambridge, CB2 2XY, United Kingdom
    J Biol Chem 276:9115-22. 2001
    ..Glycosylated native and latent PAI-1 can also form polymers under similar conditions, which may be of in vivo importance in the low pH environment of the platelet...
  87. pmc Association of alpha(1)-antichymotrypsin deficiency with milder lung disease in patients with cystic fibrosis
    R Mahadeva
    Respiratory Medicine Unit, Department of Medicine and Department of Haematology, University of Cambridge, Wellcome Trust Centre for Molecular Mechanisms in Disease, Cambridge Institute for Medical Research, Cambridge CB2 2XY, UK
    Thorax 56:53-8. 2001
    ....
  88. ncbi Inhibitory conformation of the reactive loop of alpha 1-antitrypsin
    P R Elliott
    Department of Haematology, University of Cambridge, UK
    Nat Struct Biol 3:676-81. 1996
    ..The beta-pleated strand conformation of the loop also accounts for the polymerization of the serpins in disease and for their association with other beta-sheet structures, most notably the beta-amyloid of Alzheimer's disease...
  89. pmc Childhood smoking is an independent risk factor for obstructive airways disease in women
    B D Patel
    Department of Public Health and Primary Care, Institute of Public Health, University Forvie Site, Robinson Way, Cambridge CB2 2SR, UK
    Thorax 59:682-6. 2004
    ..To assess whether starting to smoke in childhood increases the risk of obstructive airways disease (OAD) in adult life...
  90. doi What can naturally occurring mutations tell us about the pathogenesis of COPD?
    S J Marciniak
    Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust MRC Building, Hills Road, Cambridge CB2 0XY, UK
    Thorax 64:359-64. 2009
    ..Only then will we have new insights into the pathways that underlie this common condition...
  91. pmc Inactive conformation of the serpin alpha(1)-antichymotrypsin indicates two-stage insertion of the reactive loop: implications for inhibitory function and conformational disease
    B Gooptu
    Respiratory Medicine Unit, Department of Medicine University of Cambridge, United Kingdom
    Proc Natl Acad Sci U S A 97:67-72. 2000
    ....
  92. pmc Topography of a 2.0 A structure of alpha1-antitrypsin reveals targets for rational drug design to prevent conformational disease
    P R Elliott
    Department of Medicine, University of Cambridge, The Wellcome Trust Centre for Molecular Mechanisms in Disease, Cambridge Institute for Medical Research, United Kingdom
    Protein Sci 9:1274-81. 2000
    ..This structure allows us to define five cavities that are potential targets for rational drug design to develop agents that will prevent conformational transitions and ameliorate the associated disease...
  93. ncbi Siblings of patients with severe chronic obstructive pulmonary disease have a significant risk of airflow obstruction
    S C McCloskey
    Respiratory Medicine Unit, Department of Medicine, University of Cambridge, The Wellcome Trust Centre for Molecular Mechanisms in Disease, Cambridge Institute for Medical Research, Cambridge, United Kingdom
    Am J Respir Crit Care Med 164:1419-24. 2001
    ..39 (95% confidence interval, 2.49 to 11.67) when compared with matched control subjects. Taken together these results demonstrate a significant familial risk of airflow obstruction in smoking siblings of patients with severe COPD...
  94. ncbi Implications for function and therapy of a 2.9 A structure of binary-complexed antithrombin
    R Skinner
    Department of Haematology, University of Cambridge, Hills Road, Cambridge, CB2 2QH, UK
    J Mol Biol 283:9-14. 1998
    ....
  95. pmc Smoking related COPD and facial wrinkling: is there a common susceptibility?
    B D Patel
    Department of Public Health and Primary Care, University of Cambridge, UK
    Thorax 61:568-571. 2006
    ..We have tested the hypothesis that there is a common susceptibility for the development of COPD and facial wrinkling in cigarette smokers...
  96. pmc Dietary antioxidants and asthma in adults
    B D Patel
    Department of Public Health and Primary Care, Institute of Public Health, Cambridge, UK
    Thorax 61:388-93. 2006
    ..Several antioxidant nutrients have been reported to be inversely associated with asthma. A study was undertaken to assess the independent associations of these nutrients with asthma in adults...
  97. pmc The effect of sequence variations within the coding region of the C1 inhibitor gene on disease expression and protein function in families with hereditary angio-oedema
    S A Cumming
    Respiratory Medicine Unit, Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust MRC Building, Hills Road, Cambridge CB2 2XY, UK
    J Med Genet 40:e114. 2003
  98. ncbi Promiscuous beta-strand interactions and the conformational diseases
    Michelle K M Chow
    Department of Biochemistry and Molecular Biology, Monash University, VIC 3800, Australia
    Curr Med Chem 11:491-9. 2004
    ..We will discuss the successes and pitfalls of such approaches to demonstrate how similar approaches may be applied to any misfolding protein...
  99. ncbi Differential detection of PAS-positive inclusions formed by the Z, Siiyama, and Mmalton variants of alpha1-antitrypsin
    Sabina Janciauskiene
    Department of Medicine, University Hospital Malmo, Malmo, Sweden
    Hepatology 40:1203-10. 2004
    ..In conclusion, the ATZ11 monoclonal antibody detects Z alpha(1)-antitrypsin in hepatic inclusions by detecting a neoepitope that is specific to the polymeric conformer and that is localized close to residue 342...
  100. pmc Polymers and inflammation: disease mechanisms of the serpinopathies
    Bibek Gooptu
    School of Crystallography, Birkbeck College, University of London, London WC1E 7HX, England, UK
    J Exp Med 205:1529-34. 2008
    ..Here, we describe how these three mechanisms can be integrated into a new model of the pathogenesis of emphysema caused by mutations in the serpin alpha1-antitrypsin...
  101. ncbi Association between conformational mutations in neuroserpin and onset and severity of dementia
    Richard L Davis
    Department of Pathology, Upstate Medical University, Syracuse, NY, USA
    Lancet 359:2242-7. 2002
    ..To clarify this issue, we investigated five families with typical neuroserpin inclusion bodies but with various neurological manifestations...