XClose

Centre for Respiratory Biology

Menu

Research

Professor David Lomas

Professor David Lomas-

Antitrypsin deficiency and the serpinopathies: disease mechanisms and therapeutic interventions

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.

image A1AT Polymers

image A1AT Structure

image A1AT inclusion bodies

Key Publications (2017-)

Group members

Professor David Sattelle

Professor David Sattelle

 

Molecular Neurobiology

We are interested in the mechanisms underlying neurodegenerative and neuromuscular diseases and in exploring new routes to therapy. We address these goals using the powerful genetic model organism Caenorhabditis elegans with its transgenic lines, mutants as well as access to forward and reverse genetics. Current interests include Alzheimer's disease, Fronto-Temporal Dementia, Spinal Muscular Atrophy and Congenital Myasthenia. We have developed high-throughput, automated, phenotyping, which permits library-scale, in vivo, drug screening of our disease models with the aim of finding new or re-profiled drugs to ameliorate symptoms of these devastating diseases.
We also study human ligand-gated ion channels as targets for drugs aimed at ameliorating symptoms of nervous system disorders. Invertebrate ligand-gated ion channels are investigated as targets for drugs / chemicals with benefits for animal health and agriculture.

Selected publications:

  • Sleigh J.N., Buckingham S.D., Esmaeili, B.E., Viswanathan M., Westlund B.M. and Sattelle, D.B. (2011) A novel Caenorhabditis elegans allele smn-1(cb131), mimicking a mild form of spinal muscular atrophy, provides a convenient drug screening platform highlighting new and pre-approved compounds. Hum Mol Genet 20, 245-260.
  • Werren J.H. et al. (2010) Functional and evolutionary insights from the genomes of three parasitoid Nasonia species. Science 327, 343-348.
  • Briese, M., Esmaeili, B., Fraboulet, S., Burt, E., Christodoulou, S.C., Towers, P.R., Davies, K.E. and Sattelle, D.B. (2009). Deletion of smn-1, the Caenorhabditis elegans ortholog of the spinal muscular atrophy gene, results in locomotor dysfunction and reduced lifespan.  Hum Mol Genet. 18, 97-104.
  • Jones A.K., Buckingham S.D., Papadaki M., Yokota M., Sattelle B.M., Matsuda K. and Sattelle D.B. (2009) Splice-variant- and stage-specific RNA editing of the Drosophila GABA receptor modulates agonist potency. J Neuroscience 29, 4287-4292.
  • Richards, S. et al (2008) The genome of the model beetle and pest Tribolium castaneum (2008) Nature 452, 949- 955.
  • Weinstock G. et al (2006) Insights into social insects from the genome of the honeybee Apis mellifera Nature 443: 931-949.
  • Jones, A.K., Buckingham, S.D., and Sattelle, D.B (2005) Chemistry-to-gene screens in Caenorhabditis elegans. Nature Rev. Drug Discov. 4, 321-330.

Group members

Dr Freddie Partridge
Mrs Marina Nick
Dr Narinder Heyer-Chauhan
 

Respiratory Biology is part of the Division of Medicine