Download Understanding the link between transglutaminase 2 and the

Understanding the link between transglutaminase 2 and the induction of fibrosis in cystic
fibrosis.
Supervisors Prof Martin Griffin. Dr Lindsay Marshall and Dr Russell Collighan
http://www1.aston.ac.uk/lhs/staff/az-index/griffinm/
http://www1.aston.ac.uk/lhs/staff/az-index/marshall/
http://www1.aston.ac.uk/lhs/staff/az-index/collighr/
Aim: to determine the role of transglutaminase 2 (tgase2) in cystic fibrosis (CF) and its
relationship to the expression and activation of the fibrotic cytokine TGF Beta 1 and the
development of fibrosis
Background
Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance
regulator protein (CFTR); by far the commonest mutation is the deletion of F508 (F508). CF is a
disease characterised by fibrosis, although this fact has been eclipsed in recent decades by the
focus on CFTR’s function as a Cl- channel. In CF, fibrosis of unknown aetiology occurs in the
pancreas, liver and bowel.(REF 1) None of the treatments hitherto applied to CF have been
found to ameliorate this fibrosis. Transglutaminase 2 (tgase2) is predominantly thought of as a
Ca 2+ activated enzyme that post translationally modifies proteins via -γ-glutamyl-lysine
crosslinks often leading to the formation of high molecular weight complexes. (REF2) Normally
this activity is tightly regulated since its dysfunction is associated with many diseases particularly
the onset of fibrosis (REF 3) where its ability to increase the deposition of matrix proteins either
directly via their crosslinking or indirectly via activation of the fibrotic cytokine TGF Beta 1 is well
documented.
Work to be undertaken
In a recent publication (Maiuri etal REF 4 ) it was reported that increases in the inflammatory
cytokine NF- B could detected in CF cells.The hypothesis by reference to the literature and also
our own work is that this incease in NF- B is tgase 2 mediated due to deregulation of enzyme
activity in the CF cells. However to date no confirmed data for this observation has been
reported.
The main experimental objective of this project is to confirm using specific tgase 2 inhibitors and
siRNA that any increase in NF- B observed in CF cells is tgase2 mediated to investigate that this
increase in NF- B can be linked to the induction of fibrosis by a tgase2 mediated pathway
involving TGF-1. The project will also investigate the involvement of tTgase 2 in the expression
and deposition of extracellular matrix proteins in CF cells thus providing the final link in
establishing tTgase 2 as a key mediator of fibrosis in this dehabilitating disease
We will also establish whether specific site directed inhibitors of tTgase 2 synthesised in our
laboratories are capable of inhibiting this response with a view to their potential use in CF
therapy.
References
1. Cystis fibrosis. Ratjen F. and Doring G(2003 ) Lancet 361, 681-689.
2. Transglutaminases, Nature’s biological Glues (2004)Biochem. J. Reviews, 368:377- 396.Griffin. M.
Casadio, R. and Bergamini, C.M.
3.Transglutaminase inhibition ameliorates tissue scarring and fibrosis: experience in a kidney model
Johnson T.S., Fisher M. ,Haylor J L., Hau Z., Skill N J., Jones R., Saint R., Coutts I., El Nahas A M.,
Griffin M. J. American Society Neph (2008) 14 (8), 2052-2062.
4. Tissue transglutaminase activation modulates inflammation in cystic fibrosis via PAPRgamma down
regulation J Immun. (2008) 180, 7697-7705.