Edinburgh Research Explorer

Prof John Iredale, DM, FRCP, FMedSci, FRSE

Director of MRC/UoE Centre for Inflammation Research , Visitor: Staff Other UK HEI

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Education/Academic qualification

Doctor of Medicine, University of Southampton
Tissue inhibitor of metalloproteinase 1: expression by human hepatic lipocytes and its role in liver disease.
Bachelor of Medicine, Southampton University Medical School

Professional Qualifications

Fellowship of the Royal Society of Edinburgh, FRSE
Fellowship of the Royal College of Physicians of Edinburgh, FRCP (Edin)
Fellowship of the Academy of Medical Sciences, FMedSci
Fellowship of the Royal College of Physicians of London, FRCP
Part II, MRCP Diploma, Royal College of Physicians
Part I, MRCP Diploma, Royal College of Physicians

Current Research Interests

Immune Modulation and Regulation of Inflammation, Tissue Remodelling and Regeneration, Reproductive System Inflammation, Inflammation and Cancer, Imaging Inflammation

My research in a nutshell

The Iredale group is investigating the mechanisms and processes that cause scarring. Whilst scarring of the skin following cutting or trauma is clearly of benefit, when damage, caused by a toxic injury or infection, occurs to one of our internal organs; then the scarring can disturb the structure and disrupt the organ function. The Iredale lab is using a variety of models and techniques to identify new ways of treating scarring with the aim of causing it to regress.

www.nutshell-videos.ed.ac.uk/john-iredale-fibrosis-and-internal-scarri

Research Interests

 

  • First, I have previously developed models of recovery from hepatic fibrosis in order to determine the precise mechanisms that regulate this important process.  These studies have been extended to investigate the process of matrix degradation and recovery in the context of established experimental cirrhosis.  In addition, I have an extensive research programme into the regulation of survival and apoptosis of hepatic stellate cells with specific reference to changes in cell matrix interactions and regulation by local growth factors and cytokines.  I have a major interest in investigating the role of the NGF-NGF receptor family in regulating stellate cell apoptosis and with Professor Nick Hastie FRS, the role of WT-I positive mesothelial cells in fibrosis.  In addition, I have a series of studies examining the role of collagen-I and elastin degradation in the resolution of fibrotic injury in vivo using a range of murine tools. 

 

  • Linking in with the observation that specific signals from sub-cellular matrices may mediate stellate cell proliferation, survival and apoptosis, I have developed a series of studies into the specific influence of TIMP-1 on stellate cell survival in the context of ongoing and recovering fibrosis.  This work has made the key observation that TIMPs will promote survival of stellate cells, and do so via MMP inhibition.  This specific observation has led us to further examine the mechanisms via which stellate cells respond to matrix via specific integrins.  In addition, the role of MMPs in degrading cell-cell receptors, including N-cadherin, is a major subject of investigation currently.  Additionally, working with Intermediate Fellow Henderson, we have an active programme studying the role of specific integrins in the regulation of myofibroblast function and the design of myofibroblast specific knockout.  Moreover, with Training Fellow Gordon-Walker and visiting scientist Schrader, we have established a programme examining the role of matrix stiffness and oedema as a critical innate immune system regulating myofibroblast and epithelial cell behavior during the process of fibrogenesis and its resolution and importantly in hepatic oncogenesis.

 

  • In collaboration with Professor John Savill and Dr Jeremy Duffield, we have developed a model in which macrophages can be specifically and selectively depleted during both progressive fibrosis and spontaneous recovery from fibrosis.  We are currently using this model to analyse the role of macrophages in mediating recovery from fibrosis, as a source of matrix degrading metalloproteinases and as mediators of hepatic stellate cell apoptosis. Crucially we have demonstrated that macrophages are necessary for the resolution of tissue fibrosis.  Furthermore, we are accumulating data which suggests that macrophages may be critical for both the proliferation and lineage specification of hepatic progenitor cells via the TWEAK and Wnt pathways respectively.  This important collaborative research developed by Fellows co-supervised by myself and Professor Stuart Forbes has renewed interest in macrophage specific cell therapy as a treatment for fibrotic liver disorders.

    

  • Leading on from our studies of the TIMP MMP balance, we have identified that the mammalian hormone relaxin will alter stellate cell behavior to induce a matrix degrading phenotype.  Additionally, relaxin will diminish stellate cell contractility with beneficial effect on portal hypertension.  We have extensively studied these phenomena in murine and rat models of liver fibrosis and cirrhosis and are currently in negotiation with Novartis in establishing a Phase II clinical trial of relaxin as an antifibrotic and portal hypotensive agent.

 

  • Our work on antifibrotic pathways has led to the establishment of a programme collaboratively with GSK under their DPAc  scheme to explore potential antifibrotic agents (targets confidential) and bring new molecules to the clinic.  The GSK DPAc scheme is a new and exciting initiative to link the skills and knowledge of pharma with those of academe to accelerate the development of potential compounds for orphan and other areas of health needs.

 

  • Finally, I am closely involved with the Hepatocyte Group within the Centre for Regenerative Medicine. This group, co-Directed by David Hay ( http://www.crm.ed.ac.uk/research/group/pluripotent-stem-cell-hepatocyte-development) has active programmes studying the mechanisms through which hepatocytes and hepatic endoderm can be derived from human embryonic stem cells and reprogrammed (iPSC) cells.

 

 

Research Groups

Liver Fibrosis Group Members  

  • Dr L Campana, Post-doctoral Fellow
  • Dr A Pellicoro, Post-doctoral Fellow
  • Ms R Aucott, Senior Research Assistant
  • Dr T Kendall, Wellcome Trust Intermediate Fellow
  • Dr Tim Gordon-Walker, ST2 (Ex MRC CRTF)
  • Dr Jonathan Fallowfield, Academy of Medical Sciences Intermediate Fellow
  • Dr Neil Henderson, Wellcome Trust Intermediate Fellow
  • Dr Prakash Ramachandran, ST1 (Ex WT CRTF))

Hepatocyte Group

  • David Hay (co-PI)
  • Cathy Payne (Postdoctoral Fellow)
  • Judy Fletcher (Laboratory Manager)
  • Celine Filippi (Senior Research Fellow)
  • Donna Dalgetty (Research Fellow)
  • Ruchi Sharma (Research Assistant)
  • Seb Greenhough (Technician)
  • Zara Hannoun (PhD Student)

Collaborative Activity

I work collaboratively with Professor SJ Forbes (Professor of Transplantation and Regenerative Medicine, University of Edinburgh), with whom I have established a laboratory to dissect the mechanisms underpinning fibrogenesis; fibrosis resolution and liver regeneration linking the MRC Centres for Inflammation Research and Regenerative Medicine.

                       

I have substantive collaborations with the following groups:

  • Dr S Krane (Harvard, USA):  analysis of collagen I mutant mice; analysis of MMP-13 knockout mice
  • Dr S Shapiro (Boston, USA): studies of MMP-12 knockout mice.
  • Professor DH Adams (Birmingham Liver Transplant Unit): studies of TIMP and metalloproteinase expression in explanted diseased human liver and of macrophage phenotype in human liver disease.
  • Professor J Savill and Dr J Duffield (Biogen, USA): Studies of macrophage function in hepatic fibrosis.
  • Professor T Sethi (KCL): Studies of the role of Galectin-3 in liver fibrosis and studies of the desmoplastic reaction to cancer.
  • Professor N Hastie FRS: The role of WT-1 mesothelial cells in fibrogenesis.

Research activities & awards

  1. Cirrhosis

    Activity: Talk or presentationInvited talk

  2. Developing a career in academic medicine

    Activity: Talk or presentationInvited talk

  3. Keystone Conference on tissue fibrosis: From Bench to Bedside

    Activity: Participating in or organising an eventParticipation in conference

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