Applying the 3Rs to liver fibrosis research

This project aims to reduce and refine the use of mice in two aspects of liver fibrosis research. Bile-duct ligation, a common surgical technique for generating periportal liver fibrosis in animals, often gives rise to a high level of mortality. By using the chemical methapyrilene to cause periportal liver damage instead, the severity classification of the procedure under the Animals (Scientific Procedures) Act 1986 (ASPA) could be refined, from 'substantial' to 'moderate'. In addition, the project will investigate realtime imaging of the progression of liver fibrosis, using antibodies to detect myofibroblasts (the fibrosis-causing cells of the liver). This will allow repeated readouts from the same animal to be taken, thus reducing the numbers of animals used.

Probert PM, Palmer JM, Alhusainy W, Amer AO, Rietjens IM, White SA, Jones DE, Wright MC (2016).  Progenitor-derived hepatocyte-like (B-13/H) cells metabolise 1'-hydroxyestragole to a genotoxic species via a SULT2B1-dependent mechanism.  Toxicology Letters 243:98-110. doi: 10.1016/j.toxlet.2015.12.010

Amer AO, Probert PM, Dunn M, Knight M, Vallance AE, Flecknell PA, Oakley F, Cameron I, White SA, Blain PG, Wright MC (2015).  Sustained isoprostane E2 elevation, inflammation and fibrosis after acute ischaemia-reperfusion injury are reduced by pregnane X receptor activation.  PLoS One 10(8): e0136173. doi: 10.1371/journal.pone.0136173

Richter M, Fairhall EA, Hoffmann SA, Tröbs S, Knöspel F, Probert PME, Oakley F, Stroux A, Wright MC, Zeilinger K (2015).  Pancreatic progenitor-derived hepatocytes are viable and functional in a 3D high density culture system.  Toxicology Research 5:278-90. doi: 10.1039/C5TX00187K

Probert PME, Meyer SK, Alsaeedi F, Axon AA, Fairhall EA, Wallace K, Charles M, Oakley F, Jowsey PA, Blaina PG, Wright MC (2015).  An expandable donor-free supply of functional hepatocytes for toxicology. Toxicology Research 4:203-22. doi: 10.1039/C4TX00214H

Probert PME, Ebrahimkhani MR, Oakley F, Mann J, Burt AD, Manna DA, Wright MC (2014).  A reversible model for periportal fibrosis and a refined alternative to bile duct ligation.  Toxicology Research 3:98-109. doi: 10.1039/C3TX50069A

Probert PM, Chung GW, Cockell SJ, Agius L, Mosesso P, White SA, Oakley F, Brown CD, Wright MC (2014).  Utility of B-13 progenitor-derived hepatocytes in hepatotoxicity and genotoxicity studies.  Toxicological Sciences 137(2):350-70. doi: 10.1093/toxsci/kft258

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PhD Studentship

Status:

Closed

Principal investigator

Professor Matthew Wright

Institution

Newcastle University

Co-Investigator

Professor Derek Mann
Dr Fiona Oakley

Grant reference number

NC/K500471/1

Award date:

Oct 2010 - Sep 2014

Grant amount

£120,000