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.

Fairhall EA et al. (2018). Glucocorticoid-induced pancreatic-hepatic trans-differentiation in a human cell line in vitroDifferentiation 102:10-18. doi: 10.1016/j.diff.2018.05.003

Probert PM et al. (2018). Identification of a xenobiotic as a potential environmental trigger in primary biliary cholangitis. Journal of Hepatology 69(5):1123-35. doi: 10.1016/j.jhep.2018.06.027

Leitch AC et al. (2017). B-13 progenitor-derived hepatocytes (B-13/H cells) model lipid dysregulation in response to drugs and chemicals. Toxicology 386:120-132. doi: 10.1016/j.tox.2017.05.014

Meyer SK et al. (2017). Environmental Xenoestrogens Super-Activate a Variant Murine ER Beta in Cholangiocytes. Toxicological Sciences 156(1):54-71. doi: 10.1093/toxsci/kfw234

Fairhall EA et al. (2016). Pancreatic B-13 Cell Trans-Differentiation to Hepatocytes Is Dependent on Epigenetic-Regulated Changes in Gene Expression. PLoS One 11(3):e0150959. doi: 10.1371/journal.pone.0150959

Luli S et al. (2016). A new fluorescence-based optical imaging method to non-invasively monitor hepatic myofibroblasts in vivoJournal of Hepatology 65(1):75-83. doi: 10.1016/j.jhep.2016.03.021

Probert PM et al. (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

Richter M et al. (2016). Pancreatic progenitor-derived hepatocytes are viable and functional in a 3D high density bioreactor culture system. Toxicology Research 5(1):278-90. doi: 10.1039/C5TX00187K

Amer AO et al. (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 et al. (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 et al. (2015). An expandable donor-free supply of functional hepatocytes for toxicology. Toxicology Research 4:203-22. doi: 10.1039/C4TX00214H

Probert PME et al. (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 et al. (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