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Title: The role of nerve growth factor and p75 neurotrophin receptor in recovery from liver fibrosis
Author: Kendall, Timothy James
ISNI:       0000 0001 3597 070X
Awarding Body: University of Southampton
Current Institution: University of Southampton
Date of Award: 2008
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Rodent hepatic myofibroblasts are susceptible to nerve growth factor-mediated apoptosis through p75 neurotrophin receptor ligation. Hepatic myofibroblast apoptosis is critical to resolution of liver fibrosis. I show that human hepatic myofibroblasts exhibit differential responses to mature and pro-nerve growth factor/p75 neurotrophin receptor-mediated signals. Whilst mature nerve growth factor is proapoptotic, pronerve growth factor protects human hepatic myofibroblasts from serum-deprivation and cycloheximide-induced apoptosis. To define the dominant effect of p75 neurotrophin receptor-mediated events in experimental liver fibrosis I have used a mouse lacking the p75 neurotrophin receptor ligand-binding domain but expressing the intracellular domain. I show that absence of p75 neurotrophin receptor ligand-mediated signals leads to significantly retarded architectural resolution and reduced hepatic myofibroblast loss by apoptosis. Lack of the ligand-competent p75 neurotrophin receptor limits hepatocyte proliferative capacity in vivo without preventing hepatic stellate cell transdifferentiation. Moreover, in recovery from experimental liver fibrosis the fall in pro-nerve growth factor mirrors loss of hepatic myofibroblasts by apoptosis. Thus, nerve growth factor species have a differential effect on hepatic myofibroblast survival, and p75 neurotrophin receptor ligand-mediated events facilitate reduction of liver fibrosis via regulation of hepatic myofibroblast proliferation and apoptosis, and hepatocyte proliferation.
Supervisor: Iredale, John ; Benyon, Chris Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: RC Internal medicine ; QR180 Immunology ; QH426 Genetics