Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.646209
Title: The expression and function of TWEAK and FN14 in liver fibrosis
Author: Wilhelm, Annika
ISNI:       0000 0004 5361 2756
Awarding Body: University of Birmingham
Current Institution: University of Birmingham
Date of Award: 2015
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Abstract:
Liver disease is the fifth largest cause of mortality and is the only major cause of death still increasing in the UK every year. Liver disease is often associated with increased deposition of extracellular matrix, which leads to fibrosis and in many cases progresses to end stage cirrhosis. Hepatic stellate cells (HSC) are considered to be one of the main contributors to liver fibrosis. Tumour necrosis factor-like weak inducer of apoptosis (TWEAK) is a multifunctional TNF superfamily cytokine that signals through fibroblast growth factor-inducible 14 (Fnl4). TWEAK/Fnl4 signalling has been primarily associated with liver progenitor cell proliferation. In this thesis I demonstrate that expression of both Fnl4 and TWEAK were elevated in acute and chronic human liver injury, and co-localised with markers of activated HSCs. Fn14 expression was low in quiescent HSCs but was significantly induced in HSCs activated in vitro, which could be further enhanced with TGF-β. Stimulation with recombinant TWEAK induced proliferation, but not activation of HSCs. Fnl4 gene expression was also significantly upregulated in CC14 models of hepatic injury while TWEAK KO, but not Fn14 KO, mice showed significantly reduced levels of liver fibrosis following acute and chronic CC1\(_4\) injury in vivo. Furthermore, low soluble TWEAK levels in serum levels of PSC patients were an independent risk factor for death or transplantation. Overall these studies demonstrate a previously undescribed role of TWEAK in directly mediating liver fibrosis making it a potential therapeutic target in fibrotic liver disease.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.646209  DOI: Not available
Keywords: RC Internal medicine
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