| Summary: | The work presented in this thesis aims to understand the role of the Sry-box transcription factor (SOX9) in liver fibrosis as a route to novel diagnostic strategies for the disease. Fibrosis of the liver is a major cause of morbidity and mortality in the UK characterised by progressive accumulation of extracellular matrix (ECM) proteins. End-stage disease is treated by transplantation, but this is limited by donor numbers. Although potentially reversible if diagnosed early, current methods of diagnosis are invasive and prone to sampling error. There is a critical need to improve current methods or develop novel strategies to determine fibrotic activity and disease progression. To address this, better mechanistic understanding of liver fibrosis is urgently required. My supervisor (Dr Piper Hanley) previously discovered ectopic expression of SOX9 as a novel mechanism to underlie aspects of liver fibrosis. This discovery allowed me to investigate the molecular genetic network in which SOX9 operates. Given SOX9’s seemingly central role, I identified novel target genes of SOX9 action, some of which have already been highlighted as candidate biomarkers, for new diagnostic strategies in liver fibrosis. Moreover, investigating the expression of SOX9 directly during liver fibrosis in human biopsy samples highlighted the factor as a prognostic marker of the disease. This thesis focussed on four key research areas: Identification of the inflammatory glycoprotein Osteopontin (OPN) as a direct target of SOX9. In addition to OPN, identification of four other downstream SOX9 targets as potential biomarkers of liver fibrosis severity. SOX9 expression in liver biopsies is described and quantified, highlighting its role as a new method to assess liver fibrosis progression. This work is being patented as a novel prognostic test in liver fibrosis. Finally, the role of SOX9 mediating ECM through inhibition of collagenases (e.g. MMP13) is described. Taken together, these data place SOX9 as a key mediator of liver fibrosis. However, translation of novel SOX9 targets as serum biomarkers of fibrosis and SOX9 as a marker of disease progression have ramifications on clinical practice, in particular assessing liver fibrosis progression.
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