Mechanism of SOX9 action as a route to diagnostic strategies in liver fibrosis
Lead Research Organisation:
University of Manchester
Department Name: Medical and Human Sciences
Abstract
Liver fibrosis is a devastating scarring reaction that results from injury to the liver (e.g. by alcohol or infection). The scarring impairs liver function. The ultimate treatment of liver fibrosis is transplantation. Unfortunately this is limited due to the high numbers of people in need of a transplant. During early stages of the disease, fibrosis is potentially reversible. Current diagnosis is through liver biopsy sampling, which is prone to error, very invasive and often left too late. For this reason, identifying novel markers of liver fibrosis at early stages of disease would be hugely beneficial. My supervisor recently identified that the factor, SOX9, regulates collagen in the cells responsible for liver fibrosis. Here, I will discover what lies more broadly downstream of SOX9 to identify novel proteins that could be used as markers of liver fibrosis. The data are anticipated to uncover new targets for diagnostic or therapeutic use in patients with liver fibrosis.
Technical Summary
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 for non-invasive (i.e. not liver biopsy) markers of fibrotic activity and disease progression. To address this, better mechanistic understanding of liver fibrosis is urgently required. My supervisor recently discovered ectopic expression of the Sry-box transcription factor, SOX9, as a novel mechanism to underlie aspects of liver fibrosis. This discovery opens up a whole new area of exciting research into the molecular genetic network in which SOX9 operates. Given SOX9‘s seemingly central role, target genes of SOX9 action have already been highlighted as candidate biomarkers for new diagnostic strategies in liver fibrosis. More broadly understanding the role of SOX9 and its targets in liver fibrosis may accelerate progress in defining novel antifibrotic drug targets.
Objectives:
1. Career development: to secure funding for clinical training fellowship as vehicle for a career as a clinician-scientist.
2. Biomedical: to identify downstream targets of SOX9 within the activated HSC to define its mechanisms of action and uncover the potential of both SOX9 and secreted proteins for diagnostic or targeted use in anti-fibrotic drug development.
Aims:
1. Investigate the influence of SOX9 and its ECM target genes in HSC proliferation and cell migration.
2. To provide evidence of the role of SOX9 in human liver fibrosis.
Design & Methodology:
The necessary techniques are already established in my supervisors‘ laboratories where my work will be conducted alongside a postdoc and postgraduate student ensuring support for me to gain additional skills rapidly in the laboratory. The clinical aspects of this project are under the supervision of Dr Neil Guha, who has expertise in non-invasive diagnosis of liver fibrosis and who has coordinated previous phenotype-biomarker studies in this area.
Potential scientific and medical outcomes:
This project will improve mechanistic understanding of ECM deposition in liver fibrosis and discover new markers of liver fibrosis with the potential to indicate disease stage. These findings would constitute major research advances for patient benefit.
Objectives:
1. Career development: to secure funding for clinical training fellowship as vehicle for a career as a clinician-scientist.
2. Biomedical: to identify downstream targets of SOX9 within the activated HSC to define its mechanisms of action and uncover the potential of both SOX9 and secreted proteins for diagnostic or targeted use in anti-fibrotic drug development.
Aims:
1. Investigate the influence of SOX9 and its ECM target genes in HSC proliferation and cell migration.
2. To provide evidence of the role of SOX9 in human liver fibrosis.
Design & Methodology:
The necessary techniques are already established in my supervisors‘ laboratories where my work will be conducted alongside a postdoc and postgraduate student ensuring support for me to gain additional skills rapidly in the laboratory. The clinical aspects of this project are under the supervision of Dr Neil Guha, who has expertise in non-invasive diagnosis of liver fibrosis and who has coordinated previous phenotype-biomarker studies in this area.
Potential scientific and medical outcomes:
This project will improve mechanistic understanding of ECM deposition in liver fibrosis and discover new markers of liver fibrosis with the potential to indicate disease stage. These findings would constitute major research advances for patient benefit.
