Investigating the role of SOX9 in liver fibrosis

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. For this reason, identifying effective anti-fibrotic treatments at early stages of disease would be hugely beneficial. To achieve this better understanding of how the scar forms is needed. Although progress has been made in this area, unfortunately there are still no approved anti fibrotic treatments. To tackle this problem, I have identified SOX9 as a core factor responsible for mediating large components of scar formation. It is now essential to determine whether loss of SOX9 can be used as a means of reversing scar formation and ultimately fibrosis in the liver. This project will develop models to test whether loss of Sox9 prevents or ameliorates liver fibrosis and if over-expression of Sox9 worsens or accelerates the disease. In addition, I will discover what other genes lie downstream of SOX9 and integrate these with known signalling pathways important in liver fibrosis to uncover new targets and potential for therapies against liver fibrosis.
Taken together, these experiments are anticipated to prove an important role for Sox9 in organ fibrosis and assist in identifying new pathways of value in the search for new therapies.

Fibrosis of the liver is characterised by progressive accumulation of ECM proteins and is a major cause of morbidity and mortality in the UK. End-stage liver fibrosis can be treated by liver transplantation, but this is limited by donor numbers. Anti-fibrotic therapies are desperately needed during earlier phases of the disease when the fibrosis is reversible. To achieve this, better mechanistic understanding of liver fibrosis is required. Despite progress in this area, there are still no approved anti fibrotic treatments. To tackle this problem, identifying core factors and their mechanism of action will be highly influential; SOX9 represents one of these factors.
A series of data implicate ectopic expression of the Sry-box transcription factor, SOX9, as important in vitro in hepatic stellate cells and their deposition of extracellular matrix (ECM) characteristic of liver fibrosis. Two pressing challenges are now to test these data in vivo to determine if loss of Sox9 prevents or ameliorates liver fibrosis and if over-expression of Sox9 worsens or accelerates the disease; and to determine the genomic-wide binding of Sox9 to help identify direct genetic targets of Sox9 action and to elucidate the downstream pathways that may facilitate novel therapeutic intervention.
Taken together, these experiments are anticipated to prove an important role for Sox9 in organ fibrosis and assist in identifying new pathways of value in the search for new therapies.

Liver fibrosis is increasing in incidence and is a major cost to the NHS. It is associated with major morbidity and mortality. Largely, this problem comes from the lack of effective therapies at stages of the disease where the damage is reversible. This makes transplantation the last option and only then for lucky individuals where a donor organ is available. This research project will discover whether loss of the transcription factor SOX9 can ameliorate or reverse fibrosis. It will discover new genes involved in liver fibrosis as downstream targets of SOX9 action and it will place SOX9 in the context of known signalling pathways. All of these steps will increase the likelihood of identifying new candidates for targeted drug development to treat liver fibrosis prior to end-stage disease. Therefore, this work carries substantial health and wealth implications.