The role of HMGB1 in liver injury and repair - mechanisms and therapeutic interventionsUniversity of Edinburgh

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Liver disease affects millions of people worldwide. The incidence of liver disease in general is rising worldwide. The rate of increase is substantially higher in the UK than other countries in Western Europe. Liver disease constitutes the third commonest cause of premature death in the UK. Mortality rates have increased 400% since 1970, and in people younger than 65 years have risen by almost five-fold. Liver disease can result from many triggers; these include diet, alcohol, drugs, viral infection and autoimmune complications. From an economic perspective, the impact of acute and chronic liver disease is substantial. The cost to the NHS for treating paracetamol related acute liver injury is over £60 million/year, for treating alcoholic liver disease the cost is estimated at £2.7 billion/year with the treatment costs in Scotland alone being over £1m per day. For non-alcoholic fatty disease, the cost to the NHS is estimated to be £4.2 billion and will be double that by 2050. Unfortunately, the only curative option for end-stage disease is transplantation. Donor organ availability cannot even meet current demand and many patients die whilst waiting for a suitable organ.A better understanding of liver disease is required and alternative medical strategies are urgently required for the treatment of advanced liver disease.The balance of pro and anti-inflammatory pathways represent important 'tipping points' that control either injury repair or development to advanced chronic disease or acute liver failure. Paracetamol overdose and alcoholic liver disease are major medical conditions that result in acute and chronic liver injury respectively. I have previously discovered that a critical inflammatory facilitator, High Mobility Group Box-1 (HMGB1), plays a key role in the progression of these diseases. Furthermore, I have shown that by measuring HMGB1 in the blood of patients, medical doctors and researchers can gain a better understanding of the severity of the disease. This in turn may inform better treatment strategies.The objective of this project now is to determine the detail of how HMGB1 contributes to the control of acute and chronic liver injury progression or resolution by regulating the communication between different cells within the liver that orchestrate inflammatory responses. I will determine which cell types release HMGB1 and I will characterise the impact that it has on the local environment within the liver. To achieve this I will adopt an approach linking well-characterised and genetically modified animal models of liver disease with novel methods to non-invasively image the diseased or regenerating organ. This project has a clear pathway to help patients and manage acute and chronic liver disease. This will be achieved by developing improved understanding of HMGB1 as a diagnostic tool and through the further development of novel medicines targeting HMGB1 itself.