Stat2 is a therapeutic target in liver inflammation

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The number of patients dying from liver disease is rising faster than those from any other cause of death in the UK, with mortality rates increasing 400% since 1970. In the UK, alcoholic and non-alcoholic fatty liver diseases (ALD and NAFLD respectively), and viral infections are the common causes of chronic liver injury, which can lead to cirrhosis, cancer and liver failure. The mechanisms that govern this progression are not fully understood, but inflammation is a key early event and is common to the broad range of causes of liver disease. Inflammation is the principal cause of deterioration in patients with chronic liver disease (acute-on-chronic liver failure) and a key feature of acute liver failure. The only treatment currently available is organ transplantation for a select few who have reached end stage disease and are eligible for this high risk and costly procedure and supportive care for those who are not. For those who have not yet reached end-stage disease, lifestyle and behaviour modification represent the cornerstone of management, but such changes are notoriously difficult to implement and the benefits even harder to maintain. Various strategies have therefore been pursued to prevent progression, but targeting the determining step in the development of liver disease - inflammation - has received little attention so far. Inflammation involves a series of chemical reactions that results in production of special substance in injured tissues, such as the liver, and their release into the bloodstream. These substances cause white cells to leave the bloodstream and enter injured tissue to begin the healing process. When healing fails or becomes uncontrolled, chronic disease takes hold and in the liver, scarring and cirrhosis ensue. This work aims to understand this process in the liver and builds on Alazawi and colleagues' published work that has identified Stat2 as a key controller of inflammation. Although the protein has been known about for some time, this group is the first to discover its pivotal role in the major chemical reactions that lead to inflammation. This project builds on the early discovery that the Stat2 protein is an important substance in liver inflammation. It is present at low levels in healthy liver tissue that is not inflamed and is highly expressed in liver tissue from patients with the inflammatory form of NAFLD - non-alcoholic steatohepatitis (NASH). The project will use cutting edge techniques to better understand the role of Stat2 in liver inflammation using established models of liver injury. The researchers aim to understand the key cells in which Stat2 plays its pivotal role and determine the consequences of inhibiting Stat2 loss in these cells. The overall aim of the project is to test the hypothesis that targeting drugs against Stat2 (or the genes and proteins it acts on) can be used to treat liver inflammation. The project will use a relatively new technology to 'silence' genes so that the proteins they encode are no longer made in specific cells to reduce the expression of Stat2 in the liver in experimental models. It is hoped that the work completed in this project will be translated into treatment strategies for patients with inflammatory liver disease.