MICA: Molecular drivers of fibrosis at the hepatic epithelial-mesenchymal barrier

Chronic liver disease (CLD) is a major cause of death, being responsible for over one million early fatalities in 2010, equating to 2% of all deaths worldwide. These statistics are reliably expected to rise over the coming decade, in major part as a consequence of non-alcoholic fatty liver disease (NAFLD), a dangerous pathology of the liver that affects 20% of the global population, which is closely associated with diabetes and obesity. Up to 30% of patients with NAFLD can progress to end stage disease known as cirrhosis. Therefore, cirrhosis may potentially be impacting on 5% of the world population including millions of children and young adults. In addition to this shocking statistic, 350 million people are infected with the hepatitis B virus leading to 40,000 deaths per annum in Europe alone, 150 million are infected with hepatitis C causing 500,000 liver-related deaths each year. Furthermore, CLD carries a high risk of liver cancer, now the second most common cause of cancer-related deaths worldwide, preceded only by lung cancer. While arguably NAFLD may respond to lifestyle interventions; lack of robust clinical guidelines and challenges associated with patient compliance for dietary/exercise changes necessitate a multifaceted approach for care of CLD. Paramount to this approach is the urgent and unmet need for medicines that slow, halt or even reverse the disease pathway to cirrhosis and associated risk of cancer. This MICA research programme will benefit from collaboration of world-leading liver disease investigators of the Newcastle Fibrosis Research Group (NFRG) and the scientific power and resources of the global pharmaceutical company GSK. The aim of the proposed research is to understand how damage to liver cells leads to cirrhosis and to translate this research into the design of new medicines and diagnostics that bring benefit to CLD patients. Study of the biology of CLD reveals commonalities that characterize the disease irrespective of the cause of liver injury. These characteristics include repetitive damage to hepatocytes which are the main cell type in the liver, unresolved inflammation and aberrant liver tissue remodeling involving the progressive laying-down of non-functional scar tissue that gradually replaces functional liver cell mass. Scar-formation is known as fibrosis and can occur in any organ where there is repetitive cellular damage. Fibrotic scars in the liver are produced by myofibroblasts generated by 'activation' of resident specialized hepatic stellate cells in response to liver damage. Modulating the activities of the myofibroblast has the potential to halt or even reverse fibrosis. Based on preliminary data from NFRG and GSK we propose that repetitive damage to hepatocytes changes their molecular characteristics such that they repeatedly signal a need to generate scar tissue to nearby myofibroblasts. We aim to discover the nature of the molecular changes occurring in damaged hepatocytes and identify the signals they communicate to the myofibroblast. As NAFLD is such a major global concern an important focus will be placed on determining how the uptake of excess fats into hepatocytes alters their biology to stimulate fibrosis. Much of the research will make use of human liver tissue made possible by recent exciting technological advances in the NFRG laboratories. It is now possible to 'model' NAFLD in thin slices of liver tissue. Using this advance alongside modern molecular biology approaches we will discover so-called 'epigenetic' drivers that operate within fat-laden hepatocytes to stimulate fibrosis. These drivers can be exploited for the design of new blood tests that tell us which NAFLD patients are at risk from cirrhosis as well as guiding us on where to target the development of new therapies. By partnering with GSK there is tremendous opportunity for discoveries emerging from the research to be translated to healthcare products for patient benefit.