Function of IKKbeta in the progression and regression of liver fibrosis

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Liver cirrhosis is the end stage of a process known as fibrosis in which the normal healthy tissues of the liver are over several years progressively replaced with non-functional scar tissue. This process leaves the liver in a state of structural and functional disorder for which the only option is replacement by transplantation to prevent death. This disease process can be caused by a wide variety of injuries including those inflicted by viruses (hepatitis C and B), alcohol, metabolic agents and autoimmune attack. Recent work in the applicants laboratory as well as in other laboratories across the world has given new hope to the treatment of liver fibrosis by demonstrating that it is a process that can be reversed. Reversibility of fibrosis is associated with the removal from the liver of a specialised cell (hepatic myofibroblast) that is responsible for production of scar tissue, however removal of these cells is very inefficient in livers that are undergoing persistent injury. In pioneering studies the applicants have shown that drugs which target a survival factor called NF-kB will promote the removal of hepatic myofibroblasts from the liver without affecting other liver cells required for healthy function. The aim of the project for which grant income is requested is to learn more about one of the key molecules that control NF-kB. This molecule known as IKKbeta is already a target for emerging anti-inflammatory drugs which may eventually offer an alternative to transplantation if we can find evidence that it plays an important role in fibrosis. The experiments that are proposed are designed to discover if loss of IKKbeta and NF-kB activities in hepatic myofibroblasts will result in reduced severity of fibrosis and enhanced rates of recovery from liver disease. The results will be used to inform colleagues in hepatology clinics as to the likely benefits of the use of IKKbeta inhibitors in the treatment of liver disease patients. The results of the work will also be presented to the general public via press releases (organised through the University of Southampton and the Medical Research Council Press Offices and Websites) as well as in the form of public lectures and publication of data in high quality scientific journals.