Function of IKKbeta in the progression and regression of liver fibrosis

肝硬化是肝纤维化过程的最后阶段，在这个过程中，肝脏的正常健康组织在几年内逐渐被无功能的疤痕组织所取代。这个过程使肝脏处于结构和功能紊乱的状态，唯一的选择是通过移植来替代，以防止死亡。这种疾病过程可由多种损伤引起，包括由病毒（丙型肝炎和乙型肝炎）、酒精、代谢剂和自身免疫性攻击造成的损伤。申请人实验室以及世界各地其他实验室最近的工作表明，肝纤维化是一个可以逆转的过程，给肝纤维化的治疗带来了新的希望。纤维化的可逆性与肝脏中负责瘢痕组织生成的特化细胞（肝肌成纤维细胞）的移除有关，然而，在持续损伤的肝脏中，移除这些细胞的效率非常低。在开创性的研究中，申请人已经证明，靶向NF-kB存活因子的药物将促进肝脏中肝肌成纤维细胞的去除，而不会影响健康功能所需的其他肝细胞。该项目的目的是为了更多地了解控制NF-kB的关键分子之一。这种被称为IKKbeta的分子已经成为新兴抗炎药物的靶标，如果我们能找到证据证明它在纤维化中起着重要作用，它可能最终提供一种替代移植的方法。提出的实验旨在发现肝肌成纤维细胞中ikkβ和NF-kB活性的丧失是否会导致纤维化严重程度的降低和肝脏疾病恢复率的提高。该结果将用于告知肝病临床的同事使用ikkβ抑制剂治疗肝病患者的可能益处。这项工作的结果也将通过新闻稿（由南安普顿大学和医学研究委员会新闻办公室和网站组织）以及公开讲座和在高质量科学期刊上发表数据的形式向公众展示。

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.