Function of IKKbeta in the progression and regression of liver fibrosis

肝硬化是被称为纤维化的过程的终末阶段，其中肝脏的正常健康组织在几年内逐渐被非功能性瘢痕组织取代。这一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进行替代以防止死亡。这种疾病过程可以由各种各样的损伤引起，包括病毒（丙型肝炎和B型肝炎）、酒精、代谢因子和自身免疫攻击造成的损伤。申请人实验室以及世界各地其他实验室的最近工作通过证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。纤维化的可逆性与从肝脏中去除负责产生瘢痕组织的特化细胞（肝肌成纤维细胞）有关，然而在经历持续性损伤的肝脏中去除这些细胞是非常低效的。在开创性的研究中，申请人已经表明，靶向称为NF-κ B的存活因子的药物将促进从肝脏中去除肝肌成纤维细胞，而不影响健康功能所需的其他肝细胞。申请赠款收入的项目的目的是更多地了解控制NF-κ B的关键分子之一。这种被称为IKK β的分子已经成为新兴抗炎药物的靶点，如果我们能找到证据证明它在纤维化中起着重要作用，它最终可能会提供一种替代移植的方法。所提出的实验旨在发现肝肌成纤维细胞中IKK β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病恢复率的提高。结果将用于告知肝病诊所的同事使用IKK β抑制剂治疗肝病患者的可能获益。工作结果还将通过新闻稿（通过南安普顿大学和医学研究理事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.