MICA: Illuminating mechanisms regulating the birth, life and death of the myofibroblast to inform the development of antifibrotics for liver disease.

我们身体组织有效修复环境因素（病毒，细菌，毒素，饮食因素等）造成的细胞损伤的能力对于预防进一步的损伤或感染以及器官功能的健康恢复至关重要。组织修复的关键是形成临时疤痕和伤口收缩，以便在组织愈合时“隔离”损伤部位。如果组织在很长一段时间内遭受重复损伤，那么疤痕会被修改，使得它们在愈合过程中更难分解，并且它们可以扩散到影响器官的其他部分。这被称为“纤维化”，并且它可以进展到器官的正常结构和功能被转化到其失败的程度的阶段，并且目前唯一的治疗选择是移植或姑息治疗。衰老似乎降低了器官正常修复的能力，因此纤维化在普通人群中变得越来越常见，最近的估计表明，它是发达国家所有死亡人数的40%的原因。目前，我们还没有被证明有效的治疗或预防性治疗任何器官系统中的组织纤维化。肝脏是负责解毒的器官，在清除病原体方面起着重要作用，但肝脏中的细胞与身体其他部位的细胞一样容易受到损伤和感染。因此，肝脏特别容易受到毒素或病原体持续存在的纤维化的影响，并且随着年龄的增长，肝脏的再生能力开始减弱。慢性肝病是目前英国唯一的常见死亡原因，2008年报告的死亡人数为16，000人，令人担忧的是，中年人的疾病发展趋势。一种有效的抗纤维化药物，可以阻止疤痕的发展和/或帮助分解肝脏中现有的疤痕，这将对慢性肝病患者的发病率和死亡率产生重大影响。本申请中提出的5年资助研究将建立在PI及其团队实验室的工作基础上，该实验室已经确定了病变肝脏中的一种特殊细胞，该细胞促进疤痕的形成，维持和扩散。这种细胞被称为肝肌成纤维细胞，它主要是通过改变正常储存维生素A的肝细胞的性质和行为而产生的。在损伤或感染时，这些所谓的“肝星状细胞”转化为肌成纤维细胞，其产生大量的瘢痕组织，并且能够增殖和迁移以引起肝脏中的纤维化。PI是一项国际研究工作的一部分，该研究已经证实，操纵肝星状细胞衍生的肌成纤维细胞可以阻止甚至逆转纤维化。研究小组将在未来5年内解决的挑战是阐明调节肌成纤维细胞命运和功能的生化信号，目的是找到可以被操纵以阻止甚至希望逆转纤维化的生化“阿喀琉斯之踵”。该研究将结合人类细胞培养、相关小鼠疾病模型系统和患病的人类肝脏组织，以确定哪些信号可以被操纵以产生抗纤维化作用。该团队将利用这些知识寻找现有药物或新化合物（通过化学库筛选），以找到安全有效的治疗方法。这一雄心勃勃的目标将通过研究团队与全球生物制药公司葛兰素史克（GSK）之间强大的工作伙伴关系来实现，后者拥有一支由40多名科学家组成的专门团队，致力于在其Stevenage工厂发现和开发抗纤维化药物。GSK将提供人力支持，获得专业的科学知识，提供化合物和研究工具，并提供翻译到诊所的路线。

The ability of our bodily tissues to effectively repair cellular damage caused by environmental agents (viruses, bacteria, toxins, dietary factors etc) is critical for prevention of further damage or infection and for the healthy restoration of organ function. Key to tissue repair is the formation of temporary scars and contraction of wounds in order to "wall off" sites of damage while tissue healing takes place. If tissues suffer repeated damage over extended periods of time then scars are modified such that they are more difficult to break down during healing and they can spread to affect other parts of the organ. This is known as "fibrosis" and it can progress to the stage where the normal architecture and function of an organ is transformed to such an extent that it fails and the only current treatment options are transplantation or palliative care. Ageing appears to reduce the ability of organs to repair normally and as a result fibrosis is becoming more common in the general population, with recent estimates suggesting it underlies up to 40% of all deaths in the developed world. At present we have no proven effective therapies or preventative treatments for tissue fibrosis in any organ system. The liver is the organ responsible for detoxification and plays a major role in clearance of pathogens, however cells in the liver are equally susceptible to damage and infection as those in other parts of the body. As a consequence the liver is particularly susceptible to fibrosis where toxins or pathogens persist, and as we age when the regenerative capacity of the liver begins to falter. Chronic liver disease is currently the only common cause of death that is on the rise in the UK, with 16,000 deaths reported in 2008 and worryingly the trend is towards disease developing in people in their middle-life years. An effective antifibrotic that halts the development of scars and/or that helps break down existing scars in the liver would have a major impact on morbidity and mortality in patients with chronic liver disease. The research proposed in this application for a 5-year grant will build on work in the laboratory of the PI and his team that has identified a specialised cell in the diseased liver that promotes the formation, maintenance and spread of scars. This cell is known as a liver myofibroblast and it is generated chiefly by alterations in the properties and behaviour of liver cells that normally function to store Vitamin A. Upon injury or infection these so called "hepatic stellate cells" transform into myofibroblasts that produce vast quantities of scar tissue and are able to proliferate and migrate to cause fibrosis in the liver. The PI has been part of an international research effort that has confirmed that manipulating hepatic stellate cell-derived myofibroblasts can halt and even reverse fibrosis. The challenge for the next 5 years that will be tackled by the research team is to illuminate biochemical signals that regulate myofibroblast fate and function with the aim of finding biochemical "Achilles heels" that can be manipulated to stop or even hopefully reverse fibrosis. The research will use a combination of human cell culture, relevant mouse disease model systems and diseased human liver tissues to identify which signals can be manipulated to bring about antifibrotic effects. The team will use this knowledge to look for either existing drugs or new compounds (by chemical library screening) to find safe and effective treatments. This ambitious goal will be facilitated by a strong working partnership between the research team and the global biopharmaceutical company GlaxoSmithKline (GSK), the latter having a dedicated team of 40+ scientists working on discovery and development of antifibrotics at its Stevenage site. GSK will lend support with manpower, access to specialised scientific knowhow and provision of compounds and research tools as well as providing routes for translation to the clinic.