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由环境因素（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暂时的疤痕和伤口的收缩，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反复受到损伤，那么疤痕就会发生变化，在愈合过程中更难分解，并且会扩散到器官的其他部位。这就是所谓的“纤维化”，它可以发展到一个器官的正常结构和功能被改变到这种程度，以至于它失败了，目前唯一的治疗选择是移植或姑息治疗。衰老似乎会降低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普遍，最近的估计表明，发达国家40%的死亡都是由纤维化造成的。目前，对于任何器官系统的组织纤维化，我们还没有被证明有效的治疗方法或预防性的治疗方法。肝脏是负责解毒的器官，在清除病原体方面发挥着重要作用，然而肝脏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，当毒素或病原体持续存在时，肝脏特别容易发生纤维化，随着年龄的增长，肝脏的再生能力开始衰退。在英国，慢性肝病是目前唯一正在上升的常见死亡原因，2008年有16000人死亡，令人担忧的是，这种疾病的发展趋势是中年人。一种有效的抗纤维化药物可以阻止疤痕的形成和/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。这项申请为期5年的研究将建立在PI和他的团队实验室的工作基础上，他们已经在患病的肝脏中发现了一种促进疤痕形成、维持和扩散的特殊细胞。这种细胞被称为肝肌成纤维细胞，它主要是由通常储存维生素a的肝细胞的特性和行为发生改变而产生的。一旦受伤或感染，这些所谓的“肝星状细胞”就会转化为肌成纤维细胞，产生大量疤痕组织，并能够增殖和迁移，导致肝脏纤维化。PI是一项国际研究的一部分，该研究证实，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。未来5年，研究小组将面临的挑战是阐明调节肌成纤维细胞命运和功能的生化信号，目的是找到生化上的“阿喀琉斯之踵”，可以通过操纵来阻止甚至有望逆转纤维化。这项研究将结合人类细胞培养、相关的小鼠疾病模型系统和患病的人类肝脏组织来确定哪些信号可以被操纵来带来抗纤维化作用。该团队将利用这些知识寻找现有药物或新化合物（通过化学文库筛选），以找到安全有效的治疗方法。这一雄心勃勃的目标将由研究团队与全球生物制药公司葛兰素史克（GSK）之间强有力的合作伙伴关系促进，后者拥有一支由40多名科学家组成的专门团队，在其斯蒂夫尼奇基地从事抗纤维化药物的发现和开发。葛兰素史克将提供人力支持，提供专业科学知识，提供化合物和研究工具，并提供转化为临床的途径。

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.