MICA: Molecular drivers of fibrosis at the hepatic epithelial-mesenchymal barrier

慢性肝病(CLD)是死亡的主要原因，2010年导致100多万人早期死亡，相当于全球所有死亡人数的2%。预计这些统计数据在未来十年将可靠地上升，主要是由于非酒精性脂肪性肝病(NAFLD)，这是一种危险的肝脏病理，影响全球20%的人口，与糖尿病和肥胖症密切相关。高达30%的NAFLD患者可以进展为终末期疾病，即所谓的肝硬变。因此，肝硬变可能会影响世界上5%的人口，包括数百万儿童和年轻人。除了这一令人震惊的统计数字外，仅在欧洲，每年就有3.5亿人感染乙肝病毒，导致4万人死亡，1.5亿人感染丙型肝炎，每年导致50万人死于与肝脏有关的疾病。此外，慢性阻塞性肺病患肝癌的风险很高，现在是全球第二大与癌症相关的死亡原因，仅次于肺癌。虽然NAFLD可以对生活方式干预做出反应，但缺乏强有力的临床指南，以及与患者对饮食/运动改变的依从性相关的挑战，需要一种多方面的方法来治疗CLD。这种方法最重要的是对药物的迫切和未得到满足的需求，这些药物可以延缓、阻止甚至逆转疾病向肝硬变和相关癌症风险的发展。这一MICA研究计划将受益于纽卡斯尔纤维化研究集团(NFRG)世界领先的肝病研究人员的合作以及全球制药公司葛兰素史克的科学力量和资源。这项拟议研究的目的是了解肝细胞损伤如何导致肝硬变，并将这项研究转化为为CLD患者带来好处的新药和诊断方法的设计。对CLD生物学的研究揭示了这种疾病的共性，而与肝脏损伤的原因无关。这些特征包括对肝细胞的反复损伤，肝细胞是肝脏的主要细胞类型，未消退的炎症和异常的肝组织重塑涉及逐渐形成无功能的瘢痕组织，逐渐取代功能性的肝细胞团。疤痕形成被称为纤维化，可以发生在任何有重复细胞损伤的器官中。肝脏中的纤维化疤痕是由肌成纤维细胞产生的，肌成纤维细胞是常驻的特化肝星状细胞对肝脏损伤做出反应时产生的。调节肌成纤维细胞的活动有可能阻止甚至逆转纤维化。基于NFRG和GSK的初步数据，我们认为对肝细胞的重复损伤会改变它们的分子特征，使它们反复向附近的肌成纤维细胞发出需要产生疤痕组织的信号。我们的目标是发现受损肝细胞中发生的分子变化的本质，并确定它们与肌成纤维细胞之间的信号联系。由于NAFLD是一个如此重大的全球问题，一个重要的重点将放在确定肝细胞对多余脂肪的吸收如何改变它们的生物学以刺激纤维化。大部分研究将利用NFRG实验室最近令人兴奋的技术进步而实现的人类肝组织。现在有可能在肝组织的薄片中‘模拟’NAFLD。将这一进展与现代分子生物学方法结合使用，我们将发现所谓的“表观遗传”驱动因素，它们在富含脂肪的肝细胞内发挥作用，刺激纤维化。这些驱动因素可以用来设计新的血液测试，告诉我们哪些NAFLD患者有患肝硬变的风险，并指导我们将目标对准新疗法的开发。通过与葛兰素史克的合作，这项研究中出现的发现将有巨大的机会转化为保健产品，造福患者。

Chronic liver disease (CLD) is a major cause of death, being responsible for over one million early fatalities in 2010, equating to 2% of all deaths worldwide. These statistics are reliably expected to rise over the coming decade, in major part as a consequence of non-alcoholic fatty liver disease (NAFLD), a dangerous pathology of the liver that affects 20% of the global population, which is closely associated with diabetes and obesity. Up to 30% of patients with NAFLD can progress to end stage disease known as cirrhosis. Therefore, cirrhosis may potentially be impacting on 5% of the world population including millions of children and young adults. In addition to this shocking statistic, 350 million people are infected with the hepatitis B virus leading to 40,000 deaths per annum in Europe alone, 150 million are infected with hepatitis C causing 500,000 liver-related deaths each year. Furthermore, CLD carries a high risk of liver cancer, now the second most common cause of cancer-related deaths worldwide, preceded only by lung cancer. While arguably NAFLD may respond to lifestyle interventions; lack of robust clinical guidelines and challenges associated with patient compliance for dietary/exercise changes necessitate a multifaceted approach for care of CLD. Paramount to this approach is the urgent and unmet need for medicines that slow, halt or even reverse the disease pathway to cirrhosis and associated risk of cancer. This MICA research programme will benefit from collaboration of world-leading liver disease investigators of the Newcastle Fibrosis Research Group (NFRG) and the scientific power and resources of the global pharmaceutical company GSK. The aim of the proposed research is to understand how damage to liver cells leads to cirrhosis and to translate this research into the design of new medicines and diagnostics that bring benefit to CLD patients. Study of the biology of CLD reveals commonalities that characterize the disease irrespective of the cause of liver injury. These characteristics include repetitive damage to hepatocytes which are the main cell type in the liver, unresolved inflammation and aberrant liver tissue remodeling involving the progressive laying-down of non-functional scar tissue that gradually replaces functional liver cell mass. Scar-formation is known as fibrosis and can occur in any organ where there is repetitive cellular damage. Fibrotic scars in the liver are produced by myofibroblasts generated by 'activation' of resident specialized hepatic stellate cells in response to liver damage. Modulating the activities of the myofibroblast has the potential to halt or even reverse fibrosis. Based on preliminary data from NFRG and GSK we propose that repetitive damage to hepatocytes changes their molecular characteristics such that they repeatedly signal a need to generate scar tissue to nearby myofibroblasts. We aim to discover the nature of the molecular changes occurring in damaged hepatocytes and identify the signals they communicate to the myofibroblast. As NAFLD is such a major global concern an important focus will be placed on determining how the uptake of excess fats into hepatocytes alters their biology to stimulate fibrosis.Much of the research will make use of human liver tissue made possible by recent exciting technological advances in the NFRG laboratories. It is now possible to 'model' NAFLD in thin slices of liver tissue. Using this advance alongside modern molecular biology approaches we will discover so-called 'epigenetic' drivers that operate within fat-laden hepatocytes to stimulate fibrosis. These drivers can be exploited for the design of new blood tests that tell us which NAFLD patients are at risk from cirrhosis as well as guiding us on where to target the development of new therapies. By partnering with GSK there is tremendous opportunity for discoveries emerging from the research to be translated to healthcare products for patient benefit.