Stat2 is a therapeutic target in liver inflammation

在英国，死于肝病的患者人数比死于任何其他死因的人数增长都要快，自1970年以来，死亡率增长了400%。在英国，酒精性和非酒精性脂肪性肝病（分别为ALD和NAFLD）以及病毒感染是慢性肝损伤的常见原因，慢性肝损伤可导致肝硬化、癌症和肝功能衰竭。控制这一进展的机制尚不完全清楚，但炎症是一个关键的早期事件，在肝脏疾病的广泛病因中很常见。炎症是慢性肝病（急性对慢性肝衰竭）患者病情恶化的主要原因，也是急性肝衰竭的一个关键特征。目前唯一可用的治疗方法是器官移植，用于少数有资格接受这种高风险和昂贵手术的终末期患者，并为那些没有资格接受这种手术的患者提供支持性护理。对于那些尚未达到终末期疾病的人来说，生活方式和行为的改变是管理的基石，但众所周知，这种改变很难实施，而且更难以维持其益处。因此，已经采取了各种策略来防止进展，但针对肝脏疾病发展的决定步骤-炎症-迄今为止很少受到关注。炎症包括一系列化学反应，导致受伤组织（如肝脏）产生特殊物质，并将其释放到血液中。这些物质导致白细胞离开血液，进入受伤组织，开始愈合过程。当愈合失败或无法控制时，慢性疾病就会在肝脏中形成疤痕和肝硬化。这项工作旨在了解肝脏中的这一过程，并建立在Alazawi及其同事已发表的工作基础上，该工作已确定Stat2是炎症的关键控制者。尽管人们对这种蛋白质的了解已经有一段时间了，但这个研究小组是第一个发现它在导致炎症的主要化学反应中起关键作用的人。该项目建立在早期发现Stat2蛋白是肝脏炎症的重要物质的基础上。它在未发炎的健康肝组织中存在低水平，在NAFLD -非酒精性脂肪性肝炎（NASH）炎症型患者的肝组织中高表达。该项目将使用尖端技术，利用已建立的肝损伤模型，更好地了解Stat2在肝脏炎症中的作用。研究人员旨在了解Stat2发挥关键作用的关键细胞，并确定抑制这些细胞中Stat2丢失的后果。该项目的总体目标是测试针对Stat2（或其作用的基因和蛋白质）的靶向药物可用于治疗肝脏炎症的假设。该项目将使用一种相对较新的技术来“沉默”基因，使它们编码的蛋白质不再在特定细胞中产生，从而在实验模型中减少肝脏中Stat2的表达。希望本项目所完成的工作能够转化为炎症性肝病患者的治疗策略。

The number of patients dying from liver disease is rising faster than those from any other cause of death in the UK, with mortality rates increasing 400% since 1970. In the UK, alcoholic and non-alcoholic fatty liver diseases (ALD and NAFLD respectively), and viral infections are the common causes of chronic liver injury, which can lead to cirrhosis, cancer and liver failure. The mechanisms that govern this progression are not fully understood, but inflammation is a key early event and is common to the broad range of causes of liver disease. Inflammation is the principal cause of deterioration in patients with chronic liver disease (acute-on-chronic liver failure) and a key feature of acute liver failure. The only treatment currently available is organ transplantation for a select few who have reached end stage disease and are eligible for this high risk and costly procedure and supportive care for those who are not. For those who have not yet reached end-stage disease, lifestyle and behaviour modification represent the cornerstone of management, but such changes are notoriously difficult to implement and the benefits even harder to maintain. Various strategies have therefore been pursued to prevent progression, but targeting the determining step in the development of liver disease - inflammation - has received little attention so far. Inflammation involves a series of chemical reactions that results in production of special substance in injured tissues, such as the liver, and their release into the bloodstream. These substances cause white cells to leave the bloodstream and enter injured tissue to begin the healing process. When healing fails or becomes uncontrolled, chronic disease takes hold and in the liver, scarring and cirrhosis ensue. This work aims to understand this process in the liver and builds on Alazawi and colleagues' published work that has identified Stat2 as a key controller of inflammation. Although the protein has been known about for some time, this group is the first to discover its pivotal role in the major chemical reactions that lead to inflammation. This project builds on the early discovery that the Stat2 protein is an important substance in liver inflammation. It is present at low levels in healthy liver tissue that is not inflamed and is highly expressed in liver tissue from patients with the inflammatory form of NAFLD - non-alcoholic steatohepatitis (NASH). The project will use cutting edge techniques to better understand the role of Stat2 in liver inflammation using established models of liver injury. The researchers aim to understand the key cells in which Stat2 plays its pivotal role and determine the consequences of inhibiting Stat2 loss in these cells. The overall aim of the project is to test the hypothesis that targeting drugs against Stat2 (or the genes and proteins it acts on) can be used to treat liver inflammation. The project will use a relatively new technology to 'silence' genes so that the proteins they encode are no longer made in specific cells to reduce the expression of Stat2 in the liver in experimental models. It is hoped that the work completed in this project will be translated into treatment strategies for patients with inflammatory liver disease.