The role of HMGB1 in liver injury and repair - mechanisms and therapeutic interventionsUniversity of Edinburgh

肝脏疾病影响着全世界数百万人。在世界范围内，肝脏疾病的发病率总体呈上升趋势。与西欧其他国家相比，英国的增长率要高得多。在英国，肝病是导致过早死亡的第三大常见原因。自1970年以来，死亡率增加了400%，65岁以下人群的死亡率几乎增加了5倍。肝脏疾病可由多种诱因引起；这些因素包括饮食、酒精、药物、病毒感染和自身免疫性并发症。从经济角度来看，急性和慢性肝病的影响是巨大的。NHS治疗扑热息痛相关急性肝损伤的费用超过6000万英镑/年，治疗酒精性肝病的费用估计为27亿英镑/年，仅苏格兰每天的治疗费用就超过100万英镑。对于非酒精性脂肪性疾病，NHS的费用估计为42亿英镑，到2050年将翻一番。不幸的是，终末期疾病的唯一治疗选择是移植。供体器官的供应甚至不能满足目前的需求，许多患者在等待合适的器官时死亡。需要更好地了解肝脏疾病，并且迫切需要替代医学策略来治疗晚期肝脏疾病。促炎通路和抗炎通路的平衡是控制损伤修复或发展为晚期慢性疾病或急性肝衰竭的重要“临界点”。对乙酰氨基酚过量和酒精性肝病分别是导致急性和慢性肝损伤的主要疾病。我之前发现，一种关键的炎症促进剂，高迁移率组盒-1 (HMGB1)，在这些疾病的进展中起着关键作用。此外，我已经证明，通过测量患者血液中的HMGB1，医生和研究人员可以更好地了解疾病的严重程度。这反过来可能为更好的治疗策略提供信息。该项目的目标是确定HMGB1如何通过调节肝脏内协调炎症反应的不同细胞之间的交流来控制急性和慢性肝损伤的进展或解决的细节。我将确定哪些细胞类型会释放HMGB1，并描述它对肝脏局部环境的影响。为了实现这一目标，我将采用一种方法，将肝脏疾病的良好特征和转基因动物模型与新方法联系起来，对患病或再生器官进行无创成像。这个项目有一个明确的途径来帮助患者和管理急慢性肝病。这将通过提高对HMGB1作为诊断工具的理解以及通过进一步开发针对HMGB1本身的新药来实现。

Liver disease affects millions of people worldwide. The incidence of liver disease in general is rising worldwide. The rate of increase is substantially higher in the UK than other countries in Western Europe. Liver disease constitutes the third commonest cause of premature death in the UK. Mortality rates have increased 400% since 1970, and in people younger than 65 years have risen by almost five-fold. Liver disease can result from many triggers; these include diet, alcohol, drugs, viral infection and autoimmune complications. From an economic perspective, the impact of acute and chronic liver disease is substantial. The cost to the NHS for treating paracetamol related acute liver injury is over £60 million/year, for treating alcoholic liver disease the cost is estimated at £2.7 billion/year with the treatment costs in Scotland alone being over £1m per day. For non-alcoholic fatty disease, the cost to the NHS is estimated to be £4.2 billion and will be double that by 2050. Unfortunately, the only curative option for end-stage disease is transplantation. Donor organ availability cannot even meet current demand and many patients die whilst waiting for a suitable organ.A better understanding of liver disease is required and alternative medical strategies are urgently required for the treatment of advanced liver disease.The balance of pro and anti-inflammatory pathways represent important 'tipping points' that control either injury repair or development to advanced chronic disease or acute liver failure. Paracetamol overdose and alcoholic liver disease are major medical conditions that result in acute and chronic liver injury respectively. I have previously discovered that a critical inflammatory facilitator, High Mobility Group Box-1 (HMGB1), plays a key role in the progression of these diseases. Furthermore, I have shown that by measuring HMGB1 in the blood of patients, medical doctors and researchers can gain a better understanding of the severity of the disease. This in turn may inform better treatment strategies.The objective of this project now is to determine the detail of how HMGB1 contributes to the control of acute and chronic liver injury progression or resolution by regulating the communication between different cells within the liver that orchestrate inflammatory responses. I will determine which cell types release HMGB1 and I will characterise the impact that it has on the local environment within the liver. To achieve this I will adopt an approach linking well-characterised and genetically modified animal models of liver disease with novel methods to non-invasively image the diseased or regenerating organ. This project has a clear pathway to help patients and manage acute and chronic liver disease. This will be achieved by developing improved understanding of HMGB1 as a diagnostic tool and through the further development of novel medicines targeting HMGB1 itself.