Investigating hepatic p53-mediated neutrophil suppression in non-alcoholic steatohepatitis

肝癌是一种常见的致命疾病，几乎没有治疗选择。苏格兰的女性和男性的肝癌发病率都是英国最高的(都比平均水平高出约1.5倍)。由于肥胖的流行，导致肝癌的主要原因正在发生变化。历史上的病例与病毒感染有关，但这一数字正在下降。现在，越来越多的新肝癌病例是由个人首先患上一种名为非酒精性脂肪性肝炎(NASH)的疾病引起的。展望未来，NASH衍生的肝癌有望很快成为肝癌的主要形式。令人担忧的是，肥胖和2型糖尿病--导致晚期NASH的关键因素--在苏格兰和英国也是最常见的。此外，Nash来源的肝癌可能对现有的治疗方案特别耐受，这表明如果不采取紧急行动，随着Nash来源的肝癌成为主导，糟糕的情况可能会在苏格兰和整个英国变成一场危机。我们的研究重点将放在一种名为p53的基因上，它长期以来一直被认为是“基因组的守护者”，也是防止癌症发展的重要防御者。我们的初步发现表明，P53在肝脏中发挥着类似的保护作用，以回应高脂肪和高糖的西方饮食的消费。在这种情况下，我们的证据表明，P53保护肝功能，并起到对抗饮食诱导的NASH发展的作用。对于这项研究，我们特别感兴趣的是了解P53活性和称为中性粒细胞的特定免疫细胞之间的关系，中性粒细胞通常会渗透到肝脏，以应对损伤或疾病，以帮助促进组织修复。然而，在肝病中，中性粒细胞在肝脏中的过度持续可导致慢性肝脏炎症，也已被证明促进了人类NASH患者耐药肝癌的发展。在这种情况下，在癌症治疗的同时以中性粒细胞为靶点可以提高治疗效果。我们的初步证据表明，P53可能保护肝脏，至少部分是通过限制中性粒细胞的渗透来实现的。通过这项拟议的项目，我们将确定P53介导的中性粒细胞抑制是否对保护NASH具有重要意义。我们还将确定肝病进展期间中性粒细胞活性增加与疾病进展密切相关的时期，这表明有机会进行中性粒细胞靶向干预。利用这些信息，我们计划测试针对肝病中性粒细胞的早期干预是否可以延缓甚至防止NASH的发展--可能指出一种新的治疗方法(NASH)，目前没有任何批准的治疗方案。任何此类进展都将对苏格兰的患者产生巨大影响，未来以患者为中心的工作将受益于现有的基础设施和已建立的临床队列，这些患者有患肝癌的风险。

Liver cancer is a common and lethal disease with few treatment options. Rates of liver cancer in Scotland are highest in the UK for both women and men (both approximately 1.5 times higher than average). As a result of the obesity epidemic, the main causes of liver cancer are shifting. Cases were historically associated with viral infection, but this is decreasing. Now, a rising proportion of new cases of liver cancer result from individuals first developing a condition called non-alcoholic steatohepatitis (NASH). Projecting into the future, NASH-derived liver cancer is expected to shortly become the dominant form of liver cancer. Worryingly, obesity and type 2 diabetes-key contributors to developing advanced NASH-are also most common in Scotland within the UK. Moreover, NASH-derived liver cancer can be especially resistant to existing treatment options, suggesting that without urgent action, a bad situation could become a crisis in Scotland and across the UK as NASH-derived liver cancer becomes dominant. The focus of our research will be on a gene called p53, which has long been established as a 'guardian of the genome' and an important defender against the development of cancer. Our preliminary findings suggest that p53 exerts a similarly protective function in the liver in response to consumption of a high fat and high sugar 'western' diet. In this setting, our evidence suggests that p53 protects liver function and acts to oppose the development of diet-induced NASH. For this study, we are particularly interested in understanding the relationship between p53 activity and specific immune cells called neutrophils, which normally infiltrate the liver in response to damage or disease to help facilitate tissue repair. However, in liver disease, undue persistence of neutrophils in the liver can contribute to chronic liver inflammation and has also been shown to promote the development of treatment-resistant liver cancer in human NASH patients. Within this context, targeting neutrophils alongside the administration of cancer therapy can improve treatment efficacy. Our preliminary evidence suggests that p53 may protect the liver, at least in part, by also acting to restrict neutrophil infiltration. With the proposed project, we will determine whether p53-mediated neutrophil suppression is important for protection from NASH. We will also identify periods during liver disease progression where increasing neutrophil activity strongly correlates with disease advancement, suggesting an opportunity for neutrophil-targeted intervention. Using this information, we plan to test whether early intervention targeting neutrophils in liver disease can delay or even prevent the development of NASH-potentially pointing to a new therapeutic approach for a condition (NASH) without any currently approved treatment options. Any such advances would have an outsize impact on patients in Scotland, and future patient-focused work would benefit from the existing infrastructure and established clinical cohorts of patients at-risk of developing liver cancer that are already present there.