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

肝癌是一种常见且致命的疾病，治疗方法很少。苏格兰的女性和男性肝癌发病率都是英国最高的（两者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。病例历来与病毒感染有关，但这种情况正在减少。现在，越来越多的肝癌新病例是由首先发展为非酒精性脂肪性肝炎（NASH）的个体引起的。展望未来，nash源性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——发展为晚期nash的关键因素——在英国的苏格兰也最为常见。此外，nash来源的肝癌可能对现有的治疗方案特别有抵抗力，这表明如果不采取紧急行动，随着nash来源的肝癌成为主导，苏格兰和整个英国的糟糕情况可能会成为一场危机。我们的研究重点将放在一个名为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。我们的初步研究结果表明，在高脂肪和高糖的“西方”饮食中，p53在肝脏中发挥了类似的保护功能。在这种情况下，我们的证据表明p53保护肝功能，并反对饮食诱导的NASH的发展。对于这项研究，我们特别感兴趣的是了解p53活性与称为中性粒细胞的特异性免疫细胞之间的关系，中性粒细胞通常在肝脏损伤或疾病的反应中浸润，以帮助促进组织修复。然而，在肝脏疾病中，肝脏中中性粒细胞的过度持续可导致慢性肝脏炎症，并且已被证明可促进人类NASH患者治疗抵抗性肝癌的发展。在这种情况下，靶向中性粒细胞与癌症治疗的管理可以提高治疗效果。我们的初步证据表明，p53可以保护肝脏，至少在一定程度上，也可以限制中性粒细胞的浸润。在这个项目中，我们将确定p53介导的中性粒细胞抑制对NASH的保护是否重要。我们还将确定在肝病进展期间，中性粒细胞活性增加与疾病进展密切相关的时期，这表明中性粒细胞靶向干预的机会。利用这些信息，我们计划测试针对肝脏疾病的中性粒细胞的早期干预是否可以延缓甚至预防NASH的发展-潜在地为目前没有任何批准的治疗方案的疾病（NASH）提供新的治疗方法。任何这样的进展都将对苏格兰的患者产生巨大的影响，未来以患者为中心的工作将受益于现有的基础设施和已经存在的有患肝癌风险的患者的临床队列。

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.