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

研究非酒精性脂肪性肝炎中肝脏 p53 介导的中性粒细胞抑制

• 批准号: MR/X018512/1
• 负责人: Timothy Humpton
• 金额: $ 107.1万
• 依托单位: Glasgow Caledonian University
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX018512%2F1
• 关键词: Investigating; hepatic; p53; mediated; neutrophil

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.

肝癌是一种常见且致命的疾病，治疗选择很少。苏格兰的女性和男性肝癌发病率是英国最高的（均比平均水平高约 1.5 倍）。由于肥胖流行，肝癌的主要原因正在发生变化。历史上病例与病毒感染有关，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患上非酒精性脂肪性肝炎 (NASH) 的患者引起的。展望未来，NASH 衍生的肝癌预计将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）在英国苏格兰也最常见。此外，NASH 衍生的肝癌对现有的治疗方案尤其具有抵抗力，这表明，如果不采取紧急行动，随着 NASH 衍生的肝癌占据主导地位，糟糕的情况可能会成为苏格兰和整个英国的一场危机。我们研究的重点将集中在一个名为 p53 的基因上，该基因长期以来一直被认为是“基因组的守护者”和对抗癌症发展的重要防御者。我们的初步研究结果表明，p53 在肝脏中发挥类似的保护功能，以响应高脂肪和高糖“西方”饮食的消耗。在这种情况下，我们的证据表明 p53 可以保护肝功能并对抗饮食引起的 NASH 的发展。在这项研究中，我们特别感兴趣的是了解 p53 活性与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肝脏以响应损伤或疾病，以帮助促进组织修复。然而，在肝脏疾病中，中性粒细胞在肝脏中过度持续存在会导致慢性肝脏炎症，并且还被证明会促进人类 NASH 患者发展为难治性肝癌。在此背景下，在癌症治疗的同时靶向中性粒细胞可以提高治疗效果。我们的初步证据表明，p53 还可以通过限制中性粒细胞浸润来保护肝脏，至少部分如此。通过拟议的项目，我们将确定 p53 介导的中性粒细胞抑制对于预防 NASH 是否重要。我们还将确定肝脏疾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病中性粒细胞的早期干预是否可以延缓甚至阻止 NASH 的发展，这可能为目前没有任何已批准治疗方案的疾病 (NASH) 提供一种新的治疗方法。任何此类进步都会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有患肝癌风险的患者临床队列。