Circadian biology of the systemic inflammatory response during critical illness

昼夜节律是一个基本的生物过程，对维持健康和福祉至关重要。昼夜节律可能因疾病而被打乱，如急性胰腺炎。这不仅会影响整体健康，更具体地说，会影响免疫和代谢系统。因此，影响疾病如何演变和对特定治疗的反应。除此之外，考虑个体差异也很重要，例如时间型，它可以影响个体对疾病的反应以及他们对特定疾病的易感性。出于本项目的目的，急性胰腺炎将被用作被视为危重患者的疾病。急性胰腺炎每年影响英国约30，000人，并且具有高死亡率（每年1，500例死亡）。该博士学位旨在利用人类患者和小鼠模型的临床，转录组学，蛋白质组学和代谢组学数据。在小鼠模型中，患有实验性急性胰腺炎的小鼠不会随机死亡，而是在小鼠最活跃的黑暗阶段开始时（12小时光照/黑暗周期）死亡。尽管通过外部光线索夹带，这些发现表明，有一个潜在的昼夜节律元素，可能有助于在这个特定的时间点的小鼠死亡。该项目的目的是探索正常的昼夜节律生物学（基因表达和生理学）是否在危重病（急性胰腺炎）期间丢失。此外，研究在重症（急性胰腺炎）期间，昼夜节律（生理学和基因表达）是否丢失并具有负面结果（可能致命）。这两个假设将通过以下方法来解决：使用遥测危重病（急性胰腺炎）小鼠观察错乱的生理学和“螺旋死亡”不是随机的。在重症患者（急性胰腺炎）中是否发生与我们在小鼠模型中观察到的相同或相似的模式？- （使用心血管和温度数据）是否有可能在危重病（急性胰腺炎）患者的临床、转录组、代谢和蛋白质组数据集中检测昼夜节律模式？此外，疾病的严重程度（急性胰腺炎）和更大的昼夜节律失调之间是否存在相关性。将可用的（开源和已发布的）数据集与我们的数据集进行比较，看看我们是否可以根据转录偏离“规范”来定义危重病（急性胰腺炎）。上述发现是否有助于指导治疗设计，即与昼夜节律相关的定时给药。

Circadian rhythms are a fundamental biological process that are essential for the maintenance of health and wellbeing. Circadian rhythms can become disrupted due to disease, such as acute pancreatitis. Not only does this impact on overall health but more specifically, affects the immune and metabolic system. Therefore, impacting on how the disease evolves and responds to specific treatments. In addition to this, it is also important to consider individual differences, such as chronotype, which can influence how an individual responds to a disease and how susceptible they are to develop a specific disease. For the purpose of this project, acute pancreatitis will be used as the disease by which individuals are considered to be critically ill. Acute pancreatitis affects approximately 30,000 individuals within the UK per annuum and has a high rate of mortality (1, 500 deaths per year). This PhD will aim to utilise clinical, transcriptomic, proteomic and metabolomic data from human patients and mice models. In mice models, mice with experimental acute pancreatitis do not die at random but at the start of the dark phase when mice are most active (12hr light/dark cycle). Despite entrainment via external light cues, these findings suggest that there is an underlying circadian element which may contribute to the death of the mice at this specific time point. The aim of this project is to explore if normal circadian biology (gene expression and physiology) is lost in periods of critical illness (acute pancreatitis). Also, to investigate if in periods of critical illness (acute pancreatitis) the circadian rhythms (physiology and gene expression) becomes lost and has a negative outcome (potentially fatal). These two hypotheses will be addressed through the following methods:Use telemetered critically ill (acute pancreatitis) mice to observe deranged physiology and that the "spiral to death" is not random. Does the same or similar patterns occur in critically ill humans (acute pancreatitis) as we observe in mice models? - (use cardiovascular and temperature data).Is it possible to detect a circadian rhythm pattern in the clinical, transcriptomic, metabolic and proteomic datasets in critically ill (acute pancreatitis) patients? Furthermore, is there a correlation between the severity of illness (acute pancreatitis) and greater circadian rhythm dysregulation. Compare available (open source and published) datasets with our datasets to see if we can define critical illness (acute pancreatitis) according to transcriptional deviation from the "norm". Are any of the above findings useful in informing treatment designs i.e. timed drug administration in relation to circadian rhythms.