Circadian biology of the systemic inflammatory response during critical illness

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.