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Title: Ischaemia reperfusion injury in the pathogenesis of intensive care unit acquired weakness
Author: Paul, Richard
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2019
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Intensive Care Unit Acquired Weakness (ICUAW) is a syndrome of muscle wasting and weakness in response to critical illness that carries with it a considerable morbidity and mortality. It is associated with a considerable health and economic burden both during admission and beyond during the rehabilitation period in survivors of intensive care. There are currently no effective therapies for ICUAW. The purpose of this thesis, therefore, was to identify molecular mechanisms involved in the pathogenesis of ICUAW with the aim of identifying potential targets for future therapies. In an observational study of patients undergoing major aortic surgery, as a model of ICUAW, raised circulating GDF-15 was associated with raised atrophy gene expression and acute muscle wasting in the post-operative period. This muscle loss was also associated with raised circulating markers of oxidative stress and ischaemia-reperfusion injury, which positively correlated with circulating GDF-15 concentration. Additionally, a pattern of miRNA expression was observed in the muscle of patients who developed acute muscle loss after surgery compared with those who did not. These miRNAs fall into two broad categories when expressed at high levels, those that confer protection to muscle atrophy (C19MC miRNAs, miR-422a) and those that promote atrophy (miR-675, miR-424/miR-542). The differential expression of these miRNAs was shown to be able to predict acute muscle wasting after the catabolic insult of major surgery, whilst individually they may also be potential targets for therapeutic intervention. In summary, the work within this thesis supports the evidence that GDF-15 is involved the pathogenesis of ICUAW, identifies miRNAs that may be potential targets for future pharmacotherapy, and presents a set of miRNA profiles that may be used to develop a risk stratification model to aid future clinical and research interventions.
Supervisor: Griffiths, Mark ; Kemp, Paul ; Polkey, Mike Sponsor: NIHR Respiratory Biomedical Research Unit Royal Brompton and Harefield NHS Trust
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral