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Title: Studying the effects of severe sepsis on histone post translational modifications using mass spectrometry
Author: Minshull, Tom
ISNI:       0000 0004 5919 2262
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2016
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Sepsis is a very serious clinical syndrome. It results from the host's systemic response to an infectious agent. In order to treat sepsis an effective therapeutic target and robust biomarkers are required, so that the appropriate drug can be given at the right time. However, 30 clinical trials of therapies attempting to treat sepsis by blocking the action of TNF? or IL-1 have proven ineffective and a meta-analysis of 3370 studies examining 178 biomarkers found that none displayed the necessary specificity to be routinely and robustly used in clinical practice (Hotchkiss et al. 2013b; Pierrakos & Vincent 2010). Therefore, an effective and robust therapeutic target and biomarker are highly sort after for the management of sepsis. Recent research has highlighted a possible role for histone post translational modifications (PTMs) in the disease process of sepsis. This thesis sought to utilise a mass spectrometry approach to identify and quantify global levels of histone PTMs in sepsis. In order to investigate this, a novel 2D-LC-MS/MS workflow was developed using a porous graphitic column in the first dimension. This increased the number of histone peptides identified by 62.7% compared to a 1D-LC approach. Using this methodology research focused on two human primary cell types: macrophages and T-cells to examine the effects of sepsis on global levels of histone PTMs. This study for the first time identified a number of histone PTMs that were perturbed during sepsis in both primary human cell types. The results showed that significant changes in a number of histone modifications were observed, including; H3.3K27me2K36me2, H2AK5ac, H3K9me2 and H3K23ac. These results provide further insight into the role of epigenetics associated with severe sepsis and provide potential biomarkers that can be used to stage the progression of sepsis, or be targeted therapeutically in the treatment of sepsis.
Supervisor: Dickman, Mark ; Read, Robert Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available