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Title: The role of histone modifications in severe asthma
Author: Brook, Peter Owen
ISNI:       0000 0004 6496 7317
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2017
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Severe asthma is an airways disease that causes restriction of airflow to the lung leading to difficulty breathing, where even high doses of medication does not alleviate the symptoms. There are studies that have demonstrated differentially expressed genes in both CD8+ T-cells and the bronchial epithelium of severe asthmatics, however the causes of the changes in gene expression have not been elucidated. Histones, proteins which store DNA, can be acetylated or methylated which changes their binding of DNA allowing for modified transcription. I hypothesise that modifying the histone modification of Bronchial Epithelium and CD8+ T-cells would be able to limit the inflammatory effects of severe asthma, that measuring changes in histone modifications would show differences between severe and non-serere asthmatics and that by using modern analysis of gene expression and histone modifications it would be possible to discover novel genes and pathways involved in asthma. The Bromodomain and Extra terminal domain mimic JQ1 was able to suppress release of Interleukin-6 and Interleukin-8 and SGC-CBP30 the CBP/p300 inhibitor limited proliferation in bronchial epithelium. CD8+ T-cells from a small group of severe and non-severe asthmatics had gene arrays carried out and were analysed by weighted geneome coexpression network analysis which found modules containing genes involved in intracellular motility and vesicle formation that linked strongly to % predicted Forced Expiratory volume in one second. CD8+ ChIP-Seq studies of T-cell histone modifications were attempted, but not successful. A pilot test on Severe asthmatics CD8+ T-cells treated with SGC-CBP30 showed a reduction in the release of the inflammatory mediator MIP1α and suggested that this was without affecting its mRNA production or cell viability, however higher numbers of patients would be needed to confirm this.
Supervisor: Adcock, Ian ; Lavender, Paul ; Durham, Andrew Sponsor: Asthma UK
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral