- Title
- Epigenetic regulation of airway inflammation in asthma
- Creator
- Gunawardhana, Lakshitha
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2014
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Asthma is an inflammatory disease that manifests in the airways. There are an estimated 300 million people worldwide currently suffer from asthma. Common asthma symptoms include dyspnea and wheezing. These are consequences of the reversible airflow obstruction associated with airway inflammation. The symptoms can be mild or can be as severe as life threatening depending on nature of underlying inflammation. Although heredity plays a role in the disease pathogenesis, the high and rising prevalence of asthma, particularly in recent decades highlights a strong influence of the environment. To this end, epigenetic phenomena including alteration of DNA methylation and chromatin structure are likely contributors to the pathogenesis of asthma as well as a plausible source of phenotype heterogeneity. Especially subtle alteration of DNA methylation patterns which occur early in life may impact on disease development. However, the exact role of epigenetic mechanisms in the pathogenesis of asthma and inflammatory phenotypes of asthma are not well understood. This thesis investigates; 1) Alterations in infant peripheral blood DNA methylation profiles associated with pre-natal exposure to maternal asthma, 2) The role of chromatin structure by analysing histone acetyl-transferases (HAT) and histone de-acetylases (HDAC) activity of peripheral blood monocytes in inflammatory phenotypes of adult asthma, 3) Alterations in the DNA methylation profile of peripheral blood monocytes associated with inflammatory phenotype of adult asthma. The primary findings of this thesis are: 1) Maternal asthma during pregnancy is associated with alterations in peripheral blood DNA methylation in infants’. 2) Inflammatory phenotypes of asthma are associated with differential DNA methylation in peripheral blood monocytes. Gene network analyses of these differentially methylated genes revealed distinct molecular pathways, suggesting possible implications in the disease pathogenesis. 3) Neutrophilic asthma is associated with lower HDAC activity and higher HAT activity of peripheral blood monocytes compared to both eosinophilic and paucigranulocytic asthma. Collectively, the findings of this thesis emphasised the significance of epigenetic factors playing a role in the development of asthma and inflammatory phenotypes of asthma. An association of peripheral blood methylation profiles of infants with maternal asthma suggests a potential inheritance of the disease susceptibility. The characteristic alterations of DNA methylation in blood monocytes suggest an underlying epigenetic basis for the inflammatory phenotypes while the differences in HAT/HDAC activity in monocytes further emphasise a role for the epigenome in the development of inflammatory phenotypes. The findings of this thesis warrant further investigation and may help us get one step closer to understanding the role of epigenetics in airway inflammation in asthma.
- Subject
- asthma; inflammatory phenotypes; blood monocytes; airway macrophages; chromatin structure; illumina infinium methylation; neutrophilic asthma; eosinophilic asthma; paucigranulocytic asthma; mixed granulocytic asthma; epigenetics; DNA methylation; HAT; HDAC
- Identifier
- http://hdl.handle.net/1959.13/1058797
- Identifier
- uon:16473
- Rights
- Copyright 2014 Lakshitha Gunawardhana
- Language
- eng
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| Thumbnail | File | Description | Size | Format | |||
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| View Details Download | ATTACHMENT01 | Abstract | 187 KB | Adobe Acrobat PDF | View Details Download | ||
| View Details Download | ATTACHMENT02 | Thesis | 2 MB | Adobe Acrobat PDF | View Details Download |