- Title
- Molecular characterisation of severe asthma
- Creator
- Sánchez Ovando, Stephany
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2021
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- The heterogeneity of mechanisms of pathogenesis involved in severe asthma is recognised. Recent advances have led to treatments targeting Type-2 immunity, resulting in improved outcomes for those with severe allergic and eosinophilic asthma. However more than 50% of patients with asthma present Non-Type-2 mechanisms of inflammation. These mechanisms are largely unknown, relatively unresponsive to corticosteroids, and not targeted by current monoclonal antibodies. A greater understanding of the mechanisms leading to different phenotypes of severe asthma is a key step towards personalised management and crucial for the discovery of new therapies targeting Non-Type-2 pathways. This thesis sought to address this knowledge gap by investigating gene expression in endobronchial biopsies of severe asthma. Key findings of this thesis include; upregulation of DNASE1L3 and FKBP5 in asthma compared with healthy controls, and upregulation of IL1β in neutrophilic asthma compared with non-neutrophilic asthma was demonstrated (Chapter 3). 6GS was able to distinguish asthma from healthy controls, and neutrophilic from non-neutrophilic asthma, whereas TH2S was able to distinguish asthma from healthy controls, and eosinophilic from non-eosinophilic asthma. Severe neutrophilic asthma had the most distinct transcriptomic profile and novel links between neutrophilic asthma and enrichment of neuroinflammation, the role of NFAT, and PKCθ pathways were established (Chapter 4). Dysregulation of pathways associated with tissue remodelling; SUMOylation; basal cell carcinoma, and Wnt/β-catenin pathways was observed across all inflammatory phenotypes. Mechanisms associated with airway remodelling and fibrosis were identified by performing a comprehensive analysis of differentially expressed genes, altered pathways and gene-sets shared by two independent cohorts of severe asthma (Chapter 5). The identified mechanism highlighted the role of CD4+ T cells and mast cells, and demonstrating activation of SUMOylation, NRF2 pathways, and IL18R1. All three mechanisms were strongly associated with airway remodelling and fibrosis. Collectively, the findings of this thesis provide new understanding of Non-Type-2 mechanisms of pathogenesis. It provides novel insights into mechanistic pathways associated with severe neutrophilic asthma and airway remodelling in tissue samples. Further functional studies of the mechanisms identified in this thesis are required to move forward in the development of new therapies targeting Non-Type-2 mechanisms of pathogenesis.
- Subject
- severe asthma; molecular characterisation; transcriptomics; gene signatures
- Identifier
- http://hdl.handle.net/1959.13/1468379
- Identifier
- uon:48044
- Rights
- Copyright 2021 Stephany Sánchez Ovando
- Language
- eng
- Full Text
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| Thumbnail | File | Description | Size | Format | |||
|---|---|---|---|---|---|---|---|
| View Details Download | ATTACHMENT01 | Thesis | 7 MB | Adobe Acrobat PDF | View Details Download | ||
| View Details Download | ATTACHMENT02 | Abstract | 508 KB | Adobe Acrobat PDF | View Details Download |