This thesis presents studies on novel therapeutic interventions for the treatment of allergic asthma providing proof of concept through extensive investigations in mouse models of human disease. The current increase in the incidence of asthma worldwide along with inability of current medications to treat the primary causes of the disease indicates that novel therapeutic approaches are required. This will improve the quality of life and disease burden concerns of the community. I investigated two alternate therapeutic approaches in an effort to identify new candidate targets with significant therapeutic potential. The first research chapter (see chapter 3) presents an initial study on the role of miRNA in the development of allergic airways disease (AAD). This study also demonstrates proof-of-concept for the use of modified, cholesterol conjugated complementary sequences termed antagomirs to specifically inhibit the expression of miR-126 in the airways and to alleviate AAD. The second research chapter (see chapter 4) presents a comparative study in which treatment of allergic mice with an antagomir suppressing miR-145 is compared to mice treated with the current gold standard therapy, systemic glucocorticoids. Here it is demonstrated that the novel therapeutic approach of selectively inhibiting the upregulation of miR-145 in the airway wall is as potent as treatment with systemic dexamethasone to alleviate AAD. The third research chapter (see chapter 5) presents a study where miR-126 was inhibited in a chronic model of AAD. The findings of this study confirm an important role of miR-126 in the regulation of allergic airways inflammation but suggest that in this model miR-126-independent mechanisms promote the development of tissue remodelling, hallmark features of chronic asthma. These results suggest that targeting a single miRNA may not be sufficient to reduce all aspects of AAD. The fourth research chapter (see chapter 6) presents a study of the tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) induced signalling pathway in AAD and rhinovirus (RV)-induced exacerbation of AAD. Here I identify a novel role for TRAIL induced Midline-1 (Mid1) driven polyubiquination and silencing of the Protein Phosphatase 2a (PP2a). Furthermore, blocking this signalling pathway through either the silencing of Mid1 with siRNA or the synthetic reactivation of PP2a using the small molecule AAL(S) was capable of alleviating AAD and RV-induced exacerbation. This study provides proof-of-concept that modulation of the TRAIL induced signalling pathway may provide therapeutic benefit in the treatment of AAD. Together these studies have investigated novel and relevant targets for therapeutic intervention in AAD. By targeting immuno-regulatory systems such as miRNAs and TRAIL regulated signalling cascades at the initial site of allergen exposure –the airway surface, these approaches have the potential to successfully modulate the complex aberrant immune response that initiates and underpins allergic asthma.
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University of Newcastle Research Higher Degree Thesis
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