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Title: The role of WNT5a in airway remodelling in asthmatic airway epithelial repair
Author: Daud, Tariq
ISNI:       0000 0004 7428 3226
Awarding Body: University of Leicester
Current Institution: University of Leicester
Date of Award: 2018
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Asthma is heterogeneous disease characterised by distinct tissue molecular phenotypes (Choy et al, 2015). However, the process of repair and remodelling remains ambiguous in this context. Although previous reports have shown elevated protein and mRNA expression of WNT5a, there is limited evidence in the literature to the major source of and function of WNT5a in asthma. Furthermore, WNT5a acting through the non-canonical axis exhibits functional cross talk with TGF-β1, which may influence repair and remodelling in asthma. We sought to evaluate protein expression of WNT5a and TGF-β1 in bronchial biopsies from a previously described cohort of subjects (9 healthy and 23 asthmatics) in whom aggregate gene signature profiles for Th2 and Th17 activity from tissue homogenates were available. After observing co-localised protein expression of both WNT5a and TGF-b1 in the epithelium, further investigations in BEAS-2B cells as a basal cell wound repair model were undertaken. We observed increased WNT5a protein expression pattern in vivo in asthma. WNT5a protein expression was significantly elevated in the epithelium in Th17 gene expression high asthmatic biopsies and the lamina propria, but not the airway smooth muscle bundle. We found a significant correlation and colocalisation of protein expression between TGF-β1 and WNT5a immunostaining in the epithelium suggestive of crosstalk. Further evidence supportive of cross talk was that both TGF-β1 and WNT5a were shown to induce SMAD2/3 nuclear translocation, which was inhibited by BOX-5 (a WNT5a inhibitor). Furthermore, WNT5a increased [Ca2+]I suggestive of noncanonical pathway engagement. Lastly, both WNT5a and TGF-β1 dual stimulation increased wound closure in BEAS-2B cells. Finally, stimulation of BEAS-2B cells with either TGF-β1 or WNT5a increased the expression of epithelial-mesenchymal transition (EMT) markers. WNT5a protein is increased in the airway epithelium in patients with asthma displaying a mucosal Th17-dependent gene signature. Additionally, we show potential in vitro evidence of TGF-β1-WNT5a cross talk via the SMAD2/3 axis, promoting EMT and epithelial wound closure. This study potentially highlights a novel crosstalk pathway between WNT5a-TGF-β1 as a possible epithelial repair mechanism employed in asthma that warrants further molecular and functional characterisation.
Supervisor: Siddiqui, Salman ; Amrani, Yassine Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available