2021ShereeRPHD corrected.pdf (8.93 MB)
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TGF-β1 and WNT5A Functional Crosstalk and its Role in Asthmatic Epithelial Repair

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thesis
posted on 11.01.2022, 14:30 by Sheree Roberts
BACKGROUND
The epithelium is the first line of defence against inhaled pathogens, but it is found to be damaged and dysfunctional in asthma. This may predispose the airways to persistent inflammation that may drive airway remodelling. WNT5A and TGF-β1 signalling are vital for lung development, and evidence suggests they may be reinstated in airway repair. Crosstalk between WNT5A and TGF-β1 is evident in other cell types but is yet to be elucidated in the airway epithelium. Delineating this signalling crosstalk may further understanding of the repair process to provide tractable targets for new asthma therapies.

METHODS
This study sought to evaluate the impact of WNT5A and TGF-β1 (alone or synergistic) on (1) epithelial repair in BEAS-2Bs and differentiated human bronchial epithelial cells (HBECs) and (2) epithelial-mesenchymal transition (EMT) induction and SMAD2/3 phosphorylation, which have been identified as WNT5A-TGF-β1 crosstalk mechanisms in other cell types. The use of bulk transcriptional profiling in epithelial cells from moderate-severe asthmatic patients was used to identify potential mechanistic avenues to explore in the experimental in vitro models.

RESULTS
We found neither WNT5A nor TGF-β1 stimulation alone had a significant effect on wound healing, however TGF-β1 signalling was found to have a significant effect on WNT5A-mediated wound closure. Crosstalk however was not evident on EMT induction or SMAD2/3 phosphorylation. The bulk gene expression profiling analysis in moderate-severe asthmatic patients also failed to demonstrate an association between WNT and TGF-β signalling and airflow obstruction (a clinical surrogate marker of airway remodelling) in asthma.

DISCUSSION
This PhD does not support a role for WNT5A or TGF-β1 in HBEC repair, but it does suggest that negative WNT5A-TGF-β1 crosstalk may exist in HBECs. Further investigation is needed to confirm these findings.

History

Supervisor(s)

Salman Siddiqui; David Cousins

Date of award

29/09/2021

Author affiliation

Department of Respiratory Sciences,

Awarding institution

University of Leicester

Qualification level

Doctoral

Qualification name

PhD

Language

en