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Title: The functional relevance of tensin1 in chronic obstructive pulmonary disease
Author: Stylianou, Panayiota
ISNI:       0000 0004 6422 0870
Awarding Body: University of Leicester
Current Institution: University of Leicester
Date of Award: 2017
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Background: Chronic obstructive pulmonary disease (COPD) constitutes a major cause of morbidity and mortality. Genome wide association studies (GWAS) have shown significant associations between airflow obstruction or COPD with a non-synonymous single nucleotide polymorphism (SNP) in the TNS1 gene (which encodes tensin1) with COPD. This SNP generates the amino acid change R1197W in the tensin1 protein. R1197W is associated with reduced FEV1. Aim: To examine tensin1 genotype, expression and function in human airways and cells from healthy controls and patients with smoking-related COPD or asthma. Methods: Lung resections were immunostained for tensin1. Tensin1 expression in cultured human airway smooth muscle cells (HASMCs) and bronchial epithelial cells (HBECs) was evaluated using qRT-PCR, western blotting and immunofluorescent staining. siRNAs were used to downregulate tensin1 expression, and cells from healthy subjects and patients were genotyped using restriction fragment length polymorphism (RFLP) analysis. Results: Immunohistochemical staining demonstrated increased tensin1 expression in the airway smooth muscle and lamina propria in COPD tissue, but not in asthma, when compared to healthy controls. Tensin1 was expressed in HASMCs and upregulated by TGFβ1. TGFβ1 and fibronectin increased the localisation of tensin1 to fibrillar adhesions. Tensin1 and α-smooth muscle actin (αSMA) were strongly co-localised in actin stress fibres. Tensin1 depletion in HASMCs attenuated αSMA expression and their contraction of collagen gels, but not proliferation. RFLP analysis revealed the presence of R1197W in predominantly people with COPD and asthma, but rarely in healthy controls. Conclusions: Tensin1 may promote airway obstruction by enhancing the expression of contractile proteins and their localisation to stress fibres in HASMCs. R1197W is associated predominantly with COPD and asthma suggesting that the polymorphism may promote dysfunction in HASMCs.
Supervisor: Bradding, Peter ; Amrani, Yassine Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available