Imperial College London

Dr Charlotte Dean

Faculty of MedicineNational Heart & Lung Institute

Senior Lecturer
 
 
 
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Contact

 

+44 (0)20 7594 3174c.dean

 
 
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Location

 

360Sir Alexander Fleming BuildingSouth Kensington Campus

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Summary

 

Publications

Citation

BibTex format

@article{Löser:2016:10.1016/j.jaci.2016.07.033,
author = {Löser, S and Gregory, LG and Zhang, Y and Schaefer, K and Walker, SA and Buckley, J and Denney, L and Dean, CH and Cookson, WO and Moffatt, MF and Lloyd, CM},
doi = {10.1016/j.jaci.2016.07.033},
journal = {Journal of Allergy and Clinical Immunology},
pages = {1496--1507.e3},
title = {Pulmonary ORMDL3 is critical for induction of Alternaria induced allergic airways disease},
url = {http://dx.doi.org/10.1016/j.jaci.2016.07.033},
volume = {139},
year = {2016}
}

RIS format (EndNote, RefMan)

TY  - JOUR
AB - BACKGROUND: Genome-wide association studies have identified the ORMDL3 (ORM (yeast)-like protein isoform 3) gene locus on human chromosome 17q to be a highly significant risk factor for childhood-onset asthma. OBJECTIVE: We sought to investigate in vivo the functional role of ORMDL3 in disease inception. METHODS: An Ormdl3 deficient mouse was generated and the role of ORMDL3 in the generation of allergic airways disease to the fungal aeroallergen Alternaria alternata determined. An adeno-associated viral vector was also utilized to reconstitute ORMDL3 expression in airway epithelial cells of Ormdl3 KO mice. RESULTS: Ormdl3 knock-out mice were found to be protected from developing allergic airways disease and showed a marked decrease in pathophysiology, including lung function and airway eosinophilia induced by Alternaria. Alternaria is a potent inducer of cellular stress and the unfolded protein response and ORMDL3 was found to play a critical role in driving the ATF6 mediated arm of this response through Xbp1 and downstream activation of the endoplasmic reticulum-associated degradation pathway. Additionally ORMDL3 mediated uric acid release, another marker of cellular stress. In the knockout mice, reconstitution of Ormdl3 transcript levels specifically in the bronchial epithelium resulted in reinstatement of susceptibility to fungal allergen-induced allergic airways disease. CONCLUSIONS: This study demonstrates that ORMDL3, an asthma susceptibility gene identified by genome-wide association studies, contributes to key pathways that promote changes in airway physiology during allergic immune responses.
AU - Löser,S
AU - Gregory,LG
AU - Zhang,Y
AU - Schaefer,K
AU - Walker,SA
AU - Buckley,J
AU - Denney,L
AU - Dean,CH
AU - Cookson,WO
AU - Moffatt,MF
AU - Lloyd,CM
DO - 10.1016/j.jaci.2016.07.033
EP - 1507
PY - 2016///
SN - 1097-6825
SP - 1496
TI - Pulmonary ORMDL3 is critical for induction of Alternaria induced allergic airways disease
T2 - Journal of Allergy and Clinical Immunology
UR - http://dx.doi.org/10.1016/j.jaci.2016.07.033
UR - http://hdl.handle.net/10044/1/40278
VL - 139
ER -