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Novel insights into in vivo functions of the asthma susceptibility gene ORMDL3

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Title: Novel insights into in vivo functions of the asthma susceptibility gene ORMDL3
Authors: Loeser, Stephan
Item Type: Thesis or dissertation
Abstract: ORMDL3 was first identified as an asthma susceptibility gene by multiple GWA studies. Subsequent in vitro and in vivo analyses identified the protein as a negative regulator of de novo sphingolipid synthesis and inducer of ER-stress, while ORMDL3 overexpression in mice elevated IgE, eosinophilia and IL-4 induction in response to OVA application. The aim of this thesis was to decipher functions of ORMDL3 in regulating HDM and Alternaria induced allergic airways disease, utilising Ormdl3 deficient mice. Initial HDM administration regimens applied to adult and neonatal WT and Ormdl3 deficient mice, revealed that HDM induced airway pathophysiology was largely unaffected by Ormdl3 deficiency. Nonetheless, airway lumen IL-4 secretion in response to HDM was tempered in adult mice upon Ormdl3 deletion, while neonatal Ormdl3 KO mice exhibited enhanced pulmonary eosinophilia. Since adult Ormdl3 KO mice were protected from fungal allergen induced AHR, epithelial DAMP release and ER-stress induction, the ability of ORMDL3 to regulate asthma disease onset might depend on the capacity of particular allergens to directly induce Ormdl3 expression. Furthermore, protective asset of Ormdl3 deficiency was attributable to the proteins function in airway epithelial cells. Mechanistically, ORMDL3 promoted the induction of the ATF6 dependent UPR pathway, while no differences were detected in disease relevant sphingolipid metabolites. In agreement with in vitro reports, ORMDL3 was however found to negatively regulated de novo sphingolipid synthesis in vivo. Interestingly, in an acute model of Alternaria administration, Ormdl3 deficiency enhanced disease pathology, signified by the detection of elevated pulmonary type-2 cytokines levels. In summary, ORMDL3, the most significant risk factor for asthma identified by GWA studies, modulated acute allergen dependent innate immune responses, leading to elevated type-2 immunity in Ormdl3 KO mice before adaptive immune responses were established. Conversely, during long term fungal allergen exposure, gene deficiency led to protection from enhanced airway resistance and cellular damage, highlighting mechanisms whereby ORMDL3, identified by GWA studies regulates allergic immune responses.
Content Version: Open Access
Issue Date: Sep-2016
Date Awarded: Jan-2017
URI: http://hdl.handle.net/10044/1/67985
DOI: https://doi.org/10.25560/67985
Supervisor: Lloyd, Clare M
Zhang, Youming
Moffatt, Miriam F
Sponsor/Funder: Wellcome Trust (London, England)
Department: National Heart & Lung Institute
Publisher: Imperial College London
Qualification Level: Doctoral
Qualification Name: Doctor of Philosophy (PhD)
Appears in Collections:National Heart and Lung Institute PhD theses

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