A Pharmacodynamics Analysis of Glucocorticoid Receptor-Mediated Gene Expression in BEAS-2B Human Airway Epithelial Cells

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dc.contributor.advisorGiembycz, Mark
dc.contributor.advisorNewton, Robert
dc.contributor.authorJoshi, Taruna
dc.contributor.committeememberMcKay, Derek
dc.contributor.committeemembervon der Weid, Pierre
dc.contributor.committeememberHirota, Simon
dc.contributor.committeememberCameron, Lisa
dc.date.accessioned2016-06-22T22:01:28Z
dc.date.available2016-06-22T22:01:28Z
dc.date.issued2016
dc.date.submitted2016en
dc.description.abstractInternational treatment guidelines recommend that inhaled glucocorticoids be used as a monotherapy to control mild-to-moderate asthma. However, a combination of an inhaled glucocorticoid with a long-acting β2-adrenoceptor agonist is recommended for managing moderate-to-severe asthma, which cannot be controlled by glucocorticoids alone. Increasing evidence supports the idea that glucocorticoids acting through the glucocorticoid receptor (GR) can attenuate inflammatory responses either by inducing anti-inflammatory genes (a process called transactivation) or by suppressing pro-inflammatory genes (a process called transrepression). Gene transactivation by glucocorticoids was initially thought to be responsible for causing the metabolic side-effects and, hence, is relatively understudied when compared to transrepression. However, it has become increasingly clear that transactivation plays an important role in the anti-inflammatory actions of glucocorticoids. Moreover, the extent to which clinically-relevant glucocorticoids are equivalent in their ability to promote gene expression is unclear. This thesis describes the first pharmacodynamic approach to evaluate the transactivation potential of a panel of glucocorticoids alone and in combination with indacaterol (Ind), a long-acting β2-adrenoceptor agonist. Pharmacodynamic analyses showed that magnitude of luciferase gene induction was agonist dependent (i.e. seven different glucocorticoids tested displayed varying degrees of agonism). In addition, there were significant differences in agonist potency and, more importantly, the relationship between GR occupancy and response. To complement the reporter studies, similar analyses were performed on four glucocorticoid-inducible candidate genes. Three of these (GILZ, p57kip2 and CRISPLD2) are genes with potential anti-inflammatory activity and a fourth gene, PDK4 is predicted to promote metabolic side-effects. Similar to the luciferase reporter system, the expression of these genes was agonist-dependent and displayed markedly different GR occupancy-response relationships. Furthermore, Ind, when combined with the seven GR agonists tested, synergistically enhanced transactivation, the magnitude of which was agonist and gene dependent. These studies demonstrate that when gene transactivation is used as a functional output, glucocorticoids used to treat asthma are not biologically-equivalent. It is proposed that these differences may be exploited to therapeutic advantage. Thus, the generation of gene expression ‘fingerprints’ in target and off-target human tissues may allow new GR agonists to be rationally designed for asthma with an improved therapeutic index.en_US
dc.identifier.citationJoshi, T. (2016). A Pharmacodynamics Analysis of Glucocorticoid Receptor-Mediated Gene Expression in BEAS-2B Human Airway Epithelial Cells (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. doi:10.11575/PRISM/24945en_US
dc.identifier.doihttp://dx.doi.org/10.11575/PRISM/24945
dc.identifier.urihttp://hdl.handle.net/11023/3069
dc.language.isoeng
dc.publisher.facultyGraduate Studies
dc.publisher.institutionUniversity of Calgaryen
dc.publisher.placeCalgaryen
dc.rightsUniversity of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.
dc.subjectBiology--Molecular
dc.subjectPharmacology
dc.subject.classificationGlucocorticoiden_US
dc.subject.classificationGlucocorticoid Receptoren_US
dc.subject.classificationPharmacodynamicsen_US
dc.subject.classificationLong acting beta adrenergic agonisten_US
dc.subject.classificationantagonisten_US
dc.subject.classificationpartial agonisten_US
dc.subject.classificationPotencyen_US
dc.subject.classificationAffinityen_US
dc.subject.classificationEfficacyen_US
dc.subject.classificationConcentration-response curvesen_US
dc.subject.classificationGlucocorticoid response elementen_US
dc.titleA Pharmacodynamics Analysis of Glucocorticoid Receptor-Mediated Gene Expression in BEAS-2B Human Airway Epithelial Cells
dc.typedoctoral thesis
thesis.degree.disciplineCardiovascular & Respiratory Sciences
thesis.degree.grantorUniversity of Calgary
thesis.degree.nameDoctor of Philosophy (PhD)
ucalgary.item.requestcopytrue
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