Exploring the combinatorial effects of inflammatory stimuli and glucocorticoids on BIRC3 and BIRC2 expression: Differential regulation and functional investigations
| dc.contributor.advisor | Newton, Robert | |
| dc.contributor.author | Thorne, Andrew James | |
| dc.contributor.committeemember | Hirota, Simon | |
| dc.contributor.committeemember | Yipp, Bryan | |
| dc.date | 2024-05 | |
| dc.date.accessioned | 2024-01-18T23:31:20Z | |
| dc.date.available | 2024-01-18T23:31:20Z | |
| dc.date.issued | 2024-01-16 | |
| dc.description.abstract | Inflammation serves as a crucial innate mechanism in response to injury, infection, or harmful stimuli that activates the immune system and aims to restore homeostasis. Chronic inflammatory disorders like asthma present with ongoing inflammation whereby pulmonary epithelial cells release inflammatory mediators, intensifying airway inflammation, and worsening disease. Synthetic glucocorticoids represent the primary treatment for asthma by utilizing the anti-inflammatory properties of their endogenous counterparts to reduce inflammatory mediators. Their mechanism of action involves binding to the glucocorticoid receptor (GR) in cells and interacting with DNA elements to enhance anti-inflammatory gene expression. However, certain inflammatory genes play protective roles by promoting tissue repair or self-regulatory feedback mechanisms to limit inflammatory signaling. Some of these genes are spared the repressive effects of glucocorticoids and are even augmented, presumably for protection. The BIRC3 gene, while being associated with the inflammatory NF-κB pathway, is a gene upregulated in models of the pulmonary epithelium and in vivo by glucocorticoids. BIRC3, along with its family member BIRC2, may contribute to regulating NF-κB pathways, but also inhibit apoptosis, although their specific roles remain unclear. Consequently, the rationale of glucocorticoid-enhanced BIRC3 remain ambiguous. Given their similarities, BIRC3 and BIRC2 were both investigated, focusing on their expression, regulation, and the interactions between the GR and NF-κB at the gene promoter. These analyses detailed robust expression patterns differentiating BIRC3 and BIRC2 by their response to inflammatory cytokines and glucocorticoids over time. Promoter analysis revealed insights into possible GR and NF-κB interactions to explain the regulation of BIRC3 expression, thus providing an example of GR-NF-κB positive interactions leading to inflammatory gene expression. Further, investigations into the NF-κB pathway as a platform for BIRC2/3 function revealed the established canonical NF-κB pathway may challenge established dogma. This exploratory research highlighted the significance of TAK1 as central kinase within the NF-κB pathway. Moreover, possible redundancy between IKK1 and IKK2, and the presence of additional regulators within canonical NF-κB signaling may exist. While this study provided no greater insights for redundant, or individual roles for BIRC2/3 in NF-κB signaling or apoptosis, it facilitated the development of tools for future investigations. | |
| dc.identifier.citation | Thorne, A. J. (2024). Exploring the combinatorial effects of inflammatory stimuli and glucocorticoids on BIRC3 and BIRC2 expression: Differential regulation and functional investigations (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. | |
| dc.identifier.uri | https://hdl.handle.net/1880/117979 | |
| dc.identifier.uri | https://doi.org/10.11575/PRISM/42823 | |
| dc.language.iso | en | |
| dc.publisher.faculty | Graduate Studies | |
| dc.publisher.institution | University of Calgary | |
| dc.rights | University 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.subject | Inflammation | |
| dc.subject | Glucocorticoids | |
| dc.subject | BIRC3 | |
| dc.subject | BIRC2 | |
| dc.subject | Airways | |
| dc.subject | NF-kB | |
| dc.subject.classification | Biology--Cell | |
| dc.subject.classification | Biology--Molecular | |
| dc.subject.classification | Genetics | |
| dc.title | Exploring the combinatorial effects of inflammatory stimuli and glucocorticoids on BIRC3 and BIRC2 expression: Differential regulation and functional investigations | |
| dc.type | doctoral thesis | |
| thesis.degree.discipline | Medicine – Cardiovascular/Respiratory Science | |
| thesis.degree.grantor | University of Calgary | |
| thesis.degree.name | Doctor of Philosophy (PhD) | |
| ucalgary.thesis.accesssetbystudent | I do not require a thesis withhold – my thesis will have open access and can be viewed and downloaded publicly as soon as possible. |