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dc.contributor.supervisor Roussel, Marc R.
dc.contributor.supervisor Thakor, Nehal
dc.contributor.author Trofimenkoff, Elizabeth Anne Mae
dc.contributor.author University of Lethbridge. Faculty of Arts and Science
dc.date.accessioned 2022-11-09T20:29:30Z
dc.date.available 2022-11-09T20:29:30Z
dc.date.issued 2022
dc.identifier.uri https://hdl.handle.net/10133/6381
dc.description.abstract Glioblastoma is an extremely aggressive brain cancer that has a median survival time of 15 months, and a 95% mortality rate within 5 years. Standard-of-care therapy has not changed in over 15 years, and has unfortunately been limited in success. Glioblastomas tend to grow rapidly, creating hypoxic conditions within their cells. Under these conditions, the alpha subunit of eIF2 is phosphorylated, resulting in its inability to deliver the initiator tRNA to the ribosome during canonical translation initiation. In healthy cells, if the stress persists and is not alleviated, this may trigger a form of programmed cell death known as apoptosis. However, cancer cells exploit a non-canonical translation initiation pathway that replaces eIF2 with eIF5B to deliver the tRNAi to the pre-initiation complex. Some anti-apoptotic proteins are translated using this pathway, such as X-linked inhibitor of apoptosis (XIAP). The XIAP mRNA contains an IRES element which allows it to be translated using this non-canonical pathway. XIAP is up-regulated in glioblastoma cells, and therefore the eIF5B-mediated non-canonical translation initiation pathway is a promising therapeutic target for those suffering from this deadly disease. In this thesis, ordinary differential equation (ODE) and delay-differential equation (DDE) models are assembled to analyze the canonical and non-canonical translation initiation pathways. Four inhibitor classes are proposed and examined for both pathways. Results are presented in the forms of sensitivity analyses, 3D surface plots and contour plots which allow us to determine several potentially therapeutically effective combinations of inhibitor concentrations and KD values for each mode of inhibition. The results indicate that a direct eIF5B inhibitor or non-canonical ternary complex inhibitor are the most promising therapeutic targets. en_US
dc.description.sponsorship New Frontiers in Research Fund en_US
dc.language.iso en_US en_US
dc.publisher Lethbridge, Alta. : University of Lethbridge, Dept. of Chemistry and Biochemistry en_US
dc.relation.ispartofseries Thesis (University of Lethbridge. Faculty of Arts and Science) en_US
dc.subject applied mathematics en_US
dc.subject canonical translation initiation en_US
dc.subject chemotherapy targets en_US
dc.subject differential equations en_US
dc.subject eIF5B en_US
dc.subject glioblastoma en_US
dc.subject mathematical biochemistry en_US
dc.subject mathematical biology en_US
dc.subject mathematical oncology en_US
dc.subject non-canonical translation initiation en_US
dc.subject numerical analysis en_US
dc.subject translation initiation en_US
dc.subject Glioblastoma multiforme--Research en_US
dc.subject Genetic translation--Regulation--Mathematical models en_US
dc.subject Computational biology en_US
dc.subject Cellular control mechanisms--Research en_US
dc.subject Cancer cells--Growth--Regulation--Mathematical models en_US
dc.subject Differential equations en_US
dc.subject Numerical analysis en_US
dc.subject Dissertations, Academic en_US
dc.title Mathematical modeling of eIF5B-mediated non-canonical translation initiation as a chemotherapeutic target en_US
dc.type Thesis en_US
dc.publisher.faculty Arts and Science en_US
dc.publisher.department Department of Chemistry and Biochemistry en_US
dc.degree.level Masters en_US
dc.proquest.subject 0487 en_US
dc.proquest.subject 0405 en_US
dc.proquest.subject 0992 en_US
dc.proquestyes Yes en_US


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