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Holland, Seth

University of British Columbia

Inflammation, while necessary for repairing damage and preventing infection, can be pathological when it occurs at an inappropriate location or for a prolonged period; making the attenuation of inflammation an outstanding clinical need. Electrophiles are chemical species that readily accept an electron pair from nucleophiles to form a covalent bond and in the cellular context can initiate a stress state by interfering with basal function. Activating Transcription Factor 3 (ATF3) is upregulated in states of cellular stress but also has an orchestrating role in negatively regulating canonical pro-inflammatory pathways. In Chapter 1 I hypothesize that by upregulating ATF3 via exogenous electrophile treatment excessive inflammation can be attenuated. I use two electrophilic compounds to test this: 1) DMF, a cell permeable electrophile and 2) GDS, a novel compound (the adduct of reduced glutathione and DMF) – I theorize that GDS functions as a buffered electrophile that maintains a precise and stable amount of electrophile available to the cell. In Chapter 2 using cultured macrophages I demonstrate GDS’s buffered electrophile reaction dynamics, how it establishes a state of electrophilic stress resulting in ATF3 upregulation through putative succination of NRF2, its inflammation attenuatory effect, and how it differs from DMF. In Chapter 3 I use transcriptomics, epigenomics, and metabolomics to characterize the phenotype of GDS treated macrophages, interrogate the contribution of ATF3 to these altered phenotype, and comprehensively contrast its effect to that of DMF. In Chapter 4 I use GDS in vivo for the first time, establish its tolerability, and demonstrate its therapeutic efficacy in a mouse model of multiple sclerosis. Finally, in Chapter 5 I describe buffered electrophiles’ properties mathematically, propose the utility and future development of novel buffered electrophiles, and end by revisiting the hypothesis.

Text; Dataset

2025-02-20

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/90396

Cell and Developmental Biology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/