Harnessing in vivo bioluminescence imaging tools to address current issues in cancer, metabolic, and neurological research
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Bioluminescence imaging is a well-known modality that stems from a long-observed natural phenomenon. This technology's high sensitivity, selectivity, and various approaches to creating imaging tools made it popular in multiple research areas. Therefore, it was decided to develop novel tools to answer more biological questions in the key areas of biomedical research--cancer, metabolic, and neurological diseases. The first aim of this dissertation is to develop a tool that would enable imaging of the remodeling of lipid droplets. Monitoring this process is crucial for addressing the rapidly spreading nonalcoholic fatty liver disease (NAFLD). The developed probe consists of azide-labeled palmitic acid and 'caged' luciferin. We successfully tested the developed tool in vitro with enhancers and inhibitors of the remodeling of lipid droplets and inhibitors of their accumulation. In vivo application was verified in a dexamethasone-induced model of NAFLD. The second aim is to create a tool for nucleoside uptake imaging. We labeled arabinoguanosine with azide to mimic nucleoside because it has been demonstrated to target the most popular transporting proteins. The second component of the probe ('caged' luciferin) was responsible for light output upon 'uncaging'. The probe's physiological relevance has been tested and confirmed using the inhibitor of nucleoside transporters in cancer models both in vitro and in vivo. The third aim is to apply a bioluminescent tool (MAL3 probe) to assess the connection between maternal immune activation (MIA) and mitochondrial membrane potential in offspring with schizophrenia. The results suggest that MIA produces mitochondrial dysfunction that begins during neurodevelopment and persists into adulthood. Switching mice to a diet enriched with nicotinamide riboside, which is expected to improve mitochondrial function, alleviated social interaction deficits, suggesting this may be a viable therapeutic strategy.
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Ph. D.