Plasma Extracellular Vessicles, Exercise Resistnace and Cancer
2021-07
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Plasma Extracellular Vessicles, Exercise Resistnace and Cancer
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2021-07
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Extracellular vesicles (EVs) are released into blood from multiple organs and carry molecular cargo that facilitates inter-organ communication and an integrated response to physiological and pathological stimuli. Interrogation of the protein cargo of EVs is currently limited by the absence of optimal and reproducible approaches for purifying plasma EVs that are suitable for downstream proteomic analyses. We describe a size exclusion chromatography (SEC)-based method to purify EVs from platelet poor plasma (PPP) for proteomics profiling via high-resolution mass spectrometry (SEC-MS). The SEC-MS method identified more proteins with higher precision compared to several conventional EV isolation approaches. We applied the SEC-MS method to identify the unique proteomic signatures of EVs released from platelets, adipocytes, muscle cells, and hepatocytes, with the goal of identifying tissue-specific EV markers. Further, we applied the SEC-MS approach to evaluate the effects of endurance and resistance exercise on EV proteomic cargo in human plasma. A prerequisite to studying the role of EVs in metabolic disorders such as type 2 diabetes is an in-depth understanding of the molecular mechanisms involved in dysregulation of insulin sensitive tissues such as skeletal muscle. In line with this, we utilized a multi-omics approach to characterize mechanisms underpinning exercise resistance in obese individuals. In this study we characterized the difference in the response to acute exercise between healthy subjects and individuals with chronic inflammation using skeletal muscle biopsy samples. This study identified dysregulation of diverse signaling pathways, including glycogen synthesis, myogenesis and AMPK signaling in obese individuals.
Finally, we utilized the biomarker potential of SEC-MS to identify differences in protein abundance and composition in EVs isolated from individuals with the hematological malignancy multiple myeloma (MM) and its precursor disease multiple myeloma of undetermined significance (MGUS). This analysis found that CD71 was upregulated in small and large EVs in individuals with MM relative to MGUS, suggesting that iron utilization and homeostasis in the tumor micro environment may play a role in disease progression. Additionally, CD40 was upregulated in individuals with standard cytogenetik risk MM relative to MGUS but was not identified in individuals with high risk MM suggesting that adaptive immune function is correlated to cytogenetic risk. These proteins hold the potential to be useful biomarkers to monitor disease progression in the clinic.
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University of Minnesota Ph.D. dissertation. July 2021. Major: Biomedical Informatics and Computational Biology. Advisor: Surendra Dasari. 1 computer file (PDF); vi, 88 pages.
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Vanderboom, Patrick. (2021). Plasma Extracellular Vessicles, Exercise Resistnace and Cancer. Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/225011.
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