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Metabolomics Approach to Study Environmental Impact on Disease Mechanisms
Current and evolving high-throughput technologies have allowed metabolic characterization of biological systems with respect to disease state monitoring, drug response, and the impact of environmental exposure on human health. Metabolomic analysis has the potential to visualize the cellular environment of biological samples with limited bias of the system. Evolving techniques in metabolomics analysis have been leveraged to allow complimentary platforms including nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry to evaluate the diversity of molecular mechanisms and expand our understanding of disease mechanisms. This work focuses on the tools and applications of untargeted and targeted metabolomics through the lens of disease mechanisms. The first portion of this work explores the advancement of combined multiplatform metabolic analysis of disease progression and prophylactic drug response caused by acute radiation. The multiplatform untargeted approach demonstrated a unique signature of radiation exposure that persists across radiation dose and species model. This study further established a metabolic signature of recovery from acute radiation syndrome that can be utilized to guide validation and development of future radioprotective agents The second half of this work examined the use of multidimensional NMR techniques to evaluate targeted pathways perturbed by environmental exposures. The effects of histidine nutritional supplementation were examined on pancreatic cancer cell growth when combined with a known chemotherapy. The synergistic results demonstrated that paired therapies have the potential to improve health outcomes. Heavy metal toxicity in astrocytes was also evaluated through targeted metabolomics, and the results demonstrated that mitochondrial metabolism is required for detoxification of neurotoxic electrophiles, highlighting the role of glycolytic pathways in neural redox homeostasis and electrophile defense. Similarly, glycolysis and pentose phosphate pathways were interrogated by NMR metabolomics during Zika virus infection. Finally, a chemometric analysis of west coast American viticultural areas demonstrated that vineyard, region of growth, and vintage year of Pinot noir wines can be identified and characterized. Overall, this body of work demonstrated that metabolomics is a rich field with many biomedical and environmental applications to human health.
Crook, Alexandra A, "Metabolomics Approach to Study Environmental Impact on Disease Mechanisms" (2023). ETD collection for University of Nebraska - Lincoln. AAI30488658.