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Metabolomics is the measurement and analysis of metabolite perturbations in a biological system caused by disease, medication or environmental stress. Metabolites are more proximal to a phenotype or disease than either genetic or proteomics information. As a result, metabolomics gives a very immediate chemical interpretation of the phenotypical variations. NMR based metabolomics approach has a great potential to study disease pathogenesis and monitor treatments, both in pre-clinical and clinical settings. This dissertation describes the application of NMR metabolomics in two human diseases: multiple sclerosis and pancreatic cancer.
The first part of the dissertation describes the work done on Multiple sclerosis (MS). MS is a very challenging disease to diagnose where misdiagnosis and late diagnosis are common. Currently the investigation of MS metabolite biomarkers has primarily focused on the analysis of cerebrospinal fluid and serum. Little attention has been given to the analysis of urine. In an effort to address this gap, NMR based metabolomics was employed to find urinary markers of MS. Initially a pre-clinical study was conducted using the MS mouse model. The result demonstrated that urine metabolites could be used to differentiate diseased and healthy animals. Later on a proof of concept clinical study was conducted and the result demonstrated the potential of NMR metabolomics in MS diagnosis.
The second part of the dissertation is about the work done on pancreatic cancer. Pancreatic cancer is the fourth leading cause of cancer related mortalities in the United States. It has a very low 5% five-year survival rate. In this dissertation NMR metabolomics approach was applied to study pancreatic cancer metabolism. Specifically, the approach was used to discover metabolic responses of MUC1 overexpressing pancreatic cancer cells, to understand the chemotherapeutic response of gemcitabine resistance, and study the metabolic impact of ketone body treatment in pancreatic cancer. The results metabolically characterize MUC1 overexpressing pancreatic cancer cells, highlight potential therapeutic targets to enhance gemcitabine therapeutic response, and elaborate the metabolite response of ketone bodies treatment in pancreatic cancer.
