UNTARGETED METABOLOMICS ANALYSIS OF HEALTH-RELATED MICROORGANISMS AND CANCER CELL LINES

Zhihao Yu

As an important part of system biology and the last piece of ‘Omic stream’ (genomics-transcriptomics-proteomics-metabolomics), metabolomics studies aim to investigate metabolite profiles that can serve as a direct assessment of phenotype. As a broad discipline, metabolomics includes applications such as monitoring the disease progression, identifying specific disease biomarkers, and assessing the food quality. This dissertation work describes the utilization of untargeted metabolomics to develop a rapid detection method for pathogenic Naegleria fowleri in drinking water distribution systems and to study the metabolite profiles of different cancer cell lines (i.e. melanoma, radioresistant breast cancer). Naegleria fowleri, which is found in drinking water distribution systems, can cause a fatal disease with high mortality rate (> 95%). Current Naegleria fowleri detection approaches are time-consuming and labor intensive, hindering the swift action of water authorities during Naegleria fowleri outbreaks. Starting from the lab-cultured samples, this dissertation work studies the comprehensive metabolite profile of Naegleria fowleri and captures a panel of characteristic metabolite features that can efficiently distinguish the pathogenic Naegleria fowleri from its culture media (E. coli) as well as nonpathogenic Naegleria lovaniensis. Building upon the lab-culturing experiment, this work further demonstrates the studies on the field samples collected from operational drinking water distribution system covering different locations and times points. A list of diagnostic metabolite features is further expanded and validated. The prediction models based on the diagnostic features exhibit high detection accuracy. This novel Naegleria fowleri detection approach has the potential to decrease detection time from days (as required by conventional methods) to hours. In the cancer-related portion of this work, two different cancer cell lines (melanoma, breast cancer) were investigated. The major findings of these efforts include: 1) 12 differentially expressed metabolites have the potential to monitor the progression melanoma cells (primary vs. metastatic) and the corresponding pathways have biological implications for the survival and dissemination of metastatic melanoma cells. 2) 14 altered metabolites are confirmed in radioresistant breast cancer cells compared to its wild type, and the radioresistant capacity is strongly correlated with the upregulated free radical scavengers.

UNTARGETED METABOLOMICS ANALYSIS OF HEALTH-RELATED MICROORGANISMS AND CANCER CELL LINES

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