Development of Blood Metabolomics for Biomarker Discovery Using Chemical Isotope Labeling and Liquid Chromatography-Mass Spectrometry

• Author / Creator

  Han, Wei

• Blood-metabolite-based biomarkers are useful for the early-stage diagnosis, accurate prognostic prediction and personalized treatment of various diseases. Blood contains a massive number of metabolites that can potentially become biomarkers, but the metabolome coverage of current analytical techniques remains insufficient. Considering that traditional liquid chromatography-mass spectrometry (LC-MS) platforms are limited by the low metabolome coverage and quantification accuracy, our lab has developed the high-performance chemical isotope labeling (CIL) LC-MS platform which can significantly increase the metabolome coverage and efficiently overcome the detection variability. In general, blood biomarker discovery is susceptible to experimental interferences and biological variations. To improve the reliability of metabolomics discoveries, large sample sizes and time-resolved analysis are highly desirable. Towards these challenges, the major part of my thesis focuses on assessing and minimizing the experimental and biological variations that could interfere with biomarker discoveries. With the CIL LC-MS platform, experimental variations have been largely overcome and biological variability carefully evaluated. The establishment of a serum metabolome database can facilitate future studies, and the high-coverage analysis of one microliter finger blood opens new vistas for biomarker discovery and environmental exposure assessment. The major motivation of this thesis is to consider the time factor in blood metabolomics, and the reported technical improvement has made time-dependent metabolomics possible at a minimal cost. Additionally, to demonstrate the benefits of adding the time dimension to the study design, we report a cohort study for the diagnosis and prognosis of Parkinson’s disease and an intervention study for the exposure assessment of DDT, which is a banned pesticide and an endocrine disruptor. Overall, this thesis work has demonstrated enhanced analytical performance for blood biomarker discovery, and high-quality biomarkers come from well-designed experiments, careful sample handling, high-performance analysis platforms, and a solid understanding of data analysis principles.

• Subjects / Keywords

  • Biomarker discovery
  • Blood metabolomics
  • Chemical isotope labeling

• Graduation date

  Spring 2018

• Type of Item

  Thesis

• Degree

  Doctor of Philosophy

• DOI

  https://doi.org/10.7939/R3HT2GT03

• License

  This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.