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Mass Spectrometry-Based Metabolomics: Platform Development and Application to Neurodegenerative Disease

Huang, He
http://orcid.org/0000-0002-2394-0877
http://rave.ohiolink.edu/etdc/view?acc_num=akron1496678565947565

Abstract Details

2017, Doctor of Philosophy, University of Akron, Chemistry.
Metabolites are small molecules that participate in critical cellular processes that include energy production, macromolecules biosynthesis, and signaling pathways. Metabolic dysregulation is associated with changes in homeostasis and disease pathology. Measuring metabolite changes at the sites of tissue dysfunction can reveal new mechanisms that could serve as therapeutic targets and aid in the biomarker discovery. In this dissertation, we develop an untargeted metabolomic platform based on tandem mass spectrometry (TripleTOF 5600+, SCIEX). The platform consists of: hydrophilic interaction chromatography – mass spectrometry (HILIC-MS) to separate and detect polar metabolites and direct infusion-based based shotgun lipidomics. The platform allows global metabolic profiling in approximately thirty minutes. Three neurodegenerative diseases, including multiple sclerosis, normal pressure hydrocephalus (NPH), and Chiari malformation type I (CMI) are examined by this platform. First, dimethyl fumarate (DMF) treated oligodendrocytes are examined to provide mechanistic insight into potential neuroprotective pathways that may be upregulated by this treatment. Results indicate DMF alters levels of intermediates in the citric acid cycle to induce antioxidant responses in oligodendrocytes. Secondly, cerebrospinal fluid (CSF) samples were collected longitudinally from NPH patients following moderate exercise in order to elucidate pathological mechanisms of this disease as well as categorize potential biomarkers of treatment response. The results indicate that moderate exercise induces changes in CSF metabolites in NPH patient. These metabolic alterations are associated with the levels of vascular endothelial growth factor (VEGF) and patient clinical responses to shunting. Finally, both CSF and serum metabolites of CMI are investigated. Neurotransmitter and neuropeptide alterations were found to be associated with CMI. These results suggest that alterations in neurotransmission might underlie symptoms such as pain in this disorder. In this dissertation, unique metabolic alterations are detected by the untargeted metabolomic platform and suggest novel pathways that might be further examined as therapeutic interventions to alleviate neurological symptoms and promote CNS regeneration.
Leah Shriver (Advisor)
Chrys Wesdemiotis (Committee Member)
Sailaja Paruchuri (Committee Member)
Michael Konopka (Committee Member)
Francis Loth (Committee Member)
254 p.
Analytical Chemistry; Chemistry

Recommended Citations

Citations

  • Huang, H. (2017). Mass Spectrometry-Based Metabolomics: Platform Development and Application to Neurodegenerative Disease [Doctoral dissertation, University of Akron]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=akron1496678565947565

    APA Style (7th edition)

  • Huang, He. Mass Spectrometry-Based Metabolomics: Platform Development and Application to Neurodegenerative Disease. 2017. University of Akron, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=akron1496678565947565.

    MLA Style (8th edition)

  • Huang, He. "Mass Spectrometry-Based Metabolomics: Platform Development and Application to Neurodegenerative Disease." Doctoral dissertation, University of Akron, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=akron1496678565947565

    Chicago Manual of Style (17th edition)

akron1496678565947565
354
© 2017, all rights reserved.
This open access ETD is published by University of Akron and OhioLINK.