Dissertation
DISCOVERING BIOCHEMICAL SIGNATURES OF DISEASE: METABOLOMICS OF COLORECTAL CANCER VIA ION MOBILITY MASS SPECTROMETRY
Doctor of Philosophy (PhD), Washington State University
01/2014
Handle:
https://hdl.handle.net/2376/111203
Abstract
DISCOVERING BIOCHEMICAL SIGNATURES OF DISEASE: METABOLOMICS OF COLORECTAL CANCER VIA ION MOBILITY MASS SPECTROMETRY
Abstract
By Michael David Williams, Ph.D.
Washington State University
December 2014
Co-Chair: Herbert H. Hill
Co-Chair: Raymond Reeves
Metabolomics is an important area of investigation which may help reveal answers to questions left only partially understood from proteomic or genomic approaches. Increased knowledge about the relationship of genes and proteins to smaller biomolecules (metabolites) will advance our ability to diagnose, treat and perhaps, prevent cancer and other diseases that have eluded scientists for generations.
Colorectal cancer (CRC) is widely recognized as one of the leading causes of cancer related mortality worldwide. This, despite the fact that CRC is a completely curable disease, when caught early enough. There is a high rate of mortality for this disease due to the delayed detection and diagnosis of disease presence. Early identification of polyps that may progress to overt CRC is the cornerstone of CRC prevention.
HMGA1 is among the genes most enriched in CRC as compared to adjacent, nonmalignant colonic epithelium. Transgenic mice mis-expressing Hmga1 provide a consistent model for studying pre-cancerous, polyp-stage CRC.
IMMS is a flexible and rapid analytical tool that shows promise in overcoming many of the limitations inherent in other metabolomics platforms (Nuclear magnetic resonance, gas chromatography-mass spectrometry (GC-MS), liquid chromatography-MS (LC-MS)). In addition, it can easily be interfaced with LC (HPLC, UPLC, nano-LC), GC, and other platforms to provide unique and complementary information.
Here, travelling wave ion mobility mass spectrometry (TWIMMS) was applied for colorectal cancer metabolomics. Investigations were made to determine the primary biochemical pathways and metabolites that are perturbed during the development of colorectal cancer. The use of direct infusion-TWIMMS (Di-TWIMMS) to characterize the metabolic profiles of CRC tissues compared to matched non-malignant mucosae as well as transgenic compared to wild-type mouse gut tissues was performed. Directly infusing our samples significantly reduced analysis time compared to traditional metabolomics platforms. Multivariate statistical analysis was used to visualize differences between the metabolic profiles of sample types and to identify specific m/z features that led to this differentiation. Identification those m/z features was made, through mass identification, using the human metabolome and METLIN databases. Alterations in fatty acid biosynthesis, oxidative, glycolytic, bile acid, and polyamine pathways were found to be important in distinguishing various stages of CRC.
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Details
- Title
- DISCOVERING BIOCHEMICAL SIGNATURES OF DISEASE: METABOLOMICS OF COLORECTAL CANCER VIA ION MOBILITY MASS SPECTROMETRY
- Creators
- Michael David Williams
- Contributors
- Herbert H Hill (Advisor)Herbert H Hill (Committee Member)Raymond Reeves (Advisor)Raymond Reeves (Committee Member)William F Siems (Committee Member)David R Gang (Committee Member)Peter Reilly (Committee Member)
- Awarding Institution
- Washington State University
- Academic Unit
- Chemistry, Department of
- Theses and Dissertations
- Doctor of Philosophy (PhD), Washington State University
- Number of pages
- 231
- Identifiers
- 99900581734001842
- Language
- English
- Resource Type
- Dissertation