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Dissertation
Development of lectins for cancer-specific fucosylation
Doctor of Philosophy (Ph.D.), Drexel University
Jul 2019
DOI:
https://doi.org/10.17918/ym2s-8349
Abstract
Changes in serum glycosylation have long been associated with hepatocellular carcinoma (HCC), and these modifications are often detected with sugar-binding proteins called lectins. HCC is associated with increased serum fucosylation, and this sugar is often detected with the Aleuria aurantia lectin (AAL). However, this lectin binds fucose in several forms, one of which is associated with cancer ([alpha]1-6 linked fucosylation) and some of which are not. Thus, its use in clinical and tissue analysis is limited. We have created a recombinant AAL, which contains a single amino acid mutation: N224Q (rAALN224Q), within the binding site 5, and this lectin has increased sensitivity to the cancer-specific fucosylated glycan. Our analysis of rAALN224Q has shown that the mutation within one specific fucose binding pocket had a major impact upon the mutated site as well as on sites that were not mutated and led to a lectin with altered binding specificities. This lectin is currently part of a diagnostic test under evaluation for the early detection of HCC. We have further explored the changes in N-linked glycosylation associated directly with HCC tissue through a method of N-linked glycan matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS). MALDI IMS of N-linked glycan revealed inter- and intra-tumor heterogeneity shown by expression and spatial localization of glycans in the tumor. Tumors were associated with alterations in mannosylation, fucosylation, branching, and complex glycan formation. Importantly, all tumors were associated with some change in glycosylation, but there was significant glycan heterogeneity.
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Details
- Title
- Development of lectins for cancer-specific fucosylation
- Creators
- Harmin Herrera - DU
- Contributors
- Anand S. Mehta (Advisor) - Drexel University (1970-)Carol Artlett (Advisor) - Drexel University (1970-)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- xvii, 241 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Microbiology and Immunology; College of Medicine; Drexel University
- Other Identifier
- 10378; 991014632682904721