Date of Award

Fall 2007

Project Type

Dissertation

Program or Major

Biochemistry

Degree Name

Doctor of Philosophy

First Advisor

Vernon N Reinhold

Abstract

Molecular glycosylation is involved in key developmental roles including control of cell differentiation, innate immunity and signal transduction. Equally as demonstrable are numerous aspects of tumor development, from cellular proliferation to angiogenesis and metastasis. This sensitivity to cellular pathological is reflected in the diversity of glycoforms presented on glycoproteins. In spite of the potential utility of using molecular glycosylation as potential diagnostic and therapeutic agents little has been accomplished in bringing these capabilities to the clinic. Reasoning for this omission must relate to the paucity of analytical protocols to understand the full details of glycan structure. Analytical advancement in ion trap sequential mass spectrometry (MSn) methodology provides an unprecedented approach for glycoanalytic investigation. With an MSn-based approach comprehensive structural detail of individual glycan epitopes and isomeric structures become evident and demonstrate that specificity when applied to metastatic tissue. Using VM mouse brain tumor cells as a model, this these systematically uncovers an anomalous set of N-linked glycans distinct to malignant non-metastatic and metastatic tumors. By coupling specific chemical workup and utilizing ion-trap MSn disassembly, this analytical approach introduces a concept that carbohydrate epitopes can serve as a sensitive measure of physiological function. Importantly, such understanding requires an indulgence in structural detail, details uniquely available to ion trap mass spectrometry. The application of this methodology toward early detection biomarker discovery and cancer biology could be far reaching.

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