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Sensitive Glycomics for Understanding Biological Attributes of Glycans Associated With Sensitive Glycomics for Understanding Biological Attributes of Glycans Associated with Proteins By Chengyuan Liu, B.S. A Thesis In ANALYTICAL CHEMISTRY Submitted to the Graduate Faculty In Partial Fulfillment of the Requirements for the Degree of MASTER OF SCIENCE Approved Yehia Mechref Chair of Committee Dimitri Pappas Mark Sheridan Dean of the Graduate School May, 2015 Copyright 2015, Chengyuan Liu Texas Tech University, Chengyuan Liu, May 2015 ACKNOWLEDGEMENTS Three happy, enjoyable and fruitful years have passed since I first came here and many people have helped me during this time. Foremost, I want to take the opportunity to express my great appreciation to my advisor Dr. Yehia Mechref, who have guided me through all the way and taught me a lot both in academia and life. His dedication to science and family impressed me and inspires me for the future. I also want to thank my committee member Dr. Pappas for his kind and precious guidance in my project for which we met almost every week. I also appreciate the help, friendliness and kindness of my lab mates, with whom I spent almost every day during the three happy years. I want to also express my thanks to Himali Somaweera from Dr. Pappas group, my partner in the project for over 2 years, during which we have had close and nice cooperation. Last but not least, my gratitude goes to my family and friends who support and help me all the way directly or indirectly and those whose help and support may be invisible to me. Thank you! ii Texas Tech University, Chengyuan Liu, May 2015 TABLE of CONTENTS ACKNOWLEDGEMENTS ............................................................................................. ii ABSTRACT ..................................................................................................................... vi LIST OF FIGURES ......................................................................................................... viii I. INTRODUCTION ....................................................................................................... 1 Biological Attributes of Glycosylation of Proteins ...................................................... 1 Types and Complexity of Glycosylation ...................................................................... 2 Mass Spectrometry-Based Sensitive Glycomics .......................................................... 4 Immobilized Enzyme Reactors and Application in Glycomics ................................... 6 Lab-on-a-Chip Systems ................................................................................................ 8 Porous Graphitized Carbon and Application in Glycan Analysis ................................ 9 Permethylation of Glycans for Improving Sensitivity ................................................. 10 Summary ...................................................................................................................... 11 II. OPTIMIZATION OF EXPERIMENTAL CONDITIONS FOR FABRICATING POLYMERIC MONOLITHS .......................................................................................... 12 Introduction .................................................................................................................. 12 Experimental Section ................................................................................................... 13 Reagents and Materials ............................................................................................. 13 Monolith Fabrication ................................................................................................ 13 iii Texas Tech University, Chengyuan Liu, May 2015 Characterization of Monolith.................................................................................... 14 Results and Discussion ................................................................................................. 14 Morphology of Monolithic Columns ........................................................................ 14 Conclusion .................................................................................................................... 15 III. CAPILLARY IMMOBILIZED ENZYME REACTORS ............................................ 18 Introduction .................................................................................................................. 18 Experimental Section ................................................................................................... 18 Reagents and Materials ............................................................................................. 18 PNGase F Immobilization on Monolithic Matrix .................................................... 19 Sample Preparation ................................................................................................... 22 Release and Modification of Glycans ....................................................................... 22 MALDI-MS Conditions for Detection of Glycans ................................................... 23 Results and Discussion ................................................................................................. 24 N-glycan Profiling of Model Glycoproteins ............................................................. 24 Conclusion .................................................................................................................... 31 IV. ANALYSIS OF N-LINKED GLYCANS BY GLYCAN CHIP ................................. 32 Introduction .................................................................................................................. 32 Experimental Section ................................................................................................... 33 Reagents and Materials ............................................................................................. 33 iv Texas Tech University, Chengyuan Liu, May 2015 Fabrication of Glass Chips ....................................................................................... 33 Fabrication of IMER and PGC Column Packing in a Glycan Chip ......................... 33 Sample Preparation ................................................................................................... 36 Release and Purification of Glycans by Glycan Chip .............................................. 36 MS Conditions for Glycan Detection ....................................................................... 36 Results and Discussion ................................................................................................. 37 Analysis of N-glycans for Model Glycoproteins ...................................................... 37 Conclusion .................................................................................................................... 37 V. FUTURE WORK ......................................................................................................... 39 BIBLIOGRAPHY ............................................................................................................ 41 v Texas Tech University, Chengyuan Liu, May 2015 ABSTRACT Glycosylation of proteins, an important posttranslational modification (PTM) of proteins, provides an extreme diversity of proteins, which have a great number of functions in the biological and physiological processes of eukaryotic cells. Moreover, it is of no surprise that aberrant glycosylation of proteins has been associated with all kinds of human disease, especially cancers. So it is of great pathological and therapeutic significance to accurately and comprehensively profile glycans of glycoproteins, on which my research is focused. A prototype of the microfluidic device is developed for sensitive glycomics, and the device is referred to as Glycan Chip. This Chip is composed of an immobilized enzyme reactor (IMER) and a porous graphitized carbon (PGC) column. The first part of my job was to optimize the solid matrix of enzyme reactors. The solid matrix is made of poly (glycidylmetharylate-co-ethylene dimethacrylate) [poly (GMA-co- EDMA). The polymerization of the matrix, traditionally initiated by water bath incubation, was activated by microwave and the reaction time was reduced from 24h to 20min. The polymeric monolith shows similar morphology with that made by the traditional method. Moreover, the reproducibility of microwave activation for the reaction proved ideal by the fabrication of 5 replicates of the polymeric monolith. The second part of my research was to fabricate IMER in capillaries to test the activity of immobilized enzymes. Model glycoproteins, such as ribonuclease B, fetuin, and porcine vi Texas Tech University, Chengyuan Liu, May 2015 thyroglobulin were digested by IMERs, and it shows that fast and efficient release of glycans can be achieved in about 5 min. Combined with MALDI-MS, which is capable of fast first screening of glycans, IMERs can provide glycomic profiling with high turnover. This is of great advantage in the case of a large number of samples. The last part of my work focused on the development of Glycan Chip, a prototype of a microfluidic device. The integrated PGC column can purify the released glycans efficiently, which in turn facilitates the sensitive detection. Interfaced with ESI-MS, which is more sensitive than MALDI-MS, IMER has the capability of accurately profiling glycans of complex samples. In addition, the portable chips are convenient for liquid control with the aid of check valves and have potential in field application. vii Texas Tech University, Chengyuan Liu, May 2015 LIST OF FIGURES
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