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Identification and Validation Of Identification and Validation of Protein Biomarkers for Invasive Aspergillosis; Development of Surface- Induced Dissociation Device and Paper Spray Ionization Source for Protein Complex Studies Item Type text; Electronic Dissertation Authors Huang, Chengsi Publisher The University of Arizona. Rights Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author. Download date 07/10/2021 22:35:10 Link to Item http://hdl.handle.net/10150/347142 IDENTIFICATION AND VALIDATION OF PROTEIN BIOMARKERS FOR INVASIVE ASPERGILLOSIS; DEVELOPMENT OF SURFACE-INDUCED DISSOCIATION DEVICE AND PAPER SPRAY IONIZATION SOURCE FOR PROTEIN COMPLEX STUDIES By Chengsi Huang ______________________________________________ Copyright © Chengsi Huang 2014 A Dissertation Submitted to the Faculty of the DEPARTMENT OF CHEMISTRY AND BIOCHEMISTRY In Partial Fulfillment of the Requirements For the Degree of DOCTOR OF PHILOSOPHY WITH A MAJOR IN CHEMISTRY In the Graduate College THE UNIVERSITY OF ARIZONA 2014 2 The University of Arizona Graduate College As members of the Dissertation Committee, we certify that we have read the dissertation prepared by Chengsi Huang entitled “ Identification and Validation of Protein Biomarkers for Invasive Aspergillosis; Development of Surface-Induced Dissociation Device and Paper Spray Ionization Source for Protein Complex Studies ” and recommend that it be accepted as fulfilling the dissertation requirement for the Degree of Doctor of Philosophy ________________________________________________________ Date 12/19/2014 Dr. Vicki H. Wysocki ___________________________________________________________Date 12/19/2014 Dr. Craig A. Aspinwall ___________________________________________________________Date 12/19/2014 Dr. Michael Heien ___________________________________________________________Date 12/19/2014 Dr. Vahe H. Bandarian Final approval and acceptance of this dissertation is contingent upon the candidate’s submission of the final copies of the dissertation to the Graduate College. I hereby certify that I have read this dissertation prepared under my direction and recommend that it be accepted as fulfilling the dissertation requirement. ________________________________________________________Date 12/19/2014 Dissertation Director: Dr. Vicki H. Wysocki ________________________________________________________Date 12/19/2014 Dissertation Director: Dr. Craig A. Aspinwall 3 Statement by Author This dissertation has been submitted in partial fulfillment of the requirements for an advanced degree at The University of Arizona and is deposited into the University Library to be made available to borrowers under the rules of the Library. Brief quotations from this dissertation are allowable without special permission, provided that accurate acknowledgement of source is made. Requests for permission for extended quotation from or reproduction of this manuscript in whole or in part may be granted by the head of the major department or the Dean of the Graduate College when in his or her judgment the proposed use of the material is in the interests of scholarship. In all other instances, however, permission must be obtained from the copyright holder. SIGNED: Chengsi Huang 4 Acknowledgements I would like to thank my research advisor Dr. Vicki Wysocki for her continuous support, both professionally and personally through out the past six years and counting. Without her guidance, I would not be able to take my research this far. She not only taught me how to be a better scientist, but more importantly, how to be a better communicator. I would like to thank Dr. Marta Feldmesser for her support in the Aspergillus project. She has been providing incredibly useful feedback each step of the way, and has helped me to understand the medical side of this project. Her group members Dr. Jason McCarthy and Dalisa Espinosa have provided quality samples and data that have made this research possible. My committee members at the University of Arizona have provided me with guidance and feedback on my progress during my graduate career. I want to thank Dr. Craig Aspinwall, Dr. Vahe Bandarian, Dr. Michael Heine, Dr. Indraneel Ghosh, and Dr. Jeanne Pemberton for their continuous support and guidance over the years. I want to thank everyone who has helped me in my research projects. This includes several group members past and present, specifically Andrew Van Schoaick, Akiko Tanimoto, Dr. Yun Zhang, Dr. Mowei Zhou, Nilini Ranbaduge and Forrest Helfrich for 5 their help in various projects. The mass spectrometry and proteomics facility members at both the University of Arizona and The Ohio State University have been my mentors in research methodologies and instrument operations. I want to thank both facilities’ members but more specifically Dr. Linda Breci, Dr. George Tsparaillis, Dr. Arpad Somogyi, and Dr. Kari Basso. Last but not least, I want to thank my close friends (Akiko Tanimoto, Yang Song, Yun Zhang, Juliet Diong, Micaela Bagley, Aalok Shah, Natalie Flinchum, Patricia Everett) and my family members. Your continuous love and support allow me to keep pushing myself further and to better myself. 6 Dedicated to My Parents and Grandparents for their love and support 7 Table of Contents List of Figures ........................................................................................................................................ 12 List of Tables .......................................................................................................................................... 21 List of Appendices ............................................................................................................................... 23 List of Abbreviations .......................................................................................................................... 24 Abstract ................................................................................................................................................... 25 Part I: Identification and Validation of Fungal Protein Biomarker for Invasive Aspergillosis........................................................................................................................................... 28 Chapter 1 Mass Spectrometry and Its Biological Applications ................................... 29 1.1 MS Application in Proteomic Questions ...................................................................... 29 1.1.1 Overview of Discovery Proteomics ........................................................................ 29 1.1.2 Overview of Targeted Proteomics .......................................................................... 31 1.2 Introduction to Mass Spectrometry .............................................................................. 31 1.2.1 Ionization Techniques................................................................................................. 32 1.2.2 Mass Analyzers .............................................................................................................. 34 1.2.3 Ion Activation Techniques ......................................................................................... 44 1.3 Introduction to Separation Techniques ....................................................................... 46 1.3.1 Types of Chromatography ......................................................................................... 51 1.3.2 Fractionation Techniques .......................................................................................... 52 1.4 Bottom Up vs Top Down Proteomics ............................................................................ 56 1.5 Proteomic Data Analysis .................................................................................................... 58 8 1.5.1 Database Searching Algorithms .............................................................................. 59 1.5.2 Validation Methods ...................................................................................................... 60 1.6 Introduction of Pulmonary Invasive Aspergillosis (IA) ......................................... 62 Chapter 2 Materials and Methods For Biomarker Studies ............................................ 64 2.1 Aspergillus fumigatus Antigen Sample Preparation ................................................ 64 2.1.1 Precipitation Methods ................................................................................................. 64 2.1.2 Sodium DodecylSulfate – PolyAcrylamide Gel Electrophoresis (SDS- PAGE) .............................................................................................................................................. 65 2.1.3 Enzymatic Digestions .................................................................................................. 66 2.1.4 Data Acquisition and Analysis ................................................................................. 67 2.2 Mouse Model .......................................................................................................................... 68 2.2.1 Mouse Model Preparation and Sample Collection ........................................... 68 2.2.2 Protein Normalization and Enrichment ............................................................... 72 2.2.3 Enzymatic Digestions .................................................................................................
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