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Functional Restoration of Irradiated Salivary Glands Through Modulation of Apkcζ and Nuclear Yap in Salivary Progenitors

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Functional Restoration of Irradiated Salivary Glands Through Modulation of Apkcζ and Nuclear Yap in Salivary Progenitors Functional Restoration of Irradiated Salivary Glands Through Modulation of aPKCζ and Nuclear Yap in Salivary Progenitors Item Type text; Electronic Dissertation Authors Martinez Chibly, Agustin Alejandro 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 11/10/2021 05:49:05 Link to Item http://hdl.handle.net/10150/621771 FUNCTIONAL RESTORATION OF IRRADIATED SALIVARY GLANDS THROUGH MODULATION OF APKC AND NUCLEAR YAP IN SALIVARY PROGENITORS by Agustin Alejandro Martinez Chibly ___________________________________________ Copyright © Agustin Alejandro Martinez Chibly 2016 A Dissertation Submitted to the Faculty of the THE GRADUATE INTERDISCIPLINARY PROGRAM IN CANCER BIOLOGY In Partial Fulfillment of the Requirements For the Degree of DOCTOR OF PHILOSOPHY In the Graduate College THE UNIVERSITY OF ARIZONA 2016 2 THE UNIVERSITY OF ARIZONA GRADUATE COLLEGE As members of the Dissertation Committee, we certify that we have read the dissertation prepared by Agustin Alejandro Martinez Chibly entitled “Functional Restoration of Irradiated Salivary Glands Through Modulation of aPKC and nuclear Yap in Salivary Progenitors” and recommend that it be accepted as fulfilling the dissertation requirement for the Degree of Doctor of Philosophy _______________________________________________________________________ Date: 09/08/16 Kirsten Limesand _______________________________________________________________________ Date: 09/08/16 Jean Wilson _______________________________________________________________________ Date: 09/08/16 Margaret Briehl _______________________________________________________________________ Date: 09/08/16 Randy Burd 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: 09/08/16 Dissertation Director: Kirsten Limesand 3 STATEMENT BY AUTHOR This dissertation has been submitted in partial fulfillment of requirements for an advanced degree at the University of Arizona and is deposited in the University Library to be made available to borrowers under rules of the Library. Brief quotations from this dissertation are allowable without special permission, provided that accurate acknowledgment 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 Copyright holder. SIGNED: Alejandro Martinez Chibly 4 ACKNOWLEDGMENTS “It takes a village” There are three questions that every PhD student is continuously faced with throughout the journey of graduate school: Why did you choose this college? Why did you choose that lab? How did you choose your field? As if at this point we had to justify ourselves. Nonetheless, my answer to those 3 questions is the same: Kirsten Limesand. So, I first want to express my most sincere gratitude to Dr. Limesand for her commitment to change lives positively as a mentor, her continuous guidance, motivation, support, and incredible mentorship. “It [Mentorship] is a solemn duty to change lives positively. It is a noble honor to inspire and be there for others. It is an irresistible necessity to have empathy; to understand the situations and the reasons for the actions of others. Real mentoring is less of neither the candid smile nor the amicable friendship that exists between the mentor and the mentee and much more of the impacts. The indelible great footprints the mentor lives on the mind of the mentee in a life changing way. How the mentor changes the mentee from ordinariness to extra-ordinariness; the seed of purposefulness that is planted and nurtured for great fruits; the prayer from afar from the mentor to the mentee; and the great inspirations the mentee takes from the mentor to dare unrelentingly to face the storms regardless of how arduous the errand may be with or without the presence of the mentor” -Ernest Agyemang Yeboah. Second, I’d like to thank those who paved the way for my success before I was born: my family. Much of my success is only possible because of my mother (Paty) and Father (Agustin). They have supported, motivated, and encouraged me at every step of this journey, not only to achieve success, but to pursue my dreams. I owe them for my life, the many lessons they taught me, and for the many sacrifices made for me and my siblings. I am most grateful for they did not ever let me allow myself to yield to self-doubt. Gracias a mis padres, abuelita, y hermanos, por estar presentes en cada paso que he dado, y por compartir su orgullo y cariño en cada uno de mis andares. Indudablemente, cada uno de mis logros es un reflejo de mis padres, y por tanto es un logro suyo. Comparto con ustedes, mi familia, el fruto de incontables sacrificios. Espero siempre ser su orgullo. I got additional support from numerous faculty, staff, and students throughout the University, and the Cancer Biology program. Thanks to my committee members for lending me some of their valuable time. Their advice and support is deeply appreciated. I want to specially acknowledge Anne Cione, for playing the role of first-responder, student counselor, conflict mediator, problem solver, and of course, coordinator of the CBIO 5 program. Thanks to Anne, for devoting so much to better our program, and for making our dealings with bureaucracy a lot less of a nightmare. For making grad school an unforgettable and exciting adventure, I thank all of my friends. In each of them I found the strength behind every step and great moments of joy at the most demanding times of graduate school. To my roommate and gym buddy, Mitzy, who is undoubtedly exhausted of living with my bad jokes and constant teasing, thanks for taking care of me, sister. To Norma, for keeping a promise of friendship in spite of the many miles between us, thank you! Special thanks to my buddy and trainer Eddie for believing in me, pushing my limits, and giving me strength (literally and figuratively). I also want to thank Reyna, Maru, Vero, Karen, Carla, Monx, Karla G, Karla H, Fernanda, Daniela, Janine, Hannah, Claudia, Paloma, Shayan, Felipe, Sergio, Beto, Jon, and Stephen; without their friendship and support I would not be whole. I also want to acknowledge current and past members of my lab for being the best team I’ve ever been part of. Deborah and Salena, convinced me that getting a PhD was the way to go, and never doubted from the beginning that I would get to the finish line. Maria and Katie, thanks for being much more than lab peers, instead, both are excellent friends and mentors; I’m forever grateful that we were part of this journey together. Zoey, Amy, and Vicky, thanks for the continuous support, for happily and excitedly listening to my stories, and for enabling my coffee addiction. Grace, thanks for being a moral compass in times of need. Also thanks to our newest team player, Maricela, for taking over the business so that I could write my dissertation. Without her help, my mental health was in serious jeopardy. Also, thanks for the champagne! And to my mentees and friends: Asha, Allie, Brenda, Bernard, and Micah, thanks for making me proud! Finally, the completion of my dissertation was possible thanks to the financial support from CONACyT, the Graduate College at the University of Arizona, the National Institute of Health, as well as the Cancer Biology program. Thank you everyone who made this journey possible. 6 TABLE OF CONTENTS LIST OF FIGURES ............................................................................................................ 9 ABSTRACT ...................................................................................................................... 11 I. LITERATURE REVIEW .............................................................................................. 13 Clinical Significance ..................................................................................................... 13 Epidemiology............................................................................................................. 13 Treatment of head and neck cancer ........................................................................... 14 Salivary Hypofunction and Dry Mouth ..................................................................... 16 Radiation-Induced Salivary Hypofunction and Xerostomia ..................................... 17 a) Direct radiation damage to salivary epithelium ................................................ 19 b) Radiation effects on associated innervation ..................................................... 20 c) Radiation effects on associated vasculature and stroma ................................... 21 Etiology of RT-induced salivary hypofunction ............................................................. 22 DNA damage and acinar cell death ........................................................................... 23 Alterations in secretory pathways.............................................................................. 25 Disruption of salivary gland stem and progenitor cells ............................................
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