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Mechanisms of Late-Delayed Radiation Induced Brain Injury

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Mechanisms of Late-Delayed Radiation Induced Brain Injury MECHANISMS OF LATE-DELAYED RADIATION INDUCED BRAIN INJURY: INSIGHTS FROM EXTRACELLULAR MATRIX AND TRANSCRIPTIONAL PROFILING BY RACHEL N. ANDREWS, D.V.M. A Dissertation Submitted to the Graduate Faculty of WAKE FOREST UNIVERSITY GRADUATE SCHOOL OF ARTS AND SCIENCES in Partial Fulfillment of the Requirements for the Degree of DOCTOR OF PHILOSOPHY Molecular Medicine and Translational Science April 4th 2018 Winston-Salem, North Carolina Approved By: J. Mark Cline, D.V.M., Ph.D., Advisor Linda J. Metheny-Barlow, Ph.D., Chair Gretchen Neigh, Ph.D. Kerry O’Banion, M.D., Ph.D. Ann M. Peiffer, Ph.D. 1 DEDICATION To my father: without your guidance, love, and dogged persistence I would have become a graphic designer and presumably equally in debt. And to my grandfather, a hopeful scientist. I hope I have made you proud. i ACKNOWLEDGEMENTS They say it takes a village to raise a child – it apparently requires no less than four of them to develop a Ph.D. candidate. Although my academic journey has taken me many different places, I am forever grateful to those who have so generously given their time, mentorship, and support which have shaped me into the scientist I am today. I would like to thank the Department of Pathology, Section on Comparative Medicine for providing my research ‘home’ for the last 4 years and for their collegiality and continual emphasis on pursuing research intended to advance our understanding of human health. Above all, I must express my gratitude to my mentor, Dr. Mark Cline. His unwavering support, enthusiasm, and encouragement are what have inspired me to devote my career to translational research. You have truly been a fantastic mentor and I am deeply grateful for your time and dedication. I would also like to extend my thanks and warmest regards to: My committee members Dr.s Kerry O’Banion, Ann Peiffer, Gretchen Neigh and Linda Metheny-Barlow. You have always been willing to share your knowledge, insight, and constructive criticism and I am deeply appreciative of your guidance. Thank you for your time, effort and above all, kindness. I hope this dissertation and the scientist I have become makes you proud. My pathology mentors Dr. Nancy Kock and Dave Caudell for their infinite patience, willingness to teach, and occasional tough love when needed. To my colleagues Kristofer Michalson, Caralyn Labriola, Hannah Atkins, Ryne DeBo, David Hanbury, Marnie Silverstein Metzler, and Greg Dugan for your ii camaraderie, collaborative spirit, and perpetual willingness to engage in lively intellectual debate. In the infamous words of the Joint Pathology Conference, “and a lively discussion ensued!” Lisa O’Donnell, Cathy Mathis, Jean Gardin and Kelly Mahoney have been integral to this dissertation. None of the work contained within would have been feasible without their help and they have always been willing to lend a helping hand or a sympathetic ear. To my collaborators from the departments of Radiation Oncology, and Integrative Physiology and Pharmacology: thank you for your patience, tutelage, and willingness to share knowledge. Your expertise and collegiality truly embody the collaborative spirit that propels sciences forwards. I appreciatively acknowledge the financial support of the T32 Post-doctoral Fellowship in Laboratory Animal and Comparative Medicine Training through the National Institute of Health and funding from the Radiation Countermeasures Center of Research Excellence (RadCCORE) which made my education possible. I am grateful for my undergraduate training at the University of Illinois Urbana- Champaign and give a special, heartfelt thank you to my mentor and colleagues from Cooke Laboratory: Paul Cooke, Gail Ekman, Melissa Cimafranca, Liz Simon, Gaurav Tyagi, Heather Schlesser, and Juanmahel Davila. Were it not for you, I would never have discovered my passion for science. I would also like to thank the University of Wisconsin-Madison School of Veterinary Medicine and instructors there for my doctoral training and support of my development as a physician scientist. iii And finally, I would like to convey my gratitude to the Robbins family and the Mike and Lucy Robbins Fellowship for the generous support I have received from the Mike and Lucy Robbins Graduate Scholarship Award. Much of this dissertation has grown out of his original work and would not have been possible without his foresight, effort and dedication. “If I have seen further it is by standing on [the] shoulders of Giants." –Sir Isaac Newton iv TABLE OF CONTENTS Table of Contents ...............................................................................................................v List of Figures and Tables .............................................................................................. vii List of Abbreviations ....................................................................................................... ix Abstract ........................................................................................................................... xxi Chapter 1 ............................................................................................................................1 Introduction ..............................................................................................................1 References ..............................................................................................................20 Chapter 2 ..........................................................................................................................48 Cerebrovascular remodeling and neuroinflammation is a late effect of radiation-induced brain injury in nonhuman primates (Published in the Journal of Radiation Research) .....48 Abstract ...................................................................................................................49 Introduction .............................................................................................................51 Materials and Methods ............................................................................................53 Results .....................................................................................................................59 Discussion ...............................................................................................................67 Acknowledgements .................................................................................................75 References ...............................................................................................................75 Chapter 3 ..........................................................................................................................89 Fibronectin produced by cerebral endothelial and vascular smooth muscle cells contributes to perivascular extracellular matrix in late-delayed radiation-induced brain injury. (Submitted to the Journal of Radiation Research)..................................................89 Abstract ...................................................................................................................90 Introduction .............................................................................................................92 Materials and Methods ............................................................................................94 Results ...................................................................................................................104 Discussion .............................................................................................................111 Acknowledgements ...............................................................................................118 References .............................................................................................................119 Chapter 4 ........................................................................................................................131 Transcriptomic profiling reveals neuroinflammation, complement system involvement and impaired glutamatergic neurotransmission in white matter years post total body irradiation and months post fractionated whole brain irradiation ....................................131 Abstract .................................................................................................................132 Introduction ...........................................................................................................134 Materials and Methods ..........................................................................................136 Results ...................................................................................................................143 Discussion .............................................................................................................161 Acknowledgements ...............................................................................................168 References .............................................................................................................169 v Chapter 5 ........................................................................................................................186 References ........................................................................................................................204 Appendices ......................................................................................................................231 Disclaimer .............................................................................................................231
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