Metabolic Therapy for Age-Dependent Impaired Wound Healing Shannon Lynn Kesl
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University of South Florida Scholar Commons Graduate Theses and Dissertations Graduate School 3-16-2016 Metabolic Therapy for Age-Dependent Impaired Wound Healing Shannon Lynn Kesl Follow this and additional works at: http://scholarcommons.usf.edu/etd Part of the Physiology Commons Scholar Commons Citation Kesl, Shannon Lynn, "Metabolic Therapy for Age-Dependent Impaired Wound Healing" (2016). Graduate Theses and Dissertations. http://scholarcommons.usf.edu/etd/6104 This Dissertation is brought to you for free and open access by the Graduate School at Scholar Commons. It has been accepted for inclusion in Graduate Theses and Dissertations by an authorized administrator of Scholar Commons. For more information, please contact [email protected]. Metabolic Therapy for Age-Dependent Impaired Wound Healing by Shannon Lynn Kesl A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy Department of Molecular Physiology and Pharmacology Morsani College of Medicine University of South Florida Co-Major Professor: Dominic D’Agostino, Ph.D. Co-Major Professor: Mack Wu, M.D. Lisa Gould, M.D., Ph.D. Thomas Taylor-Clark, Ph.D. Paula Bickford, Ph.D. Kenneth Ugen, Ph.D. Date of Approval: December 09, 2015 Keywords: Aging, Chronic Wounds, Ketosis, Exogenous Ketone Supplementation Copyright © 2016, Shannon Lynn Kesl ACKNOWLEDGEMENTS The research included in this dissertation was made possible by support from our funding sources, including the James A. Haley Veterans Hospital’s Merit Review, the Department of Molecular Pharmacology and Physiology, Scivation Inc., and the Office of Naval Research (ONR). I would like to express my heartfelt gratitude to everyone who has supported me in my pursuit of my doctoral degree. Firstly, I want to acknowledge the contribution from all of the ratticans that have sacrificed their lives to further scientific research. To my mentor, Dr. Dominic D’Agostino thank you for your relentless encouragement, guidance, and always going above and beyond for me no matter what was going on around you. You are one of the hardest working people I know. Thank you for always being just an email or phone call away, and always working diligently through the night for the betterment of our lab, my career, and my life. Thank you for instilling in me your passion and drive for helping others through our research and for helping me to realize why our job as scientists is so important. To my Co-mentor, Dr. Mack Wu, thank you for investing in me when I needed someone and for your continuous direction and support. To Dr. Lisa Gould, thank you for believing in me as your first Ph.D. student, for always being there even when we are far apart, for giving me an opportunity to see the clinical aspect of our research, and especially for challenging me and making me a better scientist. To the members of my dissertation committee, Dr. Thomas Taylor-Clark, Dr. Paula Bickford, Dr. Kenneth Ugen, Dr. Patrick Bradshaw for their scientific guidance and support over the past five plus years. To my outside chair, Dr. Stanley Stevens Jr., thank you for stepping in last minute and handling everything efficiently. I wish I had gotten to know you earlier in my career, but am hopeful for a continued relationship in the future. To my lab family, Carol Landon, Dr. Jay Dean, Geoffrey Ciarlone, Jacob Sherwood, Dr. Christopher Rogers, Dr. Csilla Ari, Andrew Koutnik, and Nathan Ward, thank you for making work such an entertaining but reassuring environment even when I needed to order something last minute, we have had a midnight time point, or when I have forced you to listen to musicals. I will be forever grateful for the time we have shared. To Dr. Andrea Trujillo for your continued guidance and support, thank you for teaching me so much. I want to give a special recognition and thank you to my wonderful friend and colleague, Dr. Angela Poff, from my whole heart I wish to thank you for your unwavering love, support, and encouragement, none of this would have been possible without you. To my school family, Dr. Franklin Poff, Randi McCallian, Dr. Chase Lambert, and Dr. Jillian Whelan, who have always been there with wine, excellent dinners, wine, relaxing company, wine, ridiculous conversation, and wine to ease the stress of this journey. To Shelby Evans and Marilyn Rodriguez, who always listened when I gushed about science even when they didn’t understand and thought it was boring, thank you for being there whether near or far. To Myshell (Michelle) Jung, thank you for being a source of constant inspiration and love even when we didn’t get to see each other every day or get to braid hair during incubation times. To my friends and family who have always loved and encouraged me throughout my life, Beth Webster, Joshua Smith, Katie Rader, Chad Rader, Harper Rader, June Guy, Merle Guy, John Fry, Michelle Adkins, Kyle Adkins, Travis Adkins, Amanda Fox, James Fox, Keith Waldron, Jeanette Kesl, and Robert Kesl. To my Presley Rader for always being enthusiastic to learn about science, watching your face light up when you looked into a microscope for the first time restored my wonderment for science. To my hippo and chicken, thank you for your unconditional love and for always being there to melt my stress away with snuggles on the couch. To my best friend, my heart, my husband, Jason, I know it has been hard being apart for the majority of my dissertation work and prep, but know that I felt your unconditional love and support even from Germany. Thank you for the countless times of reassurance, encouragement, laughter, and inspiration. I look forward to many more years of our life together. Last but not least to my mother, Jennifer Fry, thank you for always believing in me and pushing me to achieve my dreams. None of this would have been possible without your continual words of encouragement, your unconditional love, and your unwavering support no matter where life has taken me or how long it has taken me to get there. I am forever grateful. TABLE OF CONTENTS List of Tables ................................................................................................................................. iv List of Figures ..................................................................................................................................v List of Abbreviations .................................................................................................................... vii Abstract ........................................................................................................................................ xiii Chapter 1: Wound Healing Physiology ...........................................................................................1 1.1. Chapter Synopsis .....................................................................................................1 1.2. Skin Morphology .....................................................................................................2 1.3. Wound Classification and Closure Types ................................................................2 1.4. Acute Wound Healing Cascade ...............................................................................4 1.4.1. Hemostasis ...................................................................................................5 1.4.2. Inflammation ................................................................................................5 1.4.3. Proliferation .................................................................................................7 1.4.4. Maturation ..................................................................................................10 1.5. Cellular Energy Metabolism ..................................................................................10 1.5.1. Catabolism .................................................................................................11 1.5.2. Anabolism ..................................................................................................13 1.6. Wound Healing Metabolism ..................................................................................14 1.7. Nutrition and Wound Healing ................................................................................15 1.8. Chronic Wounds ....................................................................................................17 1.8.1. Classification of Chronic Wounds .............................................................18 1.8.2. Current Standard of Care, Therapies and Their Disadvantages .................20 1.8.2.1. TIME and Amputation .................................................................21 1.8.2.2. Adjunctive Therapies ...................................................................22 1.9. Age Influence on Chronic Wounds ........................................................................26 1.9.1. Aged Related Changes in Skin Morphology .............................................26 1.9.2. Age Related Changes in the Wound Healing Cascade ..............................27 1.10. Closing Remarks ....................................................................................................30 1.11. References for Chapter 1 .......................................................................................31 Chapter 2: Oral Ketone Supplementation as a Novel Therapy for Age-Dependent Delay Wound Healing .........................................................................................................................46