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Regulation of Β-Cell Mass Expansion by Prostaglandin E2 Signaling By Regulation of b-Cell Mass Expansion by Prostaglandin E2 Signaling By Bethany A. Carboneau Dissertation Submitted to the Faculty of the Graduate School of Vanderbilt University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY in Molecular Physiology and Biophysics September 30, 2017 Nashville, TN Approved: David Jacobson, Ph.D. Wenbiao Chen, Ph.D. Roger Colbran, Ph.D. Richard Breyer, Ph.D. Laura Dugan, M.D. ACKNOWLEDGEMENTS I could not have completed this dissertation Without the help and support of so many people. I Would like to take this space to thank all of those individuals Who helped me along this journey. I apologize to anyone that I may have forgotten to include. None of this Work Would have been possible Without my advisor, Dr. Maureen Gannon. Maureen, thank you for letting me join your lab to do my dissertation Work. I have alWays appreciated your unending encouragement, positivity, dedication to your trainees, and support in all aspects of graduate school and science. There Were several times When this process became overwhelming, but you alWays found a Way to help me see the bigger picture and motivate me to continue With my Work. Thank you for supporting my interests outside of the lab as Well. I’ve really enjoyed all of the fun science trips that I got to go on With you – especially When We toured the German countryside on a German-language trip! I Would also like to thank all of my thesis committee members: Dr. David Jacobson, Dr. Wenbiao Chen, Dr. Roger Colbran, Dr. Richard Breyer, and Dr. Laura Dugan. Thank you for pushing me to be a better scientist and to think about my project in unique Ways. Thank you for taking the time to meet With me one-on-one to help me troubleshoot particularly finicky assays. Thank you to the many different departments and programs at Vanderbilt University that have contributed to my development and success as a graduate student, including the Department of Molecular Physiology and Biophysics, the Program in Developmental Biology, the Beta Cell Interest Group, and the Diabetes Research and ii Training Center. I have enjoyed being a part of such a collaborative research community. I Would like to give a very big thanks to the individuals, labs, and cores Who provided technical support for my project. I am especially grateful to Anastasia Coldren, Heather Durai, and Prasanna Dadi for performing islet isolations. Thank you for alWays finding time to fit in every islet isolation, even if the schedule Was already full for the day. I Would also like to thank the human donors from the Integrated Islet Distribution Program and the Alberta Diabetes Institute IsletCore Who donated islets for this project. The Molecular Biology Shared Resource Core, VANTAGE, and the Islet Procurement and Analysis Core also provided support for this research. Thank you to Dr. Marcela Brissova for technical assistance With the ScanScopes and Aperio analysis. Thank you to the Dr. Alvin PoWers, Dr. David Jacobson, Dr. Roland Stein, Dr. Kevin Niswender, and Dr. Richard O’Brien labs for graciously alloWing me to use your equipment or borroW reagents during my research. I had a very unique opportunity to spend four months as a Visiting Scientist in Edmonton, Alberta, Canada, in the lab of Dr. Patrick MacDonald during my third year of graduate school. Thank you to Maureen for encouraging me to apply, and a special thanks to Pat for choosing me to be one of the participants in this program! I had no idea Where Edmonton Was before I applied for this position, but it is noW a very special place to me. I loved being able to experience a neW city (and country) While still learning and groWing as a scientist. Thank you, Pat, Tina, Joss, Greg, Nancy, Richard, Austin, Jelena, Kathy, Mourad, Shara, and everyone in the MacDonald lab for making this such a Wonderful experience, for being so Welcoming, and for being patient With me as I iii learned the ropes of human islets (especially islet picking). To Inne, I am so glad that We Were able to share this experience as Visiting Scientists together. I enjoyed our shared excitement at the arrival of neW donor islets and all of our Weekend adventures around Edmonton. To Shara, thank you for being so friendly and including me in so many activities. You played a major role in making this experience so much fun! It has been a pleasure and an honor to Work With everyone in the Gannon lab, past and present. Thank you to Rockann Mosser and Maria Golson for pioneering the assays that Were the backbone of my project. Thanks to Matt Maulis for training me on all things sectioning and immunohistochemistry. To Kim Riley and Kathryn Henley, thank you both for making the lab so much fun and for being such great friends. Your encouragement has helped me through many committee meetings and seminar presentations. Thank you, Jen Dunn, for all of your technical support and for keeping me company When the boys took over the lab. Peter Kropp, Joey Elsakr, and Ray Pasek: thanks for making the lab a really fun environment and for listening to my complaints When things Weren’t going my Way. I Would also like to thank all of my rotation/summer students, Thao Le, Sing-Young Chen, Jack Allan, and Shannon ToWnsend, for all of their hard Work and being such great students to Work With. I have learned so much from all of the people I have Worked With throughout my time in the Gannon lab, and for that I am grateful. I am so lucky to have a multitude of Wonderful friends Who have provided endless emotional support throughout my graduate school career. Thanks to my graduate school ladyfriends, Lisa, Becca, Allie, Marilyn, and Theresa, for being there to make me laugh, letting me vent about lab/school, and being such aWesome role models. I Would iv also like to thank my Hanover College friends. To Amy, Kim, Lorna, Zani, Angie, Nick, and Nick: I am so glad that We Were able to see each other so often during my time in Nashville. Thank you for being such incredible friends (even surpassing “five years time”) and pretending to be interested in my research. To Kirsten, thank you for alWays checking in, visiting me in Edmonton, being so enthusiastic about everything. Finally, I Would like to thank my Wonderful boyfriend, David. Thank you for being so positive, encouraging, supportive, and patient With me during these past feW years. Thank you for inspiring me to do better than my best, alWays helping me find the bright side of things, and for bringing so much joy to my life. I am so lucky to have an extremely close-knit and large family. Thank you to my grandmas, aunts, uncles, and cousins for being my cheerleaders and taking the time to ask me hoW my research is going. A special thanks to my aunt Patty and uncle Brian for taking me in With open arms like one of your oWn, for Sunday dinners, BBC shoW vieWing parties, and alWays being there for me. I Would not be Where I am today if it Was not for my Wonderful parents, brother, sister, and brother-in-laW. I’m sorry that I can’t seem to find my Way back to Indiana but thank you for being there for me no matter Where I live! Mom and Dad, thank you for pushing me to achieve my goals (and beyond), teaching me the value of hard Work, being great role models, and supporting me in every Way possible for my entire life. To my brother, Reade, thanks for alWays providing comedic relief during tense situations and helping me navigate the job hunt process. Thank you, Kornga, for being so positive and teaching us all hoW to be more patient. To my big sister, Bria, thank you for motivating me to stay in school and letting me vent When exams Were too hard or v experiments kept failing. I’m not sure I Would’ve made it past first year if it Wasn’t for you. My success is truly a reflection of everyone that has helped me along this journey and for that I Will be forever grateful. vi TABLE OF CONTENTS Page ACKNOWLEDGEMENTS ................................................................................................. ii LIST OF TABLES ............................................................................................................. x LIST OF FIGURES .......................................................................................................... xi Chapter I. INTRODUCTION ....................................................................................................... 1 General Background .............................................................................................. 1 Significance ................................................................................................ 1 Inflammation, Obesity, and T2D ................................................................. 2 Glucose-stimulated insulin secretion .......................................................... 5 b-Cell mass dynamics ................................................................................. 8 Pancreas-specific Cre models .................................................................. 17 Current therapies to treat T2D .................................................................. 19 Islet G-proteins and GPCRs ..................................................................... 23 Prostaglandins ..................................................................................................... 28 Prostaglandin production .......................................................................... 28 Prostaglandins and PG receptors in the islet ............................................ 30 Prostaglandins and diabetes ...................................................................
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