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Title of Dissertation Goes Here in All Caps A CHEMICALLY INDUCED COLITIS SCREEN REVEALS THE NECESSITY FOR MEMBRANE TRAFFIC IN INTESTINAL HOMEOSTASIS APPROVED BY SUPERVISORY COMMITTEE Bruce Beutler, M.D. Ezra Burstein, M.D., Ph.D. Philipp Scherer, Ph.D. Sandra Schmid, Ph.D. Sebastian Winter, Ph.D. DEDICATION To my wife and our families for their unyielding support and encouragement. A CHEMICALLY INDUCED COLITIS SCREEN REVEALS THE NECESSITY FOR MEMBRANE TRAFFIC IN INTESTINAL HOMEOSTASIS by WILLIAM ELLIOTT MCALPINE DISSERTATION Presented to the Faculty of the Graduate School of Biomedical Sciences The University of Texas Southwestern Medical Center In Partial Fulfillment of the Requirements For the Degree of DOCTOR OF PHILOSOPHY The University of Texas Southwestern Medical Center Dallas, Texas May, 2019 Copyright by WILLIAM ELLIOTT MCALPINE All Rights Reserved A CHEMICALLY INDUCED COLITIS SCREEN REVEALS THE NECESSITY FOR MEMBRANE TRAFFIC IN INTESTINAL HOMEOSTASIS Publication No. William Elliott McAlpine, Ph.D. The University of Texas Southwestern Medical Center, 2019 Supervising Professor: Bruce Beutler, M.D. Inflammatory bowel disease is most commonly a complex disorder caused by the interaction of environmental and genetic aberrations. Under normal conditions, a genetic program actively prevents inflammatory bowel disease, preventing invasion of microbes without permitting severe inflammation of the gut. To identify genes that maintain this balance, we performed a sensitized screen of 49,420 third generation (G3) germline mutant mice derived from N-ethyl-N- nitrosourea-mutagenized grandsires, bearing 104,658 coding/splicing mutations. We induced mild mucosal damage in these mice by orally administering dextran sodium sulfate (DSS) and found mutations that led to diarrhea and weight loss under these conditions. Causative mutations were v mapped concurrently with screening using an automated mapping procedure. Among 114 DSS phenotypes identified and mapped, 36 have been validated by CRISPR/Cas9 targeting. Three vesicle trafficking genes, Myo1d, Smcr8, and Tvp23b, were selected for mechanistic evaluation. MYO1D is a class I myosin that binds both actin and lipid. MYO1D localizes to the basolateral membrane of enterocytes and functions in the intestinal epithelium to protect against colitis. SMCR8, along with C9ORF72 and WDR41, is a member of a tripartite complex that functions as a guanine exchange factor. SMCR8 localizes to the lysosome, and its absence results in perturbations to endocytic and phagocytic pathways. Hyperactivation of endosomal Toll-like receptors in Smcr8-/- mice causes spontaneous inflammation, and hyperactivation of multiple pathways contributes to DSS susceptibility. TVP23B is a trans-Golgi protein that binds YIPF6. Both TVP23B and YIPF6 are necessary for the formation of secretory granules in goblet and Paneth cells of the intestinal epithelium. These studies reveal non-redundant molecules required for the return of normal physiologic balance within the intestine after DSS insult. vi ACKNOWLEDGEMENTS I am extremely grateful to those who have made my research training possible. First, I must extend my gratitude to Dr. Bruce Beutler who provided a training environment second to none. He is the epitome of everything a scientist should be, and I hope that his qualities have been imprinted on me. My scientific training was also enhanced by Dr. Emre Turer who provided excellent mentorship on a daily basis. Interaction with him was always positive and productive, and we made some exciting discoveries together. I hope that we will have many more interactions over the course of our scientific careers. Members of my thesis committee, Drs. Ezra Burstein, Philipp Scherer, Sandra Schmid, and Sebastian Winter, have been very helpful in guiding my projects. Thank you to Dr. Anne Murray and Dr. Eva Moresco who edited my manuscripts for publication. A special thanks to Dr. Murray who edited this thesis as well. Members of the wet lab provided technical advice for many experiments. Thank you to Drs. Takuma Misawa, Jin Huk Choi, Zhao Zhang, Duanwu Zhang, Lei Sun, Hexin Shi, Ying Wang, Lijing Su, Xue Zhong, Evan Nair-Gill, and Subhajit Poddar. Aijie Liu, Miguel San Miguel, and Dr. Ruchi Jain provided critical assistance for FACS and molecular biology. Forward genetics in mice is quite the enterprise that requires the involvement of many individuals. Jamie Russell managed the ENU mutagenesis and the phenotypic pipeline. Kuan-wen Wang executed the DSS screen with me along with help from Braden Hayse and Jianhui Wang. The bioinformatics team which consists of Stephen Lyon, Chun Hui Bu, Darui Xu, Tao Wang, and Sara Hildebrand provided many tools including Linkage and Candidate Explorer to determine the vii likelihood that a mutation was causative for an observed phenotype. Mihwa Choi, Xiaoming Zhan, Xiaohong Li, and Miao Tang produced CRISPR/Cas9 mice for validation. Sara Ludwig managed the CRISPR mouse colony. Thank you all for the substantive support. The expansive Beutler laboratory cannot operate without proper administration and management. Thank you to Betsy Layton, Lindsay Scott, Linda Watkins, Wanda Simpson, and Jenny Geisbert in the administrative office for everything you do, but especially for the aid you provided in securing and utilizing grant funding. Thank you to Elena Mahrt for your management on the front lines of the wet lab. Stephanie Arnett and Sheila Davis took tremendous care of the mouse strains used in this dissertation. Qihua Sun, Baifang Qin, and John Santoyo performed genotyping for these strains. Rick Bearden managed our supply chain and was normally the first person I encountered each morning. I cannot think of a better way to start my day. My family has provided enormous support in my pursuit to become a physician scientist. My parents, Warren and Kelly, have always exhibited unparalleled love and sacrifice. My brothers, Warren and Coan, have always provided encouragement and interest in my educational pursuits. My sister, Sarah Grace, a budding biologist in her own right, helped me performed some of the experiments detailed in this work. Finally, I would like to express a special thank you to my wife, Katie. I can confidently state, even in the absence of a control, that I would not have survived this progression without her unflinching support. viii ix TABLE OF CONTENTS Abstract .................................................................................................................................. v Acknowledgements ............................................................................................................ .. vii Table of Contents ................................................................................................................... x Prior Publications ................................................................................................................. xii List of Figures ..................................................................................................................... xiv List of Tables ..................................................................................................................... xvii List of Abbreviations ........................................................................................................ xviii Chapter 1 - A DSS-induced colitis screen to identify non-redundant molecules required for intestinal homeostasis ............................................................................................................. 1 Preface............................................................................................................................... 1 Introduction ....................................................................................................................... 1 Results and Discussion ..................................................................................................... 7 Materials and Methods .................................................................................................... 19 Chapter 2 - The class I myosin MYO1D binds lipid and protects against colitis ................. 21 Preface............................................................................................................................. 21 Abstract ........................................................................................................................... 21 Introduction ..................................................................................................................... 21 Results ............................................................................................................................. 22 Figures............................................................................................................................. 27 Discussion ....................................................................................................................... 37 Materials and Methods .................................................................................................... 39 Chapter 3 - Loss of SMCR8 or WDR41 causes immune dysregulation and colitis susceptibility ......................................................................................................................... 45 Preface............................................................................................................................. 45 Abstract ..........................................................................................................................
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