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Elucidating the Mechanism Behind Gastric Restitution

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Elucidating the Mechanism Behind Gastric Restitution Elucidating the Mechanism Behind Gastric Restitution A dissertation submitted to the Graduate School of the University of Cincinnati in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Pharmacology and Systems Physiology of the College of Medicine by Kristen Anette Engevik B.S. 2012 Biola University, La Mirada, California Committee Chair: Marshall H. Montrose, Ph.D. Committee Members: Judith Heiny, Ph.D.; Anjaparavanda Naren, Ph.D.; Yana Zavros, Ph.D.; Tongli Zhang, Ph.D. Abstract Background: The gastric mucosa of the stomach is continually exposed to environmental and physiological stress factors which can cause local epithelial damage. While much is known about the complex nature of gastric wound repair, the stepwise process that characterizes epithelial restitution remains poorly defined. Objective: This work seeks to elucidate effectors that drive gastric epithelial repair using a reductionist culture model, gastric organoids. Major Findings: Chapter 2 Assessing permeability, repair and cell death in the gastric organoid system This work establishes approaches to assess restitution in gastric organoids as well as identify the type of cell death induced by two photon microscopy. Two photon-induced photodamage results in caspase-activated apoptosis in the damaged cell, which mirrors natural cell shedding within gastric organoids. Similar to in vivo, localized photodamage results in rapid dead cell exfoliation, coinciding with the migration of adjacent viable cells to cover the denuded area, sustaining epithelial continuity. Measurement of dead cell exfoliation and closure of the damage area are reliable analyses to assess epithelial repair in gastric organoids. Under normal conditions, Lucifer yellow serves as a consistent extracellular marker to indicate epithelial barrier integrity. However in deficiency conditions, Lucifer yellow does not yield quantitative data to shed more light upon gastric organoid repair. Chapter 3 Comparison of genetically encoded calcium sensors to assess calcium mobilization in gastric organoid repair studies While calcium is a known accelerator for gastric repair, prior studies have been limited in the available technology for measuring calcium signaling. With the recent generation of a more sensitive genetically encoded calcium indicator (GECI) ( transgenic mouse, we tested organoids from mice expressing the previously generated GECI Yellow Cameleon 3.0 (YC 3.0) and a modified Yellow Cameleon Nano-15 (YC Nano) which has been reported to have improved sensitivityto determine the most consistent and sensitive calcium reporter. While both YC Nano and YC 3.0 organoids exhibited similar organoid size and response to damage, imaging outcomes suggest YC Nano as a more sensitive and reliable calcium sensor. Chapter 4 Trefoil Factor 2 activation of CXCR4 requires calcium mobilization to drive epithelial repair in gastric organoids This work also elucidates the signaling cascade of epithelial repair using murine gastric organoids, allowing us to define which regulatory processes are intrinsic to epithelial cells. Additionally, this research allows for the validation and dissection of the signaling cascade with more precision than is possible in vivo. Following single cell damage, intracellular calcium selectively increases within cells adjacent to the damage site and is essential to promote repair. Our findings demonstrate TFF2 acts via CXCR4 and EGFR signaling, including ERK activation, to drive Ca2+ mobilization and promote gastric repair. Sodium hydrogen exchanger 2, while essential for repair, acts downstream of TFF2 and calcium mobilization. Chapter 5 Sources of localized calcium mobilization during gastric organoid epithelial repair This work seeks to identify potential sources of calcium mobilization during repair. Based upon published RNA sequence data, several highly expressed calcium associated genes were chosen to target calcium mobilization. Inhibition studies suggest that extracellular sources via voltage gated calcium channels are essential for calcium mobilization and proper repair. Furthermore, calcium mobilization via phospholipase C signaling releases calcium stores from the ER, which are required to promote repair. These studies suggest both extracellular and intracellular sources are essential for calcium dependent epithelial restitution. Acknowledgements I would like to thank my advisor, Dr. Marshall Montrose for his guidance and thoroughness during my graduate work. I would also like to thank the members of the Montrose lab for their assistance with experimental design and execution as well as for their scientific rigor. A special thanks to my sisters, Mindy and Amy, for the unwavering support, encouragement, and input they’ve given me throughout my Ph.D. candidacy. Table of Contents Abbreviations ................................................................................................................ 1 Chapter 1 Literature Review ......................................................................................... 3 1.1 Gastric physiology and anatomy ............................................................................ 4 1.2 Disruption of barrier function .................................................................................. 7 1.3 Gastric epithelial restitution .................................................................................... 9 1.4 Trefoil factor family peptides ............................................................................... 11 1.5 Epithelial Growth Factors in gastric restitution ..................................................... 14 1.6 Sodium hydrogen exchangers in gastric restitution .............................................. 16 1.7 Role of calcium in repair ....................................................................................... 17 1.8 Genetically encoded calcium indicators ................................................................. 1 1.9 Gastric cancer lines vs. gastric organoids ........................................................... 21 1.10 Major Contributions ........................................................................................... 24 Chapter 2 Assessing permeability, repair and cell death in the gastric organoid system .......................................................................................................................... 25 2.1 Abstract ............................................................................................................... 26 2.2 Introduction .......................................................................................................... 27 2.3 Materials and Methods ......................................................................................... 29 2.3.1 Animal husbandry ...................................................................................... 29 2.3.2 Mouse-derived corpus organoid culture..................................................... 29 2.3.3 Induction of two-photon laser-induced photodamage ................................ 30 2.3.4 Microinjection ............................................................................................. 31 2.3.5 Image analysis ........................................................................................... 31 2.3.6 Statistical analysis ..................................................................................... 32 2.4 Results ................................................................................................................ 33 2.4.1 Assessing organoid permeability using Lucifer Yellow .............................. 33 2.4.2 Assessing repair in various organoid models ............................................ 36 2.4.3 Assessing repair in TFF2 deficient gastric organoids ................................ 38 2.4.4 Photodamage induces caspase-activated apoptosis ................................. 39 2.5 Discussion ............................................................................................................ 43 Chapter 3 Comparison of genetically encoded calcium sensors to assess calcium mobilization in gastric organoid repair studies ....................................................... 47 3.1 Abstract ............................................................................................................... 48 3.2 Introduction .......................................................................................................... 49 3.3 Materials and Methods ......................................................................................... 53 3.3.1 Animal husbandry ...................................................................................... 53 3.3.2 Mouse-derived corpus organoid culture..................................................... 53 3.3.3 Induction of two-photon laser-induced photodamage ................................ 54 3.3.4 Image analysis ........................................................................................... 54 3.3.5 Statistical analysis ..................................................................................... 55 3.4 Results ................................................................................................................ 56 3.4.1 Organoid size of YC 3.0 and YC Nano is consistent with other organoid models ..................................................................................................... 56 3.4.2 Quality of imaging and date from YC 3.0 and
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