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Natural Genetic Variation Affecting Calcium Homeostasis Rebecca Anna Replogle Purdue University

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Natural Genetic Variation Affecting Calcium Homeostasis Rebecca Anna Replogle Purdue University Purdue University Purdue e-Pubs Open Access Dissertations Theses and Dissertations Fall 2013 Natural Genetic Variation Affecting Calcium Homeostasis Rebecca Anna Replogle Purdue University Follow this and additional works at: https://docs.lib.purdue.edu/open_access_dissertations Part of the Genetics Commons, Human and Clinical Nutrition Commons, and the Physiology Commons Recommended Citation Replogle, Rebecca Anna, "Natural Genetic Variation Affecting Calcium Homeostasis" (2013). Open Access Dissertations. 70. https://docs.lib.purdue.edu/open_access_dissertations/70 This document has been made available through Purdue e-Pubs, a service of the Purdue University Libraries. Please contact [email protected] for additional information. Graduate School ETD Form 9 (Revised 12/07) PURDUE UNIVERSITY GRADUATE SCHOOL Thesis/Dissertation Acceptance This is to certify that the thesis/dissertation prepared By Rebecca Replogle Entitled NATURAL GENETIC VARIATION AFFECTING CALCIUM HOMEOSTASIS Doctor of Philosophy For the degree of Is approved by the final examining committee: Dr. James C. Fleet Chair Dr. Connie M. Weaver Dr. Min Zhang Dr. Scott Radcliffe To the best of my knowledge and as understood by the student in the Research Integrity and Copyright Disclaimer (Graduate School Form 20), this thesis/dissertation adheres to the provisions of Purdue University’s “Policy on Integrity in Research” and the use of copyrighted material. Approved by Major Professor(s): ____________________________________Dr. James C. Fleet ____________________________________ Approved by: Dr. James C. Fleet 11/25/2013 Head of the Graduate Program Date i NATURAL GENETIC VARIATION AFFECTING CALCIUM HOMEOSTASIS A Dissertation Submitted to the Faculty of Purdue University by Rebecca A. Replogle In Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy December 2013 Purdue University West Lafayette, Indiana ii To my husband and best friend John, who has weathered much, and supported me always. iii ACKNOWLEDGEMENTS First and foremost, I would like to acknowledge my advisor, Dr. James C. Fleet, without whom I would not have grown into the scientist I am today. His mentorship has instilled the critical thinking skills and commitment to high standards that I carry forward in my career. I would also like to acknowledge my committee members; Dr. Connie M. Weaver, Dr. Scott Radcliffe, and Dr. Min Zhang for their valuable help and input on this dissertation research. Many thanks go to my Fleet Lab friends and colleagues, especially Fa Wang, Perla Reyes-Fernandez, Alexandra Kostaras, Bernardine Frankel, Dr. Robert Johnson, and Dr. Marsha DeWitt. I’m very grateful to have worked alongside and learned from you every day. Special thanks go to the most fun, encouraging, and supportive group of friends I could ask for; John Replogle, Emily Hohman, Dr. TusaRebecca Schap, and Drew and Whitney Sayer. Last but not least, thank you to my family for always encouraging my curiosity and supporting my ambitions. Without all of you, this dissertation would not have been possible. Thank you. iv TABLE OF CONTENTS Page LIST OF TABLES ........................................................................................................... viii LIST OF FIGURES ........................................................................................................... ix LIST OF ABBREVIATIONS ............................................................................................. x ABSTRACT ....................................................................................................................... xi CHAPTER 1. LITERATURE REVIEW ...................................................................... 1 1.1 Introduction ............................................................................................... 1 1.2 Calcium Homeostasis ................................................................................ 2 1.2.1 The Three Tissue Axis ....................................................................... 2 1.2.2 Mechanisms of Intestinal Calcium Absorption .................................. 4 1.2.3 Regulation by Dietary Calcium .......................................................... 7 1.3 The Role of Vitamin D in Calcium Homeostasis ...................................... 9 1.3.1 Overview of Vitamin D Metabolism .................................................. 9 1.3.2 Genetic Disruption of Vitamin D and Calcium Metabolism in Mice .................................................................................................. 10 1.4 Genetic Variation and Gene-by-Diet Interactions Influence Calcium Homeostasis ............................................................................................ 14 1.4.1 Overview of Forward Genetic Methodologies ................................. 14 1.4.2 Mouse Models Allow Investigation of Natural Genetic Variation and Gene-by-Diet Interactions ................................................................ 16 1.4.3 Genetic Variation Affects Calcium and Bone Metabolism .............. 18 1.4.4 Do Gene-by-diet interactions Influence Calcium Homeostasis? ..... 23 1.5 Gaps Remain in Our Understanding of Calcium Homeostasis and Its Regulation ............................................................................................... 26 v Page 1.6 References ............................................................................................... 28 CHAPTER 2. GENE-BY-DIET INTERACTIONS INFLUENCE CALCIUM ABSORPTION AND BONE DENSITY IN MICE ............................ 43 2.1 Abstract ................................................................................................... 44 2.2 Introduction ............................................................................................. 45 2.3 Materials and Methods ............................................................................ 47 2.3.1 Experimental Design ........................................................................ 47 2.3.2 Intestinal Calcium Absorption ......................................................... 48 2.3.3 Gene Expression ............................................................................... 49 2.3.4 Bone Phenotyping ............................................................................ 49 2.3.5 Statistical Analysis ........................................................................... 50 2.4 Results ..................................................................................................... 52 2.4.1 Ca Absorption and Its Adaptation to Low Dietary Ca Intake .......... 52 2.4.2 Bone Parameters, and Their Adaptation to Low Dietary Ca Intake . 53 2.4.3 Ca Absorption Efficiency Is Correlated to Bone Mass .................... 53 2.4.4 Regulation of Intestinal Ca Absorption by 1,25(OH)2D .................. 54 2.4.5 Correlations between Duodenal mRNA Levels and Ca Absorption 55 2.4.6 Renal mRNA Levels ........................................................................ 56 2.4.7 Principal Components Analysis (PCA) ............................................ 56 2.5 Discussion ............................................................................................... 56 2.6 Acknowledgements ................................................................................. 62 2.7 References ............................................................................................... 62 CHAPTER 3. NATURAL GENETIC VARIATION AFFECTING THE RESPONSE OF SERUM 1,25(OH)2D TO DIETARY CALCIUM RESTRICTION IN MICE .............................................................................................. 78 3.1 Abstract ................................................................................................... 79 3.2 Introduction ............................................................................................. 80 3.3 Materials and Methods ............................................................................ 82 3.3.1 Animal Models ................................................................................. 82 3.3.2 Experimental Design ........................................................................ 82 vi Page 3.3.3 Statistical Analysis ........................................................................... 83 3.3.4 QTL Mapping ................................................................................... 84 3.3.5 Bioinformatic Characterization ........................................................ 85 3.4 Results ..................................................................................................... 87 3.4.1 Variation Related to Vitamin D Metabolites and Metabolic Enzymes Was Seen across the Diverse 11 Inbred Line Population ................. 87 3.4.2 Genetic Loci Controlling Serum 25(OH)D ...................................... 87 3.4.3 Genetic Loci Controlling Serum 1,25(OH)2D and Its Adaptation to Low Ca Intake .................................................................................. 88 3.5 Discussion ............................................................................................... 89 3.6 Acknowledgements ................................................................................. 96 3.7 References ............................................................................................... 96 CHAPTER 4. NATURAL GENETIC VARIATION AFFECTING INTESTINAL CALCIUM ABSORPTION AND ITS RESPONSE TO DIETARY CALCIUM RESTRICTION IN MICE .............................................. 113 4.1 Abstract
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