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Investigating the Role of the RNA Binding Protein LIN28 in The University of South Florida Scholar Commons Graduate Theses and Dissertations Graduate School November 2018 Investigating the Role of the RNA Binding Protein LIN28 in the Human Placenta: Implications for Preeclampsia John Canfield University of South Florida, [email protected] Follow this and additional works at: https://scholarcommons.usf.edu/etd Part of the Molecular Biology Commons Scholar Commons Citation Canfield, John, "Investigating the Role of the RNA Binding Protein LIN28 in the Human Placenta: Implications for Preeclampsia" (2018). Graduate Theses and Dissertations. https://scholarcommons.usf.edu/etd/7483 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]. Investigating the Role of the RNA Binding Protein LIN28 in the Human Placenta: Implications for Preeclampsia by John Canfield A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy Department of Molecular Pharmacology and Physiology College of Medicine University of South Florida Major Professor: Hana Totary-Jain, Ph.D. Bruce Lindsey, Ph.D. Jay Dean, Ph.D. Narasaiah Kolliputi, Ph.D Date of Approval: November 9, 2018 Keywords: trophoblast, hypoxia, invasion, DOHaD Copyright © 2018, John Canfield Acknowledgments I would like to express my thankfulness to my mentor, Dr. Hana Totary-Jain, for her continuous support, mentoring, and insight as I completed my graduate studies. Her dedication to my training ensured my success and greatly helped in the completion of this dissertation. Her door was always open, and no question was too small or too big. This comprehensive and insightful guidance has put me on a great path to becoming a successful scientist and my gratitude to her will last long after I move on from the lab. I would also like to thank the members of my dissertation committee: Dr. Bruce Lindsey, Dr. Jay Dean, and Dr. Narasaiah Kolliputi. Their guidance and assistance along this journey have been a tremendous help and has assisted me as I grow into a successful scientist and as a professional in general. The many committee meetings and general conversations were always pleasant and productive, and for that I thank them. I would also like to thank Dr. Charles Lockwood and his lab for always being available for questions and conversations. Without the skills and knowledge gained by working with Dr. Lockwood and Dr. Umit Kayisli, any many others in the lab, this dissertation would not have been possible. I am very appreciative of their assistance and I will be always grateful that they took time out of their own research to assist in mine. Furthermore, I would like to express my thanks to Dr. John Tsibris for always being available to provide tissue samples for analysis, and for providing constructive conversation. The many conversations about science, professionalism, and life in general were always pleasant and enjoyable. In addition, I would like to thank Dr. Ronald Magness and Dr. Fred Schatz for always being available for conversation and for providing excellent feedback on abstract and manuscript submissions. Also, I would like to express thanks to Dr. Ananth Karumanchi for providing RNA samples for analysis for this dissertation. Thank you to the members of my lab, Ezinne, Jeff, and Jay, for always being available for assistance and for a lot of laughs during our time in the lab. In addition to always being willing to assist on experiments and lab work, these other members of my lab made day-to-day work more enjoyable and pleasant. Finally, I would like to thank my wife, Clare, for her continued love and support over the years. Without her motivation and assurance, I simply would not be where I am today. Whether it is talking science, troubleshooting experiments, or just talking about life in general, she is always an open ear and always has insightful advice and conversation. Her intelligence and passion are inspiring, and I am forever grateful to have her by my side through this journey of life. Table of Contents List of Tables ................................................................................................................... iv List of Figures .................................................................................................................. v List of Abbreviations ....................................................................................................... vii Abstract ........................................................................................................................... xi Chapter One: Trophoblast Differentiation and Preeclampsia .......................................... 1 Preeclampsia ........................................................................................................ 1 Risk factors associated with preeclampsia ........................................................... 2 Long- and short-term adverse health effects associated with preeclampsia .................................................................................................. 3 Decidualization ..................................................................................................... 3 Development of the trophectoderm and inner cell mass ....................................... 5 The placenta ........................................................................................................ 9 Placentation in early pregnancy ............................................................................ 9 Interstitial EVT invasion ...................................................................................... 10 Vascular EVT invasion ....................................................................................... 11 Syncytialization ................................................................................................... 13 Impaired vascular remodeling in preeclampsia................................................... 15 Soluble FLT-1 in preeclampsia ........................................................................... 18 Soluble endoglin in preeclampsia ....................................................................... 19 C19MC in the placenta and preeclampsia .......................................................... 20 Inflammation in preeclampsia ............................................................................. 20 Chapter Two: The RNA Binding Protein LIN28 ............................................................. 22 Introduction to LIN28 .......................................................................................... 22 Regulation of Let-7 by LIN28A and LIN28B ........................................................ 25 Gene regulation by LIN28A and LIN28B independent of Let-7 ........................... 28 Regulation of cellular growth and metabolism by LIN28A and LIN28B ............... 29 Upstream regulation of LIN28A and LIN28B ...................................................... 30 LIN28A and LIN28B in embryogenesis and pluripotent stem cells ..................... 31 LIN28A and LIN28B in cancer and cellular invasion ........................................... 32 Gap in knowledge and purpose of this dissertation ............................................ 34 Chapter Three: Materials and Methods ......................................................................... 36 Ethical approval .................................................................................................. 36 Criteria for inclusion in the study ......................................................................... 36 i Placental tissue collection .................................................................................. 37 Isolation and culturing of primary DCs ................................................................ 37 Isolation and culturing of primary CTs ................................................................ 38 Isolation and culturing of primary STs ................................................................ 38 Immunohistochemistry ........................................................................................ 39 Quantification of immunohistochemistry ............................................................. 39 Cell culture.......................................................................................................... 40 Cell line authentication ....................................................................................... 40 Transfections ...................................................................................................... 40 Cell proliferation analysis .................................................................................... 41 Hypoxia experiments .......................................................................................... 41 RNA extractions .................................................................................................. 42 Protein extractions .............................................................................................. 42 Immunoblotting ................................................................................................... 43 qRT-PCR ............................................................................................................ 43 Scratch wound assays .......................................................................................
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