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Linking Two Seemingly Unrelated Diseases, Cancer And LINKING TWO SEEMINGLY UNRELATED DISEASES, CANCER AND ACUTE RESPIRATORY DISTRESS SYNDROME, THROUGH A DICTYOSTELIUM SECRETED PROTEIN A Dissertation by SARAH E. HERLIHY Submitted to the Office of Graduate and Professional Studies of Texas A&M University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Chair of Committee, Richard Gomer Committee Members, Michael Criscitiello Luis Rene Garcia Michael Polymenis Kathryn Ryan Head of Department, Thomas McKnight August 2014 Major Subject: Biology Copyright 2014 Sarah Herlihy ABSTRACT The work in this dissertation links two diseases through a protein secreted by Dictyostelium discoideum cells. The protein, AprA, inhibits cell proliferation and induces chemorepulsion (movement away) of Dictyostelium cells. This has implications in both cancer research and the study of Acute Respiratory Distress Syndrome. Cancer is a misregulation of cellular proliferation. Often the removal of a primary tumor results in rapid metastatic cell proliferation. The rapid proliferation of metastatic cells indicates the presence of a factor, called a chalone, secreted by the primary tumor cells, that inhibits metastatic cell proliferation. The ability of AprA to inhibit proliferation of the cells that secretes it classifies it as a chalone. Using the model organism Dictyostelium and the protein AprA allows us to study chalone signaling mechanisms. Acute Respiratory Distress Syndrome (ARDS) is characterized by an excess influx of neutrophils into the lungs. Neutrophils damage the lung tissue and ultimately recruit more neutrophils that repeat the process. A need exists to remove these cells and allow resolution to occur. One way to accomplish this is through chemorepulsion, the directional movement of cells away from an external cue. We can use AprA to study the mechanisms of chemorepulsion. In this dissertation, I have found that the PTEN-like protein CnrN, which is an inhibitor of proliferation and chemotaxis, is involved in both AprA proliferation inhibition and chemorepulsion of Dictyostelium cells. I have shown that the human ii protein DPPIV, which is structurally similar to AprA, causes chemorepulsion of human neutrophils. Additionally, aspirated DPPIV reduces the accumulation of neutrophils in the lungs of a mouse model of ARDS. Work shown in the appendices suggests that AprA signals through specific G protein-coupled receptors. The work in this dissertation studies the role of chalones and chemorepellents. It allows the unique opportunity to study chemorepulsion in both Dictyostelium and human cells. The hope and goal is that the work in this dissertation could lead to novel therapies for diseases such as cancer and ARDS. iii DEDICATION I would like to dedicate this dissertation first to my husband, Kevin Herlihy, without whom I would not have been so successful. Secondly, I would like to dedicate this to my families who have supported and encouraged me. Thank you all. iv ACKNOWLEDGEMENTS I would like to thank my committee chair, Dr. Gomer for his support, guidance, and patience throughout my graduate career. I also would like to thank my committee members, Dr. Criscitiello, Dr. Garcia, Dr. Polymenis, and Dr. Ryan, for their advice and support throughout the course of this research. I also want to extend my gratitude to Dr. Robert Insall who provided the Insall chambers, which were essential to this work. A huge thanks to my current and past undergraduates with their contributions to my work including Hannah Strake, Jose Ting, Francisco Brito, and Michael Teach. Thanks also go to my friends and colleagues and the department faculty and staff for making my time at Texas A&M University a great experience. A special thanks to my former and current lab mates who make each day unique (Nehemiah Cox, Dr. Jeff Crawford, Dr. Anu Maharjan, Dr. Jonathan Phillips, Dr. Darrell Pilling, Patrick Suess, Rachel Sterling, Michael White, and Ivy Zheng). Thanks to Simone Lepage for her constant support and Dr. Lindsay Bennett for guiding me through the dissertation writing process. Finally, thank you to my two wonderful families for their encouragement and to my husband for his patience, love, and unfailing support. v TABLE OF CONTENTS Page ABSTRACT .......................................................................................................................ii DEDICATION .................................................................................................................. iv ACKNOWLEDGEMENTS ............................................................................................... v TABLE OF CONTENTS .................................................................................................. vi LIST OF FIGURES ............................................................................................................ x LIST OF TABLES ......................................................................................................... xiii CHAPTER I INTRODUCTION AND LITERATURE REVIEW ................................... 1 Chalones ......................................................................................................................... 1 Dictyostelium discoideum .............................................................................................. 2 Dictyostelium Chalones .................................................................................................. 3 Chemotaxis ..................................................................................................................... 5 Dipeptidyl Peptidase IV ................................................................................................. 8 Acute Respiratory Distress Syndrome ......................................................................... 10 CHAPTER II A DICTYOSTELIUM SECRETED FACTOR REQUIRES A PTEN- LIKE PHOSPHATASE TO SLOW PROLIFERATION AND INDUCE CHEMOREPULSION ..................................................................................... 12 Summary ...................................................................................................................... 12 Introduction .................................................................................................................. 13 Materials and Methods ................................................................................................. 15 Results .......................................................................................................................... 17 cnrN¯ cells show aberrant proliferation inhibition by AprA and CfaD ................... 17 cnrN¯ cells have fast proliferation ........................................................................... 18 cnrN¯ cells secrete AprA and CfaD ......................................................................... 22 cnrN¯ cells are multinucleate ................................................................................... 22 CfaD decreases the multinucleate phenotype of cnrN¯ cells ................................... 24 CnrN does not regulate growth on a per nucleus basis ............................................ 25 CnrN affects spore viability ..................................................................................... 28 AprA and CfaD affect CnrN localization ................................................................. 29 CnrN is necessary for chemorepulsion by AprA ...................................................... 31 Discussion .................................................................................................................... 33 vi Page CHAPTER III DIPEPTIDYL-PEPTIDASE IV IS A HUMAN AND MURINE NEUTROPHIL CHEMOREPELLENT .......................................................... 35 Summary ...................................................................................................................... 35 Introduction .................................................................................................................. 36 Materials and Methods ................................................................................................. 38 Structure prediction, alignment, and superimposition .............................................. 38 Neutrophil isolation .................................................................................................. 38 Insall chamber assays ............................................................................................... 39 Effect of DPPIV peptidase activity on albumin stability ......................................... 41 Neutrophil influx in mice ......................................................................................... 41 Immunohistochemistry ............................................................................................. 42 Neutrophil survival ................................................................................................... 43 Statistics .................................................................................................................... 44 Results .......................................................................................................................... 44 AprA has structural similarity to the human protein dipeptidyl-peptidase IV ......... 44 Neutrophils show biased movement away from a source of DPPIV ....................... 45 DPPIV gradients affect the probability of directional movement but do not affect cell speed .................................................................................................................
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