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Investigating Regulators of the Alternative Pathway of Complement and The INVESTIGATING REGULATORS OF THE ALTERNATIVE PATHWAY OF COMPLEMENT AND THE MODULATORY ROLE OF FACTOR H AND FACTOR H­RELATED PROTEINS by ALEXANDRA HOPE ANTONIOLI B.S., Yale University, 2007 A thesis submitted to the Faculty of the Graduate School of the University of Colorado in Partial fulfillment of the reQuirements for the degree of Doctor of PhilosoPhy Molecular Biology Program 2016 This thesis for the Doctor of PhilosoPhy degree by Alexandra HoPe Antonioli has been aPProved for the Molecular Biology Program by Arthur Gutierrez­Hartmann, Chair V. Michael Holers, Advisor JosePh A. Brzezinski Elan Z. Eisenmesser Thomas E. Morrison Date: 08/19/2016 ii Antonioli, Alexandra HoPe (Ph.D., Molecular Biology) Investigating Regulators of the Alternative Pathway of Complement and the Modulatory Role of Factor H and Factor H­Related Proteins Thesis directed by Professor V. Michael Holers ABSTRACT Immune­mediated diseases such as rheumatoid arthritis (RA), age­related macular degeneration (AMD), systemic luPus erythematosus (SLE), and atypical hemolytic uremic syndrome (aHUS) are chronic and costly illnesses. Although the Pathogenesis of each of these diseases is complex, it is known that dysregulation of the complement system Plays a key contribution. Therefore, a better understanding of complement regulation and specific complement regulatory Proteins is crucial for develoPing theraPies that could improve the lives of many individuals. The overall objective of this work was to explore the interrelationshiPs between the complement regulatory Protein Factor H (FH) and a grouP of closely related molecules called the Factor H­Related (FHR) Proteins. FH regulates complement activation on self­surfaces, thus allowing the innate immune response to discriminate between self and Pathogens. FH and the FHR Proteins consist in their entirety of compact rePeating domains known as short consensus rePeats (SCRs). The FHRs share a subset of structural and functional traits with FH including the caPacity to bind complement component C3b and glycosaminoglycans (GAGs). However, few functional studies have been carried out on the FHR Proteins, and they have not been studied in any in vivo models of inflammatory disease. Here we rePort the generation and characterization of recombinant murine FH and three iii FHR Proteins. Results from hemolytic assays using erythrocytes indicate that two of the FHR Proteins, mFHR­A and mFHR­B, antagonize the Protective function of FH on some cell surfaces. For example, both mFHR­A and mFHR­B increase cell­ surface C3b dePosition on a human retinal Pigment ePithelial cell line (ARPE­19) and a murine kidney Proximal tubular cell line (TEC). We also determined the aPParent KD values of murine FH and the murine FHR Proteins for a Putative binding Partner, murine C3d. To better understand the role of FHR Proteins in vivo, Preliminary experiments were Performed to investigate the effects on complement activation on kidney cells in a murine model of complement­mediated kidney injury. The results from this work suggest that like their human counterparts, mFHR Proteins aPPear to have an important role in complement regulation. Further work is warranted to define their in vivo context­dePendent roles and determine whether the FHR Proteins are suitable theraPeutic targets for the treatment of complement­driven diseases. The form and content of this abstract are aPProved. I recommend its Publication. ApProved: V. Michael Holers iv I dedicate this work to my family. v ACKNOWLEDGEMENTS I would like to thank my mentor, V. Michael Holers, for the oPPortunity to work with a world leader in the field of complement research. I am grateful for the many oPPortunities to attend extraordinary scientific conferences and for Providing me with space to grow as a scientist. I also would like to acknowledge Liuda Kulik for sharing her knowledge of complement and antibodies with me. Thank you to Joshua Thurman and members of his lab, Jennifer Laskowski and Brandon Renner, for their time and help with animal experiments. Thank you to Shaun Bevers and the BioPhysics Core for their helP and Lori Sherman and Michelle RandolPh in the Cancer Core. My training would not have been the same without PhiliPPa Marrack, who gave me the oPPortunity to work in her laboratory and learn about a new area of science. I am thankful for her mentorshiP and guidance and for a truly wonderful experience in her lab. I would also like to thank John KaPPler for our discussions about Protein biochemistry. I am thankful to Janice White who Provided helP and expertise with the antibody develoPment in this Project and to Fran Crawford for her excePtional knowledge of Protein biochemistry and her assistance with biacore experiments. Thank you also to other members of the KaPPler­Marrack (KM) lab including Gina Clayton, Haolin Liu, Alana Montoya and Ella Kushner. I would also like to acknowledge Jo Alamri for her suPPort and encouragement. In addition to the KM lab, I am very aPPreciative to the Clinical Complement Lab at National Jewish Hospital and in Particular, Ashley Frazer­Abel and Patricia Giclas, for allowing me the oPPortunity to Perform certain experiments and for Providing me with reagents. vi I would like to acknowledge the members of my thesis committee including Arthur Gutierrez­Hartmann, JosePh Brzezinski, Elan Eisenmesser, Thomas Morrison, and Rui Zhao, for their helP and guidance throughout my training. I am also aPPreciative of the suPPort of the Molecular Biology Program. In Particular, I would like to express my gratitude to the Victor W. and Earleen D. Bolie Family for Providing financial suPPort for my graduate training and also for Providing funding to attend an international conference. Thank you to both Arthur Gutierrez­Hartmann and Angie Ribera for their mentorshiP and for always having time to talk with their students about science or life. I would like to thank our Molecular Biology and MSTP administrators, Sabrena Heilman, Jodi CroPPer, and Emily Dailey. Additionally, I would like to also acknowledge Dr. Liron CaPlan who served as my clinical PrecePtor for my Foundations of Doctoring course. Dr. CaPlan has tremendous clinical skills and working with him for five years was inspiring and a true Privilege. On a more Personal note, I would also like to thank my friends and numerous colleagues for their helP and companionshiP during graduate school. The Past five years have been an amazing journey, and I am blessed to have had their suPPort and encouragement. Finally, I would like to thank my Parents, Sandra and Peter as well as my sister, Gabrielle, and uncle Milt for all of their love, suPPort, and endless encouragement. While my grandParents, Milt, Ruth, and Della, and my uncle Mark are no longer with us, I would like to acknowledge them for Providing me with a magical childhood full of love and for encouraging me to dream big and stay strong. vii TABLE OF CONTENTS CHAPTER I. INTRODUCTION ........................................................................................ 1 Immune System Network............................................................................ 1 Complement Pathways ............................................................................... 2 The Classical Pathway ........................................................................... 4 The Lectin Pathway ................................................................................ 5 The Alternative Pathway ........................................................................ 6 Complement Regulation ............................................................................. 8 Membrane­Bound Complement Regulators ........................................... 8 Cell Surface RecePtors for Complement Components ........................ 10 Fluid Phase Regulators ........................................................................ 11 Regulation by Factor H ............................................................................. 13 CFH Genomic Position and Structure ...................................................... 16 MaPPing of the CFHR Genomic Region ................................................... 19 Human FHR Proteins ............................................................................... 22 FHR­1 ................................................................................................... 24 FHR­2 ................................................................................................... 24 FHR­3 ................................................................................................... 25 FHR­4 ................................................................................................... 26 FHR­5 ................................................................................................... 27 Human Disease Associations ................................................................... 28 C3 GlomeruloPathy .............................................................................. 29 Atypical Hemolytic Uremic Syndrome .................................................. 30 Age­Related Macular Degeneration ..................................................... 32 viii FH and FHR Protein Involvement with Pathogens ................................... 33 Murine Factor H­Related Gene Family ..................................................... 36 Initial Characterization of Murine FHR TranscriPts ............................... 36 Initial Characterization of Two Murine Factor H­Related Proteins ......
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