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Prokineticin 2 Signaling: Genetic Regulation and Preclinical Assessment in Rodent Models of Parkinsonism Jie Luo Iowa State University

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Prokineticin 2 Signaling: Genetic Regulation and Preclinical Assessment in Rodent Models of Parkinsonism Jie Luo Iowa State University Iowa State University Capstones, Theses and Graduate Theses and Dissertations Dissertations 2018 Prokineticin 2 signaling: Genetic regulation and preclinical assessment in rodent models of Parkinsonism Jie Luo Iowa State University Follow this and additional works at: https://lib.dr.iastate.edu/etd Part of the Toxicology Commons Recommended Citation Luo, Jie, "Prokineticin 2 signaling: Genetic regulation and preclinical assessment in rodent models of Parkinsonism" (2018). Graduate Theses and Dissertations. 17254. https://lib.dr.iastate.edu/etd/17254 This Dissertation is brought to you for free and open access by the Iowa State University Capstones, Theses and Dissertations at Iowa State University Digital Repository. It has been accepted for inclusion in Graduate Theses and Dissertations by an authorized administrator of Iowa State University Digital Repository. For more information, please contact [email protected]. Prokineticin 2 signaling: Genetic regulation and preclinical assessment in rodent models of Parkinsonism by Jie Luo A dissertation submitted to the graduate faculty in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Major: Toxicology Program of Study Committee: Anumantha Kanthasamy, Co-major Professor Arthi Kanthasamy, Co-major Professor Mark Ackermann Cathy Miller Thimmasettappa Thippeswamy The student author, whose presentation of the scholarship herein was approved by the program of study committee, is solely responsible for the content of this dissertation. The Graduate College will ensure this dissertation is globally accessible and will not permit alterations after a degree is conferred. Iowa State University Ames, Iowa 2018 Copyright © Jie Luo, 2018. All rights reserved. ii DEDICATION To God, my dear mother Leanne, and my girlfriend Haiyang iii TABLE OF CONTENTS Page ACKNOWLEDGMENTS .................................................................................................. v ABSTRACT ....................................................................................................................... vi CHAPTER 1. GENERAL INTRODUCTION ................................................................... 1 Dissertation Layout and Organization ...................................................................... 1 Introduction .............................................................................................................. 2 Background and Literature Review I ............................................................................. 7 Parkinson’s Disease .................................................................................................. 7 Genetic Risk Factors in PD Pathogenesis ................................................................ 9 Environmental Risk Factors and Role of Mn Exposure in development of PD and PD-Like Pathologies ........................................................................................ 10 Induction of Neuroinflammation from Exposure to Environmental Neurotoxicants........................................................................................................ 14 Hypotheses Regarding PD Pathogenesis ................................................................ 23 Animal Models of PD for Studying Gene-Environment Interactions .................... 26 Background and Literature Review II ......................................................................... 27 Current Clinical Trials for Experimental Therapies ............................................... 28 Glial-cell line Derived Neurotrophic Factor .......................................................... 30 Background and Literature Review III ........................................................................ 40 Structure of Prokineticins ....................................................................................... 40 PK1 and PK2 Signaling Through PKR1 and PKR2............................................... 42 PK1-GDNF Signaling in the Enteric Nervous System .......................................... 47 PK2 Signaling in the Brain ..................................................................................... 47 PKR1/PKR2 Agonists and Antagonists ................................................................. 50 CHAPTER 2. TRANSCRIPTIONAL REGULATION OF PROKINETICIN-2 PROMOTER BY EGR1, HIF1Α, AND NRF1 IN CELL CULTURES OF DOPAMINERGIC NEURODEGENERATION .............................................................. 54 Abstract .................................................................................................................. 54 Introduction ............................................................................................................ 55 Results .................................................................................................................... 59 Discussion .............................................................................................................. 72 Materials and Methods ........................................................................................... 76 Acknowledgements ................................................................................................ 79 References .............................................................................................................. 79 Figures .................................................................................................................... 89 iv CHAPTER 3. PROKINETICIN 2 PROTECTS AGAINST MANGANESE- INDUCED NEUROTOXICITY BY INDUCING MITOCHONDRIAL BIOGENESIS IN DOPAMINERGIC CELLS ............................................................... 102 Abstract ................................................................................................................ 102 Introduction .......................................................................................................... 103 Results .................................................................................................................. 108 Discussion ............................................................................................................ 114 Materials and Methods ......................................................................................... 118 References ............................................................................................................ 121 Figures .................................................................................................................. 131 CHAPTER 4. PHARMACOLOGICAL MODULATION OF ASTROCYTE- DERIVED GDNF BY PROKINETICIN 2 RECEPTOR AGONIST IS20: PRECLINICAL ASSESSMENTS USING MPTP AND MITOPARK RODENT MODELS OF PARKINSON’S DISEASE ..................................................................... 146 Abstract ................................................................................................................ 146 Introduction .......................................................................................................... 147 Results .................................................................................................................. 151 Discussion ............................................................................................................ 160 Materials and Methods ......................................................................................... 167 References ............................................................................................................ 171 Figures .................................................................................................................. 180 CHAPTER 5. CONCLUSIONS AND FUTURE DIRECTIONS .................................. 202 PK2 Transcriptional Regulation during Neurodegeneration ................................ 202 Neuroprotective Effects of PK2 signaling............................................................ 205 Induction of Neurotrophic Factors by PK2 .......................................................... 206 Further Considerations: Use of Appropriate Animal Models of PD .................... 207 Other Future Directions: Role of PK2 in Neurogenesis ....................................... 208 v ACKNOWLEDGMENTS I would like to thank my committee chair, Dr. Anumantha Kanthasamy and Dr. Arthi Kanthasamy and my committee members, Dr. Mark Ackermann, Dr. Cathy Miller, and Dr. Thimmasettappa Thippeswamy, for their guidance and support throughout the course of this research. I want to also offer my appreciation to all DRKLAB members who had collaborated with me in numerous experiments, and who had helped me grow as a student of the Sciences. I would like to thank Dr. Huajun Jin, Gary D. Zenitsky, and Lizabeth Lueck, who had spent numerous hours in proofreading manuscripts and my dissertation. In addition, I would also like to thank my friends, colleagues, the department faculty and staff for making my time at Iowa State University a wonderful experience. vi ABSTRACT Parkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer’s disease. The etiology of PD is currently not fully understood, but strong evidence has existed pointing to gene-environmental interactions that contribute to various pathogenic mechanisms of neurodegeneration: oxidative stress, neuroinflammation, mitochondrial dysfunction, and epigenetic modulation. While cell signaling mechanisms underlying neurotoxic injury have been actively studied in recent years, the signaling molecules contributing
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