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Multipronged Approach to Study Glaucoma-Associated Phenotypes University of Tennessee Health Science Center UTHSC Digital Commons Theses and Dissertations (ETD) College of Graduate Health Sciences 8-2016 Multipronged Approach to Study Glaucoma- Associated Phenotypes Sumana Rameshbabu Chintalapudi University of Tennessee Health Science Center Follow this and additional works at: https://dc.uthsc.edu/dissertations Part of the Neurosciences Commons Recommended Citation Chintalapudi, Sumana Rameshbabu (http://orcid.org/0000-0003-1079-0950), "Multipronged Approach to Study Glaucoma- Associated Phenotypes" (2016). Theses and Dissertations (ETD). Paper 404. http://dx.doi.org/10.21007/etd.cghs.2016.0410. This Dissertation is brought to you for free and open access by the College of Graduate Health Sciences at UTHSC Digital Commons. It has been accepted for inclusion in Theses and Dissertations (ETD) by an authorized administrator of UTHSC Digital Commons. For more information, please contact [email protected]. Multipronged Approach to Study Glaucoma-Associated Phenotypes Document Type Dissertation Degree Name Doctor of Philosophy (PhD) Program Integrated Program in Biomedical Sciences Track Neuroscience Research Advisor Monica M. Jablonski, Ph.D. Committee Edward Chaum, M.D., Ph.D. Dianna A. Johnson, Ph.D. Rajendra Raghow, Ph.D. Vanessa Morales-Tirado, Ph.D. Robert W. Williams, Ph.D. ORCID http://orcid.org/0000-0003-1079-0950 DOI 10.21007/etd.cghs.2016.0410 Comments One year embargo expires August 2017. This dissertation is available at UTHSC Digital Commons: https://dc.uthsc.edu/dissertations/404 Multipronged Approach to Study Glaucoma-Associated Phenotypes A Dissertation Presented for The Graduate Studies Council The University of Tennessee Health Science Center In Partial Fulfillment Of the Requirements for the Degree Doctor of Philosophy From The University of Tennessee By Sumana Rameshbabu Chintalapudi August 2016 . Chapter 3 © 2016 by John Wiley & Sons. Chapter 4 © 2016 by 2007-2016 Frontiers Media, SA. All other material © 2016 by Sumana Rameshbabu Chintalapudi. All rights reserved. ii DEDICATION To my parents, Ramesh Babu Chintalapudi Usha Rani Chithirala And My better half, Purav Trivedi iii ACKNOWLEDGEMENTS First of all, I wish to thank the Almighty Lord for helping me start, pursue and successfully complete my PhD. Working as PhD student in UTHSC was a magnificent as well as challenging experience for me. This dissertation was the product of a large measure of serendipity, fortuitous encounters with people who have changed the course of my academic career. It would not have been possible without the help of so many people in so many ways. Here is a tribute to all those people. I want to thank my supervisor Prof. Dr. Monica M. Jablonski for giving me this wonderful opportunity to pursue PhD and introducing me to the world of glaucoma research. I will cherish the time I have spent as your mentee for the rest of my life. The academic and research freedom you provided me is unparalleled, and the intellectually stimulating discussions regarding work and research, and conversations about all things non-academic have benefitted me immensely. Above all and the most needed, she provided me unflinching encouragement and support in various ways. Dr. Vanessa Morales-Tirado has been supportive throughout the doctoral program, her cheerful enthusiasm and ever-friendly nature was a constant inspiration, she has provided tremendous help in the study design and analytical methodology in my research studies. Dr. Robert Williams has always asked thought-provoking questions and provided insightful feedback that has helped me in improving my research studies. Dr. Dianna Johnson has been kind to meet me several times on short notice and provided great feedback and inputs regarding research and life in academics. Dr. Edward Chaum has provided great feedback and inputs for my research studies during the vision research seminars and committee meetings. Dr. Rajender Raghow has been very supportive and provided valuable guidance to improve my research studies. My wonderful family stood by me and encouraged me in each and every endeavor that I have embarked upon. With enduring patience, they stood by me during the ups and downs of my life. I can barely find words to express all the wisdom, love and support given to me by my beloved parents, Dr. Ramesh Babu Chintalapudi and Mrs. Usha Rani Chithirala for their unconditional love, fidelity, endurance and encouragement. I am deeply indebted to my best friend and husband, Purav Trivedi, for giving me untiring support during my years of Doctoral study. I am wordless in expressing my sincere gratefulness for his constant encouragement and love. He has helped me to see and practice life altogether in a different perspective, to stay focused and to go after my dreams. I thank my brother Anil Kumar Chintalapudi and his wife Leena Kora for their unconditional love and support at all times in life, and especially during my doctoral education. I would like to thank my wonderful in-laws, Mr. Tuhinanshu Trivedi and Mrs. Meha Trivedi, for their love and support, and blessings during this critical phase in my life. I thank my sister-in-law, Pankti Trivedi, for her support and affection. Many friends and colleagues from both India and US have helped me stay sane throughout my PhD. Their support and care helped me overcome setbacks and stay focused on my graduate study. I greatly value their friendship and I deeply appreciate iv their belief in me. I want to thank current and past members of Jablonski, XiangDi Wang, Doaa Maria, Mohamed Mostafa Ibrahim, Samy Maria, Yunfeng Shi, Mallika Palamoor, Liyuan Li, Huiling Li, Hong Lu, Xiaofei Wang. Also to members of Morales lab, Bradley Gao, Levon Djenderedjian and Zachary Goldsmith. My tribute…..to a number of animals who have paid a price with their lives and suffering in the name of human protection. I pay my tribute to their sacrifice and pray that it is not in vain. In all, the journey to my Ph.D. has been a long and challenging road. And I am thrilled it is done. But most of all, I am excited for what the future holds…. v ABSTRACT Glaucoma refers to a group of conditions characterized by death of RGCs, increase in intraocular pressure is usually a precursor to glaucoma and irreversible optic neuropathy leads to visual impairment and blindness. Recent advances have seen a surge of new ideas and technologies to aid in the early detection, efficacious treatments and neuroprotection. Despite advances we face several challenges in understanding the pathophysiology of glaucoma. One of the many challenges scientists and ophthalmologists are facing is, to better understand IOP, its role in glaucomatous damage and design safer, more predictable IOP-lowering therapies. Another challenge is to find a practical method or develop tools to understand the molecular pathways to study RGC function and health to develop novel therapies for vision loss. This work leads to three complementary insights on how to address these challenges. First, we used a novel systems genetics approach to identify and validate genetic modifiers of IOP using the enlarged BXD family of strains in combination with human GWAS glaucoma cohorts. This will pave the way for improved drug development tailored to individual genotypes for POAG. Second, we have combined systems genetics, bidirectional studies using multiple species, meta-analyses, immunohistochemistry, FACS sorting and gene knockdown studies to identify and validate the identity of a genetic modulator of Sncg, a gene that has been previously implicated in RGC death in glaucoma. Outcomes of the investigation may provide clues to understanding the molecular mechanisms that account for the degenerative changes in RGCs in glaucoma. Third, we optimized a feasible, reproducible, standardized flow cytometry-based protocol for the isolation and enrichment of homogeneous RGC. This will allow for future careful assessment of important cell specific pathways in RGC to provide mechanistic insights into the declining of visual acuity in aged populations and those suffering from retinal neurodegenerative diseases. Taken together these studies offer a concise outlook on use of integrated systems science, molecular and imaging technologies as a needs-led innovation in ophthalmology and visual health. vi TABLE OF CONTENTS CHAPTER 1. INTRODUCTION .....................................................................................1 Primary Open Angle Glaucoma .......................................................................................1 IOP as a major risk factor ............................................................................................1 Role of RGCs in POAG ...............................................................................................2 Genetics of POAG .......................................................................................................3 Candidate gene studies ............................................................................................ 3 Genome-wide studies .............................................................................................. 4 Systems Genetics Approach to Study Glaucoma ............................................................5 Recombinant inbred strains ..........................................................................................5 DBA/2J inbred strain as glaucoma mouse model ................................................... 6 BXD strains ............................................................................................................
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