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Alterations in Ocular Surface System During the Pathogenesis of Herpes Stromal Keratitis

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Alterations in Ocular Surface System During the Pathogenesis of Herpes Stromal Keratitis Wayne State University Wayne State University Dissertations January 2019 Alterations In Ocular Surface System During The Pathogenesis Of Herpes Stromal Keratitis Pushpa Durgesh Rao Wayne State University, [email protected] Follow this and additional works at: https://digitalcommons.wayne.edu/oa_dissertations Part of the Immunology and Infectious Disease Commons Recommended Citation Rao, Pushpa Durgesh, "Alterations In Ocular Surface System During The Pathogenesis Of Herpes Stromal Keratitis" (2019). Wayne State University Dissertations. 2181. https://digitalcommons.wayne.edu/oa_dissertations/2181 This Open Access Dissertation is brought to you for free and open access by DigitalCommons@WayneState. It has been accepted for inclusion in Wayne State University Dissertations by an authorized administrator of DigitalCommons@WayneState. COPYRIGHT The Contents of Chapter 1 including Figure 13-23 has been Originally published in The Journal of Immunology. Pushpa Rao, Susmit Suvas. 2019. Development of Hypoxia and the Prevalence of Glycolytic Metabolism in Progressing Herpes Stromal Keratitis Lesions J. Immunol. Vol:202; 514-526. Copyright © [2019] The American Association of Immunologists, Inc. DEDICATION To my God Father, Dr. M.B Vasudevachari My parents, Mr. Durgesh Jadkal and Mrs. Anuradha Durgesh Rao And My Dear Friends, All this work was made possible through your blessings and best wishes. ii ACKNOWLEDGMENTS I extend my heartiest thanks to Dr. Susmit Suvas for being an excellent mentor. I appreciate Dr. Suvas to not only steer my research project in a precise direction but also to be my cheerleader. Dr. Suvas has provided state-of-the-art training in his laboratory and I am proud to have published quality peer-reviewed journals in the Dr.Suvas laboratory. My special thanks to the research grant received by Dr. Suvas from the National Eye Institute for supporting the research work throughout my Ph.D. career. I am also grateful to Thomas. C. Rumble graduate fellowship awarded by the Wayne State University graduate school for financial support during my graduate education. I am thankful to my dissertation committee members, Dr. Jena Steinle, Dr. Lalit Pukhrambam and, Dr. Izabela Podgorski for their valuable time and to provide me with thoughtful inputs in the preparation of my thesis. I immensely appreciate my committee members for their guidance all through my Ph.D. career. My special thanks to Dr. Linda Hazlett, the Vice Dean of Research and Graduate Programs, Wayne State University School of Medicine to incessantly care about the upliftment of graduate students and to promote research by providing advanced facilities at the Vision core, Dept of Ophthalmology Visual and Anatomical Sciences. I extend my gratitude to the Association of Research in Vision and Ophthalmology (ARVO) foundation Travel Award (2017), the Gordon Research Conference (GRC) Travel Award (2018) and, the Wayne State University Travel Award (2015-2018). This award has provided me with a great platform to present my research work and to meet with the pioneers in the field. iii My sincere thanks to the members of Dr. Suvas laboratory, Subhash Gaddipati, Ph.D., Bala Burugula, Ph.D., the former post-doctoral fellows who have helped me with the experiments. Andrew Jerome, Ph.D., as a fellow student has helped me in managing accessory laboratory work and for a good chat. Nicholas Ciavattone, the graduate student, has helped me acclimatize to a new laboratory environment when I had just joined the Dr.Suvas laboratory. This research work would have been an ordeal without the unconditional love and emotional support provided by my parents. My mom, Mrs. Anuradha has always kept me motivated and strong to face challenging events in life. My dad, Mr. Durgesh feels proud of my achievements and my research work in the laboratory. My parent's happiness and blessings have been a driving force for all my accomplishments. My heartiest thanks to Dr. M.B. Vasudevachari, Late Dr. Vasanta Srikantan and, Ms. Prema Shenoy to wish me success. Last, but not least, I cannot forget to mention my special thanks to all my dear friends for their enormous help in financially supporting me when required during the hard times in life. Without their financial and emotional support, it would have been impossible to pursue my career and accomplish my dream. iv TABLE OF CONTENTS DEDICATION ...................................................................................................................ii ACKNOWLEDGMENTS .................................................................................................. iii LIST OF FIGURES ………………………………………………………………………….vii LIST OF TABLES………………………………………………………………………………..x INTRODUCTION ............................................................................................................. 1 1. Herpes Simplex Virus 1 ......................................................................................... 1 1.1 Epidemiology ......................................................................................................... 1 1.2. HSV-1 Structure and Lytic Life Cycle .................................................................... 2 1.3. Pathogenesis of Herpes Stromal Keratitis ............................................................. 3 2. Cornea ................................................................................................................... 5 2.1. Structure of normal cornea and tear film ............................................................... 5 2.2. Corneal nerves ...................................................................................................... 9 2.3. Corneal hem-angiogenesis ................................................................................. 13 3. Hypoxia Inducible factor ...................................................................................... 14 3.1. HIF Pathway ........................................................................................................ 14 4. Lacrimal gland ..................................................................................................... 16 4.1. Anatomy and functional role of lacrimal gland ..................................................... 16 5. Conjunctiva.......................................................................................................... 19 5.1. Anatomy and functional role of conjunctiva ......................................................... 19 6. Insulin like growth factor binding protein (IGFBPs) .............................................. 20 6.1. Insulin growth factor (IGF) and IGFBP-3 ............................................................. 20 6.2. IGF dependent action of IGFBPs ........................................................................ 22 6.3. IGF independent action of IGFBPs ...................................................................... 24 MATERIALS AND METHODS ...................................................................................... 33 v CHAPTER 1: DEVELOPMENT OF INFLAMMATORY HYPOXIA AND PREVALENCE OF GLYCOLYTIC METABOLISM IN PROGRESSING HERPES STROMAL KERATITIS LESIONS ....................................................................................................................... 56 Abstract ......................................................................................................................... 56 Introduction ................................................................................................................... 57 Results .......................................................................................................................... 58 Discussion ..................................................................................................................... 65 CHAPTER 2: EVALUATION OF EXTRAORBITAL LACRIMAL GLAND AND CONJUNCTIVAL INFLAMMATION DURING HSV-1 INFECTION……………………....82 Abstract ......................................................................................................................... 82 Introduction ................................................................................................................... 83 Results .......................................................................................................................... 86 Discussion ..................................................................................................................... 94 CHAPTER 3: MORPHOLOGICAL ALTERATIONS IN THE CORNEAL EPITHELIUM DURING OCULAR HSV-1 INFECTION ...................................................................... 105 Abstract ....................................................................................................................... 106 Introduction ................................................................................................................. 107 Results ........................................................................................................................ 109 Discussion ................................................................................................................... 113 CHAPTER 4: IGF-1 DEPENDENT MECHANISM OF IGFBP-3 IN THE PATHOGENESIS OF HERPES STROMAL KERATITIS ............................................. 124 Abstract ....................................................................................................................... 124 Introduction ................................................................................................................
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