University of New Hampshire University of New Hampshire Scholars' Repository Doctoral Dissertations Student Scholarship Winter 2020 THE ROLE OF GLI3 IN INFLAMMATION Stephan Josef Matissek University of New Hampshire, Durham Follow this and additional works at: https://scholars.unh.edu/dissertation Recommended Citation Matissek, Stephan Josef, "THE ROLE OF GLI3 IN INFLAMMATION" (2020). Doctoral Dissertations. 2552. https://scholars.unh.edu/dissertation/2552 This Dissertation is brought to you for free and open access by the Student Scholarship at University of New Hampshire Scholars' Repository. It has been accepted for inclusion in Doctoral Dissertations by an authorized administrator of University of New Hampshire Scholars' Repository. For more information, please contact [email protected]. THE ROLE OF GLI3 IN INFLAMMATION BY STEPHAN JOSEF MATISSEK B.S. in Pharmaceutical Biotechnology, Biberach University of Applied Sciences, Germany, 2014 DISSERTATION Submitted to the University of New Hampshire in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy In Biochemistry December 2020 This dissertation was examined and approved in partial fulfillment of the requirement for the degree of Doctor of Philosophy in Biochemistry by: Dissertation Director, Sherine F. Elsawa, Associate Professor Linda S. Yasui, Associate Professor, Northern Illinois University Paul Tsang, Professor Xuanmao Chen, Assistant Professor Don Wojchowski, Professor On October 14th, 2020 ii ACKNOWLEDGEMENTS First, I want to express my absolute gratitude to my advisor Dr. Sherine Elsawa. Without her help, incredible scientific knowledge and amazing guidance I would not have been able to achieve what I did. It was her encouragement and believe in me that made me overcome any scientific struggles and strengthened my self-esteem as a human being and as a scientist. There was never a time where her door was not open, and she was always reachable even at late hours or holidays. Her heartful manner and positive presence was one of the main reasons that kept me motivated in my Ph.D. studies and her scientific skillset and plethora of knowledge was always a standard I tried to achieve. Dr. Elsawa taught me that no goal is too big to be reached as long as I keep working consistently ,always try to improve and always believe in myself and it is without a doubt that without her I would not be sitting here finishing my dissertation. I consider my Ph.D. as one of the biggest achievements in my life which I would have never reached without the guiding hand of Dr. Elsawa. Besides Dr. Elsawa I also would like to deeply express my gratitude to my committee members, Dr. Linda Yasui, Dr. Don Wojchowski, Dr. Paul Tsang and Dr. Xuanmao Chen for their professional insights, kind help and amazing scientific suggestions. iii This research was supported by grant P20GM113131 from the National Institute of General Medical Sciences of the NIH. I also would like to thank the NIU Office of Vice President for Research and Innovation Partnerships (OVPRIP) for financial support for this project. Additionally, I would like to thank UNH for proving travel funds which allowed me to attend several conferences. These conferences were very valuable experiences from which I gained many important connections. Finally, I want to thank UNH for providing graduate student teaching assistantships and linked financial support. I absolutely want to thank my family and friends for their never-ending emotional (but also financial) support in my studies. Doing a Ph.D. can be very exhausting and without them supporting me and believing in me I would have never finished my studies. In particular, I want to thank following people: My mother, for always believing in me especially when I had trouble believing in myself and for being the most supportive person in my life. There was never a struggle that I faced without having my mother’s encouraging words in my ear. She is my role model for how to deal with problems since without her teaching me to be patient with myself and solving issues by putting one foot in front of the other I would not be where I am today. My sister Karina for being an extremely accomplished scientist who never fails to achieve any goal she sets. Her love to science motivated me to start my Ph.D. My sister Astrid whose discipline seeks its equal and motivated me to push through any late-night shifts in lab. My father, for being such a tough person and him seeing how he iv pushed through problems gave me, besides other things, the strength to push through mine. I also want to express my gratitude to past and present members of the Elsawa Lab. I want to thank for all the professional help provided, for the fun times we shared and contributions to my project. v TABLE OF CONTENT ACKNOWLEDGEMENTS ............................................................................................... iii TABLE OF CONTENT ....................................................................................................vi LIST OF FIGURES..........................................................................................................ix ABSTRACT .....................................................................................................................xi CHAPTER 1 .................................................................................................................... 1 Inflammation, a double-edged sword .............................................................................. 1 Acute inflammation; the good response ....................................................................... 2 General principles of an acute inflammatory response ................................................ 2 Principles of inflammation: para-inflammation .............................................................. 3 Principles of inflammation: acute inflammation ............................................................ 4 Exogenous stimuli ........................................................................................................ 5 Infection .................................................................................................................... 5 Toll-like receptors (TLRs) and their signaling pathways ........................................... 6 Extracellular TLRs ................................................................................................. 7 TLR2 only complexes with TLR1 or TLR6.......................................................... 7 TLR4 .................................................................................................................. 9 MYD88 pathway .................................................................................................. 10 TRIF pathway ...................................................................................................... 11 TLR5 ................................................................................................................ 12 TLR10 .............................................................................................................. 13 Intracellular TLRs ................................................................................................ 13 TLR3 ................................................................................................................ 13 TLR7/8 ............................................................................................................. 14 TLR9 ................................................................................................................ 15 Endogenous stimuli .................................................................................................... 17 Role of adaptive immune system in inflammation ...................................................... 18 Chronic inflammation, the bad one ............................................................................ 19 vi Infections related to chronic inflammation .............................................................. 20 Cellular stress related to chronic inflammation (DAMPs) ........................................ 21 Molecular characteristics involved in diseases caused by chronic inflammation ........................................................................................................... 22 Autoimmunity ....................................................................................................... 22 Cancer ................................................................................................................. 25 Molecular pathways linking chronic inflammation to cancer ............................. 26 NF-κB, STAT and SHH........................................................................................ 26 GLI3: A mediator of genetic diseases, development and cancer ............................... 28 Regulation and Structure ........................................................................................ 29 Hedgehog ligands and their function ................................................................... 29 Classic (canonical) Hh signaling .......................................................................... 30 In mammals ......................................................................................................... 31 Non-classical (non-canonical) HH signaling ........................................................ 34 Regulation of GLI3.................................................................................................