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Expression and Regulation of the Rate-Limiting Enzymes of the Kynurenine Pathway in the Mouse Brain by Alexandra Kelly Brooks Di

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Expression and Regulation of the Rate-Limiting Enzymes of the Kynurenine Pathway in the Mouse Brain by Alexandra Kelly Brooks Di EXPRESSION AND REGULATION OF THE RATE-LIMITING ENZYMES OF THE KYNURENINE PATHWAY IN THE MOUSE BRAIN BY ALEXANDRA KELLY BROOKS DISSERTATION Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Neuroscience in the Graduate College of the University of Illinois at Urbana-Champaign, 2017 Urbana, Illinois Doctoral Committee: Research Assistant Professor Robert H. McCusker, Chair Assistant Professor Andrew J. Steelman Assistant Professor Monica Uddin Professor Rodney W. Johnson P a g e | ii ABSTRACT During the mid-1900’s, early anti-depressants were developed to increase levels of catecholamines within the brain, leading to the theory that depression symptomology was a result of an imbalance of neurotransmitters within the brain. To date, the catecholamine theory of depression is still held to be the prevailing theory as selective serotonin reuptake inhibitors being the most commonly prescribed anti-depressants. However, the incidence of depression is still rising with a vast amount of patients failing to respond to current treatments, and with this knowledge, additional theories of the neurobiology of depression have arisen over the past 30 years. A leading theory is Kynurenine Pathway activation in relation to inflammation- or stress- induced depression-like behaviors. There has been a tremendous amount of data connecting activated immune system (or hypothalamic-pituitary-adrenal axis), increased kynurenine production and depression symptomology. Thus, understanding the factors that activate this pathway, as well as determining a relationship between anti-depressants and regulation of the Kynurenine Pathway, is an important next step in understanding the complex etiology of depression. My work has focused on 1) describing interactions between inflammation and stress to accentuate the expression of rate-limiting enzymes (indoleamine/tryptophan-2,3-dioxygenase: DOs) that metabolize the essential amino acid tryptophan to kynurenine, 2) detailing a novel interaction between galectins and interferon-gamma to accentuate DO expression within the brain, and finally 3) discuss the ability of current anti-depressant desipramine to block these interactions and attenuate DO expression within the brain and periphery as a possible new mechanism by which anti-depressants may be working to reduce depression symptomology. P a g e | iii ACKNOWLEDGEMENTS I could not have completed this degree or dissertation without the support of my advisor and mentor, Dr. Robert (Bob) McCusker. Thank you for encouraging me to develop my own ideas and test them out and for creating a supportive environment to discuss theories and new projects. I may have cried a few times in your office, but you were always there to help pick me back up, set me on track, and laugh about it later. We had a discussion in one of the neuroscience ethics seminar’s about an advisor also being a mentor, and we all agreed that an advisor should be (at minimum) a decent advisor with the hope that they would also be a mentor. Bob, you have been more than an advisor over the past three years; you have been the most amazing mentor, and I hope a close colleague and friend in the future. Thank you for working endlessly to help make my manuscripts great. Another key member of the lab, without whom I would not be finishing as quickly as I am, is Marc Lawson. I cannot thank you enough for all of your help working with mice and helping me slowly gain confidence with all the laboratory techniques over the years. Marc, you were my second mentor in the lab, and truly a wonderful lab mate, colleague and friend. Our long talks delving into different theories and molecular mechanisms helped shape my scientific mind, while our fun and crazy talks helped break up the monotony of the day. With both you and Bob by my side these past few years, I was given the opportunity to learn from some of the greatest scientists I know and will hopefully become even ½ of the researcher you both are in the future. I also could not have completed this dissertation without my wonderful undergrads that worked with me from the beginning: Tiffany Janda and Cecilia Ocampo-Solis. Thank you for working hard over the past three years, for dedicating your time to help me finish this degree, P a g e | iv and for your unwavering friendship. You are both going places, and I truly can’t wait to see you guys succeed; I’ll be there every step of the way cheering you on and will always be there if you need me. Similarly, without the help of Dr. McCusker’s other fantastic undergrads, Jill Braun and Nic Gamsby, I couldn’t have made it through the longest (and earliest morning) experiments. I believe you both are fantastic workers and beautiful people. Thank you for your help in the lab over the past two years, and more importantly, for being a listening ear that I could rely on when days were stressful. Bet you guys are going to miss those week long 8 am morning experiments! Finally, I would like to thank my husband, Sean Brooks, and parents (Barbara and Kevin Kelly). Sean, thank you for putting up with my late nights and weekends at the lab and for being understanding when I (we) needed to stay in Champaign during breaks instead of seeing family. Thank you for all of the hugs when I needed them after a rough day, for giving me support and praise after completely messing up an experiment, and for allowing me to be the best person and scientist I could be, even when that meant being separated for an extended amount of time. I don’t know what the future holds for us, but I know it’s going to be amazing because I have you. Mom and Dad, I know you never envisioned me going to get a PhD in neuroscience, and especially not from Dad’s alma mater! I truly can’t believe I’m graduating with a doctorate from the same school as you, Dad, exactly 20 years later. I want you to know that part of my decision to go to UIUC was for us (both you and me) to remember the past when I was growing up here, and remember all of the great times we had when Dad was in grad school. I have always wanted you both to support me in my decision to leave music, and I hope now you can be proud of all that I’ve accomplished. Thank you for the long phone calls home twice a week, for taking the time to listen to my “drama,” and for helping me figure out the next chapter of my life. P a g e | v TABLE OF CONTENTS CHAPTER 1: Introduction ..................................................................................................1 1.1 Inflammation ......................................................................................................1 1.2 Stress ..................................................................................................................2 1.3 Tryptophan Metabolism .....................................................................................3 1.4 DO and Behavior ...............................................................................................5 1.5 DO Transcripts ...................................................................................................6 1.6 Overlapping Pathways .......................................................................................7 1.7 Clinical Relevance .............................................................................................8 1.8 Conclusion .........................................................................................................9 CHAPTER 2: Interactions between inflammatory mediators and corticosteroids regulate transcription of genes within the Kynurenine Pathway in the mouse hippocampus .............................................................................11 2.1 Abstract ............................................................................................................11 2.2 Introduction ......................................................................................................13 2.3 Methods............................................................................................................17 2.4 Results ..............................................................................................................22 2.5 Discussion ........................................................................................................35 CHAPTER 3: Immunomodulatory factors galectin-9 and interferon-gamma synergize to induce expression of rate-limiting enzymes of the Kynurenine Pathway in the mouse hippocampus ......................................41 3.1 Abstract ............................................................................................................41 3.2 Introduction ......................................................................................................43 3.3 Methods............................................................................................................46 3.4 Results ..............................................................................................................51 3.5 Discussion ........................................................................................................64 CHAPTER 4: Desipramine decreases expression of human and murine indoleamine-2,3-dioxygenases...................................................................70 4.1 Abstract ............................................................................................................70 4.2 Introduction ......................................................................................................72 4.3 Methods............................................................................................................75
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