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Characterization of Kallikrein-Related Peptidase-8 in Normal Human Epidermis and Psoriasis

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Characterization of Kallikrein-Related Peptidase-8 in Normal Human Epidermis and Psoriasis Characterization of Kallikrein-related Peptidase-8 in Normal Human Epidermis and Psoriasis by Azza Eissa A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy Laboratory Medicine and Pathobiology University of Toronto © Copyright by Azza Eissa 2013 Characterization of Kallikrein-related Paptidase-8 in Normal Human Skin Epidermis and Psoriasis Azza Eissa Doctor of Philosophy Department of Laboratory Medicine and Pathobiology University of Toronto 2013 Abstract Kallikrein-8 (KLK8) is a relatively-uncharacterized epidermal protease. Although proposed to regulate wound-healing and barrier repair in KLK8-deficient mouse skin, KLK8-catalytic activity was never demonstrated in human epidermis and its regulators and targets remain largely unknown. KLK8 overexpression was reported in inflammatory skin diseases, but the underlying mechanisms are poorly understood. In this thesis, we elucidated for the first time KLK8-specific activity in normal human non-palmoplantar stratum corneum and sweat, and identified epidermal regulators and targets that augment its involvement in a skin-barrier proteolytic cascade. Given that inflammatory skin diseases have interlinked immune and epidermal roots, we hypothesized that epidermal KLK8 expression is distinctly regulated by the aberrant T-cell immunity implicated in the two common skin diseases, psoriasis and atopic dermatitis, independent of skin- barrier insults. We profiled secretion of KLK8 by normal human keratinocytes post-treatment with T-helper (Th1, Th17 and Th2) cell-derived cytokines, and investigated the effect of KLK8 overexpression on terminal keratinocyte differentiation and innate immunity gene expression. Our results show that TNFα and IL-17A synergistically induce potent KLK8 hyper-secretion, while IL4 and IL13 reduce its expression. TNFα and IL-17A overexpression and KLK8 ii hyperactivity resulted in hyperkeratosis and upregulation of keratinocyte innate defense genes’ expression mimicking psoriatic lesions. Consistently, KLK8 expression was reduced in lesional skin of atopic dermatitis patients and significantly elevated in lesional skin and sera of psoriatic patients. KLK8 levels correlated with psoriasis skin severity and were significantly reduced by effective treatment with biologic TNFα-blockers, correlating positively with psoriasis clearance. Thus, KLK8 is a new epidermal psoriasis therapeutic target. We performed high throughput screens of small molecule compound libraries to identify KLK8-specific inhibitors and discovered promising KLK8 small molecule inhibitors with IC50s in the nanomolar range. This thesis provides original findings corroborating KLK8 as an active serine protease in normal human skin and a down-stream epidermal respondent to TNFα and IL17A overexpression in psoriatic skin. Our novel KLK8-specific inhibitors may have future potential as topical barrier- enhancing agents in psoriasis. iii Acknowledgments Though my name appears on the cover of this dissertation, it would not have come into existence without the following remarkable individuals: My supervisor, Dr. Eleftherios P. Diamandis – Thank you for providing me with exceptional professional opportunities and teachable moments. I joined the lab as a naïve and enthusiastic young student and will be graduating as a mature professional. Thank you for pushing me to work independently and supporting me continuously. I learned valuable skills from you and I feel fortunate to have you as my supervisor and mentor. Our LMP graduate department coordinator, Dr. Harry Elsholtz – Thank you for being so approachable and resourceful. I appreciate your guidance and open door policy over the years. My thesis advisory committee, Dr. David Irwin, Dr. Sylvia Asa, Dr. Nades Palaniyar and Dr.Herman Yeger – I appreciate all your valued contributions! Thank you for your insightful feedback and advice. Your supervision and thoughtful review of my thesis was most helpful. My sincere appreciation to my external thesis advisor, Dr. Alain Hovnanian, for taking the time to contribute to my thesis and traveling long distance to be present during my thesis defense. Last but not least, the ACDC lab members of the near past and present, my work family – Thank you all for your valuable friendships. Your presence and support in the lab was a blessing. Special thanks to Ferzeen Sammy, Rama Ponda, Denitza Roudeva, Yiannis Prassas, Yijin Yu, Connie Zao, Vanessa Amodeo, Daniela Cretu, Antoninus Scoospialli, Dr. Gennady Poda, Dr. Martin Steinhoff, Dr. Ulf Meyer-Hoffert, Dr. Vinod Chandran, and Dr. Morely Hollenberg for helping me maneuver around some unexpected bumps in my research path and for being great friends, mentors and collaborators. Also, a big thank you to the Natural Science and Engineering Research Council (NSERC), Canada Graduate Scholarship, Ontario Graduate Scholarship (OGS), Helen Marion Walker- Soroptimist Women’s Health Research scholarship and LMP department for funding my research. iv Dedication To My Wonderful Family! To Mama & Baba – for all the sacrifices you made and your endless love and support. Thank you for encouraging me to be fearless in seeking insight and facing challenges. You taught me how to cultivate the right attitude and learn from every single life lesson. You had blind faith in me and supported my aspirations even when you were not sure where they were taking me. Thank you! I am who I am today because of you. To Omer ‘amoory’ – I couldn’t have asked for a better brother & best friend! I am very proud of you. You’ve been our rock. Thank you for being you! To ‘bit al siroor al azama’ Fatma, my extraordinary grandmother who raised six children on her own and faced tough challenges with unequivocal strength, and to our family guru, my dear uncle, ‘amo’ Abdel Salam– If you ask me about superheroes: “Superwoman” and “Superman”, I would say: I know them! Despite the oceans and lands separating us, your superpowers reach and move me. Your leadership, intellect, empathy and wisdom are legendary. They transcend time and place to inspire generations to care and do more. I plan to share your life stories with the world one day! For now, this thesis dedication will serve as a small token of my love and admiration. Thank you for being my inspiring role models! To ‘Denitza’ & ‘Puneet’ – my amazing girlfriends, my sisters! Living together and sharing over 10 years of friendships and laughs was a blast! Our incredible journey as young best friends from completely different backgrounds made me a better person. Thank you for always being there and for cheering me on through my entire undergrad and graduate programs. I couldn’t have done it without you. I love you both. Thank you all for allowing me to live “like a river flows, carried by the surprise of its own unfolding” ~ John O’Donahue. v Table of Contents Chapter 1 ......................................................................................................................................... 1 1 Introduction ................................................................................................................................. 2 1.1 Serine Proteases: Digesting the Basics ................................................................................ 2 1.1.1 General protease classification .................................................................................. 2 1.1.2 Serine proteases catalytic mechanism ........................................................................ 4 1.1.3 Human trypsin-like serine proteases of family S1 clan PA ....................................... 7 1.2 Kallikrein-related Peptidase-8 At a Glance .......................................................................... 7 1.2.1 Discovery of the Kallikrein-related peptidases .......................................................... 7 1.2.2 Genomic and proteomic structure of Kallikrein-related peptidases......................... 10 1.2.3 Molecular properties of Kallikrein-related peptidase-8 ........................................... 12 1.2.4 Kallikrein-related peptidase-8 knock out mouse ..................................................... 14 1.3 Kallikrein-related peptidases in Normal Human Epidermis .............................................. 15 1.3.1 Normal skin structure and function .......................................................................... 15 1.3.2 Kallikrein expression in the skin .............................................................................. 18 1.3.3 Dermatological roles of Kallikrein-related peptidases ............................................ 21 1.3.4 Regulation of epidermal Kallikrein-related peptidases ........................................... 23 1.4 Kallikrein-related peptidases in Skin Diseases .................................................................. 28 1.5 Psoriasis and Atopic Dermatitis ......................................................................................... 33 1.6 Kallikrein-related peptidase-8 in normal and inflamed skin 1.5 Psoriasis and Atopic Dermatitis .......................................................................................................................... 36 1.7 Rationale, Hypotheses and Objectives ............................................................................... 37 1.7.1 Rationale .................................................................................................................. 37 1.7.2 Hypotheses ..............................................................................................................
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