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Inaugural – Dissertation INAUGURAL – DISSERTATION zur Erlangung der Doktorwürde der Naturwissenschaftlich - Mathematischen Gesamtfakultät der Ruprecht - Karls - Universität Heidelberg vorgelegt von M.Sc. (Molekulare Medizin) Tina Ruckdeschel aus: Lichtenfels Tag der mündlichen Prüfung: 4. Oktober 2017 Characterization of the novel pericyte receptors S1PR3 and PTGER2 Gutachter: Prof. Dr. Ursula Klingmüller Prof. Dr. Hellmut Augustin Die vorliegende Arbeit wurde in der Abteilung „Vaskuläre Onkologie und Metastasierung“ am Deutschen Krebsforschungszentrum (DKFZ) in Heidelberg zwischen Oktober 2012 und Oktober 2017 durchgeführt. Acknowledgement Acknowledgement – Danksagung Schreiben musste ich diese Arbeit zwar allein – aber ohne die Unterstützung jeder Menge Menschen, wäre die Fertigstellung dieser Arbeit nicht gelungen. Daher möchte ich mich bei allen bedanken, die mich während meiner Promotion begleitet haben. Besonderem Dank gilt meinem Doktorvater Prof. Dr. Hellmut G. Augustin für die Betreuung meiner Dissertation in der Abteilung Vaskuläre Onkologie und Metastasierung am Deutschen Krebsforschungszentrum in Heidelberg. Durch dich habe ich gelernt selbstständig zu arbeiten, mich durchzusetzen und vor allem durchzuhalten. Prof. Dr. Ursula Klingmüller danke ich, dass sie mir die Möglichkeit gegeben hat, meine Doktorarbeit an der Mathematisch-Naturwissenschaftlichen Gesamtfakultät der Ruprecht-Karls- Universität und dem DKFZ in Heidelberg durchzuführen. Vielen Dank an Sie und Guillem Genové für die wissenschaftlichen Diskussionen und Ratschläge zu meinem Projekt während der Thesis Advisory Committee Treffen. Ebenfalls möchte ich mich bei Prof. Dr. Bartenschlager und Prof. Dr. Amir Abdollahi für die Teilnahme an meinem Prüfungskommitee bedanken. Frank van der Hoeven und Ulrich Kloz gilt ein großer Dank. Ihr ward beide an dem mühsamsten und problematischsten Teil meiner Doktorarbeit beteiligt und ich bin euch für eure Unterstützung und eurem Optimismus sehr dankbar! Speziell bedanken möchte ich mich bei der ´Pericyte for president` Gruppe: Laura Milde, Katharina Schlereth, Stella Hertel, Lena Vogelbacher, Stephanie Kapel und unser ehemaliges Mitglied Martin ´El Sabotage´ Teichert. Unsere regelmäßigen Meetings, die uneingeschränkte Hilfsbereitschaft in schwierigen Phasen und die gemeinsame ´Hass-Liebe´ zu Perizyten haben mich immer wieder motiviert und ihr seid mir wirklich sehr ans Perizyten-Herz gewachsen. Großer Dank geht auch an Karin Laaber, die ihre Masterarbeit den Perizyten gewidmet hat. Wir hatten eine tolle Zeit und du hast mich wirklich sehr unterstützt! Ich wünsche dir viel Erfolg in deiner weiteren Karriere! Katharina Schlereth und Laura Milde möchte ich für die intensive Korrektur meiner Dissertation danken. Und einen großen Dank an Courtney König für die Unterstützung bei der Formatierung der finalen Version. Ein besonderer Dank geht an alle Augustiner: ein kunterbunter, verrückter Haufen, in dem es nie langweilig wurde und in dem jeder immer ein offenes Ohr hatte. Die Arbeit mit euch allen hat es um vieles leichter und vor allem lustiger gemacht! Ein großes Dankeschön geht speziell an meine Bay (die coole 4. Bay): Anja Runge, Courtney König, Maria Riedel, Lise Roth und Moritz Jakab. Ihr habt mehr als alle anderen meine Launen über gute als auch vor allem schlechte Ergebnisse zwangsläufig mit mir geteilt. Ich danke euch für die wirklich sehr ungezwungene und abwechslungsreiche Atmosphäre im Laboralltag! I Acknowledgement Weiterhin möchte ich mich wirklich sehr bei den „Mädels“ bedanken: Anja Runge, Courtney Barbie König, Lise Postdoc Roth, Stephanie Hüribert Kapel, Katharina Mutti Schlereth, Soniya Christian Savant, Laura Milde, Silvia Sonsilvia La Porta, Eva Giannakouri, Claudia Fatty Korn, Beate Motzi Scholz, Chefsekretärin Maike Deckers, Aida Monster Freire. Ihr seid alle wirklich echte Freunde geworden, habt mich in Krisen unterstützt und auch meine kleinen Erfolge mit mir ausgiebig gefeiert. Frei nach dem Motto „What happened in/at Barcelona, Vasto, Stockholm, Cambridge, Europapark, Karneval, Kopenhagen stays in/at Barcelona, Vasto, Stockholm, Cambridge, Europapark, Karneval, Kopenhagen” haben wir viele Ausflüge ausserhalb des Labors unternommen. Es war eine super Zeit mit Euch und ich werde mich immer an diese Zeit erinnern! Ein besonderer Dank geht auch an die „technischen“ helfenden Hände: Maria Riedel, Eva Besemfelder, Jessica Wojtarowicz, Benni Schieb, Carleen Spegg, Doro Terhardt, Lukas Schmitt und Stella Hertel. Ihr habt so einiges ermöglicht und habt mich immer unterstützt, wenn Not an der Bench war. Mein größter Dank geht an die Menschen, die mich am besten kennen und in jeder Situation meines Lebens unterstützt und bestärkt haben. Besonderer Dank geht hierbei vor allem an meine Eltern, meine Schwester Sandra, meinen Schwager Michi, meine Großeltern und auch meine Nichten Mia und Leana, die mir mit ihrem Kinderlachen so einiges leichter gemacht haben. Ihr alle habt mir immer einen Rückzugsort geboten und neue Motivation gegeben, so dass ich mit neuer Energie weiterkämpfen konnte. Alles, was ich bisher erreicht habe, habe ich Eurer Unterstützung zu verdanken. Ein großes DANGE geht an Marc. Ich weiss, dass du den größten Unmut und die Frustration abbekommen hast und viele Stunden im Auto auf mich warten musstest. Umso mehr danke ich Dir, dass du wie kein anderer geduldig und verständnisvoll warst. Auch wenn ich oft verzweifelt war, hast du mich immer wieder angespornt und hast die schwere Zeit mit mir ausgesessen. Danke, dass du einfach immer da bist! II Table of Contents Table of Contents ACKNOWLEDGEMENT – DANKSAGUNG............................................................................................... I TABLE OF CONTENTS .................................................................................................................... III LIST OF FIGURES ......................................................................................................................... VI LIST OF TABLES .......................................................................................................................... VII ZUSAMMENFASSUNG……………………………………………………………………………………………………….…………… 1 SUMMARY ..................................................................................................................................3 1. INTRODUCTION .........................................................................................................................5 1.1 THE VASCULAR SYSTEM ................................................................................................................ 5 1.1.1 Vessel architecture and function ................................................................................. 5 1.1.2 Developmental blood vessel formation ....................................................................... 6 1.1.3 Physiological angiogenesis ........................................................................................... 6 1.1.3.1 Phases of angiogenesis ....................................................................................... 6 1.1.3.2 Signaling pathways in EC .................................................................................... 7 1.2 PERICYTES .................................................................................................................................. 8 1.2.1 Morphology .................................................................................................................. 8 1.2.2 Origin ............................................................................................................................ 9 1.2.3 Molecular signature of pericytes ................................................................................. 9 1.2.3.1 PDGFRβ .............................................................................................................10 1.2.3.2 NG2 ...................................................................................................................10 1.2.3.3 αSMA and Desmin ............................................................................................11 1.2.3.4 RGS5 and Endosialin .........................................................................................12 1.2.4 EC-pericyte interactions .............................................................................................14 1.2.5 Functions of pericytes ................................................................................................16 1.2.5.1 Pericytes in health ............................................................................................16 1.2.5.2 Pericytes in disease ...........................................................................................17 1.3 SPHINGOSINE-1-PHOSPHATE RECEPTOR FAMILY .............................................................................19 1.3.1 S1P ..............................................................................................................................19 1.3.2 S1P receptors .............................................................................................................21 1.3.3 S1P in health and disease ...........................................................................................23 1.4 PROSTAGLANDIN SIGNALING .......................................................................................................24 1.4.1 Prostaglandins ............................................................................................................24 1.4.2 Prostaglandin E receptors and their functional
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