Regulation of Death Receptor-Mediated Cell Demise by Glutathione DISSERTATION

I am deeply indebted to my supervisor Albrecht Wendel, who initiated and conducted this study. Besides providing outstanding working facilities, his constant encouragement, his personal support, and his unique sense for bringing together scientific concerns and social commitment created the solid basis for the success of this PhD thesis. Their personal efforts to run this institution by organizing excellent courses and seminars, by sharing all their experience and by providing lively and constructive discussions on scientific projects are deeply treasured. Leist for reviewing my thesis and lending me their expertise. Leist for valuable scientific discussions, representing an inestimable contribution to this thesis. I consider Markus Latta as a model colleague, and his friendship and help are deeply appreciated. I want to express my gratitude to Ulla Gebert for skillful technical support and for bringing in her hands-on experience with in vivo experiments. I would like to extend my appreciation to all members of the department of Biochemical Pharmacology for their comradeship, patience and valuable help-each of you contributed to this fruitful and enjoyable time. My experimental work greatly benefited from several collaborations, and the following friends and colleagues are gratefully acknowledged for their technical or experimental advice: Dr. Ingo Schmitz (DKFZ Heidelberg) for introducing me into the secrets of APO-1 (also known as CD95, maybe Fas) immunoprecipitation, Dr. Alexandra K. Kiemer (University of Munich) for her help with the NF-κB EMSA, Prof. Jose Vina (University of Valencia, Spain), in whose department the glutathione determinations by HPLC were carried out, and Dr. for his competent and kind support with histological studies. Tanja Bürrlein significantly contributed to this project during the Vertiefungskurs Biochemische Pharmakologie and are therefore gratefully acknowledged. Finally, a personal note to my parents for supporting me in whatever I intended to do, be it Jazz or science, and to Christiane for always being with me. (1999) Murine CD95-mediated hepatic apoptosis requires an intact glutathione status. (2000) Depletion of hepatic glutathione prevents death receptor-dependent apoptotic and necrotic liver injury in mice. mice against T cell-dependent, TNF-mediated apoptotic liver injury. caspase activity prevents CD95-mediated hepatic microvascular perfusion failure and restores Kupffer cell clearance capacity. A hepatotoxicity in mice: TNF-mediated organ failure independent of caspase-3-like protease activation. Sepsis following severe injury interrupts caspase-dependent processing of IL-18. fragments in the blood plasma of cancer patients: quantitations and evidence for their origin from apoptotic and necrotic cells. (submitted) in contrast to CD95-induced neutrophil apoptosis …