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Targeting Heme with Single Domain Antibodies

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Targeting Heme with Single Domain Antibodies Targeting Heme with Single Domain Antibodies Zélia Licínia Ferreira Gouveia Dissertation presented to obtain the Ph.D degree in Biochemistry Instituto de Tecnologia Química e Biológica António Xavier | Universidade Nova de Lisboa Oeiras, June, 2015 Targeting Heme with Single Domain Antibodies Zélia Licínia Ferreira Gouveia Dissertation presented to obtain the Ph.D degree in Biochemistry Instituto de Tecnologia Química e Biológica António Xavier | Universidade Nova de Lisboa Research work coordinated by: Oeiras, Junho, 2015 Targeting Heme with Single Domain Antibodies Zélia Licínia Ferreira Gouveia Supervisor: Dr. Miguel P.Soares Instituto Gulbenkian da Ciência Co-Supervisor: Dr. Smilja Todorovic Instituto de Tecnologia Química e Biológica PhD fellowship financed by Fundação para a Ciência e Tecnologia (Apoio financeiro da FCT e do FSE no âmbito do Quadro Comunitário de apoio, BD: SFRH/BD/44828/2008) Oeiras, Junho, 2015 Acknowledgements Firstly and primarily I would like to express my most sincere gratitude to my Ph.D supervisor Dr. Miguel P. Soares for accepting me as his Ph.D student and to trust me this Ph.D project. I want to thank him for his help, advices and for non-stop teaching and extremely helpful and constructive scientific discussions. Today, I am the scientist that you help to build, thank you very much! I extremely grateful to Dr. Miguel P. Soares for his understanding and support, in a particular period of my life in which I had to take several weeks of my work time to be and support my family as we were having a extremely difficult time in our life. For all of this and more, thank you very much! I am grateful to Dr. Smilja Todorovic, for giving me the opportunity to join in her laboratory and for accepting me as Ph.D student, for her advices, support and precious and fundamental help in Resonance Raman spectroscopy. I also want to thank to all the present and past members of Inflammation groups for their help, support, discussion and the most diverse moments spent together. A special thanks to Sofia, for her advices, support and many other things. To Viktória Jeney, for all the help and teach in the begining of this project and for the beautiful words and advices. Thanks the wonderful person, Ramus, for showing me that the comprehension and the calm can be your best friends in the moments that everything seems to be under tumult. Thanks to Raffi, for all your help. Sílvia, thank you very much for been always so friendly. To Rita Carlos, Susana Ramos and Sebastian Weiss thanks for the comments and the correction of the introduction part of the thesis. To my previous group member and now good friend Ana Cunha, my thanks for being always present and supportive and for all her scientific and non scientific help. I To my good friend Ana Rita Mateus, my thanks for the support and for always been presence in the good or less good moments. Ana Regalado, my sincere and most adorable friend, thank you very much for being always present and willing to listen and share ideas and advices. I am also grateful to the people involved in the many collaborations that support this work (chapter 2), including Dr. João Gonçalves from Faculdade de Farmácia e Instituto de Medicina Molecular, for receiving me in his research group for almost two years and to supervise my work in the development of single domain antibodies against heme using phage display technology. Thanks also to all his group members, for their help, support and time. Dr. Frederico Aires-da-Silva, from Technophage for providing me many useful suggestions about Phage display technology and many other things. Also, for all the scientific discussions and for being always available to take time to teach me and sharing his scientific knowledge. Dr. Claúdio Gomes from Instituto tecnologia Química e Biológica, for his kindness, availability and all his scientific help to performed spectroscopic techniques Dr. Olga Iranzo from Instituto tecnologia Química e Biológica, for her precious help in the biotinylation of Heme. Dr. Iqbal Hamza from the University of Maryland, for his kindness, availability and discussion on this work. Also, for receiving me his laboratory and providing me all the material and support required to perform HPR assay. To all his group members and in special Tamika Samuel and Carine White for their kindness, availability and scientific or non scientific help, as well as Jason Sinclair and Xiaojing Yuan for their kindness and availability. And to all the other collaborators, my thanks. I am also grateful to my Thesis committee, Dr. Alekos Athanasiadis, IGC and Dr. Miguel Teixeira, ITQB. II I want to thank to Instituto Gulbenkian da Ciência and all IGC community, for providing an amazing scientific environment. All this work was only possible because I have amazing people supporting me at all the moments, my loved companion and my family and of course my good friends. I want to thank my beloved family and specially my mother, Felismina Pereira Ferreira and my father, José da Assunção Gouveia, for so many things that there is no space in this thesis to mention them. My most and important thank you. Ao meu querido pai, José da Assunção Gouveia, o meu Muito Obrigada para todo o sempre! Se hoje defendo esta tese é sem dúvida graça a ti e à mãe! To my companion Pierre Crozet, first I would like to thank you for being such an amazing friend and for all the love demonstrated and shared. Thank you for all the support, help and comments/discussions in non and scientific fields. Thanks for helping me in my thesis, correcting/commenting it. I am also grateful to his amazing and adorable family to receive me like family. Merci à tous, et surtout à Joёlle Crozet-Vaugelade, Jean Jeacques Crozet et Elisabeth Crozet. I would like to acknowledge the Fundação para a Ciência e Tecnologia (Apoio financeiro da FCT e do FSE no âmbito do Quadro Comunitário de apoio, BD: SFRH/BD/44828/2008), Instituto Gulbenkia da Ciência and Inflammation Group of Dr. Miguel P. Soares, who have finantially supported my Ph.D Work. I would like to apologize in advance to the many people that I might not have mention in this section but for sure help me along these years to develop this work. For all of them, my sincere thanks. I would like to finalize with these two popular proverbs “Não importa o tamanho da montanha, ela não pode tapar o sol (Doesn’t matter the size of the mountain, she cannot be cover by the sun)” and “Quando as nuvens passam o Sol brilha” (When III the clouds pass, the sun shines) and by dedicating this thesis to my family, but specially to my beloved father José da Assunção Gouveia, who will always be with us and to my beloved mother Felismina Pereira Ferreira, without them this thesis could not be possible. My eternal thanks! Z.Gouveia IV Abreviations [wav(x), wav(y); Eg]; Waving Bach2; Basic leucine zipper transcription 5c; Five coordinate factor 2 6c; Six coordinate BCP; Breast cancer resistance protein aa; amino acids Biotin; N-[-5- (Hydrazinocarboxy) pentyl]-D- Ab(s); Antibodie (s) biotinamide ABCB10 or ABC-me; ATP-binding cassette Blimp-1; B lymphocyte-induced maturation sub-family B member 10 protein-1 ABCB6; ATP-binding cassette sub-family B BR; Bilirubin member 6 BV; Biliverdin ABCG2; ATP-binding cassette transporter BVR; Biliverdin reductase G2 BW; Body weight ACN; Acetonitrile CCD; Charge coupled device ACTH; Adrenocorticotropic hormone ccm; System I cytochrome c maturation Ala, A; Alanine CcmE; Cytochrome c maturation E ALA; δ-aminolevulinic acid CD; Circular dichroism ALAS; δ -aminolevulinate synthase CD14; Cluster of differentiation 14 ALAS-E; δ -aminolevulinate synthase CD163; Cluster of differentiation 163 erythroid-specific (=ALAS2) cDNA; Complementary DNA ALAS-N; Delta-aminolevulinate synthase CDR; Complementarity-determining regions nonspecific (=ALAS 1) cGMP; Cyclic guanosine monophosphate ANOVA; Analysis of variance CH; Heavy chain constant domain ApoE; Apolipoprotein E ChEBI; Chemical entities of biological Arg, R; Arginine interest Asp, N; Asparagine Cl; Chloride ATP; Adenoside triphosphate CL; Liht chain constant domain ATPase; Adenylpyrophosphatase CLP; Cecal ligation and puncture ATR-FTIR; Attenuated total reflection Fourier CN; Cysteine‑ asparagine transform infrared CO; Carbon monoxide BACH1; Basic leucine zipper transcription CO2; Carbon dioxide factor 1 CoPP; Cobalt protoporphyrin IX COPRO III; Coproporphyrinogen III V CORMs; Monoxide releasing molecules Fe3+; Ferric ion CPOX; Coproporphyrinogen oxidase FECH; Ferrochelatase CS; Cysteine-serine FePP; Hemin Ctrl; Control sdAb FePPCH3; Iron protoporphyrin IX dimethyl CY; Cyanine dyes ester chloride Cys, C; Cysteine FF; Fast flow Cytc; Cytochrome c FITC; Fluorescein isothiocyanate DAPI; 4',6-diamidino-2-phenylindole FLVCR2; Feline leukemia virus subgroup C DETAPAC; Diethylenetriaminepentaacetic receptor 2 acid FR; Framework region DeutP; Iron deuteroporphyrin IX Ft; Ferritin DHB; 2,5-dihydroxybenzoic acid FtH; Heavy/heart chain DMEM; Dulbecco's modified eagle medium FtL; Light/liver chain h DMF; Dimethylformamide Fv; Variable fragment domain DMSO; Dimethylsulfoxide Gly, G; Glycine DNA; Deoxyribonucleic acid GaPP; Gallium protoporphyrin IX dom, A2u; Doming GATA1; GATA binding protein 1 (globin E.coli; Escherichia cole transcription factor 1) EDTA; Ethylenediaminetetraacetic acid GSH; Reduced glutathione EEA; Early endosomes GSSG; Oxidized glutathione ELISA; Enzyme-linked immunosorbent GST; Glutathione S-transferase B assay H2O2; Hydrogen peroxide ER; Endoplasmatic reticulum H2SO4; Sulfuric acid
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