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Revealing Host Factors Important for Hepatocyte Infection by Plasmodium

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Revealing Host Factors Important for Hepatocyte Infection by Plasmodium Universidade de Lisboa Faculdade de Ciências Departamento de Biologia Vegetal Revealing Host Factors Important for Hepatocyte Infection by Plasmodium Cristina Dias Rodrigues Doutoramento em Biologia Biologia Celular 2007 Cover image | An Anopheles gambiae female mosquito feeding on a mammalian host (adapted from http://www.abc.net.au/science/news/img/health/mosquito190804.jpg). Universidade de Lisboa Faculdade de Ciências Departamento de Biologia Vegetal Revealing Host Factors Important for Hepatocyte Infection by Plasmodium. Cristina Dias Rodrigues Dissertation submitted to obtain a PhD Degree in Biology, speciality of Cellular Biology by the Universidade de Lisboa. Supervisor Maria Manuel Mota, MsD, PhD. Principal Investigator of Instituto de Medicina Molecular and Auxiliary Professor at Faculdade de Medicina, Universidade de Lisboa. Co-Supervisor Maria da Graça Alves Vieira, PhD. Auxiliary Professor of Faculdade de Ciências, Universidade de Lisboa. Research is to see what everybody else has seen, and to think what nobody else has thought. Albert Szent-Györgi All truths are easy to understand once they are discovered; the point is to discover them. Galileo Galilei Preface The present thesis embraces the data obtained during my Ph.D. research project developed from November 2003 to June 2007. The experimental work was supervised by Prof. Doutora Maria Manuel Mota and was carried out at Instituto de Medicina Molecular, in Lisboa and Instituto Gulbenkian de Ciência, in Oeiras, Portugal. The RNAi screens were performed at Cenix BioScience, Dresden, Germany. This Ph.D. was supervised by Prof. Maria da Graça Alves Vieira from Departamento de Biologia Vegetal, Faculdade de Ciências, Universidade de Lisboa, Portugal. The financial support was provided by the portuguese Fundação para a Ciência e Tecnologia, through the Ph.D. fellowship grant SFRH/BD/14232/2003. This thesis is structured in 5 chapters, which are preceded by a summary, both in Portuguese and in English. Chapter 1 comprises a general introduction to malaria and its current world situation, followed by an overview on the Plasmodium life cycle, the state of the art on the liver stage biology and the objectives of this thesis. Chapters 2 to 4 consist of the results obtained throughout the research project, which are presented in a publication format. Each results chapter includes an abstract, an introduction, the results and discussion, as well as the methods, acknowledgments and references. Chapter 5 encloses a general discussion and the future perspectives of the work develop. In Appendix are supplied my Curriculum Vitae and the publications in which I have participated until the date of printing this thesis. i Agradecimentos Acknowledgements Ao longo do meu doutoramento “cresci” em termos científicos mas acima de tudo como pessoa. Estes quatro anos foram muito intensos em sentimentos totalmente diferentes: entusiasmo vs. desânimo, alegria vs. tristeza, partilha vs. inibição, convicção vs. dúvida, sorrisos vs. lâgrimas, companheirismo vs. momentos de solidão. Durante esta jornada foram várias as pessoas que me acompanharam e às quais faço questão de agradecer. À Maria. Um bem-haja à minha orientadora científica e amiga. É díficil conseguir expressar em palavras tudo pelo qual gostaria de te agradecer. Obrigada pela oportunidade de poder trabalhar contigo e pela tua constante presença e apoio. Obrigada pela orientação científica e por me ensinares a fazer Ciência, pelo teu entusiasmo contagiante, pelas discussões científicas, por compreenderes os meus erros, por toda a preocupação, carinho e amizade e por respeitares as minhas ideias e o meu ritmo de trabalho e de escrita. À Professora Graça. Obrigada por ter aceite ser a minha orientadora interna ao nível da Faculdade de Ciências da Universidade de Lisboa. Foi um prazer partilhar e discutir o meu trabalho consigo... Muito obrigada por todo o apoio, ajuda e carinho. Ao Miguel. Quando começámos a trabalhar juntos foi um pouco difícil para mim. De repente ter de partilhar ideias, opiniões, horários, material, preocupações, definir prioridades e até partilhar uma vida/casa num país frio foi um desafio. Aprendi imenso contigo durante o meu doutoramento e sem ti os 6 meses em Dresden teriam sido ainda mais difíceis. Crescemos como colegas e amigos! Miguelito, muito obrigada por todo o apoio científico e pessoal. À Sónia. Muito obrigada pela constante boa disposição, companheirismo, ânimo, amizade no lab e principalmente durante as nossas mil viagens épicas. Estás nas minhas memórias de NY, Dresden, Berlim, Praga, Budapeste e Londres. E espero que em breve de Barcelona, mas desta vez espera-se que sem quedas!! To Michi. When I think about the first time that I went to Cenix BioScience, it comes to my mind the picture of you and Christian. Two friendly guys!! At that time I had never thought that we would still be working together after 4 years, which is spectacular. We were involved since the beginning and together we have been able to build an amazing story. Thank you for your Agradecimentos/ Acknowledgements support to the development of malaria research at Cenix. Many thanks for all the help, your work and input, your enthusiasm and all the scientific discussions. To Cécilie. I have learned a lot working with you, especially in what regards a good laboratory methodology. Thank you for your excellent work, your availability to answer my questions, your support and friendship and for the evenings and dinners while we were in Dresden. I hope to see you and Régis soon here in Lisbon. To Chris. Thank you for embracing the malaria research. To be able to work directly with you is a great honor and I have been learning constantly. Thanks for all your amazing input to our work and I will never forget your support and advices at the Keystone Meeting. À Sílvia. Agradeço-te pela tua constante disponibilidade em ajudares e especialmente por o fazeres com um sorriso. Sei que posso contar sempre contigo. Muito obrigada pelo apoio, energia e positivismo em termos profissionais e pessoais. O teu bom humor e espírito de amiga têm- me contagiado! Si, mil “thanks”. À Sabrina. Muito obrigada pela ajuda no trabalho, pelo apoio na recente cruzada de se fazer hepatócitos primários, pela tua amizade repleta de energia e sabedoria de vida. Desejos de muitas felicidades e havemos de nos cruzar algures no mundo! Não desanime nunca! À Lígia. Muito obrigada pelos teus maravilhosos hepatócitos primários de ratinhos, por me ensinares o protocolo que tão arduamente optimizaste e por estares sempre disponível a ajudar. Obrigada por todo o apoio e carinho. Mantém esse sorriso lindo! A todos os meus colegas que constituem a Unidade de Malária. Vocês estiveram presentes durante o meu doutoramento em fases diferentes... Se não me falha a memória, aqui vai por ordem de chegada ao grupo. Patrícia, muito obrigada por toda a ajuda, constante disponibilidade, amizade e contagiante gosto de se fazer Ciência sem deixar de se viver e explorar o Mundo e os sentidos. Admiro a tua capacidade de conciliar tantas actividades. Bjinho gde Linda! Daniel, muito obrigada pela paciência e muitos ensinamentos aquando da minha chegada ao grupo. Foste espectacular! Casanova, pelo apoio inicial e por me ensinares princípios laboratoriais básicos. Força para o teu doutoramento. Pensamento positivo! Bruno, muito obrigada por todo o apoio e força de que tudo vai correr bem. Desejos de muitas felicidades e se falhei na Holanda espero não falhar em Itália. Tudo de bom. iv Agradecimentos/ Acknowledgements Margarida, marcaste-me desde o primeiro dia em que fui ao IGC. Ainda me lembro da tua disponibilidade e simpatia a falares comigo. Foi muito bom trabalhar contigo, muito obrigada por todos os teus concelhos. Fica bem! Ana, o teu percurso constitui para mim um exemplo de como é possível mudar. Admiro a tua coragem, perseverança e luta. Obrigada por todo o apoio, ombro amigo e concelhos. Coragem, energia e sorriso estampado! Marta, a tua forte personalidade em prosseguires as tuas convicções é marcante. Muito obrigada pelas constantes perguntas e pelo apoio e compreensão em momentos difíceis. Desejos de muitas felicidades na tua nova etapa de vida em Londres and “see u”! Nuno, aprendi muito ao trabalhar contigo e obrigada por toda a ajuda. Espero que alcances todos os teus objectivos profissinais e pessoais. Nunca desistas! Cristina, muito obrigada pela tua visão do que é fazer Ciência, pelo exemplo de organização e capacidade de trabalho, pelo apoio e amizade. Ao te observar parece tão fácil! Ataíde, obrigada pelo trabalho indispensável com os nossos amigos mosquitos, pela constante boa disposição, companheirismo e gargalhadas. Boa sorte na Austrália e vê-se estás por lá em Fevereiro para fazeres as honras. Arrasa! Iana, thanks for your example of courage for going after of what you really wanted. I wish you all the best. Carina, és um exemplo de perseverança e insistência. Não percas estas qualidades e apesar de o tempo passar a correr lembra-te que durante um doutoramento também se deve aproveitar. Força! Kirsten, thanks for all the scientific questions, conversations about different subjects and help with the english. A smile! Catarina, obrigada pelo teu empenho no trabalho de produção de mosquitos. Bjinho! Luís, muito obrigada por toda a tua ajuda preciosa nesta fase final e por respeitares a minha agitação. Boa sorte por NY e aproveita ao máximo esta nova fase da tua vida. Inês e Ana, parte essencial do grupo sem vocês tudo seria muito mais difícil. Ana, um especial obrigado por todo o teu apoio. A special thanks to all at Cenix BioScience. Thank you for the exceptionable working environment, all the help and company outside the lab that has allowed me to enjoy Dresden. Thank you to Geert-Jan Gemert and Robert Sauerwein for providing precious P. berghei infected mosquitoes. Thank you to Jean-François Franetich and Dominique Mazier for the primary human hepatocytes and P. falciparum sporozoites.
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