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Repositório Da Universidade De Lisboa UNIVERSIDADE DE LISBOA FACULDADE DE CIÊNCIAS DEPARTAMENTO DE BIOLOGIA ANIMAL TOWARDS THE IDENTIFICATION OF BIOMARKERS FOR CYSTIC FIBROSIS BY PROTEOMICS NUNO MIGUEL ANTUNES GARCIA CHARRO DOUTORAMENTO EM BIOLOGIA ESPECIALIDADE BIOLOGIA MOLECULAR 2011 ii iii iv UNIVERSIDADE DE LISBOA FACULDADE DE CIÊNCIAS DEPARTAMENTO DE BIOLOGIA ANIMAL TOWARDS THE IDENTIFICATION OF BIOMARKERS FOR CYSTIC FIBROSIS BY PROTEOMICS Tese orientada pela Doutora Deborah Penque e Professora Doutora Ana Maria Viegas Gonçalves Crespo NUNO MIGUEL ANTUNES GARCIA CHARRO DOUTORAMENTO EM BIOLOGIA (BIOLOGIA MOLECULAR) 2011 v The research described in this thesis was conducted at Laboratório de Proteómica, Departamento de Genética, Instituto Nacional de Saúde Dr. Ricardo Jorge (INSA, I.P.), Lisbon, Portugal; Clinical Proteomics Facility, University of Pittsburgh Medical Centre, Pennsylvania, USA; and Laboratory of Proteomics and Analytical Technologies, National Cancer Institute at Frederick, Maryland, USA. Work partially supported by Fundação para a Ciência e a Tecnologia (FCT), Fundo Europeu para o Desenvolvimento (FEDER) (POCI/SAU-MMO/56163/2004), FCT/Poly-Annual Funding Program and FEDER/Saúde XXI Program (Portugal). Nuno Charro is a recipient of FCT doctoral fellowship (SFRH/BD/27906/2006). vi Agradecimentos/Acknowledgements “Nothing is hidden that will not be made known; Nothing is secret that will not come to light” Desde muito pequeno, a minha vontade em querer saber mais e porquê foi sempre presença constante. Ao iniciar e no decorrer da minha (ainda) curta na investigação científica, as perguntas foram mudando, o método também e várias pessoas contribuíram para o crescimento e desenvolvimento da minha personalidade científica e pessoal. Espero não me esquecer de ninguém e, se o fizer, não é intencional; apenas falibilidade. A realização deste trabalho não seria de todo possível sem a grande contribuição da Doutora Deborah Penque. A sua orientação, empenho na minha formação científica e as possibilidades que me abriu no seu laboratório permitiram dar mais um contributo na problemática da Fibrose Quística. Obrigado pela recepção, acompanhamento, vontade de aprender e entusiasmo que demonstrou nas várias etapas do trabalho. A oportunidade que me deu em colaborar com outros excelentes laboratórios abrindo portas para que este trabalho fosse mais sólido e tivesse a perspectiva de outros que o olhassem “de fora” foi, sem dúvida, fundamental. Realço também o seu lado humano, não de “chefe chata” mas de orientadora preocupada e que sabe perceber quando as coisas correm menos bem. À Prof.ª Ana Maria Crespo por todo apoio institucional prestado assim como a confiança e entusiasmo depositados neste trabalho e confirmados pelos sucessivos convites para a apresentação no âmbito do Mestrado que coordena na FCUL. Um obrigado especial à equipa de Pneumologia do Hospital de Santa Maria em Lisboa, coordenada pelo Prof. António Bugalho de Almeida, em especial à Dr.ª Pilar Azevedo e Dr. Carlos Lopes pelo interesse em participar na investigação científica, no recrutamento e caracterização dos doentes de Fibrose Quística e pela disponibilidade demonstrada para deslocações ao INSA quando este trabalho estava ainda no início. A investigação científica e a prática clínica têm tudo a ganhar com colaborações sólidas, interessadas e empenhadas nas suas diversas vertentes. vii A todos os doentes e suas famílias por nos aceitarem na privacidade da consulta de rotina, pela partilha de informações e disponibilidade para, mais uma vez, participarem na recolha de amostras biológicas nem sempre de forma tão indolor quanto se apregoa. Espero que este trabalho venha um dia a beneficiar-vos a todos pois, em última instância, ele é para vós. As melhoras e tenham toda a esperança possível num futuro melhor! Ao grupo do Prof. Francisco Couto da FCUL e aos seus alunos, em especial à Cátia Pesquita e ao Daniel Faria, pelo tempo passado em frente ao computador a ajudar-nos a responder a perguntas que às vezes nem sequer sabíamos formular. As vossas “ferramentas” permitiram tornar a análise de resultados mais fácil e rápida. Espero que esta tese contribua para as divulgar a tantas pessoas quanto possível e aproveitar o seu potencial. Obrigado ao INSA nos seus vários departamentos mas em especial a todos no Departamento de Genética por me terem recebido sempre tão bem, pela simpatia diária nos corredores e pelos bons momentos que passámos nas nossas festas de Natal. Aos meus colegas e amigos de laboratório: Patrícia, Bruno e João. Pelas nossas (meias) torradas e meias de leite matinais quando a vontade era pouca ou quando o entusiasmo e a pressa nos faziam engoli-las à pressa. A companhia e amizade não são traduzíveis em palavras e vários são os momentos passados que me deixam a rebentar de orgulho de ser vosso amigo. Relembro em especial o “Prada Gang” quando a noite já ia bem longa nas nossas maratonas de colheita de amostras ou o “Green Day” quando, mesmo sem palavras, aparecemos todos vestidos da mesma cor. Obrigado por crescerem comigo, obrigado por me deixarem crescer convosco. À Isabel que foi a minha primeira mentora de bancada naqueles dias mesmo antes do Natal em que o desafio de começar um projecto novo com pessoas que ainda não conhecia se misturava com o medo de poder não corresponder às expectativas. Às mais recentes “aquisições” do laboratório: Fátima, Tânia, Sofia e Vukie. Apesar de “metidas todas no mesmo saco”, cada uma de vocês tem aquela contribuição única para viii o nosso grupo. Fui aprendendo a ouvir alguma da vossa música sem ter palpitações ou ansiedade no peito. Aos meus amigos, todos aqueles que me acompanharam nesta demanda e que, como eu, também se debatiam (debatem?) sobre o papel da investigação e qual será afinal o nosso lugar nela. As aulas na FCUL afastaram-nos mas sabe sempre bem quando nos reunimos todos para voltar a recordar o passado e olharmos para o futuro. À minha família no geral e aos meus pais e irmã no particular. Obrigado por nunca me terem fechado quaisquer portas e caminhos por explorar, por manterem em aberto todas as minhas opções. Obrigado por terem aturado os meus momentos mais entusiasmantes quando talvez vos apetecesse perguntar “Mas de que raio está ele a falar?!” ou quando não me apetecia falar em nada e mesmo assim divergíamos a conversa para outro assunto de forma a deixar-me voar. Numa fase mais final, ao Filipe por me ter permitido encontrar um equilíbrio, um balanço na vida e dar-me aquela esperança de que amanhã será melhor e que amanhã seremos melhores. Obrigado a todos os que passaram e continuam a passar pela minha vida nas suas várias vertentes. É da conjugação de todas elas que sou hoje alguém melhor e mais atento. No final de contas, sou E.U. ix x List of Publications Sousa PM, Silva ST, Hood BL, Charro N , Carita JN, Vaz F, Penque D, Conrads TP, Melo AM, Supramolecular organizations in the aerobic respiratory chain of Escherichia coli , Biochimie. 2010 Oct 30, PMID: 21040753 Charro N , Hood BL, Faria D, Pacheco P, Azevedo P, Lopes C, de Almeida AB, Couto FM, Conrads TP, Penque D, Serum proteomics signature of cystic fibrosis patients: a complementary 2-DE and LC-MS/MS approach , J Proteomics. 2011 Jan 1;74(1):110- 26, PMID: 20950718 Hood BL, Grahovac J, Flint MS, Sun M, Charro N , Becker D, Wells A, Conrads TP, Proteomic analysis of laser microdissected melanoma cells from skin organ cultures , J Proteome Res. 2010 Jul 2;9(7):3656-63, PMID: 20459140 Carvalho-Oliveira IM, Charro N , Aarbiou J, Buijs-Offerman RM, Wilke M, Schettgen T, Kraus T, Titulaer MK, Burgers P, Luider TM, Penque D, Scholte BJ, Proteomic analysis of naphthalene-induced airway epithelial injury and repair in a cystic fibrosis mouse model , J Proteome Res. 2009 Jul;8(7):3606-16, PMID: 19438287 Santos MR, Rodríguez-Gómez MJ, Justino GC, Charro N, Florencio MH, Mira L, Influence of the metabolic profile on the in vivo antioxidant activity of quercetin under a low dosage oral regimen in rats , Br J Pharmacol. 2008 Apr;153(8):1750-61, PMID: 18311191 Simões T, Charro N , Faria D, Chan KC, Isaaq HJ, Couto FM, Waybright T, Veenstra TD, Blonder J, Penque D, Proteomic Analysis of Human Nasal Epithelium: a Molecular Portrait , Submitted to Journal of Proteomics Special Issue, 4 th EuPA Meeting 2010 Proteomics Odyssey Towards Next Decades Charro N , Simões T, Faria D, Chan KC, Isaaq HJ, Couto FM, Waybright T, Veenstra TD, Blonder J, Penque D, Deep Proteome Profiling of Nasal Epithelial Cells: xi Consequences for Impaired Respiratory Function in Cystic Fibrosis Patients , Manuscript under final preparation Charro N, Hood BL, Fonseca A, Zerimech F, Hagenfeldt M, Gomes F, Martins F, Neto D, Conrads TP, Peneda J, Penque D, Proteome profiling of immunodepleted serum from individuals undergoing an alcoholic abstinence program , Submitted to Journal of Proteomics Special Issue, 4 th EuPA Meeting 2010 Proteomics Odyssey Towards Next Decades xii List of Abbreviations ααα-CHCA : α-Cyano-4-hydroxycinnamic acid 2-DE : Two-Dimensional Electrophoresis ∆∆∆F508 : Deletion of the phenylalanine (F) residue in position 508 Ab : Antibody ABC family : ATP-Binding Cassette transporters family ACN : Acetonitrile ASL : Airway Surface Liquid ATP : Adenosine Triphosphate BALF : Bronchoalveolar Lavage Fluid BMI : Body Mass Index bp : base pair CaCC : Calcium activated Chloride Channel cAMP : Cyclic Adenoside Monophospate CBAVD : Congenital Bilateral Absence of Vas Deferens CBB : Coomassie Brilliant Blue cDNA : Complementary Deoxyribonucleic Acid CF: Cystic Fibrosis CFRD : Cystic Fibrosis Related
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