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Sara Carina Duarte Da Silva Uminho|2015 Rastreio De Estratégias Terapêuticas Num Modelo De Ratinho Da Doença De Machado-Joseph: Foco Na Proteostase

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Sara Carina Duarte Da Silva Uminho|2015 Rastreio De Estratégias Terapêuticas Num Modelo De Ratinho Da Doença De Machado-Joseph: Foco Na Proteostase Universidade do Minho Escola de Ciências da Saúde ase. t teos asis. t teos ting pro arge Sara Carina Duarte da Silva Searching for therapeutic strategies in a mouse model of Machado-Joseph disease: targeting proteostasis Rastreio de estratégias terapêuticas num modelo de ratinho da doença de Machado-Joseph: foco na proteostase trategies in a mouse model of Machado-Joseph disease: t herapeutic s tratégias terapêuticas num modelo de ratinho da doença Machado-Joseph: foco na pro treio de es Searching for t Ras e da Silva t a Carina Duar Sar 5 1 outubro de 2015 UMinho|20 Universidade do Minho Escola de Ciências da Saúde Sara Carina Duarte da Silva Searching for therapeutic strategies in a mouse model of Machado-Joseph disease: targeting proteostasis Rastreio de estratégias terapêuticas num modelo de ratinho da doença de Machado-Joseph: foco na proteostase Tese de Doutoramento em Ciências da Saúde Trabalho efectuado sob a orientação da Professora Doutora Patrícia Espinheira de Sá Maciel outubro de 2015 This work was supported by Fundação para a Ciência e Tecnologia (FCT) and COMPETE through a Bolsa de Doutoramento (SFRH/BD/78388/2011). iv Agradecimentos/Ackonlowgments Paixão. Perseverança. Curiosidade. Equipa. Companheirismo. Luta. Derrota. Conquista. Desânimo. Lágrimas. Risos. Sorrisos. Alento. Conforto. Amizade. Extra. Êxtase. Ciência. As palavras impressas hoje são o meu reconhecimento público a todos os que me de alguma forma contribuíram para a realização deste trabalho de tese. Por tudo, a todos, muito obrigada! The words today printed here are my public gratitude to those that contributed in any way to this thesis. Thank you all for everything! ICVS À Patrícia, pela oportunidade de integrar a sua equipa ao longo destes 9 anos, pela orientação, apoio e acompanhamento. Por acompanhar o meu crescimento, pelos desafios. Pela energia com que luta por fazer Ciência onde, nem sempre é fácil atingir os objetivos. Pela perseverança, pela paixão. Por me fazer sentir orgulho de pertencer a esta equipa. Pela exigência e rigor. Por querer sempre mais. Obrigada. À Professora Doutora Cecília Leão e restantes membros do Concelho Científico, em particular ao Professor Doutor Jorge Pedrosa presidente do Instituto de Investigação em Ciências da Vida e da Saúde (ICVS) e ao Professor Doutor Nuno Sousa presidente do Domínio de Investigação em Neurociências (NeRD), por me terem aceitado como aluna de doutoramento da Escola de Ciências da Saúde (ECS) e do seu Instituto de Investigação e por terem reunido todas as condições necessárias à realização deste trabalho. A todos os funcionários do ICVS, que contribuem diariamente para o bom funcionamento do laboratório. Obrigada pelo apoio e disponibilidade. À Fundação para a Ciência e Tecnologia (FCT) pelo financiamento. v Domínio de Neurociências A todos os NERDs, pelo espírito crítico, pelas discussões de terça à 1 p.m., por tudo que nos une. Pelas risadas na cozinha, pelos excelentes Retiros, pela amizade. A todos, muito obrigada! Em especial… À Carina Cunha, por ter sido a “minha” primeira “aluna”. Por ter vindo na melhor altura e por ter estado sempre à altura. Pelo jeito especial de ser, pela personalidade forte, por me fazer ver as coisas tal e qual como elas são. Por me permitir entrar na sua vida profissional e pessoal. Por simplesmente ser um exemplo para todos os alunos de doutoramento. Por ser minha amiga. Por perceber quando preciso de ajuda. Tenho tanto orgulho em ti. À Joana Silva (aka Joaninha), pelos miminhos, pelas palavras de apoio, pelas bolachinhas. Por seres teimosa e acreditares sempre. Por colaborares nos meus projetos, por me revelares westerns, por toda a ajuda no laboratório. Por todas as palavras de encorajamento. Pelos belos jantares em tua casa. Por me teres formatado a tese! Muito obrigada por tudo! À Bárbara Coimbra (aka Barbarita), pelo jeito único de ser. Pelas palavras (bem baixinho) de carinho. Por achares que tudo é “bem bom”. Pelos teus conhecimentos preciosos de informática que tanto me ajudaram! Obrigada! Ao John, que já devias entender o que te estou a escrever. Obrigada, thank you, σας ευχαριστώ. Because you are always there for me. Thank you for your scientific input to this thesis and for your support. Thank you for all the advices. Thank you for being just you. À Ana João (aka Joni) por tudo que me ensinaste até hoje. Contigo aprendi o mundo maravilhoso dos Western-blots: troubleshooting, troubleshooting!! Obrigada pela amizade. Ao Fábio (aka Fabinho) por todos os mimos! Pela boa disposição e amizade! vi À Mónica Morais, pela companhia no baroke! Ao Hugo Almeida por seres um exemplo a seguir. Pela paixão pela ciência. Por partilhares o gosto pelos Beatles comigo. Perseverança e Ciência sont des mots qui vont bien ensemble. Macielitas (o) A todos os alunos da Patrícia que já não estão no ICVS, muito obrigada! Em especial à Andreia Carvalho, Marina Amorim, Carmo Costa e Mónica Santos. Mice team Anabela (aka Belita): por sermos a equipa! Silva & Silva Lda. Por me teres acompanhado desde o início. Por me teres ensinado a caminhar na ciência. Por seres o meu exemplo. Pelo teu rigor. Pela tua capacidade de trabalho. Mereces o melhor! Pela nossa roulotte de serviços de genotipagem e churros. Pelas (longas) conversas no biotério. Por não seres simplesmente uma colega de trabalho, mas por seres uma das minhas amigas. Obrigada por tudo Anabela. Sofia Esteves, ainda não comecei a escrever e já me estou a rir. E foram tantos momentos que passamos juntas. Começamos o dito PhDesc (aka PhDoc) juntas, e foi uma grande aventura! Nunca me esquecerei da época em que vivemos juntas. Pelo teu esforço (e não era preciso muito) para me fazeres rir para eu adormecer. Pelo trabalho que fizemos juntas. Pelas horas infindáveis no biotério amarelo. Por arranjarmos sempre forma de trabalhar juntas num espaço condicionado e sempre com boa disposição. Pelas palhaçadas filmadas durante o beam walk. Em especial, neste reta final, pelo teu apoio incondicional. Pela ajuda constante no sítio do costume ao fim de semana. Pelo salmo 91. És uma lutadora! Obrigada. C.elegans team Andreia Castro (aka De Castro), pelo teu espirito crítico e rigor científico. Pelos conselhos e ajuda. Por lutares em prol da equipa. Obrigada pela ajuda durante todos estes anos, pela honestidade. Obrigada por tudo. vii Ana Jalles, pela companhia e partilha. Pelos nossos contrastes. Pelos breaks. Pelo cafezinho em tua casa. Pela paixão incondicional pela ciência. Obrigada pela amizade. Liliana Santos (aka Li), por teres integrado na equipa e teres trazido novas energias e novas ideias. Por seres o meu braço direito nas encomendas, por teres sido a única a compreender que a burocracia das encomendas é mais difícil do que aquilo que se imagina! Obrigada por seres tão terra-a-terra. Marta Costa, por estares todos os dias à minha frente. Pela tua ajuda com os qRT-PCR’s. Pelo teu rigor com o desvio padrão. Pela tua capacidade de multitasking e hard working…é sempre a bombar! Obrigada por fazeres parte desta equipa. Dulce Mary, pela boa disposição diária e por estar sempre tudo bem. Stephanie, pela discrição e calma. Obrigada por integrares (muito recentemente) no mundo das ratices. A tua calma é perfeita para fazer animal behavior! Neurodevelopment team Carlos Bessa, pela tua pacificidade e capacidade de nos resolveres todos os problemas informáticos. Obrigada pela partilha de conhecimento. Fátima Lopes, pelo teu timing perfeito. Pelo sentido de responsabilidade e rigor científico. Um agradecimento (muito) especial… Ao Gonçalo Gonçalves. Por ter tido uma importância imensurável na reta final desta tese. Por ter sido, para mim, uma motivação diária. Por ser um excelente aluno. Pelas horas (e foram muitas!) passadas a trabalhar. Por me ouvires a reclamar da vida sempre com um sorriso e com uma palavra de conforto. Por seres um gentleman. Por corares com elogios. lalalalala. Tenho a certeza que serás um excelente médico e um GRANDE homem! Do fundo do coração, obrigada. Teşekkürler! viii Aos meus amigos Andreia Carvalho, por toda a amizade ao longo destes anos. Por estares sempre presente em todos os momentos da minha vida. Por todas as horas passadas a trabalhar e a discutir ciência. Pelo companheirismo. Pelas lágrimas e pelas gargalhadas. Por não me deixares desistir nunca. Por me teres convencido a entrar nesta aventura chamada PhD. Por acompanhares todos os meus sonhos e todos os meus pesadelos. Por me saberes de cor. Simplesmente, obrigada. Loirinha, por seres como uma irmã. Por muito que não entendas aquilo que realmente faço, sempre entendes-te a minha paixão pela ciência. Por estares SEMPRE comigo. És simplesmente a minha mana do coração. Obrigada ao Zé por compreender e se interessar comigo por ciência. Obrigada pelo orgulho que sentem por mim. Joana, Gonçalo, Tiago e Cláudia, por serem amigos de sempre e para sempre! Por todos os bons (e maus) momentos passados juntos. Obrigada por tudo!!! À minha família Avô Cristiano, avô Carino, avó Maria, Sr. Joaquim, embora longe, estão sempre comigo no meu coração. Por tudo que me ensinaram. A vós devo grande parte da pessoa que sou hoje. Obrigada. D.Mena, por ser como uma verdadeira mãe. Por me tratar por “minha filha”. Pela comidinha boa ao domingo. Obrigada. Carla, Jorge, Bela, Vitor, Lando e Céu, obrigada por me mimarem tanto! Obrigada por fazerem parte da minha vida. Zé Lando, Catarina, Francisca e Matilde, os “meus” meninos! Por ser a tia “emprestada”. Por me fazerem sorrir mesmo quando a vontade é chorar. Pela azáfama que criam nos dias de festa. Por tornarem a minha vida colorida e cheia de esperança! Um agradecimento especial à família da Isabel (D.Conceição, Branca, Beto, Rui, Mónica e restantes familiares), por me receberem tão bem e me fazerem sentir em casa. Obrigada! ix Avó Mimi, pelos ensinamentos ao longo de toda a minha vida.
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