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Claudia Macedo Universidade de São Paulo Faculdade de Medicina de Ribeirão Preto Departamento de Genética Área de Pós-Graduação em Genética O papel modulador do gene Aire (autoimmune regulator) sobre redes de expressão gênica em células tímicas epiteliais medulares. Claudia Macedo Ribeirão Preto 2008 Claudia Macedo O papel modulador do gene Aire (autoimmune regulator) sobre redes de expressão gênica em células tímicas epiteliais medulares. Tese apresentada ao Programa de Pós- Graduação em Genética da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo para obtenção do Título de Doutor em Ciências (Genética). Orientador: Prof. Dr. Geraldo A. S. Passos Ribeirão Preto 2008 Macedo, Claudia O papel modulador do gene Aire (autoimmune regulator) sobre redes de expressão gênica em células tímicas epiteliais medulares. Ribeirão Preto, 2008 289 p. 30cm Tese de Doutorado apresentada à Faculdade de Medicina de Ribeirão Preto, USP, Área de Concentração: Genética. Orientador: Passos, Geraldo Aleixo da Silva 1. cDNA microarrays 2. mTEC 3. Sistema Imune APOIO E SUPORTE FINANCEIRO Este trabalho foi realizado no laboratório de Imunogenética Molecular, localizado no Departamento de Genética da Faculdade de Medicina de Ribeirão Preto (FMRP) – USP com o apoio financeiro das seguintes entidades e instituições: 9 Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) 9 Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) 9 Fundação de Apoio ao Ensino, Pesquisa e Assistência do Hospital das Clínicas da FMRP – USP (FAEPA) 9 Faculdade de Medicina de Ribeirão Preto – FMRP – USP Dedico Especialmente este Trabalho Meu marido, Leandro Por todo o seu amor, respeito, cuidado, dedicação, incentivo e apoio em todos os momentos desta etapa da minha vida. Por compreender a ausência, principalmente na etapa final. Obrigada por estar sempre ao meu lado!!! Eu te amo muito!!! Ofereço Especialmente este Trabalho À minha amada família Meus pais, Jamil e Iracy, por absolutamente tudo! Pelo amor incondicional, por todo incentivo e apoio durante a minha vida. Por todo exemplo que vocês são para mim. Minhas irmãs, Vanessa e Ana Paula, apoio e consolo. Por terem tornado minha vida melhor. Companheiras de toda a minha existência. Amo muito vocês!!! Agradecimentos Agradeço do fundo do meu coração a todas as pessoas que de modo direto ou indireto participaram na realização deste trabalho. Agradeço ao meu orientador, Prof. Dr. Geraldo Aleixo da Silva Passos, por seu exemplo de seriedade, profissionalismo e dedicação, por toda confiança e incentivo durante esses mais de 10 anos de envolvimento entre mim e a pesquisa. Aos professores do Departamento de Genética, em especial às professoras Dra. Elza Tiemi Sakamoto-Hojo e Dra. Catarina Satie Takahashi, pela colaboração e amizade, que auxiliaram no andamento da pesquisa. Ao Professor Dr. Eduardo A. Donadi pelo apoio ao longo do trabalho. Aos pós-graduandos e funcionários do Departamento de Genética da Faculdade de Medicina de Ribeirão Preto (FMRP) por toda amizade e dedicação concedida nestes anos. Às secretárias Maria Aparecida e Susie por todo carinho atenção. Ao Departamento de Genética da Faculdade de Medicina de Ribeirão Preto, em particular, ao Laboratório de Imunogenética Molecular, onde foi realizado esse trabalho. À todos os amigos do Grupo de Imunogenética Molecular com os quais convivi nos últimos dez anos, inclusive os que já partiram. Obrigada pelas alegrias, os ensinamentos, colaborações e pela convivência extremamente agradável que marcaram estes anos... Adoro vocês!!!! Aos amigos do laboratório de Citogenética e Mutagênese, pelo carinho e disponibilidade todas as vezes que precisei utilizar o laboratório. Ao laboratório TAGC INSERM de Marseille, França, onde realizei meu estágio de doutorado. À minha família, inclusive minha sogra Silvana, por estarem sempre me apoiando e incentivando em todos os momentos. Ao CNPq, pelo auxílio concedido por meio de bolsa de doutorado (Processo 140380/2003-05), e estágio sanduíche no exterior (Processo 200992/2005-8). Remerciements spéciaux Moi même et mon directeur de thése, le Professeur Geraldo Passos, nous voudrions remercier vivement toute l’ Équipe de recherche ‘ Technologies Avancées pour le Génome et la Clinique (TAGC) URM206 de l’ Institut National de la Santé et la Recherche Médicale (INSERM) de Marseille, France, en particulier le Docteur Catherine Nguyen par l’accueil au sein de cette Équipe et pour l’orientation scientifique en ce qui concerne l’importance du thymus. Je voudrais aussi remercier Beatrice Loriod, Nicolas Boulanger, Murielle Saade, Geneviève Victorero et Docteur Denis Puthier par toute aide et amitié accordées. Finalement nous sommes très reconnaissants aux Instituitions brésiliennes et françaises suivantes ; Université de São Paulo, FAPESP, CNPq, INSERM et Université de Marseille, Campus de Luminy. Je vous en remercie !!! Claudia Macedo Índice RESUMO ..........................................................................................................................i ABSTRACT .....................................................................................................................ii 1. INTRODUÇÃO .......................................................................................................... 2 1.1. A maturação e o papel das células tímicas epiteliais medulares (mTECs) 2 1.1.1. Ontogenia do timo .......................................................................................... 2 1.1.2. Estrutura do timo ........................................................................................... 4 1.1.3. Migração das células precursoras linfóides para o timo ................................. 8 1.1.4. Maturação dos timócitos em células T............................................................ 9 1.1.5. As células medulares epiteliais tímicas (mTECs)......................................... 14 1.2. Expressão gênica promíscua no timo e a indução de tolerância central... 18 1.3. O papel do gene Autoimmune regulator (Aire)........................................... 23 1.4. Testando a hipótese da ação indireta do gene Aire: Construção de redes gênicas a partir de dados de microarrays ............................................................ 26 2. HIPÓTESES............................................................................................................... 32 3. OBJETIVOS ............................................................................................................... 34 4. MATERIAL E MÉTODOS ...................................................................................... 36 4.1. Linhagem celular mTEC 3.10 (células tímicas epiteliais medulares) ....... 36 4.2. Inibição seletiva do transcrito do gene Aire com RNA interferente (RNAi). ...................................................................................................................... 38 4.2.1. Determinação da seqüência de RNAi anti-Aire. .......................................... 38 4.2.2. Silenciamento do transcrito do gene Aire em cultura de células mTEC 3.10. .. 40 4.3. Extração de RNA total...................................................................................... 41 4.3.1. Quantificação de RNA total ......................................................................... 43 4.4. Eletroforese de RNA total em gel denaturante (Sambrook et al., 1989) ... 44 4.4.1. Preparação do gel .......................................................................................... 44 4.4.2. Preparação das amostras de RNA................................................................. 44 4.5. PCRs semi-quantitativas para os genes Aire e HPRT. ................................ 45 4.6. Preparação de cDNA microarrays em lâminas de vidro ............................ 45 4.6.1. Biblioteca de cDNAs murinos ...................................................................... 45 4.6.2. Amplificação de cDNA para a confecção de microarrays ............................. 46 4.6.3. Purificação dos produtos de PCR ................................................................. 47 4.6.4. Confecção das lâminas de microarrays ......................................................... 48 4.7. Delineamento das hibridações em microarrays ........................................... 49 4.8. Marcação das sondas complexas de cDNA com fluorocromos CY3 e CY5.............. 52 4.9. Hibridação das lâminas de microarrays........................................................ 58 4.10. Aquisição de imagens de microarrays......................................................... 58 4.11. Quantificação e normalização dos dados de microarrays ........................ 59 4.11.1. Nomenclatura dos genes............................................................................. 65 4.12. Análise da expressão gênica promíscua...................................................... 65 4.13. GeneNetwork .................................................................................................. 66 5. DELINEAMENTO EXPERIMENTAL................................................................... 69 6. RESULTADOS.......................................................................................................... 71 6.1. Inibição seletiva do transcrito do gene Aire com RNA interferente (RNAi). ...................................................................................................................... 71 6.1.1. Monitoramento da transfecção e determinação da seqüência de RNAi anti- Aire. .......................................................................................................................
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