MANUSCRITOKyewski B, Derbinski J, Gotter J, Klein L (2002). Promiscuous <strong>gene</strong> expressionand central T-cell tolerance : more than meets the eye. Trends Immunol.23: 364Gallegos AM, Bevan MJ (2006). Central tolerance: good but imperfect.Immunol Rev. 209: 290-6.Magalhães DA, Silveira EL, Junta CM, Sandrin-Garcia P, Fachin AL, DonadiEA, Sakamoto-Hojo ET, Passos GA (2006). Promiscuous <strong>gene</strong> expressionin the thymus: the root of central tolerance. Clin Dev Immunol.13(2-4):81-99.Sousa Car<strong>do</strong>so R, Magalhães DAR, Baião AMT, Junta CM, Mace<strong>do</strong> C,Marques MMC, Sakamoto-Hojo ET, Donadi EA, Passos GAS (2006).Onset of promiscuous <strong>gene</strong> expression in murine fetal organ culture.Immunology 119: 369–375.Sospedra M, Ferrer-Francesch X, Dominguez O, Juan M, Foz-Sala M, Pujol-Borrel R. (1998) Transcription of broad range of self-antigens in humanthymus suggests a role for central mechanisms in tolerance towardperipheral antigens. J. Immunol. 161 : 5918Bruno R, Sabater L, Sospedra M, Ferrer-Francesch X, Escudero D, Martı´nez-Ca´ceres E, Pujol-Borrel R. Multiple sclerosis candidate autoantigensexcept myelin oligodendrocyte glycoprotein are transcribed in the humanthymus. Eur J Immunol 2002; 32:2737–47.Finnish-German APECED Consortium (1997). An autoimmune disease,APECED, caused by mutations in a novel <strong>gene</strong> featuring two PHD-typezinc-finger <strong>do</strong>mains. Nature Genetics 17, 399–403.Nagamine K, Peterson P, Scott HS, Ku<strong>do</strong>h J, Minoshima S, Heino M, Krohn KJ,Lalioti MD, Mullis PE, Antonarakis SE, Kawasaki K, Asakawa S, Ito F,Shimizu N (1997). Positional cloning of the APECED <strong>gene</strong>. NatureGenetics 17: 393–398.Anderson MS, Venanzi ES, Klein L, Chen Z, Berzins SP, Turley SJ, vonBoehmer H, Bronson R, Dierich A, Benoist C, Mathis D (2002). Projectionof an immunological self-sha<strong>do</strong>w within the thymus by aire protein.Science 298: 1395.Anderson MS, Venanzi ES, Chen Z, Berzins SP, Benoist C, Mathis D (2005).The NOD mouse: a model of immune dysregulation. Annu. Rev.Immunol. 23: 447.Kishimoto H, Sprent J (1997). Negative selection in the thymus includessemimature T cells. J. Exp. Med. 185: 263–271.Kyewski B, Klein L (2006). A central role for central tolerance. Annu. Rev.Immunol. 24: 571-606.Ramsey C, Winqvist O, Puhakka L, Halonen M, Moro A, Kämpe O, Eskelin P,Pelto-Huikko M, Peltonen L (2002). Aire deficient mice develop multiplefeatures of APECED phenotype and show altered immune response.Hum. Mol. Genet. 11, 397409.Kuroda N, Mitani T, Takeda N, Ishimaru N, Arakaki R, Hayashi Y, Ban<strong>do</strong> Y,Izumi K, Takahashi T, Nomura T, Sakaguchi S, Ueno T, Takahama Y,217
MANUSCRITOUchida D, Sun S, Kajiura F, Mouri Y, Han H, Matsushima A, Yamada G,Matsumoto M (2005). Development of autoimmunity againsttranscriptionally unrepressed target antigen in the thymus of Aire-deficientmice. J. Immunol. 174, 18621870 (2005).Derbinski J, Gäbler J, Brors B, Tierling S, Jonnakuty S, Hergenhahn M,Peltonen L, Walter J, Kyewski B (2005). Promiscuous <strong>gene</strong> expression inthymic epithelial cells is regulated at multiple levels. J. Exp. Med. 202(1):33-45.Mathis D & Benoist C (2007) A decade of <strong>AIRE</strong>. Nat Rev Immunol. 7(8):645-50.Bottomley MJ, Collard MW, Huggenvik JI, Liu Z, Gibson TJ, Sattler M. (2001).The SAND <strong>do</strong>main structure defines a novel DNA-binding fold intranscriptional regulation. Nat Struct Biol. 8(7):626-33.Isaac A, Wilcox KW, Taylor JL. (2006). SP100B, a repressor of <strong>gene</strong> expressionpreferentially binds to DNA with unmethylated CpGs. J Cell Biochem.98(5):1106-22.Pitkanen J, Doucas V, Sterns<strong>do</strong>rf T, Nakajima T, Aratani S, Jensen K, Will H,Vähämurto P, Ollila J, Vihinen M, Scott HS, Antonarakis SE, Ku<strong>do</strong>h J,Shimizu N, Krohn K, Peterson P (2000). The autoimmune regulator proteinhas transcriptional transactivating properties and interacts with thecommon coactivator CREB-binding protein. J Biol Chem. 275(22):16802-9.Pitkänen J, Rebane A, Rowell J, Murumägi A, Ströbel P, Möll K, Saare M,Heikkilä J, Doucas V, Marx A, Peterson P (2005). Cooperative activation oftranscription by autoimmune regulator <strong>AIRE</strong> and CBP. Biochem BiophysRes Commun. 333(3):944-53.Hedge P, Qi R, Abernathyk, Gay C, Dharap S, Gaspard R, Eaele-Hugues J,Snesrud E, Lee N, Quackenbush J (2000). A concise guide to cDNAmicroarray analysis. Biotechniques. 29(3):548-562.Smyth GK (2004). Linear models and empirical Bayes methods for assessingdifferential expression in microarray experiments. Stat. Appl. Genet. Mol.Biol. 3.Tusher VG, Tibshirani R, Chu G (2001). Significance analysis of microarraysapplied to the ionizing radiation response. Proc. Natl. Acad. Sci, USA 98(9): 5116-5121.Eisen, M. B., Spellman, P. T., Brown, P. O., and Botstein, D. (1998). Clusteranalysis and display of genome-wide expression patterns. Proc. Natl.Acad. Sci. USA 95, 14863-14868.Wu CC, Huang HC, Juan HF, Chen, ST (2004). GeneNetwork: an interactivetool for reconstruction of <strong>gene</strong>tic networks using microarray data.Bioinformatics 20(18): 3691-3.Derbinski J, Schulte A, Kyewski B, Klein L (2001). Promiscuous <strong>gene</strong>expression in medullary thymic epithelial cells mirrors the peripheral self.Nature Immunology 2: 1032-1039.218
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Universidade de São PauloFaculdade
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Macedo, ClaudiaO papel modulador do
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Dedico Especialmente este TrabalhoM
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AgradecimentosAgradeço do fundo do
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ÍndiceRESUMO .....................
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INDICE DE FIGURASFigura 1. Desenvol
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Promiscuous gene expression in medu
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INTRODUÇÃO1. INTRODUÇÃO1.1. A m
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INTRODUÇÃORecentemente surgiram e
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INTRODUÇÃOmigram para a região s
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INTRODUÇÃOCD4 + CD8 + , e Ccl21 (
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INTRODUÇÃOos timócitos duplo-pos
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INTRODUÇÃOgrande diversidade nas
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INTRODUÇÃOAs células mTECs são
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INTRODUÇÃODerbinski (2004). Os ti
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INTRODUÇÃOinvertebrados multicelu
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INTRODUÇÃOCoraçãoLínguaEstôma
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INTRODUÇÃO1.3. O papel do gene Au
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INTRODUÇÃOdefinido pela atividade
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INTRODUÇÃOpara abordarmos nossa p
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INTRODUÇÃOesses modelos levam em
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Hipóteses
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Objetivos
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Material e Métodos
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MATERIAL E MÉTODOSFigura 6. Padrã
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MATERIAL E MÉTODOScom estes RNAs f
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MATERIAL E MÉTODOSdos complexos de
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MATERIAL E MÉTODOSAo RNA total rec
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4.5. PCRs semi-quantitativas para o
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MATERIAL E MÉTODOSminutos a 4 °C.
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MATERIAL E MÉTODOS(Merck), soluç
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MATERIAL E MÉTODOSEnsaios de co-hi
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MATERIAL E MÉTODOSRNA TotalANELAME
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MATERIAL E MÉTODOSa) Preparação
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MATERIAL E MÉTODOScentrifugação
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MATERIAL E MÉTODOScanais (Cy3 e Cy
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MATERIAL E MÉTODOSSpotfinderQuanti
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MATERIAL E MÉTODOSOnde Xp(i) e Xc(
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MATERIAL E MÉTODOSO programa SAM p
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MATERIAL E MÉTODOSextrair automati
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DELINEAMENTO EXPERIMENTAL5. DELINEA
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RESULTADOS6. RESULTADOS6.1. Inibiç
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RESULTADOSPCR semiquantitativa gene
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RESULTADOS6.3. RT-PCRs semi-quantit
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RESULTADOS11.00%6,50%AdequadaNão A
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RESULTADOS6.6. Quantificação e no
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RESULTADOSPara um melhor entendimen
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RESULTADOSFigura 25. Agrupamento hi
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RESULTADOSFigura 26. Gráfico ilust
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RESULTADOS6.8. Influência do silen
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Discussão
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DISCUSSÃOA tolerância do repertó
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DISCUSSÃOCom relação à técnica
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DISCUSSÃOgene AIRE (do inglês aut
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DISCUSSÃOdesse modo a tolerância
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DISCUSSÃOPML (leucemia promielocit
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DISCUSSÃOBoehm et al. (2003) afirm
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DISCUSSÃOprograma Genenetwork (Wu
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Conclusões
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Referências Bibliográficas
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REFERÊNCIAS BIBLIOGRÁFICASBarthlo
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REFERÊNCIAS BIBLIOGRÁFICASDissert
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REFERÊNCIAS BIBLIOGRÁFICASGotter
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REFERÊNCIAS BIBLIOGRÁFICASMatsumo
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REFERÊNCIAS BIBLIOGRÁFICASby mito
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REFERÊNCIAS BIBLIOGRÁFICASRossi S
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REFERÊNCIAS BIBLIOGRÁFICASof thym
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Anexo I123
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ANEXO IEST IMAGE:582370 Expressed s
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ANEXO IDhps IMAGE:583332 Deoxyhypus
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ANEXO IMapkapk2 IMAGE:572979 MAP ki
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ANEXO IGm608 IMAGE:583350 Gene mode
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ANEXO ICcdc72 IMAGE:640628 Coiled-c
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ANEXO ITranscribed locusTranscribed
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ANEXO IEST IMAGE:583221 Expressed s
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ANEXO ITranscribed locusTranscribed
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ANEXO Irepair deficiency, complemen
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ANEXO Imember 1EST IMAGE:583824 Exp
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ANEXO ITranscribed locus IMAGE:5830
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ANEXO ITfdp1 IMAGE:640119 Transcrib
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ANEXO IEST IMAGE:583902 Expressed s
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ANEXO I2410022M11Rik IMAGE:640727 R
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ANEXO Icontaining 1Kif14 IMAGE:5836
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ANEXO Imember 3In multiple clusters
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ANEXO IEST IMAGE:639632 Expressed s
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ANEXO IAnkrd10 IMAGE:583740 Ankyrin
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ANEXO IEST IMAGE:641035 Expressed s
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ANEXO IVcam1 IMAGE:576563 Vascular
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ANEXO ITegt IMAGE:639877 Testis enh
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- Page 184 and 185: ANEXO IEST IMAGE:583217 Expressed s
- Page 186 and 187: ANEXO IEST IMAGE:640851 Expressed s
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- Page 192 and 193: ANEXO IEST IMAGE:640642 Expressed s
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- Page 196 and 197: ANEXO IEST IMAGE:640824 Expressed s
- Page 198 and 199: ANEXO IEST IMAGE:582998 Expressed s
- Page 200 and 201: Anexo II
- Page 202 and 203: ANEXO II1500002B03RikIMAGE:1330385
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- Page 210 and 211: Anexo III
- Page 212 and 213: ANEXO III197Ifit1RelaIMAGE:575632Gr
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- Page 216 and 217: Manuscrito da Tese
- Page 218 and 219: MANUSCRITOAbstractThe expression of
- Page 220 and 221: MANUSCRITOdominated the scenario in
- Page 222 and 223: MANUSCRITOserum autoantibodies, all
- Page 224 and 225: MANUSCRITOwere transfected with 10
- Page 226 and 227: MANUSCRITOwere analyzed using the M
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- Page 234 and 235: MANUSCRITOBruno R, Sabater L, Tolos
- Page 236 and 237: MANUSCRITOFigure 3. The gene expres
- Page 238 and 239: MANUSCRITOABFigure 5. Genetics netw
- Page 240 and 241: SÚMULACURRICULUM VITAE (Janeiro 20
- Page 242 and 243: ESTÁGIO NO EXTERIORSÚMULA• Labo
- Page 244 and 245: SÚMULAtranscript finishing initiat
- Page 246 and 247: SÚMULAlinhagens isogênicas de cam
- Page 248 and 249: SÚMULABOLSAS DE ESTUDO• Bolsa de
- Page 250 and 251: T cell signaling gene networks duri
- Page 252 and 253: IntroductionThe thymus is an import
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- Page 262 and 263: cells, including human herpesvirus-
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- Page 268 and 269: 4) Finally, Prrg2 was also identifi
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- Page 274 and 275: IMMUNOLOGYORIGINAL ARTICLEOnset of
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- Page 278 and 279: Promiscuous gene expression in muri
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R.S. Cardoso et al. / Molecular Imm
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R.S. Cardoso et al. / Molecular Imm
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R.S. Cardoso et al. / Molecular Imm
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R.S. Cardoso et al. / Molecular Imm
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Molecular Immunology 42 (2005) 1043
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D.A.R. Magalhães et al. / Molecula
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D.A.R. Magalhães et al. / Molecula
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Molecular and Cellular Biochemistry
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225Table 1. Target cDNA sequences a
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227coincided (CBA/J) with expressio