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Doctoral Thesis
DOI
10.11606/T.42.2008.tde-31032009-104038
Document
Author
Full name
Margoth Mitchela Moreno Vigo
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2008
Supervisor
Committee
Zingales, Bianca Silvana (President)
Cotrim, Paulo Cesar
Silveira Filho, José Franco da
Uliana, Silvia Reni Bortolin
Winter, Lucile Maria Floeter
Title in Portuguese
Microarranjos de DNA para análise da expressão gênica em cepas de Trypanosoma cruzi suscetíveis e resistentes a benznidazol.
Keywords in Portuguese
Trypanosoma cruzi
Doença de Chagas
Expressão gênica
Quimioterapia
Resistência às drogas
Transporte através da membrana
Abstract in Portuguese
Benznidazol (BZ) é uma das duas drogas usadas no tratamento da doença de Chagas. Falhas terapêuticas são observadas em muitos pacientes, que foram atribuídas, principalmente, às diferenças na suscetibilidade de cepas do Trypanosoma cruzi a essa droga. Alguns genes foram implicados na resistência induzida a BZ, mas não na resistência natural. O objetivo geral deste estudo foi investigar diferenças de expressão gênica em cepas de T. cruzi naturalmente resistentes e suscetíveis a BZ, utilizando microarranjos de DNA. Quantificamos a sensibilidade à droga em cepas de laboratório e isolados obtidos de pacientes crônicos submetidos a quimioterapia com BZ. Concluímos que os valores de CI50 não são preditivos cura. Os experimentos de microarranjos e ensaios de RT-PCR mostram que a abundância de transcritos do gene TcABCG1, foi maior em cepas naturalmente resistentes a BZ. Não observamos variação na abundância de transcritos de alguns genes implicados no fenótipo de resistência induzida. Nossos dados sugerem o envolvimento do transportador TcABCG1 na resistência a BZ.
Title in English
DNA microarray for gene expression analysis of Trypanosoma cruzi strains sensitive and resistant to benznidazole.
Keywords in English
Trypanosoma cruzi
Chagas disease
Chemiotherapy
Drug resistance
Gene expression
Transport across membrane
Abstract in English
Benznidazole (BZ) is one of the two drugs used to treat Chagas disease. Therapeutic failures were reported in many chronic patients, which were mostly attributed to different susceptibilities of Trypanosoma cruzi strains to BZ. A few genes have been implicated in the induced resistance to BZ, but none in the natural resistance. The general goal of this study was to investigate differences in gene expression between susceptible and naturally resistant T. cruzi strains employing DNA microarray technology. We have quantified the drug activity for laboratory strains and for isolates retrieved from chronic patients submitted to BZ therapy. Our results indicate that the IC50 values are not predictive of cure. The microarray and RT-PCR experiments showed the higher abundance of transcript of TcABCG1 gene in naturally resistant strains as compared to sensitive strains. We observed no variation in the transcripts levels of the genes implicated in the induced drug resistance. Our data suggest that TcABCG1 transporter may be involved in natural drug resistance in T. cruzi.
 
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ANEXO_A.pdf (85.27 Kbytes)
ANEXO_B.pdf (69.76 Kbytes)
Publishing Date
2009-04-06
 
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