• Refine Query
  • Source
  • Publication year
  • to
  • Language
  • 2
  • 2
  • Tagged with
  • 4
  • 2
  • 2
  • 2
  • 2
  • 2
  • 2
  • 2
  • 2
  • 2
  • 2
  • 2
  • 2
  • 2
  • 2
  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
1

Planejamento e relação estrutura-atividade de inibidores da MARK3 em câncer de cabeça e pescoço / Design and structure-activity relationship of inhibitors of MARK3 in head and neck cancer

Volpini, Josiana Garcia de Araujo 29 September 2010 (has links)
O Projeto Genoma Humano do Câncer (PGHC), financiado pela FAPESP e pelo Instituto Ludwig de Pesquisa sobre o câncer, buscou identificar os genes expressos nos tipos mais comuns de câncer no Brasil. Tal projeto conseguiu identificar aproximadamente um milhão de sequências de genes de tumores frequentes no Brasil. A contribuição brasileira foi maior para tumores de cabeça e pescoço, mama e cólon. Uma das iniciativas mais recentes e estimuladas pelo PGHC é o projeto Genoma Clínico, o qual visa desenvolver novas formas de diagnóstico e tratamento do câncer através do estudo de genes expressos. A partir da análise molecular de tecidos saudáveis e neoplásicos em diferentes estágios, é possível identificar marcadores de prognóstico, permitindo escolhas de terapias mais adequadas e eficientes. A proteína MARK3 foi identificada como um desses marcadores, em neoplasias de tecidos de cabeça e pescoço, sendo o objetivo deste estudo a aplicação de técnicas de bioinformática e modelagem molecular no planejamento baseado em estrutura de candidatos a fármacos antineoplásicos que bloqueiem a atividade da proteína MARK3. Após screening virtual em bases de dados de compostos (1.000.000 aproximadamente) com propriedades drug-like, 20 compostos com potencial de inibidor da MARK3 foram selecionados. Os modos de ligação para cada um dos mesmos no sítio ligante da proteína MARK3 foram sugeridos por simulações de docking e apresentaram um bom encaixe espacial com os sítios receptores virtuais calculados pelos campos de interação molecular (MIF). Simulações de dinâmica molecular foram realizadas com o intuito de avaliar a estabilidade dos compostos selecionados, que também foram avaliados quanto à presença de grupamentos toxicofóricos em sua estrutura. / The Brazilian Project Genoma Câncer (PGHC) supported by FAPESP and the Ludwig Institute for Cancer Research, intended to identify the genes involved in the most common cases of cancer in Brazil. In this project about a million of gene sequences were identified. The major contribution was made in breast, colorectal and head and neck cancers. The results obtained stimulated the creation of another project, called Genoma Clínico, which intend to develop new trends in treatments and diagnosis of cancer based on the study of expressed genes. Analyzing healthy and neoplasic tissues in different stages, it is possible to identify molecular markers related to the prognosis of cancer, allowing the use of more efficient therapies. The MARK3 protein was identified as a molecular marker in head and neck cancer, where the objective of this work lies in the application of bioinformatics and molecular modeling strategies by structure-based drug design to identify potential antineoplasic drug candicates that could act against MARK3 protein. After the virtual screening simulations performed with drug-like compound databases, containing approximately 1.000.000 compounds, 20 were selected as potential ligands of MARK3 protein. The binding modes suggested for these compounds, by docking simulations, presented a good spatial fit when compared with the virtual receptor sites calculated by molecular interaction fields (MIF). Molecular dynamics simulations were performed in order to evaluate de stability of the binding modes suggested. The potential ligands were also evaluated to identify toxicophoric features in its chemical structures.
2

Planejamento e relação estrutura-atividade de inibidores da MARK3 em câncer de cabeça e pescoço / Design and structure-activity relationship of inhibitors of MARK3 in head and neck cancer

Josiana Garcia de Araujo Volpini 29 September 2010 (has links)
O Projeto Genoma Humano do Câncer (PGHC), financiado pela FAPESP e pelo Instituto Ludwig de Pesquisa sobre o câncer, buscou identificar os genes expressos nos tipos mais comuns de câncer no Brasil. Tal projeto conseguiu identificar aproximadamente um milhão de sequências de genes de tumores frequentes no Brasil. A contribuição brasileira foi maior para tumores de cabeça e pescoço, mama e cólon. Uma das iniciativas mais recentes e estimuladas pelo PGHC é o projeto Genoma Clínico, o qual visa desenvolver novas formas de diagnóstico e tratamento do câncer através do estudo de genes expressos. A partir da análise molecular de tecidos saudáveis e neoplásicos em diferentes estágios, é possível identificar marcadores de prognóstico, permitindo escolhas de terapias mais adequadas e eficientes. A proteína MARK3 foi identificada como um desses marcadores, em neoplasias de tecidos de cabeça e pescoço, sendo o objetivo deste estudo a aplicação de técnicas de bioinformática e modelagem molecular no planejamento baseado em estrutura de candidatos a fármacos antineoplásicos que bloqueiem a atividade da proteína MARK3. Após screening virtual em bases de dados de compostos (1.000.000 aproximadamente) com propriedades drug-like, 20 compostos com potencial de inibidor da MARK3 foram selecionados. Os modos de ligação para cada um dos mesmos no sítio ligante da proteína MARK3 foram sugeridos por simulações de docking e apresentaram um bom encaixe espacial com os sítios receptores virtuais calculados pelos campos de interação molecular (MIF). Simulações de dinâmica molecular foram realizadas com o intuito de avaliar a estabilidade dos compostos selecionados, que também foram avaliados quanto à presença de grupamentos toxicofóricos em sua estrutura. / The Brazilian Project Genoma Câncer (PGHC) supported by FAPESP and the Ludwig Institute for Cancer Research, intended to identify the genes involved in the most common cases of cancer in Brazil. In this project about a million of gene sequences were identified. The major contribution was made in breast, colorectal and head and neck cancers. The results obtained stimulated the creation of another project, called Genoma Clínico, which intend to develop new trends in treatments and diagnosis of cancer based on the study of expressed genes. Analyzing healthy and neoplasic tissues in different stages, it is possible to identify molecular markers related to the prognosis of cancer, allowing the use of more efficient therapies. The MARK3 protein was identified as a molecular marker in head and neck cancer, where the objective of this work lies in the application of bioinformatics and molecular modeling strategies by structure-based drug design to identify potential antineoplasic drug candicates that could act against MARK3 protein. After the virtual screening simulations performed with drug-like compound databases, containing approximately 1.000.000 compounds, 20 were selected as potential ligands of MARK3 protein. The binding modes suggested for these compounds, by docking simulations, presented a good spatial fit when compared with the virtual receptor sites calculated by molecular interaction fields (MIF). Molecular dynamics simulations were performed in order to evaluate de stability of the binding modes suggested. The potential ligands were also evaluated to identify toxicophoric features in its chemical structures.
3

Les partenaires d'interactions de Cirhin, la protéine portant la mutation responsable de la Cirrhose Amérindienne Infantile (NAIC)

Ruest, Marie-Ève 03 1900 (has links)
La Cirrhose Amérindienne Infantile (CAI, NAIC) est une forme de cholestase non-syndromique héréditaire à transmission autosomique récessive, décrite uniquement chez les enfants autochtones du Nord-Ouest québécois et issue d’un effet fondateur. La maladie se présente d’abord sous la forme d’une jaunisse néonatale chez un enfant autrement en bonne santé, qui progresse en cirrhose de type biliaire dans l’enfance et dans l’adolescence. Le taux de survie à l’âge adulte est inférieur à 50% et la seule thérapie efficace à ce jour pour les patients avancés dans la maladie demeure la transplantation hépatique. Les recherches antérieures menées par le groupe ont permis d’identifier le locus ainsi que le gène responsable de NAIC, qui encode la protéine nucléolaire Cirhin. Cirhin est exprimée uniquement dans le foie et tous les patients sont homozygotes pour la mutation R565W. La fonction de Cirhin est inconnue, mais les motifs WD40 retrouvés dans sa séquence indiquent qu’elle participerait à des interactions protéine-protéine et serait impliquée dans un mécanisme moléculaire de base. Cirhin interagit avec la protéine nucléaire Cirip, qui a un effet positif important sur la transcription de l’élément activateur HIV-1 LTR et qui a un rôle dans la prolifération cellulaire. L’interaction de Cirhin et Cirip est affectée par la mutation R565W. À l’aide de la technique du double hybride chez la levure, la protéine nucléolaire Nol11 a été identifiée comme étant un partenaire d’interaction de Cirhin. Par son interaction avec MARK3 et c-Myc, Nol11 serait impliquée dans des processus cellulaires tels que le contrôle du cycle cellulaire, la polarité, la croissance cellulaire et possiblement la biogenèse des ribosomes. La portion C-terminale de Nol11 interagirait avec Cirhin, et la mutation R565W abolit cette interaction. Le résidu R565 serait donc important pour la fonctionnalité de Cirhin. / North American Indian childhood cirrhosis (NAIC) is a nonsyndromic form of hereditary autosomal recessive cholestasis, described only in children of Algonquin origin from the Abitibi region of north-western Québec and issued from a founder effect. NAIC typically presents with transient neonatal jaundice in a child who is otherwise healthy, but progresses to biliary fibrosis in childhood or young adulthood. The survival rate at adulthood is lower than 50% and liver transplantation is currently the only effective therapy for patients with advanced disease. Previous research by the group allowed the identification of the locus and the gene responsible for NAIC, which encodes the nucleolar protein Cirhin. Cirhin is expressed only in the liver and all patients are homozygous for the R565W mutation. Cirhin’s function is unknown, but it is a WD40-repeat containing protein, which indicates that it would participate in protein-protein interactions and would be involved in a basic molecular mechanism. Cirhin interacts with the nuclear protein Cirip, which has a significant positive effect on the transcription of the HIV-1 LTR enhancer element and has a role in cellular proliferation. The interaction between Cirhin and Cirip is affected by the R565W mutation. Using the yeast two-hybrid technique, the nucleolar protein Nol11 was identified as an interacting partner of Cirhin. By its interaction with MARK3 and c-Myc, Nol11 may be involved in cellular processes such as cell cycle control, polarity, cell growth and possibly ribosome biogenesis. The C-terminal portion of Nol11 interacts with Cirhin and the R565W mutation abolishes the interaction. The residue R565 may thus be important for Cirhin’s functionality.
4

Les partenaires d'interactions de Cirhin, la protéine portant la mutation responsable de la Cirrhose Amérindienne Infantile (NAIC)

Ruest, Marie-Ève 03 1900 (has links)
La Cirrhose Amérindienne Infantile (CAI, NAIC) est une forme de cholestase non-syndromique héréditaire à transmission autosomique récessive, décrite uniquement chez les enfants autochtones du Nord-Ouest québécois et issue d’un effet fondateur. La maladie se présente d’abord sous la forme d’une jaunisse néonatale chez un enfant autrement en bonne santé, qui progresse en cirrhose de type biliaire dans l’enfance et dans l’adolescence. Le taux de survie à l’âge adulte est inférieur à 50% et la seule thérapie efficace à ce jour pour les patients avancés dans la maladie demeure la transplantation hépatique. Les recherches antérieures menées par le groupe ont permis d’identifier le locus ainsi que le gène responsable de NAIC, qui encode la protéine nucléolaire Cirhin. Cirhin est exprimée uniquement dans le foie et tous les patients sont homozygotes pour la mutation R565W. La fonction de Cirhin est inconnue, mais les motifs WD40 retrouvés dans sa séquence indiquent qu’elle participerait à des interactions protéine-protéine et serait impliquée dans un mécanisme moléculaire de base. Cirhin interagit avec la protéine nucléaire Cirip, qui a un effet positif important sur la transcription de l’élément activateur HIV-1 LTR et qui a un rôle dans la prolifération cellulaire. L’interaction de Cirhin et Cirip est affectée par la mutation R565W. À l’aide de la technique du double hybride chez la levure, la protéine nucléolaire Nol11 a été identifiée comme étant un partenaire d’interaction de Cirhin. Par son interaction avec MARK3 et c-Myc, Nol11 serait impliquée dans des processus cellulaires tels que le contrôle du cycle cellulaire, la polarité, la croissance cellulaire et possiblement la biogenèse des ribosomes. La portion C-terminale de Nol11 interagirait avec Cirhin, et la mutation R565W abolit cette interaction. Le résidu R565 serait donc important pour la fonctionnalité de Cirhin. / North American Indian childhood cirrhosis (NAIC) is a nonsyndromic form of hereditary autosomal recessive cholestasis, described only in children of Algonquin origin from the Abitibi region of north-western Québec and issued from a founder effect. NAIC typically presents with transient neonatal jaundice in a child who is otherwise healthy, but progresses to biliary fibrosis in childhood or young adulthood. The survival rate at adulthood is lower than 50% and liver transplantation is currently the only effective therapy for patients with advanced disease. Previous research by the group allowed the identification of the locus and the gene responsible for NAIC, which encodes the nucleolar protein Cirhin. Cirhin is expressed only in the liver and all patients are homozygous for the R565W mutation. Cirhin’s function is unknown, but it is a WD40-repeat containing protein, which indicates that it would participate in protein-protein interactions and would be involved in a basic molecular mechanism. Cirhin interacts with the nuclear protein Cirip, which has a significant positive effect on the transcription of the HIV-1 LTR enhancer element and has a role in cellular proliferation. The interaction between Cirhin and Cirip is affected by the R565W mutation. Using the yeast two-hybrid technique, the nucleolar protein Nol11 was identified as an interacting partner of Cirhin. By its interaction with MARK3 and c-Myc, Nol11 may be involved in cellular processes such as cell cycle control, polarity, cell growth and possibly ribosome biogenesis. The C-terminal portion of Nol11 interacts with Cirhin and the R565W mutation abolishes the interaction. The residue R565 may thus be important for Cirhin’s functionality.

Page generated in 0.0127 seconds