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Dissertation (Ph.D.)--University of South Florida, 2009. / Title from PDF of title page. Document formatted into pages; contains 86 pages. Includes vita. Includes bibliographical references.

Dissertation (Ph.D.)--University of South Florida, 2009. / Includes vita. Includes bibliographical references. Also available online.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Estudos demonstram a associação de alterações da apolipoproteína E (ApoE) e do receptor do LDL (RLDL) com a ocorrência de doenças cardiovasculares e dislipidemia. O objetivo principal deste trabalho foi investigar a associação entre genótipos diferenciais da ApoE e do RLDL com a persistência de alterações de variáveis lipídicas em indivíduos jovens acompanhados há 28 anos no Estudo do Rio de Janeiro (ERJ). Através de um estudo longitudinal, tipo coorte, investigou-se 56 indivíduos (35M) em três avaliações. Em A1 (13.301.53 anos), A2 (22.091.91 anos) e A3 (31.231.99). Nas três ocasiões foi realizada avaliação clínica. Em A2 e A3 foram dosados colesterol total, HDL, LDL e triglicerídeos. Em A3 acrescentou-se o estudo dos polimorfismos genéticos da ApoE e do RLDL. Os fragmentos de interesse neste estudo foram amplificados por PCR (polymerase chain reaction) e os genótipos foram identificados através de reações de restrição. As frequências genotípicas de ApoE foram ε3/ε3 (62,5%), ε3/ε4 (25%), ε2/ε3 (5,4%) ,ε2/ε4 (5,4%) e ε4/ε4 (1,8%) e para os genótipos de RLDL foram AA (85,7%), AT (12,5%) e TT (1,8%). O genótipo ε2/ε2 não foi observado. A análise da distribuição dos genótipos de ApoE segundo a permanência de dislipidemia mostrou que todos os indivíduos com genótipo de ApoE dos tipos ε2/ε4 e ε4/ε4 mantiveram pelo menos um lípide alterado em A2 e A3 entretanto, todos os indivíduos com genótipo de ApoE do tipo ε2/ε3 não apresentaram lípides alterados em A2 e A3. Para o genótipo do RLDL não houve diferença significativa. Quando analisadas isoladamente, não foi identificado nenhum resultado significativo em A2 e/ou A3 associado a estes genótipos. O polimorfismo do gene da ApoE esteve associado à permanência de dislipidemia em indivíduos jovens acompanhados em estudo de seguimento longitudinal / Studies have shown the association of changes in the apolipoprotein E (ApoE) and LDL receptor (LDLR) with the occurrence of cardiovascular diseases and dyslipidemia. The objective of this study was to investigate the association between different ApoE genotypes and LDLR with the persistence of changes in lipid variables in young individuals followed-up 28 years in the study of Rio de Janeiro (ERJ). Through a longitudinal study cohort, 56 subjects (35M) in A1(13.30 1.53 years), A2(22.09 1.91 years) and A3(31.23 1.99) were investigated. On all three occasions clinical evaluation was conducted. In A2 and A3: total cholesterol, HDL, LDL and triglycerides. In A3 was added to the study of genetic polymorphisms of the ApoE and LDLR. The fragments of interest in this study were amplified by PCR (polymerase chain reaction) and the genotypes were identified by reaction with the restriction enzyme HhaI and HaeIII for ApoE and LDLR polymorphisms, respectively. ApoE genotypes were identified as ε3/ε3 (62.5%), ε3/ε4 (25%), ε2/ε3 (5.4%), ε2/ε4 (5.4%) and ε4/ε4 (1.8%) and the LDLR genotypes identified as AA (85.7%), AT (12.5%) and TT (1.8%). ε2/ε2 genotype was not observed. The analysis of the distribution of ApoE and LDLR genotypes according to the permanence of the dyslipidemia in the study sample showed that all individuals with the ApoE genotype ε2/ε4 and ε4/ε4 kept at least one lipid changes in A2 and A3 and all individuals ApoE genotype ε2/ε3 had not altered lipids in A2 and A3, while for RLDL genotype no difference was found. When analyzed individually, no lipid variable altered in A2 and/or A3, associated with these genotypes, were found. The ApoE gene polymorphism was associated with the permanence of dyslipidemia in young individuals in a longitudinal follow-up study

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Estudos demonstram a associação de alterações da apolipoproteína E (ApoE) e do receptor do LDL (RLDL) com a ocorrência de doenças cardiovasculares e dislipidemia. O objetivo principal deste trabalho foi investigar a associação entre genótipos diferenciais da ApoE e do RLDL com a persistência de alterações de variáveis lipídicas em indivíduos jovens acompanhados há 28 anos no Estudo do Rio de Janeiro (ERJ). Através de um estudo longitudinal, tipo coorte, investigou-se 56 indivíduos (35M) em três avaliações. Em A1 (13.301.53 anos), A2 (22.091.91 anos) e A3 (31.231.99). Nas três ocasiões foi realizada avaliação clínica. Em A2 e A3 foram dosados colesterol total, HDL, LDL e triglicerídeos. Em A3 acrescentou-se o estudo dos polimorfismos genéticos da ApoE e do RLDL. Os fragmentos de interesse neste estudo foram amplificados por PCR (polymerase chain reaction) e os genótipos foram identificados através de reações de restrição. As frequências genotípicas de ApoE foram ε3/ε3 (62,5%), ε3/ε4 (25%), ε2/ε3 (5,4%) ,ε2/ε4 (5,4%) e ε4/ε4 (1,8%) e para os genótipos de RLDL foram AA (85,7%), AT (12,5%) e TT (1,8%). O genótipo ε2/ε2 não foi observado. A análise da distribuição dos genótipos de ApoE segundo a permanência de dislipidemia mostrou que todos os indivíduos com genótipo de ApoE dos tipos ε2/ε4 e ε4/ε4 mantiveram pelo menos um lípide alterado em A2 e A3 entretanto, todos os indivíduos com genótipo de ApoE do tipo ε2/ε3 não apresentaram lípides alterados em A2 e A3. Para o genótipo do RLDL não houve diferença significativa. Quando analisadas isoladamente, não foi identificado nenhum resultado significativo em A2 e/ou A3 associado a estes genótipos. O polimorfismo do gene da ApoE esteve associado à permanência de dislipidemia em indivíduos jovens acompanhados em estudo de seguimento longitudinal / Studies have shown the association of changes in the apolipoprotein E (ApoE) and LDL receptor (LDLR) with the occurrence of cardiovascular diseases and dyslipidemia. The objective of this study was to investigate the association between different ApoE genotypes and LDLR with the persistence of changes in lipid variables in young individuals followed-up 28 years in the study of Rio de Janeiro (ERJ). Through a longitudinal study cohort, 56 subjects (35M) in A1(13.30 1.53 years), A2(22.09 1.91 years) and A3(31.23 1.99) were investigated. On all three occasions clinical evaluation was conducted. In A2 and A3: total cholesterol, HDL, LDL and triglycerides. In A3 was added to the study of genetic polymorphisms of the ApoE and LDLR. The fragments of interest in this study were amplified by PCR (polymerase chain reaction) and the genotypes were identified by reaction with the restriction enzyme HhaI and HaeIII for ApoE and LDLR polymorphisms, respectively. ApoE genotypes were identified as ε3/ε3 (62.5%), ε3/ε4 (25%), ε2/ε3 (5.4%), ε2/ε4 (5.4%) and ε4/ε4 (1.8%) and the LDLR genotypes identified as AA (85.7%), AT (12.5%) and TT (1.8%). ε2/ε2 genotype was not observed. The analysis of the distribution of ApoE and LDLR genotypes according to the permanence of the dyslipidemia in the study sample showed that all individuals with the ApoE genotype ε2/ε4 and ε4/ε4 kept at least one lipid changes in A2 and A3 and all individuals ApoE genotype ε2/ε3 had not altered lipids in A2 and A3, while for RLDL genotype no difference was found. When analyzed individually, no lipid variable altered in A2 and/or A3, associated with these genotypes, were found. The ApoE gene polymorphism was associated with the permanence of dyslipidemia in young individuals in a longitudinal follow-up study

Submitted by Luciana Ferreira (lucgeral@gmail.com) on 2015-10-15T12:44:52Z No. of bitstreams: 2 Dissertação - Maira Chiquito Alves - 2015.pdf: 2795650 bytes, checksum: df30e15f25e56e8cea5234d554455c1b (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) / Approved for entry into archive by Luciana Ferreira (lucgeral@gmail.com) on 2015-10-15T12:46:45Z (GMT) No. of bitstreams: 2 Dissertação - Maira Chiquito Alves - 2015.pdf: 2795650 bytes, checksum: df30e15f25e56e8cea5234d554455c1b (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) / Made available in DSpace on 2015-10-15T12:46:45Z (GMT). No. of bitstreams: 2 Dissertação - Maira Chiquito Alves - 2015.pdf: 2795650 bytes, checksum: df30e15f25e56e8cea5234d554455c1b (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) Previous issue date: 2015-03-20 / Fundação de Amparo à Pesquisa do Estado de Goiás - FAPEG / To verify the relationship between the polymorphisms rs18011282 in PPAR-gamma gene and rs429358 + rs7412 in apolipoprotein E gene and lipid profile of adolescents under cardiovascular risk factors. Material and methods: The study sample was composed of 115 adolescents aged 10-19 years, which presented cardiovascular risk factors. The students were evaluated regarding socioeconomic, anthropometric, biochemical, genetic and dietetic variables. ANOVA or Kruskal-Wallis tests were used in the analysis of ungrouped genotypes, while Student’s t-test or Mann-Whitney test were applied to the analysis of the grouped genotypes. Results: The overweight adolescents presented lower HDL-c concentrations (p=0.0016). Those carrying PPAR-gamma Ala allele showed higher serum TAG (p=0.0423) and VLDL-c (p=0.0410) levels when compared to those carrying the Pro allele. For the apolipoprotein E gene polymorphism, it was observed a tendency of higher TAG (p=0.0712) and VLDL-c (p=0.0758) levels in the adolescents carrying the E4 allele when compared to those who did not carry this allele. Conclusion: The polymorphisms PPAR-gama rs18011282 and apolipoprotein E rs429358 + rs7412 seem to be related to the development of lipid profile alterations in adolescents. / Verificar a relação dos polimorfismos rs18011282 no gene do PPAR-gama e rs429358 + rs7412 no gene da apolipoproteína E com o perfil lipídico de adolescentes com fatores de risco cardiovascular. Material e métodos: A amostra foi constituida por 115 adolescentes com idade entre 10-19 anos e com fatores de risco cardiovascular. Os estudantes foram avaliados quanto as variáveis socioeconômicas, antropométricas, bioquímicas, genéticas e dietéticas. Os testes ANOVA ou Kruskal-Wallis foram utilizados para os genótipos não agrupados, e as análises dos genótipos agrupados foram realizadas por meio dos testes t de Student e Mann-Whitney. Resultados: Os adolescentes com excesso de peso apresentaram concentrações inferiores de HDL-c (p=0,0016). Carreadores do alelo variante Ala (PPAR-gama) apresentaram concentrações séricas superiores de TG (p=0,0423) e de VLDL-c (p=0,0410) em relação ao carreadores do alelo selvagem Pro. Para o polimorfismo no gene da ApoE foram observadas concentrações séricas de TG (p=0,0712) e de VLDL-c (p=0,0758) marginalmente maiores nos carreadores do alelo E4 em relação aos não carreadores deste alelo. Conclusão: Os polimorfismos rs18011282 no gene que codifica o PPAR-gama e rs429358 + rs7412 no gene que codifica a ApoE podem estar relacionados ao desenvolvimento de dislipidemias em adolescentes.

La maladie d’Alzheimer (MA) est un désordre neuro-dégénératif chronique fatal et la forme la plus répandue des démences chez l’adulte qui touchent plus de 28 millions de personnes dans le monde. En absence de traitement pour les démences neurodégénérative dont la maladie d’Alzheimer, le coût de celles-ci est estimé à 1 trillion d’USD en 2018 ce qui représente des enjeux économiques et sociétaux majeurs au niveau national et mondial. La MA est une forme d’amylose qui est caractérisée par l’agrégation du peptide amyloïde beta (Aβ) dans le cerveau des patients. Le facteur de risque génétique principal de la forme tardive (après 65 ans) de cette maladie est l’isoforme E4 de l’apolipoprotéine E (apoE) qui intervient dans le transport et le métabolisme des lipides et interagit avec le peptide Aβ. La modulation de la structure des isoformes d’apoE et de leur interaction avec l’Aβ apparaît comme une cible prometteuse dans la conception rationnelle de thérapies de la maladie. Celle-ci nécessite néanmoins une compréhension approfondie des propriétés structurales et dynamiques des deux partenaires moléculaires. Dans le cadre de cette thèse, nous avons étudié la structure de trois isoformes (E2, E3 et E4) de l’apoE par différentes techniques de biologie structurale et principalement par la réticulation chimique couplée à la spectrométrie de masse (CXMS) quantitative et par la bioinformatique structurale. Ces données complémentées par la spectroscopie infrarouge ont permis de construire des modèles structuraux de l’apoE2, E3 et E4. Nous avons mis en évidence l’interaction des domaines N- et C-terminal et la présence de multiples conformations de l’apoE chez les trois isoformes. Nos données suggèrent un équilibre entre deux principales conformations de l’apoE dont la population relative diffère entre les trois isoformes. Nous proposons les interfaces à cibler dans le cadre de thérapie visant à moduler les propriétés structurales des isoformes de l’apoE.Nous avons également mis en évidence que chaque isoforme d’apoE (E2, E3 et E4) interfère avec l’agrégation d’Aβ. Le peptide interagit avec les deux domaines N- et C- terminal de l’apoE. L’étude quantitative de l’interaction par CXMS a révélé des différences entre les cross-links formés en présence des isoformes. La modélisation du complexe apoE-Aβ a permis de mettre en évidence les interfaces impliquées dans l’interaction. Celle-ci possède une composante hydrophobe et électrostatique qui diffère chez les isoformes d’apoE. Nous proposons un mécanisme de l’interaction apoE-Aβ qui est initié par les propriétés hydrophobes des deux partenaires et qui est stabilisé par la suite via des contacts électrostatiques. Par ailleurs, une étude permettant d’explorer le potentiel de la nouvelle chimie de réticulation des résidues acides de protéine dans des applications en protéomique structurale a été effectuée. / Doctorat en Sciences / info:eu-repo/semantics/nonPublished

The trypanolytic factor of human serum :a trojan horse.<p><p><p>African trypanosomes, the prototype of which is Trypanosoma brucei, are protozoan parasites of huge clinical, veterinary and economical importance. They develop in the body fluids of various mammals (including humans) where they face and manipulate many different aspects of the immune system. The extent of this interplay is pivotal to both host and parasite survival, and depending on parasite virulence and host susceptibility, infection duration ranges from some months to several years. At the end, host survival is invariably compromised.<p><p>Humans and few other primates provide however a striking exception to this fatal outcome. They are indeed fully protected against most trypanosome infections through the presence in their blood of a so-called trypanosome lytic factor (TLF). The TLF is known to circulate mainly in the form of a high density lipoprotein particle characterized by the simultaneous presence of two primate-specific proteins: haptoglobin-related protein (Hpr) and apolipoprotein L-I (apoL-I).<p><p>We have contributed to delineate the respective roles played by Hpr and apoL-I in the lysis process.<p><p>ApoL-I was shown to be the exclusive toxin of the TLF. In its absence humans get fully susceptible to any trypanosome infection. The toxin was shown to kill the parasite after endocytosis through the generation of ionic pores in the lysosomal membrane. Those pores dissipate membrane potential and trigger the influx of chloride ions from the cytoplasm into the lysosomal compartment, leading to an eventually fatal uncontrolled osmotic phenomenon. <p><p>ApoL-I efficient delivery to the parasite relies on Hpr. African trypanosomes indeed fulfil their heme nutritional requirements by receptor-mediated internalization of the complex formed by haptoglobin, an evolutionary conserved acute-phase protein, and hemoglobin, resulting from physiological intravascular hemolysis. This heme uptake by the auxotrophic parasites contributes to both growth rate and resistance against host oxidative burst. In human serum, the trypanosome receptor is unable to discriminate between Hp and the closely related TLF-bound Hpr, explaining TLF efficient endocytosis.<p><p>As such, the TLF acts as a Trojan horse, killing the parasite from inside the cell after having deceived its vigilance through the high similarity between heme-delivering haptoglobin and toxin-associated Hpr. <p> / Doctorat en Sciences / info:eu-repo/semantics/nonPublished