Variantes genéticas, expresión génica, metilación y búsqueda de blancos terapéuticos en vías de respuesta inflamatoria en una muestra de población universitaria colombiana con problemas de consumo de alcohol

ilustraciones, gráficas, tablas

Autores:
Rey Buitrago, Mauricio
Tipo de recurso:
Doctoral thesis
Fecha de publicación:
2022
Institución:
Universidad Nacional de Colombia
Repositorio:
Universidad Nacional de Colombia
Idioma:
spa
OAI Identifier:
oai:repositorio.unal.edu.co:unal/84041
Acceso en línea:
https://repositorio.unal.edu.co/handle/unal/84041
https://repositorio.unal.edu.co/
Palabra clave:
610 - Medicina y salud::615 - Farmacología y terapéutica
Perfilación de la Expresión Génica
Variantes Farmacogenómicas
Alcohólicos
Gene Expression Profiling
Pharmacogenomic Variants
Alcoholics
Gene Expression
Methylation
Genetic polymorphism
Alcoholism
Therapeutic target
Polimorfismo genético
Alcoholismo
Expresión génica
Metilación
Blanco terapéutico
Rights
openAccess
License
Reconocimiento 4.0 Internacional
id UNACIONAL2_722620bd0a147473f76a436df6632882
oai_identifier_str oai:repositorio.unal.edu.co:unal/84041
network_acronym_str UNACIONAL2
network_name_str Universidad Nacional de Colombia
repository_id_str
dc.title.spa.fl_str_mv Variantes genéticas, expresión génica, metilación y búsqueda de blancos terapéuticos en vías de respuesta inflamatoria en una muestra de población universitaria colombiana con problemas de consumo de alcohol
dc.title.translated.eng.fl_str_mv Genetic variants, gene expression, methylation and search for therapeutic targets in inflammatory response pathways in a sample of a colombian university population with alcohol use problems
title Variantes genéticas, expresión génica, metilación y búsqueda de blancos terapéuticos en vías de respuesta inflamatoria en una muestra de población universitaria colombiana con problemas de consumo de alcohol
spellingShingle Variantes genéticas, expresión génica, metilación y búsqueda de blancos terapéuticos en vías de respuesta inflamatoria en una muestra de población universitaria colombiana con problemas de consumo de alcohol
610 - Medicina y salud::615 - Farmacología y terapéutica
Perfilación de la Expresión Génica
Variantes Farmacogenómicas
Alcohólicos
Gene Expression Profiling
Pharmacogenomic Variants
Alcoholics
Gene Expression
Methylation
Genetic polymorphism
Alcoholism
Therapeutic target
Polimorfismo genético
Alcoholismo
Expresión génica
Metilación
Blanco terapéutico
title_short Variantes genéticas, expresión génica, metilación y búsqueda de blancos terapéuticos en vías de respuesta inflamatoria en una muestra de población universitaria colombiana con problemas de consumo de alcohol
title_full Variantes genéticas, expresión génica, metilación y búsqueda de blancos terapéuticos en vías de respuesta inflamatoria en una muestra de población universitaria colombiana con problemas de consumo de alcohol
title_fullStr Variantes genéticas, expresión génica, metilación y búsqueda de blancos terapéuticos en vías de respuesta inflamatoria en una muestra de población universitaria colombiana con problemas de consumo de alcohol
title_full_unstemmed Variantes genéticas, expresión génica, metilación y búsqueda de blancos terapéuticos en vías de respuesta inflamatoria en una muestra de población universitaria colombiana con problemas de consumo de alcohol
title_sort Variantes genéticas, expresión génica, metilación y búsqueda de blancos terapéuticos en vías de respuesta inflamatoria en una muestra de población universitaria colombiana con problemas de consumo de alcohol
dc.creator.fl_str_mv Rey Buitrago, Mauricio
dc.contributor.advisor.spa.fl_str_mv Aristizábal Gutiérrez, Fabio Ancizar
dc.contributor.author.spa.fl_str_mv Rey Buitrago, Mauricio
dc.contributor.researchgroup.spa.fl_str_mv Farmacogenética del Cáncer
Genética Clínica
dc.contributor.cvlac.spa.fl_str_mv https://scienti.minciencias.gov.co/cvlac/visualizador/generarCurriculoCv.do?cod_rh=0000589004
dc.contributor.researchgate.spa.fl_str_mv https://www.researchgate.net/profile/Rey-Mauricio
dc.contributor.googlescholar.spa.fl_str_mv https://scholar.google.cl/citations?hl=es&user=nyGPDOIAAAAJ&view_op=list_works&gmla=AHoSzlVOSAyt4NYTrjTrIIq3ClUxGDka6IjPHad-tGLyv1pR_VWQp6O0n9uTJbpaP_LFg6-_qXfD3BkbypDimP2-k6tOc7PnImIS9NMD
dc.subject.ddc.spa.fl_str_mv 610 - Medicina y salud::615 - Farmacología y terapéutica
topic 610 - Medicina y salud::615 - Farmacología y terapéutica
Perfilación de la Expresión Génica
Variantes Farmacogenómicas
Alcohólicos
Gene Expression Profiling
Pharmacogenomic Variants
Alcoholics
Gene Expression
Methylation
Genetic polymorphism
Alcoholism
Therapeutic target
Polimorfismo genético
Alcoholismo
Expresión génica
Metilación
Blanco terapéutico
dc.subject.decs.spa.fl_str_mv Perfilación de la Expresión Génica
Variantes Farmacogenómicas
Alcohólicos
dc.subject.decs.eng.fl_str_mv Gene Expression Profiling
Pharmacogenomic Variants
Alcoholics
dc.subject.proposal.eng.fl_str_mv Gene Expression
Methylation
Genetic polymorphism
Alcoholism
Therapeutic target
dc.subject.proposal.spa.fl_str_mv Polimorfismo genético
Alcoholismo
Expresión génica
Metilación
Blanco terapéutico
description ilustraciones, gráficas, tablas
publishDate 2022
dc.date.issued.none.fl_str_mv 2022-10-27
dc.date.accessioned.none.fl_str_mv 2023-06-21T19:57:02Z
dc.date.available.none.fl_str_mv 2023-06-21T19:57:02Z
dc.type.spa.fl_str_mv Trabajo de grado - Doctorado
dc.type.driver.spa.fl_str_mv info:eu-repo/semantics/doctoralThesis
dc.type.version.spa.fl_str_mv info:eu-repo/semantics/acceptedVersion
dc.type.coar.spa.fl_str_mv http://purl.org/coar/resource_type/c_db06
dc.type.content.spa.fl_str_mv Text
dc.type.redcol.spa.fl_str_mv http://purl.org/redcol/resource_type/TD
format http://purl.org/coar/resource_type/c_db06
status_str acceptedVersion
dc.identifier.uri.none.fl_str_mv https://repositorio.unal.edu.co/handle/unal/84041
dc.identifier.instname.spa.fl_str_mv Universidad Nacional de Colombia
dc.identifier.reponame.spa.fl_str_mv Repositorio Institucional Universidad Nacional de Colombia
dc.identifier.repourl.spa.fl_str_mv https://repositorio.unal.edu.co/
url https://repositorio.unal.edu.co/handle/unal/84041
https://repositorio.unal.edu.co/
identifier_str_mv Universidad Nacional de Colombia
Repositorio Institucional Universidad Nacional de Colombia
dc.language.iso.spa.fl_str_mv spa
language spa
dc.relation.indexed.spa.fl_str_mv Bireme
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spelling Reconocimiento 4.0 Internacionalhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccesshttp://purl.org/coar/access_right/c_abf2Aristizábal Gutiérrez, Fabio Ancizar196f772bcb4f1fb1e8c0176079d58f54600Rey Buitrago, Mauricio6901d8aa13d0a96f75a55e493dcbf73cFarmacogenética del CáncerGenética Clínicahttps://scienti.minciencias.gov.co/cvlac/visualizador/generarCurriculoCv.do?cod_rh=0000589004https://www.researchgate.net/profile/Rey-Mauriciohttps://scholar.google.cl/citations?hl=es&user=nyGPDOIAAAAJ&view_op=list_works&gmla=AHoSzlVOSAyt4NYTrjTrIIq3ClUxGDka6IjPHad-tGLyv1pR_VWQp6O0n9uTJbpaP_LFg6-_qXfD3BkbypDimP2-k6tOc7PnImIS9NMD2023-06-21T19:57:02Z2023-06-21T19:57:02Z2022-10-27https://repositorio.unal.edu.co/handle/unal/84041Universidad Nacional de ColombiaRepositorio Institucional Universidad Nacional de Colombiahttps://repositorio.unal.edu.co/ilustraciones, gráficas, tablasIntroducción La dependencia al alcohol y fenotipos relacionados poseen patrones de herencia del tipo multifactorial. El componente genético es muy variable étnicamente hablando y muy dependiente de la evolución personal de la enfermedad. Aunque se han identificado múltiples loci, las variantes funcionales no se han identificado en la mayoría de los casos. En este trabajo seleccionamos genes candidatos de la vía de respuesta inflamatoria y determinamos variantes genéticas en la región promotora, su estado de metilación y expresión en forma de ARNm y proteína comparando controles y casos con uso problemático del alcohol de una población universitaria de la sede Bogotá de la Universidad Nacional de Colombia. Con estos datos proponemos candidatos a diana terapéutica, los cuales se caracterizaron. Métodos Para la selección de la muestra se realizó una convocatoria dentro de la sede de la Universidad y se aplicaron estrictos criterios de inclusión y exclusión. Se realizaron extracciones de ADN y ARN total. Empleamos la PCR convencional seguida de secuencia de Sanger para la determinación de polimorfismos e identificar las variantes génicas asociadas con el uso problemático del alcohol. Con el empleo de diversas herramientas bioinformáticas se realizó el estudio de haplotipos, desequilibrio de ligamiento y epistasis. La expresión diferencial de ARNm se determinó por RT-q-PCR mientras la proteica por ELISA. El estado de metilación se evaluó indirectamente por modificación del ADN por la técnica del bisulfito seguida PCR, marcaje fluorescente y electroforesis capilar. La obtención y caracterización de los candidatos a blanco terapéutico se realizó por modelado por homología y docking molecular, además del empleo de numerosas herramientas bioinformáticas adicionales. Resultados En el presente estudio se obtuvo la información genética de un marcador STR, de 28 variantes de nucleótido simple (SNV) en once genes relacionados con respuesta inflamatoria, reportando por primera vez sus frecuencias alélicas y genotípicas para población colombiana. Además de encontrar haplotipos asociados a la protección contra la enfermedad e interacciones génicas con efectos acumulativos que se asocian con el fenotipo bebedor. De esta primera parte del estudio se perfilaron como candidatos a seguir con el estudio, los genes SNCA, TNFR1, INFGR1 y MIF. Seguidamente se determinaron los niveles de proteínas y ARNm evidenciando una expresión diferencial hacia la baja en forma de ARNm para los genes TNFR1 y MIF y proteica para MIF, mientras se detecta expresión diferencial de las proteínas SNCA, IL6R1 y MIF dependiendo del sexo de los participantes, en hombres hacia la baja. Nuestros datos indican que hay cambios del estado de metilación en el promotor de los genes MIF en los casos de la muestra general y en SNCA de los casos de sexo masculino que conllevarían a disminución en la síntesis de mARN y proteína. Se seleccionaron las proteínas MIF y SNCA como blancos terapéuticos y se generó modelos que se caracterizaron y así proporcionar una base útil para proponer vías para mejorar la terapia dirigida contra esta patología. Conclusión Los haplotipos en los genes SNCA, TNFR1 e INFGR1 identificados son variantes funcionales que pueden afectar la susceptibilidad al consumo de riesgo de alcohol y fenotipos relacionados. Además, que su interacción parece ser fundamental para el establecimiento de estos fenotipos. Nuestro estudio proporciona información sobre la expresión y regulación de estos genes de respuesta inflamatoria en estos fenotipos de consumo problemático de alcohol y se propone dos proteínas candidatas como blanco terapéutico. (Texto tomado de la fuente).Introduction Alcohol dependence and related phenotypes have multifactorial inheritance patterns. The genetic component is very variable ethnically speaking and highly dependent on the personal evolution of the disease. Although multiple loci have been identified, functional variants have not been identified in most cases. In this work, we select candidate genes of the inflammatory response pathway and determine genetic variants in the promoter region, their methylation status and expression in the form of mRNA and protein, comparing controls and cases with problematic alcohol use in a university population from the Bogotá campus. from the National University of Colombia. With these data we propose candidates for therapeutic targets, which were characterized. Methods For the selection of the sample, a call was made within the University headquarters and strict inclusion and exclusion criteria were applied. DNA and total RNA extractions were performed. We used conventional PCR followed by Sanger sequencing to determine polymorphisms and identify gene variants associated with problematic alcohol use. With the use of various bioinformatic tools, the study of haplotypes, linkage disequilibrium and epistasis was carried out. The differential expression of mRNA was determined by RT-q-PCR while protein expression was determined by ELISA. Methylation status was indirectly assessed by DNA modification by the bisulfite technique followed by PCR, fluorescent labeling, and capillary electrophoresis. The obtaining and characterization of the therapeutic target candidates was carried out by homology modeling and molecular docking, in addition to the use of numerous additional bioinformatic tools. Results In the present study, the genetic information of a STR marker of 28 single nucleotide variants (SNV) in eleven genes related to inflammatory response was obtained, reporting for the first time its allelic and genotypic frequencies for the Colombian population. In addition to finding haplotypes associated with protection against disease and gene interactions with cumulative effects that are associated with the drinking phenotype. From this first part of the study, the SNCA, TNFR1, INFGR1 and MIF genes were outlined as candidates to continue with the study. Next, protein and mRNA levels were determined, showing a downward differential expression in the form of mRNA for the TNFR1 and MIF genes and protein for MIF, while differential expression of the SNCA, IL6R1 and MIF proteins was detected depending on the sex of the participants. , in men downwards. Our data indicate that there are changes in the methylation state in the promoter of the MIF genes in the cases of the general sample and in the SNCA of the male cases that would lead to a decrease in the synthesis of mRNA and protein. The MIF and SNCA proteins were selected as therapeutic targets and models were generated that were characterized and thus provide a useful basis for proposing ways to improve targeted therapy against this pathology. Conclusion The haplotypes in the SNCA, TNFR1, and INFGR1 genes identified are functional variants that may affect susceptibility to hazardous drinking and related phenotypes. Furthermore, their interaction seems to be fundamental for the establishment of these phenotypes. Our study provides information on the expression and regulation of these inflammatory response genes in these phenotypes of problematic alcohol consumption and two candidate proteins are proposed as therapeutic targets.Incluye anexosDoctoradoDoctor en Ciencias FarmacéuticasGenética de las adiccionesxxi, 209 páginasapplication/pdfspaUniversidad Nacional de ColombiaBogotá - Ciencias - Doctorado en Ciencias FarmacéuticasFacultad de CienciasBogotá, ColombiaUniversidad Nacional de Colombia - Sede Bogotá610 - Medicina y salud::615 - Farmacología y terapéuticaPerfilación de la Expresión GénicaVariantes FarmacogenómicasAlcohólicosGene Expression ProfilingPharmacogenomic VariantsAlcoholicsGene ExpressionMethylationGenetic polymorphismAlcoholismTherapeutic targetPolimorfismo genéticoAlcoholismoExpresión génicaMetilaciónBlanco terapéuticoVariantes genéticas, expresión génica, metilación y búsqueda de blancos terapéuticos en vías de respuesta inflamatoria en una muestra de población universitaria colombiana con problemas de consumo de alcoholGenetic variants, gene expression, methylation and search for therapeutic targets in inflammatory response pathways in a sample of a colombian university population with alcohol use problemsTrabajo de grado - Doctoradoinfo:eu-repo/semantics/doctoralThesisinfo:eu-repo/semantics/acceptedVersionhttp://purl.org/coar/resource_type/c_db06Texthttp://purl.org/redcol/resource_type/TDColombiahttp://vocab.getty.edu/page/tgn/1000050Bireme1. 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Food Funct. 2018;9(12):6414–26.Estudio de genes de neuroinflamación, su expresión y estado de metilación en sujetos alcohol-dependientes ColombianosUniversidad Nacional de ColombiaEstudiantesGrupos comunitariosInvestigadoresMaestrosLICENSElicense.txtlicense.txttext/plain; charset=utf-85879https://repositorio.unal.edu.co/bitstream/unal/84041/1/license.txteb34b1cf90b7e1103fc9dfd26be24b4aMD51ORIGINAL79495627.2022.pdf79495627.2022.pdfTesis de Doctorado en Ciencias Farmacéuticasapplication/pdf4106692https://repositorio.unal.edu.co/bitstream/unal/84041/2/79495627.2022.pdfafbe3e9ad814a9a432a25f114a46fd77MD52THUMBNAIL79495627.2022.pdf.jpg79495627.2022.pdf.jpgGenerated Thumbnailimage/jpeg4285https://repositorio.unal.edu.co/bitstream/unal/84041/3/79495627.2022.pdf.jpg4937ec6bc8d7626b80c28239bbf4a526MD53unal/84041oai:repositorio.unal.edu.co:unal/840412024-08-12 01:59:42.943Repositorio Institucional Universidad Nacional de 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