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dc.contributor.advisorLaissue, Paul 
dc.creatorQuintero Ronderos, Paula Juliana 
dc.date.accessioned2019-01-28T13:20:53Z
dc.date.available2019-01-28T13:20:53Z
dc.date.created2018-12-03
dc.date.issued2018 
dc.identifier.urihttp://repository.urosario.edu.co/handle/10336/18933
dc.descriptionEl aborto espontáneo recurrente (AER) se define como dos o más pérdidas consecutivas de la gestación antes de la semana 20 del desarrollo intrauterino. Esta patología afecta a aproximadamente entre el 1% y el 5% de las parejas. La etiología del AER se puede dividir en causas no-genéticas como genéticas. Sin embargo, ~50% de los casos se considera idiopático. De manera análoga, la etiología molecular de la falla de implantación recurrente (FIR), definida como la falla de la implantación en al menos 2 o más ciclos consecutivos de fertilización in vitro, es poco conocida. La etiología molecular del AER y de la FIR está asociada potencialmente a variantes de secuencia en cientos de genes candidato que participan en las cascadas moleculares fisiológicas de la implantación y durante toda la gestación. La aproximación gen candidato, usando la secuenciación de Sanger, ha sido de utilidad para la descripción de pocos genes implicados en el AER. La secuenciación de siguiente generación (NGS) ha sido una herramienta eficiente puesto que permite el estudio simultáneo de múltiples genes relacionados con enfermedades complejas. En la primera parte de este trabajo de tesis se utilizó la aproximación NGS-exoma para identificar nuevos genes y mutaciones potencialmente implicadas en el desarrollo del AER. Algunas de las mutaciones encontradas por este abordaje fueron estudiadas mediante ensayos funcionales in vitro para determinar su posible efecto deletéreo. La identificación de la variante THBD p.Trp153Gly en mujeres colombianas con AER y su validación mediante ensayos funcionales in vitro sugiere, por primera vez, una relación directa entre formas mutantes de esta proteína y la fisiopatología del AER, considerándose como un posible marcador molecular para el diagnóstico en pacientes colombianas con AER idiopático. En la segunda parte del presente trabajo de tesis identificamos y estudiamos funcionalmente nuevas mutaciones de FOXD1, un gen relevante en la fisiología endometrial y placentaria, identificadas en pacientes FIR, AER, preeclampsia (PE) y retardo del crecimiento intrauterino (RCIU). Los ensayos funcionales in vitro demostraron que las mutaciones FOXD1-p.His267Tyr y FOXD1-p.Arg57del. modifican la transactivación del promotor de C3, contribuyendo con el fenotipo. FOXD1 podría considerarse en consecuencia un marcador molecular diagnóstico para las pacientes con AER, FIR, RCIU y PE. Por último, ensayos por inmunoprecipitación de la cromatina secuenciación NGS (ChIP-seq) permitieron determinar potenciales nuevos genes blanco directos de FOXD1 (CTSC, CD86, CMA1 y TRPC6) en un contexto placentario. La información generada durante este trabajo de tesis aporta al conocimiento sobre el origen genético del AER, la FIR, y el RCIU/PE. Estos resultados podrían ser de utilidad para los especialistas clínicos en el contexto del desarrollo de la medicina traslacional.
dc.description.abstractRecurrent pregnancy loss (RPL) is defined as the loss of two or more consecutive and spontaneous miscarriages before the 20th week of gestation. This pathology affects ~1% to 5% of the couples. The RPL aetiology is classified as non-genetics and genetics. However, the 50% of the cases remains idiopathic. Similarly, the aetiology of the recurrent implantation failure (RIF), defined as the implantation failure in at least 2 or more consecutive cycles of in vitro fertilization (IVF), is poorly understood. To note, the molecular RPL and RIF aetiology is potentially associated with hundreds of genes which participate in the physiological molecular pathways related to the implantation and gestation. The candidate gene approach using Sanger sequencing has been useful to identify some genes associated with RPL. However, the next generation sequencing (NGS) has been an effective tool to overcome this limitation because it allows the simultaneous study of multiple genes related to complex diseases. In first part of this thesis, we used the NGS-exome approach to identify new genes and mutation potentially implicated in the development of RPL. Some of the mutations found by this approach were tested by functional in vitro assays to determine their possible deleterious effect within the pathology. The identification of the variant THBD p.Trp153Gly in Colombian women with RPL and its validation through functional in vitro assays suggested, for the first time, a direct association with the RPL pathophysiology. Therefore, it may be considered as a molecular biomarker for the RPL diagnosis in Colombian patients. In the second part of this thesis, we identified and studied the potential implication of new FOXD1 mutations, a relevant gene in the endometrium and placenta physiology, in patients with RIF, RPL, preeclampsia (PE) and intrauterine growth restriction (IUGR). The functional in vitro assays demonstrated that FOXD1 p.His267Tyr and FOXD1 p.Arg57del mutations modify the C3 promoter transactivation, thus contributing to the phenotype. Therefore, FOXD1 could be considered a molecular biomarker for the diagnosis of RPL, RIF, PE and IUGR patients. The chromatin immunoprecipitation assays (ChIP) allowed to determine new direct FOXD1 target genes (CTSC, CD86, CMA1 y TRPC6) within the placenta context. The information generated during this thesis contributes to the general knowledge about the origin and development of RPL, RIF, PE/IUGR. These results might be useful for the clinical specialist in a context of translational medicine.
dc.format.mimetypeapplication/pdf
dc.language.isospa
dc.rightsAtribución-NoComercial-SinDerivadas 2.5 Colombia
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/2.5/co/
dc.sourceinstname:Universidad del Rosario
dc.sourcereponame:Repositorio Institucional EdocUR
dc.subjectPérdida recurrente de la gestación
dc.subjectFalla de la implantación
dc.subjectGenética
dc.subjectGenómica
dc.subjectMutaciones
dc.subjectFOXD1
dc.subjectBiomarcadores moleculares
dc.subject.ddcGinecología & otras especialidades médicas 
dc.subject.lembAborto espontáneo
dc.subject.lembAborto habitual
dc.subject.lembGenes
dc.subject.lembGenética molecular
dc.titleGenómica funcional y disección molecular de FOXD1 para la identificación de nuevos biomarcadores genéticos asociados a patologías de la reproducción de origen endometrial y placentario
dc.typedoctoralThesis
dc.publisherUniversidad del Rosario
dc.creator.degreeDoctor en Ciencias Biomédicas
dc.publisher.programDoctorado en Ciencias Biomédicas
dc.publisher.departmentFacultad de Ciencias Naturales y Matemáticas
dc.subject.keywordRecurrent pregnancy loss
dc.subject.keywordRecurrent implantation failure
dc.subject.keywordMolecular biomarkers
dc.subject.keywordFOXD1
dc.subject.keywordGenetics
dc.subject.keywordGenomics
dc.subject.keywordMutations
dc.rights.accesRightsinfo:eu-repo/semantics/embargoedAccess
dc.type.spaTesis de doctorado
dc.rights.accesoRestringido (Temporalmente bloqueado)
dc.date.embargoEndinfo:eu-repo/date/embargoEnd/2021-01-28
dc.type.hasVersioninfo:eu-repo/semantics/acceptedVersion
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dc.rights.licenciaEL AUTOR, manifiesta que la obra objeto de la presente autorización es original y la realizó sin violar o usurpar derechos de autor de terceros, por lo tanto la obra es de exclusiva autoría y tiene la titularidad sobre la misma. PARGRAFO: En caso de presentarse cualquier reclamación o acción por parte de un tercero en cuanto a los derechos de autor sobre la obra en cuestión, EL AUTOR, asumirá toda la responsabilidad, y saldrá en defensa de los derechos aquí autorizados; para todos los efectos la universidad actúa como un tercero de buena fe. EL AUTOR, autoriza a LA UNIVERSIDAD DEL ROSARIO, para que en los términos establecidos en la Ley 23 de 1982, Ley 44 de 1993, Decisión andina 351 de 1993, Decreto 460 de 1995 y demás normas generales sobre la materia, utilice y use la obra objeto de la presente autorización. -------------------------------------- POLITICA DE TRATAMIENTO DE DATOS PERSONALES. Declaro que autorizo previa y de forma informada el tratamiento de mis datos personales por parte de LA UNIVERSIDAD DEL ROSARIO para fines académicos y en aplicación de convenios con terceros o servicios conexos con actividades propias de la academia, con estricto cumplimiento de los principios de ley. Para el correcto ejercicio de mi derecho de habeas data cuento con la cuenta de correo habeasdata@urosario.edu.co, donde previa identificación podré solicitar la consulta, corrección y supresión de mis datos.
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