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Maria Fernanda Garcés Gutiérrez Estudio de factores moleculares y séricos durante la gestación en la rata y en el humano Maria Fernanda Garcés Gutiérrez Universidad Nacional de Colombia Programa Interfacultades de Doctorado en Biotecnología Facultad de Ciencias Bogotá D.C., Colombia 2016 Estudio de factores moleculares y séricos durante la gestación en la rata y en el humano Maria Fernanda Garcés Gutiérrez Tesis presentada como requisito parcial para optar al título de: Doctor en Biotecnología Director: PhD., MSc., Químico. Jorge Eduardo Caminos Pinzón Codirector: MSc., MEd., MD. Ariel Iván Ruiz Parra Línea de Investigación: Estudio de las bases moleculares de la fisiología de la gestación. Grupo de Investigación: Endocrinología y nutrición básica. Universidad Nacional de Colombia Programa Interfacultades de Doctorado en Biotecnología Facultad de Ciencias Bogotá D.C., Colombia 2016 Este trabajo lo dedico a cada persona que acompaño de forma paciente y desinterasada la ejecución del mismo, desde los pacientes, investigadores, profesores y consultores, hasta mi director de tesis y amigo incondicional y por supuesto mi familia, quienes nunca perdieron la fe en mí. Estudio de factores moleculares y séricos durante la gestación en la rata y en el humano Agradecimientos El presente trabajo se realizó en el marco del proyecto “Valor de biomarcadores séricos en la predicción del desenlace materno-perinatal de la gestante y su evolución a 6 meses”, el cual fue un proyecto financiado por Colciencias código: 110154531660. Adicionalmente, se recibió el apoyo en la convocatoria del Programa Nacional de Proyectos para el Fortalecimiento de la Investigación, la Creación y la Innovación en Posgrados de la Universidad Nacional de Colombia 2013-2015. Un componente del presente trabajo, se realizó en los consultorios de Promoción y Prevención del Hospital del Engativá, Bogotá D.C. bajo la dirección de los docentes del Departamento de Gineco-Obstetricia de la Facultad de Medicina de la Universidad Nacional de Colombia y con la colaboración permanente del personal de enfermería de Promoción y prevención entre los años 2012 a 2014. Labor sin la cual, el presente trabajo habría sido posible. El presente, constituye un componente de seguimiento multidisciplinario en el cual intervinieron profesionales de áreas médicas y sociales, cuyos aportes es justo reconocer, ya que gracias a esta multidisciplinariedad y a la competencia de este equipo, fue posible la realización del mismo y la proyección que este estudio ha alcanzado. En este sentido en el área médica quisiera agradecerles al Dr. Ariel Ruiz y la Dra. Edith Ángel quienes participaron desde el diseño y la ejecución del proyecto, hasta el análisis de los resultados. El Dr. Mario Parra, quien realizo el seguimiento mediante análisis de imágenes diagnosticas a las pacientes, en los dos años de seguimiento. Estudio de factores moleculares y séricos durante la gestación en la rata y en el humano La Dra. Alexandra Rovira, medica encargada del seguimiento de las pacientes, la Dra. Lucia Alejandra Torres, bacterióloga encargada de la captación y procesamiento de muestras en el componente clínico. La Dra. Natalia Elvira Poveda, nutricionista a cargo del seguimiento de las pacientes y la Dra. Yurani Curtidor, trabajadora social del proyecto quien asumió de forma responsable y diligente, la labor de garantizar la adherencia en un proyecto que requería un seguimiento individual por más de un año. Ademas quisiera agradecer al Ing. Luis Guillermo Leal, quien diligente y acertadamente nos apoyo en el análisis de datos provientes del secuenciamiento. Sin embargo, todo este engranaje no habría sido posible sin la dirección de un profesional con altas capacidades en planeación y coordinación de proyectos, como lo es el profesor Jorge Eduardo Caminos, quien comprendió desde el inicio las virtudes del equipo de trabajo y el gran potencial del proyecto, lo que hizo posible el éxito en el desarrollo del mismo. Resumen y Abstract Resumen La gestación es un estado fisiológico dinámico, que se caracteriza por cambios transitorios en la fisiología materna, los cuales garantizan la viabilidad del feto. La placenta es un órgano transitorio, que soporta una gran cantidad de funciones metabólicas y endocrinas en la madre y constituye el principal medio de comunicación entre la madre y el feto. El entendimiento de los diferentes procesos de adaptabilidad que tienen lugar en la placenta, requieren del estudio de modelos que expliquen los mecanismos moleculares que subyacen a la fisiología placentaria. De esta manera, la rata ha sido considerada como un modelo animal en el estudio de la reproducción femenina y durante la gestación, dada la similitud en las características anatómicas y de invasión que presenta la placenta de la rata en comparación con la placenta humana. De esta manera, en el presente estudio se realizó un abordaje traslacional, a partir del análisis del transcriptoma de la placenta de la rata durante tres periodos de la gestación, hacia la fisiología de la gestación humana. Se realizó el seguimiento de una cohorte longitudinal a un grupo de mujeres de Bogotá, durante tres periodos de la gestación y tres meses posparto. Adicionalmente, en el presente estudio, se analizó un subgrupo de mujeres gestantes con diagnóstico de preeclampsia, de la misma cohorte. Es así, como a partir de los resultados obtenidos en el presente trabajo, se hace un aporte a la comprensión de la fisiología de la gestación humana, mediante un abordaje en modelo animal de rata. Palabras clave: RNA mensajero, microRNA, gestación, placenta, preeclampsia. Estudio de factores moleculares y séricos durante la gestación en la rata y en el humano Abstract Pregnancy is a dynamic physiological condition characterized by transient changes in maternal physiology, which guarantee the viability of the fetus. The placenta is a temporary organ, which supports a large number of metabolic and endocrine functions in the mother and is the primary means of communication between mother and fetus. Understanding the different adaptability processes taking place in the placenta, require the study of models that explain the molecular mechanisms underlying placental physiology. Thus, the rat has been regarded as an animal model for the study of female reproduction and during pregnancy, given the similarity in the anatomical and invasion characteristics presented by the rat placenta compared with human placenta. Thus, in this study a translational approach was used, based on the analysis of the transcriptome of the rat placenta during three periods of gestation, to the physiology of human pregnancy. Tracking a longitudinal cohort a group of women from Bogotá, for three periods of pregnancy and three months postpartum was performed. Additionally, in the present study, a subset of pregnant women with diagnosis of preeclampsia, from the same cohort were studied. Thus, as from the results obtained in this work, a contribution to the understanding of the physiology of human pregnancy is done through an approach in rat animal model. Keywords: messenger RNA, microRNA, gestation, placenta, preeclampsia Contenido Contenido Pág. 1. Introducción primer capítulo – mRNA .................................................................... 5 2. Materiales y Métodos ............................................................................................... 8 2.1. Animales ............................................................................................................ 8 2.2. Aislamiento de RNA ........................................................................................... 9 2.3. Preparación de librerías y secuenciamiento de RNA ........................................ 10 2.4. Procesamiento de datos provenientes de mRNAseq ........................................ 10 2.4.1. Procesamiento de las lecturas ....................................................................... 11 2.4.2. Análisis de Componentes Principales ............................................................ 11 2.4.3. Reglas de Asociación .................................................................................... 11 2.5. Confirmación de resultados ............................................................... …… .. 12 2.5.1. Selección de genes para estudio ................................................................... 12 2.5.2. Análisis mediante PCR en tiempo real ........................................................... 13 2.5.3. Determinación sérica ..................................................................................... 14 2.5.4. Inmunohistoquímica ....................................................................................... 15 2.6. Análisis estadístico ........................................................................................... 16 3. Resultados .............................................................................................................. 17 3.1. Secuenciamiento .............................................................................................. 17 3.2. Manejo de los datos ......................................................................................... 17 3.3. Análisis de componentes principales de las muestras ...................................... 18 3.4. Análisis de agrupación ..................................................................................... 20 3.5. Reglas de Asociación ....................................................................................... 22 3.6. Análisis de genes de Interés ...........................................................................
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