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Estudio De La Regulación Post-Transcripcional De Genes Mediada Por Microrna En Pacientes Con Colitis Ulcerosa Tratados Con Glucocorticoides

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Estudio De La Regulación Post-Transcripcional De Genes Mediada Por Microrna En Pacientes Con Colitis Ulcerosa Tratados Con Glucocorticoides ADVERTIMENT. Lʼaccés als continguts dʼaquesta tesi queda condicionat a lʼacceptació de les condicions dʼús establertes per la següent llicència Creative Commons: http://cat.creativecommons.org/?page_id=184 ADVERTENCIA. El acceso a los contenidos de esta tesis queda condicionado a la aceptación de las condiciones de uso establecidas por la siguiente licencia Creative Commons: http://es.creativecommons.org/blog/licencias/ WARNING. The access to the contents of this doctoral thesis it is limited to the acceptance of the use conditions set by the following Creative Commons license: https://creativecommons.org/licenses/?lang=en Tesis doctoral Juan Enrique Naves TESIS DOCTORAL Autor: JUAN ENRIQUE NAVES Barcelona, 2016 Tesis doctoral Juan Enrique Naves Tesis doctoral Juan Enrique Naves Departamento de Medicina Facultad de Medicina Universitat Autònoma de Barcelona Estudio de la regulación post-transcripcional de genes mediada por microRNA en pacientes con colitis ulcerosa tratados con glucocorticoides Tesis Doctoral presentada para optar al grado de Doctor por la Universitat Autònoma de Barcelona Autor: JUAN ENRIQUE NAVES Tutor: RAMON PLANAS VILA Directores: Dr. EUGENI DOMÈNECH i MORRAL Dr. EDUARD CABRÉ i GELADA Dr. JOSEP MANYÉ i ALMERO Barcelona, 2016 Tesis doctoral Juan Enrique Naves Tesis doctoral Juan Enrique Naves Tesis doctoral Juan Enrique Naves Tesis doctoral Juan Enrique Naves A mi hijo Joaquín y a mi mujer Paula, por el amor que me dan, por el apoyo incondicional, por compartir la vida conmigo, por darme fuerzas cada día. Tesis doctoral Juan Enrique Naves Tesis doctoral Juan Enrique Naves A mi Madre, a mi Padre, y a mis hermanos, por estar a mi lado en cada paso que doy, por los valores que me han inculcado, por el cariño que me llega cada día desde la distancia. Tesis doctoral Juan Enrique Naves Tesis doctoral Juan Enrique Naves A mis abuelos, en especial a Tito, siempre presente. A Elsa y a Miguel, por la enorme ayuda de estos últimos años. A mis amigos, los de aquí y los de allá! Tesis doctoral Juan Enrique Naves Tesis doctoral Juan Enrique Naves Índice de contenidos INDICE DE FIGURAS 5 INDICE DE TABLAS 6 INDICE DE IMÁGENES 7 ABREVIATURAS 8 1. INTRODUCCIÓN 15 1.1. Colitis Ulcerosa........................................................................................................................................... 15 1.1.1. Generalidades de la Colitis Ulcerosa 15 1.1.2. Etiopatogenia de la Colitis Ulcerosa 17 1.1.2.1. Microbiota intestinal 17 1.1.2.2. Factores inmunológicos 18 1.1.2.3. Factores genéticos 21 1.1.2.4. Otros factores asociados a la patogenia de CU 21 1.1.3. Diagnóstico de la Colitis Ulcerosa 23 1.1.4. Clasificación de la Colitis Ulcerosa 25 1.1.5. Estrategias de tratamiento de la Colitis Ulcerosa 27 1.1.5.1. Tratamiento de los brotes de actividad 27 1.1.5.2. Tratamiento de mantenimiento 29 1.2. Glucocorticoides ........................................................................................................................................ 30 1.2.1. Glucocorticoides sistémicos y Colitis Ulcerosa 30 1.2.2. Valoración de la respuesta a GC sistémicos 31 1.2.3. Corticoesteroides naturales y sintéticos 33 1.2.4. Mecanismos de acción de los glucocorticoides 34 1.2.4.1. Mecanismos genómicos 35 1.2.4.2. Mecanismos no genómicos 37 1.2.5 Mecanismos asociados a la resistencia a GC 38 1.2.5.1. Receptor de glucocorticoides 39 1.2.5.2. Heterocomplejo proteico y otras proteínas 40 1.2.5.3. Alteración a nivel de la transcripción 40 1.2.5.4. Mediadores pro-inflamatorios 41 1.2.5.5. Gen de multiresistencia a drogas y bombas de eliminación de fármacos 42 1.2.5.6. Otros potenciales mecanismos de resistencia a GC 43 1.3. El transcriptoma y los microRNA ....................................................................................................... 44 1.3.1. Generalidades sobre el transcriptoma 44 1.3.2. Generalidades sobre los MicroRNAs 45 1.3.3. Biogénesis de los miR 46 1.3.4. MicroRNA en la Enfermedad Inflamatoria Intestinal 47 2. ANTECEDENTES 55 3. HIPOTESIS 61 4. OBJETIVOS 65 1 Tesis doctoral Juan Enrique Naves 5. MATERIAL Y MÉTODOS 69 5.1. Diseño del estudio ..................................................................................................................................... 69 5.2. Selección de individuos .......................................................................................................................... 69 5.3. Valoración, seguimiento y recolección de muestras ................................................................. 70 5.3.1. Individuos con CU activa 70 5.3.2. Individuos controles sanos 72 5.3.3. Confección de los grupos del estudio 73 5.4. Recolección y almacenamiento de las muestras ........................................................................ 73 5.5. Homogenización de las muestras, extracción del RNA, extracción de las proteínas, y comprobación de la calidad de las muestras ........................................................................................ 73 5.6. Análisis de las muestras y estudios experimentales realizados .......................................... 74 5.6.1. Secuenciación de miR 74 5.6.2. Microarrays para el estudio del transcriptoma de las muestras 75 5.6.3. Validación del resultado del microarray mediante real time Polymerase Chain Reaction 76 5.7. Procesamiento de los resultados ....................................................................................................... 76 5.7.1. Software y criterios estadísticos aplicados 76 5.7.2. Comparaciones realizadas 77 5.8. Estudios in silico a partir de los datos experimentales obtenidos ..................................... 78 5.8.1. Búsqueda de dianas potenciales de los miR diferenciales 78 5.8.2. Búsqueda de vías enriquecidas a partir de las dianas potenciales 79 5.8.3. Búsqueda de miR a partir de dianas potenciales (Reversión del sistema) 79 5.8.4. Vías y genes asociados a los RNAm diferenciales del microarrays 79 5.8.5. Integración de los datos obtenidos del estudio in silico 80 5.9. Estudio de la expresión proteica mediante Western Blot ....................................................... 81 6. RESULTADOS 85 6.1. Pacientes incluidos ................................................................................................................................... 85 6.2. Muestras útiles para el análisis del transcriptoma ..................................................................... 87 6.3. Resultados de la secuenciación y comparación entre grupos ............................................. 87 6.4. Resultados del microarrays y comparaciones entre grupos ................................................. 95 6.5. Estudios in silico a partir de los datos de la secuenciación .................................................. 98 6.5.1. Predicción de RNAm dianas a partir de miR diferenciales 98 6.5.2. Vías enriquecidas a partir de las dianas potenciales 98 6.5.3. Reversión del sistema 100 6.6. Estudios in silico a partir de los resultados del microarrays ............................................. 101 6.7. Integración de los resultados de la secuenciación y microarrays ................................... 103 6.8. Modelos de respuesta y refractariedad ........................................................................................ 105 6.9. Western Blot de transcritos diferenciales y relevantes de los modelos ........................ 109 2 Tesis doctoral Juan Enrique Naves DISCUSIÓN 115 7. DISCUSIÓN 117 8. CONCLUSIONES 131 ANEXOS 133 ANEXO 1- Metodología para la extracción del RNA total y de las proteínas de las muestras de tejido cólico ............................................................................................................................. 135 ANEXO 2 – Metodología utilizada para realizar RT-PCR ................................................................ 138 ANEXO 4 - Resultado de la integridad, y lista de las muestras utilizadas para los estudios experimentales .............................................................................................................................. 143 ANEXO 5 – Resultados de la secuenciación de miR ....................................................................... 145 ANEXO 6 - Resultados del microarrays ................................................................................................ 163 ANEXO 7 - Resultados de la regresión lineal y análisis de Pearson comparando los resultados del microarrays y la RT-PCR de las muestras de tejido cólico ........................... 175 ANEXO 8 – Dianas potenciales de los miR diferenciales de la secuenciación ................... 185 ANEXO 9 – Vías enriquecidas a partir de dianas potenciales de los miR diferenciales de la secuenciación. ............................................................................................................................................. 218 ANEXO 10 - Interacciones entre componentes de mTOR y miR diferenciales .................... 236 ANEXO 11 – Niveles de expresión de proteína DDIT4 (Western Blot), RNAm de DDIT4 (microarrays), nivel de expresión de miR-200c-3p, y del miR-183-5p (secuenciación) ... 238 9. BIBLIOGRAFÍA 241 3 Tesis doctoral Juan Enrique Naves 4 Tesis doctoral Juan Enrique Naves INDICE DE FIGURAS Figura 1 – Etiopatogenia de la Colitis Ulcerosa …………………………………………… 17 Figura 2 – Loci asociados a la Enfermedad Inflamatoria Intestinal ……………………... 22 Figura 3 – Principales mecanismos de acción de los glucocorticoides ……………….... 37 Figura 4 – Resumen de sucesos que ocurren del
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