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Universidad Nacional Autónoma De México Plan De Estudios Combinados En Medicina Instituto Nacional De Medicina Genómica

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Universidad Nacional Autónoma De México Plan De Estudios Combinados En Medicina Instituto Nacional De Medicina Genómica UNIVERSIDAD NACIONAL AUTÓNOMA DE MÉXICO PLAN DE ESTUDIOS COMBINADOS EN MEDICINA INSTITUTO NACIONAL DE MEDICINA GENÓMICA ESTUDIO POST-MORTEM DE LAS ALTERACIONES EN LA EXPRESIÓN DE RNA EN EL CEREBRO DE PACIENTES SUICIDAS TESIS QUE PARA OPTAR POR EL GRADO DE DOCTORA EN MEDICINA PRESENTA: BRENDA CABRERA MENDOZA DIRECTOR DE TESIS: DR. JOSÉ HUMBERTO NICOLINI SÁNCHEZ INSTITUTO NACIONAL DE MEDICINA GENÓMICA COMITÉ TUTOR: DRA. MARTHA PATRICIA OSTROSKY-SHEJET INSTITUTO DE INVESTIGACIONES BIOMÉDICAS DR. DAVID COLIN GLAHN ESCUELA DE MEDICINA DE HARVARD Ciudad Universitaria, CD. MX., diciembre de 2020 TABLA DE CONTENIDOS Resumen ........................................................................................................................................................................ 1 Abstract .......................................................................................................................................................................... 2 Definición y epidemiología del suicidio ............................................................................................................ 3 Epidemiología global del suicidio ..................................................................................................................... 5 Epidemiología del suicidio en América ........................................................................................................... 8 Epidemiología del suicidio en México ............................................................................................................10 Factores de riesgo para suicidio ..........................................................................................................................11 Factores distales .......................................................................................................................................................13 Neurobiología del suicidio...................................................................................................................................20 Estudios de neuroimagen en suicidio .......................................................................................................21 Alteraciones epigenéticas en el cerebro de suicidas .........................................................................23 Alteraciones en la expresión génica en el cerebro de suicidas ....................................................26 Factores moderadores ..........................................................................................................................................29 Factores proximales ...............................................................................................................................................31 Suicidio y trastorno por uso de sustancias ....................................................................................................32 Trastorno por uso de sustancias: generalidades................................................................................32 Asociación entre suicidio y trastorno por uso de sustancias ........................................................37 Patología dual ...........................................................................................................................................................39 Justificación .....................................................................................................................................................................39 Objetivo general ...........................................................................................................................................................40 Objetivos específicos..................................................................................................................................................40 Hipótesis ...........................................................................................................................................................................40 Métodos y materiales ................................................................................................................................................41 Consideraciones éticas .....................................................................................................................................41 Sujetos y muestras ..............................................................................................................................................41 Aislamiento de RNA ............................................................................................................................................42 Síntesis de RNA biotinilado ............................................................................................................................46 Hibridación de RNA a microarreglos ........................................................................................................48 Pre-procesamiento de los datos del microarreglo .............................................................................49 Análisis de expresión diferencial ................................................................................................................51 Análisis de anotación funcional ...................................................................................................................53 Reanálisis de datos: patología dual en suicidas ..................................................................................53 Resultados .......................................................................................................................................................................56 Resultados generales .......................................................................................................................................56 4 Expresión génica en individuos con trastorno por uso de sustancias que murieron por suicidio .....................................................................................................................................................................57 Discusión: Expresión génica en individuos con trastorno por uso de sustancias que murieron por suicidio .......................................................................................................................................68 Expresión génica en individuos con patología dual que murieron por suicidio .................74 Discusión: Expresión génica en individuos con patología dual que murieron por suicidio .....................................................................................................................................................................85 Limitaciones, conclusiones y perspectivas ....................................................................................................89 Artículos Publicados a partir del presente proyecto de Tesis ............................................................91 Brain Gene Expression Pattern of Subjects with Completed Suicide and Comorbid Substance Use Disorder ........................................................................................................................................91 Brain gene expression profiling of individuals with dual diagnosis who died by suicide ........................................................................................................................................................................................ 105 Otros artículos publicados durante el doctorado ................................................................................... 119 Referencias ................................................................................................................................................................... 126 ANEXO A: Dictámenes de Comité de Ética ................................................................................................... 170 ANEXO B: Soluciones ............................................................................................................................................... 172 ANEXO C: Sondas de control del microarreglo Human H12-v4 de Illumina ............................ 173 5 Resumen A pesar de que los individuos con trastorno por uso de sustancias (TUS) tienen un alto riesgo suicida, la mayoría de los estudios de expresión génica en suicidio han excluido a los sujetos con este trastorno. Por lo tanto, poco se sabe sobre el perfil de expresión génica en suicidas con TUS. La identificación de procesos biológicos alterados en el cerebro de suicidas con TUS es crucial para comprender los efectos de la comorbilidad de TUS y la conducta suicida. La presente tesis describe la evaluación de diferencias en expresión génica en la corteza prefrontal dorsolateral de suicidas y no suicidas con y sin TUS. Sesenta y seis muestras de tejido cerebral fueron colectadas y clasificadas en los siguientes grupos: i) 23 suicidas con TUS, ii) 20 suicidas sin TUS, iii) 9 no suicidas con TUS y iv) 14 no suicidas sin TUS. Los resultados de este estudio sugieren que los suicidas con TUS tienen un perfil de expresión génica en la corteza prefrontal distinto al de los sujetos con solo una de estas condiciones, presentando diferencias en la expresión de genes involucrados en la proliferación celular y neurotransmisión glutamatérgica. Realizamos un reanálisis de los datos de expresión génica de 38 suicidas con un enfoque a patología dual y suicidio. La patología dual es la co-ocurrencia de al menos
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