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Cíbridos Transmitocondriales Como Modelo in Vitro Para Estudiar La Programa de Doctorado en Ciencias de la Salud Cíbridos transmitocondriales como modelo in vitro para estudiar la asociación existente entre el ADN mitocondrial y la patología artrósica Andrea Dalmao Fernández A Coruña 2020 TESIS DOCTORAL (memoria presentada para optar al grado de doctor internacional) Directores: Dr. Francisco Javier Blanco García Dra. Mercedes Fernández Moreno Grupo de Investigación en Reumatología (GIR). Instituto de Investigación Biomédica da Coruña (INIBIC). El Dr. Francisco Javier Blanco García y la Dra. Mercedes Fernández Moreno, investigadores del Grupo de Investigación en Reumatología (GIR) del Instituto de Investigación Biomédica de la Coruña (INIBIC) y directores del presente trabajo de tesis doctoral, CERTIFICAN QUE: La presente memoria de tesis titulada “Cíbridos transmitocondriales como herramienta in vitro para estudiar la asociación entre el ADN mitocondrial y la patología artrósica” presentada por Doña Andrea Dalmao Fernández, ha sido realizada bajo nuestra dirección y supervisión en el Grupo de Investigación en Reumatología en el INIBIC y reúne las condiciones necesarias para ser defendida públicamente optando al Grado de Doctor con mención Internacional. Para que así conste, firman el siguiente certificado en A Coruña, con fecha: Dr. Francisco J Blanco García Dra. Mercedes Fernández Moreno Parte de la investigación desarrollada a lo largo de esta Tesis Doctoral ha sido realizada durante una estancia de investigación predoctoral de un mes en el año 2017 bajo la supervisión del Profesor Arild C. Rustan, líder del Muscle Research Group en el Department of Pharmaceutical Biosciences, School of Pharmacy, en la Universidad de Oslo (Oslo, Noruega). Dicha estancia se financió a través de las ayudas Short Term Scientific Missions por parte de la acción COST Action MitoEAGLE con el objetivo de establecer y consolidar colaboraciones internacionales que proporcionen la posibilidad de mejorar el conocimiento de la función mitocondrial en relación a la evolución, edad, género, estilo de vida y ambiente. Parte de la investigación desarrollada a lo largo de esta Tesis Doctoral ha sido realizada durante una estancia de investigación predoctoral durante 3 meses en el año 2018 bajo la supervisión de la Dra. Jenny Lund, investigadora postdoctoral del Muscle Research Group en el Department of Pharmaceutical Biosciences, School of Pharmacy, en la Universidad de Oslo (Oslo, Noruega). Dicha estancia se financió a través de las ayudas para estancias predoctorales Inditex-UDC con el objetivo de proporcionar la posibilidad de optar al Grado de Doctor con mención internacional, no solo facilitando el aprendizaje del estudiante en otro entorno al habitual, sino que también contribuyendo a establecer nuevas redes de trabajo y colaboraciones internacionales que permiten compartir métodos y conocimiento en el ámbito en el que se desarrolla la tesis doctoral. A mi hermano, a mis padres. AGRADECIMIENTOS Y pensar que, una vez llegados a este punto, esta es la parte de la tesis que más terror me da escribir... Los que me conocen saben que la parte sentimental no es mi fuerte, pero intentaré expresar todo lo agradecida que estoy por la ayuda y el apoyo que he recibido a lo largo de todos estos años dejando la lógica a un lado. En primer lugar, me gustaría agradecer a los donantes, sin las muestras y sin su participación, la investigación básica en biomedicina y su avance sería imposible. También agradecer a todas aquellas instituciones que han aportado su granito de arena financiando y proporcionándome la oportunidad de completar mi formación académica: Fundación Profesor Novoa Santos, Sociedad Española de Reumatología, Instituto de Salud Carlos III, Short Term Scientific Misions from COST Action and Mitoeagle y las ayudas UDC-INDITEX. Gracias también a las plataformas de proteómica, ProteoRed, genómica e histomorfología del INIBIC, así como a los servicios de apoyo a la investigación (SAI) de la Universidad de la Coruña (UDC), sin todos estos profesionales mi formación como investigadora se reduciría considerablemente, gracias por permitirme aprender de vosotros. En tercer lugar, y desde luego dos, de los pilares más importantes en el desarrollo de este trabajo de tesis, agradecer de todo corazón las decisiones y directrices de mis directores de tesis, el Dr. Francisco Blanco García y la Dra. Mercedes Fernandez Moreno. Gracias por haber confiado en mis capacidades y por haberme dedicado todo el tiempo del mundo. En especial a Merce, gracias por tu tesón, tu constancia, por haberte implicado tanto en mi formación, aprendizaje, crecimiento y mejora, a nivel del laboratorio y a nivel personal. Gracias a los dos por preocuparos siempre por poner a mi alcance los medios y los recursos disponibles y necesarios para llevar a cabo una investigación novedosa y de calidad. Simplemente gracias por esta oportunidad. Me gustaría continuar agradeciendo al grupo de Genómica. Mencionar que, sin la ayuda y colaboración de Nacho, mi situación actual no sería la misma, así que gracias por apoyar y valorar el esfuerzo que conllevan estos 4 años de trabajo. Mi más sincero, profundo, grande, infinito y cariñoso gracias de todo corazón a Sara, contigo empezó todo. Te ofreciste siempre a ayudarme, enseñarme, formarme y hacerme responsable de lo que significa trabajar en grupo. Pusiste a mi disposición todo tu conocimiento y te estaré eternamente agradecida por introducirme en el mundo de la ciencia. Aunque no te guste, siempre serás “mi técnico de laboratorio” (y del grupo de genómica ;). Morena, María Eugenia, Duran y Pauli, a vosotros cuatro, gracias por haber formado parte de esta etapa. More, me has demostrado que siempre se puede y que a pesar de que las cosas no siempre son como uno quiere, me has enseñado a aceptarlas y adaptarlas a las circunstancias, así que, allá voy, espero, en mi futuro, tener tu fuerza. María gracias por todo el apoyo y por resolverme todas las dudas, creo que he aprendido mucho de ti y también de tu forma de ser, siempre altruista y disponible para los demás. Duri y Pauli me lo he pasado genial con vosotros, nuestra ironía y retranca no nos la quitará nadie y quiero daros las gracias por el simple hecho de haber estado ahí y hacerme las cosas mucho más sencillas en esta etapa de mi vida. Gracias al grupo de REUMA, clínicos e investigadores, realmente he aprendido que la clínica aporta un punto de vista fundamental en la investigación básica ya que nos acerca al objetivo final, ayudar a los pacientes. Gracias a Bea y Uxía por ayudarme y enseñarme siempre que lo he necesitado e Irene por dejarme ofrecerle mi ayuda. Valentina gracias por ayudarme e involucrarte hasta el último momento en mi formación, lo valoro muchísimo. Tami, sin ti no hay células, y sin células, esta tesis…, infinitamente gracias por tu paciencia y ayuda, eres una parte fundamental de este trabajo y siempre intentaré impregnarme de tu conocimiento y capacidad didáctica. El INIBIC, y como piezas centrales de todo el instituto, María Moreno y Fani. María a ti, muchas gracias por haberme facilitado siempre la existencia y el trabajo. Eres como el clip de Word, yo creo que hasta solucionas el error 404 de internet. Fani a ti por ser nuestro nexo de unión con la parte clínica, con la parte administrativa, con la parte directiva, pieza fundamental del grupo de Reuma, gracias por toda la ayuda que nos das. Todos los demás grupos agradeceros toda la ayuda que me habéis ofrecido, siempre disponibles. Con mención especial a Susana y a Pauliña por facilitarnos la atención y el material necesarios a la hora de realizar los experimentos. Creo que la convivencia, en cualquier lugar, es complicada, y el trabajo en grupo se construye entre todos, por ello, gracias a muchos de vosotros este trabajo se me ha hecho más llevadero. Agradezco el que estuvierais en el momento y el lugar adecuado durante todo este proceso, ya que todos los comentarios y críticas me han permitido conoceros y crecer con vosotros. Me llevo un cachito de cada uno: ONCO, Inflamación, CellCOM, Terapia, Micro... I would like to thank Arild Rustan for giving me the opportunity to improve my knowledge in cell metabolism and meeting new interesting people in another international lab. I really appreciate you and your lovely personality, which made me feel like home from the first day I met you. Jenny, I don’t think I have enough words to describe how grateful I am for all your work, teaching, taking care, worrying, helping and solving problems for me. One of the things I really appreciated from the first day we met Is our communication and understanding of each other.I really hope that we will keep in touch with each other regardless of time, country, work or life. I would also like to thank to all the people in the lab for the positive environment, you made It one of the greatest experiences of my life! Sin amigos la vida en general no va a ningún sitio y a pesar de que estos últimos años se haya impuesto la distancia entre nosotros, y se haya hecho más complicado de lo esperado, me alegro de que forméis parte de diferentes momentos de mi vida. Rakel, gracias por tu ayuda, por tus consejos y por tus críticas, aunque te pienses que ha sido poco, todo ha valido para que yo esté ahora en esta situación, esto también es parte de ti. Noemi, admiro todo de ti, gracias por cada uno de los detalles que envuelven nuestra relación. Andrea, gracias por dejarme aprender de ti y por estar en el labo, conmigo, juntas. PMCEX, gracias por haber estado ahí todos estos años, nos deseo todo lo mejor a todos y cada uno de nosotros, creo que realmente nos merecemos verlo. Lucia, llevo fatal el tenerte lejos, qué bien estoy cuando estoy contigo, simplemente gracias por formar parte de mi vida.
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