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“Protective Function of Specific Micronutrients Against Cardiovascular and Neurodegenerative Diseases”

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“Protective Function of Specific Micronutrients Against Cardiovascular and Neurodegenerative Diseases” UNIVERSIDAD AUTÓNOMA DE MADRID FACULTAD DE MEDICINA DEPARTAMENTO DE FARMACOLOGÍA Y FISIOLOGÍA TESIS DOCTORAL “PROTECTIVE FUNCTION OF SPECIFIC MICRONUTRIENTS AGAINST CARDIOVASCULAR AND NEURODEGENERATIVE DISEASES” IMDEA Alimentación (Instituto Madrileño de Estudios Avanzados en Alimentación) MARÍA DEL CARMEN CRESPO LORENZO MADRID, 2018 UNIVERSIDAD AUTÓNOMA DE MADRID FACULTAD DE MEDICINA DEPARTAMENTO DE FARMACOLOGÍA Y FISIOLOGÍA TESIS DOCTORAL “PROTECTIVE FUNCTION OF SPECIFIC MICRONUTRIENTS AGAINST CARDIOVASCULAR AND NEURODEGENERATIVE DISEASES” Instituto Madrileño de Estudios Avanzados en Alimentación (IMDEA Food) Mª DEL CARMEN CRESPO LORENZO Madrid, 2018 UNIVERSIDAD AUTÓNOMA DE MADRID FACULTAD DE MEDICINA DEPARTAMENTO DE FARMACOLOGÍA Y FISIOLOGÍA “PROTECTIVE FUNCTION OF SPECIFIC MICRONUTRIENTS AGAINST CARDIOVASCULAR AND NEURODEGENERATIVE DISEASES” Instituto Madrileño de Estudios Avanzados en Alimentación (IMDEA Food) Memoria presentada por Mª Del Carmen Crespo Lorenzo Para optar al grado de: DOCTOR EN FARMACOLOGÍA Y FISIOLOGÍA Directores de la Tesis: Dr. Francesco Visioli y Dr. Alberto Dávalos Investigadores Senior del Instituto IMDEA Alimentación D. FRANCESCO VISIOLI, DR. EN BIOTECNOLOGÍA POR LA UNIVERSIDAD DE BRESCIA (ITALIA) Y D. ALBERTO DÁVALOS, DR. EN FARMACIA POR LA UNIVERSIDAD COMPLUTENSE DE MADRID, ACTUALMENTE INVESTIGADORES DE IMDEA ALIMENTACIÓN INFORMAN: Que el presente trabajo titulado “Protective function of specific micronutrients against cardiovascular and neurodegenerative diseases” que constituye la memoria que presenta Dª. María Del Carmen Crespo Lorenzo para optar al grado de Doctor en Farmacología y Fisiología, ha sido realizada en el Instituto Madrileño de Estudios Avanzados en Alimentación (IMDEA Alimentación) bajo su dirección, y cumple las condiciones exigidas para optar al grado de Doctor por la Facultad de Medicina de la Universidad Autónoma de Madrid. Y para que así conste, firman el presente informe: Dr. Francesco Visioli Dr. Alberto Dávalos This work was developed in the framework of two Spanish State Program projects whose references are: - AGL2011-28995 titled “Foodomics of hydroxytyrosol: insights into its molecular effects and search of new markers and targets” at Instituto Madrileño De Estudios Avanzados en Alimentación (IMDEA Food). - AGL2014-56464 titled “Evaluation of a nutritional supplement enriched with bioactive phospholipids designed to prevent age-associated mild cognitive impairment” at Instituto de Investigación en Ciencias de la Alimentación and Consejo Superior de Investigaciones Científicas (CIAL- CSIC). - In addition, support was obtained from ALIBIRD (ALIBIRD-CM S2013/ABU-2728). Don`t let your happiness depend on something you may lose. Cs. Lewis ACKNOWLEDGEMENTS En primer lugar me gustaría agradecer a mis directores de Tesis, Francesco Visioli y Alberto Dávalos la oportunidad que me han dado para poder hacer realidad mi sueño, realizar esta tesis doctoral. Francesco Visioli, agradecerte la confianza que has depositado en mí, agradecerte cada palabra, consejo, explicación, me has dado mucho, y te debo mucho, ¡eres una persona increíble! Alberto Dávalos, gracias por creer en mí, por darme esta confianza, tu sabes que siempre he tenido poca confianza en mí misma, y tú, has sido capaz de devolvérmela, y no solo eso, sino que tu pasión por la ciencia, ha despertado en mí, una mayor pasión por ella, es increíble verte trabajar, ver como lo disfrutas y vives, ¡me encanta! Doy gracias de verdad de la suerte que he tenido de teneros como jefes, estoy eternamente agradecida. Al departamento de Farmacología y fisiología de la UAM, en especial a Concha, agradecerte todo tu tiempo invertido en mí, tus consejos, todas las respuestas a mis miles de preguntas, primero por mail, y después ya directamente por móvil, gracias de verdad por todo. Al director de IMDEA Alimentación Guillermo Reglero, a la subdirectora Ana Ramírez y a la gerente del centro, Inmaculada Galindo, agradeceros también la oportunidad que me habéis dado de poder formar parte de IMDEA Alimentación y haberme apoyado siempre, incluso en momentos difíciles. A mi grupo de Laboratorio, LABAFUN, el laboratorio más divertido, jejeej, el laboratorio de alimentos funcionales. A João, un grandísimo investigador, inteligentísimo y con un potencial increíble ¡vales un montón! No solo eso, sino una bellísima persona que he tenido el placer de toparme en el camino, y que gracias a él, he podido avanzar en este laborioso camino acompañada siempre de su mano, además he recibido siempre todo su apoyo en momentos malos y buenos, muito obrigado, você é incrível. A Emma, una investigadora que estoy segura de que llegara lejos no, ¡lejísimos! Una gran profesora, me has enseñado un montón, en todos los ámbitos de la vida, no solo profesionalmente, sino también como persona, me ha encantado vivir a tu lado cada segundo cuando estuviste aquí, fue enorme la pena que sentí cuando te fuiste. Pero gracias por estar ahí a pesar de todo, eres un gran apoyo, y me gusta mucho tenerte cerca. A Judit Gil, mi compañera, mi amiga, mi apoyo mayoritario en IMDEA, no sé qué hubiese hecho sin ti aquí, me has acompañado en cada paso, me has apoyado y ayudado siempre un montón, que gran suerte que una tal Raquel renunciase a su plaza, porque si ella no hubiese renunciado quizás no te hubiese podido conocer, menos mal que te cruzaste en mi camino, espero de corazón, que siempre estés en él, que a pesar de nuestras diferencias o que podamos seguir caminos distintos en un futuro, siempre querré tenerte a mi lado. Te quiero, no mucho, ¡muchísimo! A Lamia, Elenita, Maika, Almu y Diana, además de compañeras, amigas, me ha gustado mucho poder conoceros a todas, y compartir momentos geniales no solo en IMDEA, si no fuera de aquí, ¡Sois todas geniales! A Josune, que sin ella apagándome millones de qPCR por las tardes no hubiese sido posible acabar esta tesis a tiempo, jeje, me has ayudado mucho, no solo en eso, si no también explicándome la técnica, resolviendo mis dudas si algo no me salía (como cuando puse una RT en unos minutillos…), recogiendo nitrógeno líquido para mis experimentos en el centro de tu marido, diseñando primers, eres una gran investigadora y sobre todo, una gran persona. A todos mis compañeros de IMDEA, Moni, Silvia, Jorge, Víctor, Roberto… no puedo nombraros a todos porque sois tantísimos y muchos ya no estáis en el centro, pero gracias a todos, cada uno de vosotros me habéis aportado algo positivo, a pesar de que con algunos no he podido establecer una amistad fuera, para mí sois todos geniales, y habéis hecho que me sienta completamente como en casa. A la Plataforma Genyal, en especial a Vivi, Isa, Helena, Jesús y Susana, sin vosotros no hubiese podido realizar el ensayo clínico con hidroxitirosol en muestras humanas, muchas gracias de verdad, por conseguir que esto fuese posible y por toda vuestra ayuda. Y muchas gracias Isa, me has ayudado un montón explicándome todos los trámites y papeles que tenía que entregar, eres una chica especial y vales muchísimo! A las Dras. Cristina Andrés Lacueva y Olha Khymenets, por llevar a cabo las evaluación de las muestras de orina del ensayo clínico, en el Departamento de Bromatología y Nutrición, de la Universidad de Barcelona. A los Dres. Eduardo Gomez-Acebo y David Auñon Calles de la empresa Seprox Biotech, Madrid, por suministrarnos de manera gratuita el compuesto Hidroxitirosol, muchísimas gracias. A Javier Fontecha IP en el CIAL, a Alba García Serrano y Pilar Castro Gómez, gracias a todos por dejarme formar parte de vuestro equipo en el proyecto AGL2014, ha sido un verdadero placer conoceros, me habéis enseñado mucho, y gracias a vosotros he podido llevar a cabo casi la mitad de mi tesis, ya que sin vuestras dietas, no hubiera podido llevar a cabo este estudio. Y sobre todo a ti, Javier, gracias por contar con nosotros como equipo de trabajo en tu proyecto, y gracias por tu apoyo económico que con él, pude irme de congreso a Suiza, y para mí fue una gran experiencia, y te lo agradezco un montón. A Cesar Venero IP de la UNED, a Shishir y a Inma, también gracias por dejarme formar parte de vuestro equipo de trabajo en el proyecto AGL2014, por alimentar cada día a las ratas, por confiar en mí para el sacrificio de estas, por poder participar juntos en el congreso EBBS, por enseñarme y apoyarme tanto. Gracias a todos y en especial a Cesar. A mis amigos de toooda la vida, Iria, Dani, Sara Alcol, Sara García, Mercedes, Ángel, Berta, Marta, Nacho a sus compañeros o maridos y mujeres, espero seguir a vuestro lado como hasta ahora, siendo amigos para siempre! A mis amigos más especiales de la Universidad, Maru y Javi, ¡¡¡os echo de menos!!! A amigos nuevos, Ana, Adri, Ana, Iñaki, Bea, Fer, Carla, Carlos, Chio, Diego, Sandra, Aitor…. Gracias a TODOS por vuestro apoyo, aunque la mayoría no entendáis a lo que me dedico, gracias por vuestra compañía, amistad y por hacerme pasar momentos especiales a vuestro lado. Pero en especial a ti Dani, muchas gracias, porque sin tu ayuda ésta tesis hubiese sido muy sosa, y con tu talento ha quedado preciosa, eres un artista, vales muchísimo y sé que llegaras muuuy lejos, que orgullosa estoy de ti, eres un gran profesional. ¡Te quiero un montón! A toda mi familia, en especial a mis hermanos, Carol y Manu, os quiero muchísimo, a mis cuñados, Nacho y Ana, gracias a todos por apoyarme, cuidarme, quererme tanto y por darme tantos sobrinos (Cris, Pablo, Alfonso, Gon, Lucía, Inés) son todos geniales y los quiero un montón. Gracias Carol por todo tu apoyo, tengo muchísima suerte por tenerte tan cerca, siempre estás cuando te necesito, de verdad muchísimas gracias. A mis padres, que me lo han dado todo, me han ayudado en cada paso de mi vida, siempre a mi lado cuidándome y protegiéndome, gracias por haber sido tan maravillosos y especiales conmigo, por todo vuestro esfuerzo y tiempo invertido en mí. Gracias Papa, por seguir aquí, cuidándome, me estas ayudando muchísimo, y estas siempre que te necesito, no sabes cuanto te lo agradezco, te quiero muchísimo.
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