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Characterization and Regulation of Kv1.5-Kvβ1.3 Complex

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Characterization and Regulation of Kv1.5-Kvβ1.3 Complex UNIVERSIDAD AUTÓNOMA DE MADRID Departamento de Bioquímica Characterization and regulation of Kv1.5-Kvβ1.3 complex. ÁLVARO MACÍAS MARTÍNEZ Madrid 2014 Departamento de Bioquímica Facultad de Medicina UNIVERSIDAD AUTÓNOMA DE MADRID Characterization and regulation of Kv1.5-Kvβ1.3 complex. Memoria presentada para optar al grado de Doctor con Mención Internacional por la Universidad Autónoma de Madrid presenta el Licenciado en Biología: ÁLVARO MACÍAS MARTÍNEZ Bajo la dirección de: Dra. Carmen Valenzuela Miranda Dra. Teresa González Gallego Instituto de Investigaciones Biomédicas “Alberto Sols” (CSIC-UAM) Madrid, 2014 El trabajo descrito en la presente Tesis Doctoral ha sido llevado a cabo en el Departamento de Modelos Experimentales de Enfermedades Humanas del Instituto de Investigaciones Biomédicas ‘Alberto Sols’ (CSIC-UAM) y ha sido financiado por los siguientes proyectos de investigación: Mecanismos implicados en la regulación por kinasas del ensamblaje entre Kvα1.5 y Kvβ1.3. CICYT (SAF2007-65868). 2007-2010. Investigador principal: Carmen Valenzuela Miranda. Red Temática de Investigación Cooperativa RECAVA. FIS (RD06/0014/0006). 2007-2010. Investigador principal: Lisardo Boscá Gomar. Modulación adrenérgica de los canales Kv1.5-Kvβ1.3 expresados en diferentes tipos de células cardiovasculares. CICYT (SAF2010- 14916) 2011-2014. Investigador principal: Carmen Valenzuela Miranda. Red de Investigación Cardiovascular. FIS (RD12/0042/0019). 2012-2014. Investigador principal: Carmen Valenzuela Miranda. Además, la realización de esta Tesis Doctoral ha sido posible gracias al disfrute de una beca predoctoral de la Junta de Ampliación de Estudios (JAE-Predoc), del Consejo Superior de Investigaciones Científicas. A mi familia, a ti que lees estas líneas y sobre todo, a mis chicas, Sonia y Emma, mis pilares, mi equilibrio, mi todo. “-¿Y piensas pasarte el resto de tu vida encerrado entre estas cuatro paredes, tomando notas y alimentándote a base de bocadillos? -Tal vez algún día encuentre las respuestas que busco. Lo que si tengo muy claro, es que si no estoy aquí, nunca las encontraré. […] Si tengo que pasarme el resto de mi vida aquí encerrado para conseguir que una sola persona no sufra como mi madre sufrió por culpa de aquel maldito cáncer, o un solo niño no vea morir a su madre como yo vi morir a la mía, puedes estar segura de que aquí me quedaré. […] -¿Realmente confías en conseguir algo positivo? -Aún es pronto para saberlo. Cuando inicias una investigación de este tipo se te ofrecen mil caminos, y el problema estriba en que pronto o tarde tienes que decidirte por uno sin saber hacia dónde conduce. Tal vez no lleve a ninguna parte y hayas perdido media vida, pero ese esfuerzo nunca resulta totalmente inútil, puesto que sirve para indicar a los que vienen detrás que ésa era una vía sin salida. Los grandes descubrimientos suelen hacerse de ese modo: eliminando rutas erróneas hasta que se encuentra la correcta.” Alberto Vázquez-Figueroa “El Señor de las Tinieblas”, 2001 Agradecimientos No me puedo creer que ya haya llegado este momento… escribir los Agradecimientos de mi Tesis Doctoral… Increíble!!!! Quién me iba a decir que iba a llegar este momento cuando estaba en el colegio, aunque, ya por aquel entonces sabía que algo relacionado con las Ciencias Naturales era ‘lo mío’. Sonrío siempre al recordar una de mis mayores revelaciones y lo que sin duda alguna grabó en mí la idea de estudiar Biología, sin importarme mucho las garantías de futuro laboral que acompañaran a esa decisión… “comprender el mecanismo físico-químico que le permite al jabón quitar la grasa de las manos, pero al mismo tiempo ser compatible con el agua”. Gracias a Antonio Pastor por haberme transmitido la ilusión por saber, por ir más allá, sin duda alguna a ti te debo ser Biólogo hoy en día. Recuerdo como mi padre, pensando en mi futuro, intentaba que estudiara otra carrera con más salida como medicina pero pocas cosas he tenido tan claras en mi vida, aunque me arrepintiese, necesitaba saber lo que era estudiar Biología. Tras los años en la universidad, y coger experiencia en el trabajo de laboratorio, me llegó la oportunidad ‘de refilón’ de ampliar mis conocimientos en alguna materia y/o técnica que no pudiera aprender en el laboratorio que ya estaba. De este modo, me tropecé con el laboratorio de electrofisiología de la Dra. Carmen Valenzuela Miranda, y como aquello era algo que en la carrera siempre me había atraído y con la simple intención de saber un poquito más, decidí atreverme a ponerme en contacto con ella. Aún recuerdo la primera vez que entré en el C.S.I.C. y, aun tremendamente nervioso por el simple hecho de estar entre aquellas paredes y delante de ‘Investigadores Científicos de verdad’, Carmen me hablaba sobre su mundo (la electrofisiología cardiovascular) con esa naturalidad y esa pasión con la que sólo ella sabe hacerlo. Tras dejarme entrar en su casa, porque el laboratorio llega a convertirse en eso, consiguió que me enamorara de este campo y conseguimos una beca para poder hacer Mi Tesis. Mil gracias, Carmen, por dejarme seguir siendo ‘El Lechón’ del laboratorio, espero serlo siempre; por tu apoyo incondicional y confianza en mí, por enseñarme no sólo ciencia sino humanidad y respeto hacia los demás y hacia nosotros mismos, y por supuesto, por transmitirme el respeto y la admiración a este trabajo… gracias de corazón!!! Atrás quedan ya cuatro años y medio de congresos, risas, aprendizaje, momentos muy buenos y otros no tanto… gracias por todos ellos. También, por supuesto, a la Dra. Teresa González Gallego (‘Doc!’) porque los inicios nunca fueron fáciles y a ti te “tocó” estar codo con codo conmigo cuando siendo Lechón-Lechón entré en el labo. Gracias por tu entrega, por tu apoyo y por la pasión que demuestras en cada cosa que haces. Gracias a ambas por todo lo vivido en todos estos años, han hecho de mí una persona nueva. Espero, siguiendo el consejo de Valentín Fuster, seguir teniéndoos de tutoras, y amigas, el resto de mi carrera. Por supuesto, a todas las componentes del laboratorio. A la Dra. Miren David, tú me ensañaste la perseverancia y el trabajo duro, a elaborar todos los controles posibles aunque eso suponga cuadruplicar (y en algunos casos mucho más) el volumen de trabajo, y por supuesto, el amor por el PowerPoint. Gracias por tu sentido del humor y por tus críticas siempre constructivas. A, la ya Doctora (qué fuerte), Cristina Moreno Vadillo, juntos hemos vivido casi todo el camino de la Tesis, con momentos buenos y otros no tanto. Siempre hemos intentado conjugar el trabajo duro con el mejor ambiente y, a mi juicio, si no lo hemos conseguido hemos estado muy cerca. Ojalá el tiempo y la ciencia nos vuelvan a juntar en algún congreso en los que otros becarios nos señalarán con el dedo y dirán: Mira, no son ellos los del trabajo… Alicia y Ángela, las últimas en entrar al laboratorio pero que desde el principio conseguisteis integraros de un modo admirable. Gracias chicas por los momentos de risas, de mucho curro, las tertulias del café, por todo vuestro apoyo. Cada día estoy más contento, si es que influyó en algo, de haberos soltado el chaparrón de ‘Lo bueno y lo malo de este laboratorio (por ser de electrofisiología)’. Gracias también a aquellas personas que pasaron por el laboratorio Gema, Ulyana, Carmen, Mariela o Najib, de todos he aprendido algo y habéis cambiado algo dentro de mí, gracias por dejarme compartir vuestro tiempo conmigo. A todos y cada uno de los compañeros del Instituto con los que cada día he compartido uno de los mejores momentos del día… la hora de comer! Gracias a Mario (mi gordi), Antonio, María, Eva, Rafa, Ale, Ana Rosa, Blanca, Pepa, Toño, Miryam, Daniela… una gran familia científica. Aún tratando la ciencia como un tema tabú en la comida (que para eso es de descanso), habéis hecho que este camino sea muuucho más fácil. Gracias por todos esos momentos de risas hasta perder el aliento, el apoyo en los momentos de decadencia, por los chistes (unos buenos, y otros no tanto)… por todo. De verdad, esta Tesis tampoco habría sido posible sin vosotros. A todo el laboratorio 1.9, gracias por dejarme ser uno más. Gracias a Jose (el otro macho alpha), Marina, Sandra, Elena, Diana… mi otro laboratorio. Gracias por enseñarme que ser grandes científicos y mejores personas no está reñido. Después de conoceros creo que otra ciencia es posible. Sois, todas (admítelo Jose, somos una más) y cada una de vosotras, extraordinarias. A ‘Los de la Complu’, es decir, al grupo de los Dres. Francisco Pérez-Vizcaíno y Ángel Cogolludo, a Quique, Javi, Bianca, Laura, Carmen, Dani y Raquelle. Gracias por abrirme siempre las puertas de vuestra casa, por todas las colaboraciones realizadas, hayan llegado o no a buen término, porque siempre se puede contar con vosotros, pero sobre todo porque es un placer haber compartido celebraciones profesionales y personales. A los Dres. Pilar de la Peña, Francisco Barros, Walter Stühmer y Luis A. Pardo, y a vuestros respectivos laboratorios, por supuesto. Gracias a todos vosotros por abrirme las puertas de vuestra casa y enseñarme tantas y tantas cosas, personales y profesionales. Espero poder seguir aprendiendo de vosotros siempre que me lo permitáis. De vuestros laboratorios me llevo muy buenos recuerdos y grandes amigos. A todos vosotros, Jorge, Araceli, Camilo, Joassia, Piotrek, Juan Carlos, Vincenzo, Ulrike, Diana, Adam, Estefanía, Rayco,… espero veros pronto y recordar viejos tiempos. Gracias a todos por haberme hecho sentir como un miembro más de vuestra familia. No puedo olvidarme de mis amigos de siempre, los de fuera del labo, los de toda la vida. Juanan y Alex, muy diferentes pero muy iguales a la vez, siempre dispuestos a hacer lo que sea necesario para introducir momentos relajados en los más tensos de la vida; gracias por hacerme la vida más agradable y por apoyar 'al niño' en todas las cosillas raras que hace.
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