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ROLE of the CAROTID BODY in METABOLIC DISTURBANCES Abril, 2016

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ROLE of the CAROTID BODY in METABOLIC DISTURBANCES Abril, 2016 ROLE OF THE CAROTID BODY IN METABOLIC DISTURBANCES MARIA JOÃO RODRIGUES FERREIRA RIBEIRO Tese para obtenção do grau de Doutor em Ciências da Vida na Especialidade em Biomedicina Abril, 2016 ROLE OF THE CAROTID BODY IN METABOLIC DISTURBANCES Maria João Rodrigues Ferreira Ribeiro Orientadora: Sílvia Margarida Vilares Conde, Professora Auxiliar, NOVA Medical School/ Faculdade de Ciências Médicas da Universidade Nova de Lisboa Tese para obtenção do grau de Doutor em Ciências da Vida na Especialidade em Biomedicina Abril, 2016 - Aos meus pais Leonida e João, Ao meu sobrinho Afonso - Agradecimentos Finalizada uma etapa particularmente importante na minha vida não podia deixar de agradecer: À minha orientadora Professora Doutora Sílvia Vilares Conde, tudo que possa descrever aqui não será de todo suficiente para agradecer tudo o que fez por mim nestes últimos anos. Obrigada por ser a principal impulsionadora deste meu envolvimento nesta área tão fascinante, pela qual nutro uma grande paixão. Por estar sempre presente, pela orientação, pelos ensinamentos, pela confiança, motivação, paciência, e sobretudo pela amizade que sempre me dedicou. Será sempre mais que a minha orientadora. À professora Doutora Maria P. Guarino, pela disponibilidade, incentivo, apoio, pelas palavras sempre tão sábias, rigor e por contribuir tão ativamente para a minha formação profissional. Agradeço também a correção minuciosa deste trabalho. À professora Doutora Emília Monteiro pela disponibilidade sempre demonstrada. Ao professor Doutor Constâncio Gonzalez e à Professora Doutora Ana Obeso pelo carinho e pelo espírito crítico. Foi um privilégio poder conhecer e aprender como estes grandes investigadores. Ao Professor Doutor Pedro Lima pelos ensinamentos do patch clamp, pelo conhecimento, pela boa disposição, assim como ajuda para progressão deste trabalho. Ao meu grupo de investigação, especialmente à Joana Sacramento, minha parceira desde de sempre, e à Bernardete Melo, pelo apoio incondicional, pela partilha de conhecimento, disponibilidade, boa disposição, espírito de equipa, bons momentos no laboratório e amizade. Queria agradecer também à Cristiana Ferreira, Jesus Prieto- lloret, Inês Martins assim como ao Duarte Antunes e Inês Faustino pelo apoio, amizade e boa disposição. Queria agradecer a Aline Marinho, Nádia Grilo, Lucília Diogo, Sofia Pereira e Joana Batuca por me acompanharem desde de início nesta minha viagem, pela disponibilidade, boa disposição, ânimo e por contribuírem tão afincadamente para o bom ambiente no laboratório. Queria também agradecer aos restantes e mais recentes membros da Farmacologia Clara Dias, Rita Lemos, Maria João Correia, Catarina Sequeira e Nuno Coelho por todo o apoio. Às amizades que nasceram no laboratório e que são para a vida, Fátima Martins e Joana Gaspar pela amizade, pelas risadas, desabafos e horas tão bem passadas, dentro e fora do laboratório. Agradeço também à Inês Lima, pelo carinho e pela disponibilidade. Ao André Bastos, Marisa Sousa, Clara Patrício e Joana Serrão e pela partilha de conhecimento, ajuda, disponibilidade, animo e pelas horas bem passadas no laboratório de Fisiologia, durante o “encontro com a célula desejada”. Aos meus amigos de sempre e para sempre, Filipa Guedes, Diana Silva, Diana Sousa, Mónica Martins, Raquel Ortiga, Ana Plácido, António Borges e Ricardo Fidalgo, pelo carinho e amizade que sempre me dedicaram, muitas das vezes longe fisicamente, mas sempre perto do meu coração. Por nunca me deixarem cair, mesmo quando me senti sem forças, por me fazerem sentir tão especial e por nunca me deixarem esquecer do meu valor. Os amigos são a melhor coisa, e eu tenho os melhores do mundo. Um agradecimento especial ao João Aranha por tornar esta etapa menos dolorosa, por me descomplicar, por em momento algum deixar de acreditar em mim…e por me fazer sorrir de uma forma tão simples. A toda a minha família, que sempre acreditou e continua acreditar em mim e no meu valor, por me fazerem ver o lado mágico da investigação mesmo quando, por vezes me sentia “fora de orbita”. Um agradecimento especial aos meus tios babados, Tânia Augusto, Henrique Augusto, Fernanda Ferreira, Toninho Ferreira, minha cunhada Liliana Valdemar e prima Catarina Augusto. À memória do meu querido avô Norberto que mesmo não estando entre nós, ilumina todos os meus dias. Por me ter marcado, por ter partilhado comigo toda a sua experiência de vida, por me fazer sentir uma neta tão especial…Estejas onde estiveres, sei que estas orgulhoso. Aos meus pilares, “meu core” familiar, aos meus pais, Leonida Rodrigues e João Ribeiro, ao meu irmão Hugo Ribeiro que por mim se doam por inteiros renunciando aos seus próprios sonhos em prol dos meus. Por todo o amor, compressão, ânimo e apoio incondicional, que tornou possível este percurso. O melhor de mim, devo a vocês… Um agradecimento final, ao meu querido sobrinho Afonso Ribeiro, com feitio da tia, e à minha afilhada Matilde Santos pelo amor genuíno que me dedicam, pelos sorrisos, por verem em mim um exemplo e simplesmente por existirem. A todos aqueles que que direta ou indiretamente contribuíram para a realização deste trabalho, deste sonho que é meu e que hoje se torna uma realidade, o meu muito OBRIGADA! Uma emoção que jamais será traduzida por palavras…. O trabalho apresentado nesta tese foi realizado no CEDOC – Centro de Estudos de Doenças Crónicas da FCM|NOVA MEDICAL SCHOOL, da Universidade Nova de Lisboa e foi financiado por fundos FEDER através do Programa Operacional Fatores de Competitividade – COMPETE e por Fundos Nacionais através da FCT – Fundação para a Ciência e a Tecnologia no âmbito do projeto PTDC/SAU-ORG/111417/ 2009. A candidata realizou o trabalho experimental com o apoio de uma bolsa de investigação da FCT com a referência SFRH/BD/88983/2012. Thesis Publications This work originated the following publications: Ribeiro MJ, Sacramento JF, Guarino MP, Gonzalez C, Monteiro EC, Conde SV (2013) Carotid body denervation prevents the development of insulin resistance and hypertension induced by hypercaloric diets. Diabetes, 62(8):2905–2916. Conde SV, Sacramento JF, Guarino MP, Gonzalez C, Obeso A, Diogo LN, Monteiro EC, Ribeiro MJ (2015) Carotid body, insulin, and metabolic diseases: unraveling the links. Frontiers in Physiology, 5(418): 1-14. Vera-Cruz P, Guerreiro F, Ribeiro MJ, Guarino MP and Conde SV (2015) Hyperbaric oxygen therapy improves glucose homeostasis in type 2 diabetes patients: a likely involvement of the carotid bodies. Advance in Experimental Medicine and Biology, 860:221-225. Conde SV, Ribeiro MJ, Melo BF, Guarino MP and Sacramento JF (2016) Insulin resistance: a new consequence of altered carotid bodychemoreflex? J Physio 2016; doi: 10.1113/JP271684. Ribeiro MJ, Lima PA, Obeso A, Patricio C, Conde SV (2016) Kv1.3 channels mediate insulin action in the rat carotid body (Submitted to Journal of General Physiology). Was presented in Scientific Meetings as: Oral Communications: In International Congresses: Ribeiro MJ, Gonzalez C, Guarino MP, Monteiro EC, Conde SV (2012) Is insulin a stimulus for carotid body activation? 6th European Congress of Pharmacology, 17 – 20th July, Granada, Spain. Ribeiro MJ, Sacramento JF, Monteiro EC and Conde SV (2012) Chronic carotid sinus nerve resection prevents the development of insulin resistance in rats fed with hypercaloric diets. 48th Annual Meeting of the European Association for the Study of Diabetes (EASD). 1-5th October Berlin, Germany. Ribeiro MJ, Lima PA, Obeso A, Patricio C, Gonzalez C, Conde SV (2014) Kv1.3 mediates insulin signaling in the rat carotid body. 19th International Society for Arterial Chemoreception (ISAC) Congress, 29-3rd Leeds, United Kingdom. In National Congresses: Ribeiro MJ, Gonzalez C, Guarino MP, Monteiro EC, Conde SV (2012) Insulin triggers carotid body activation. XLII Anual Reunion of Portuguese Society of Pharmacology/ XI Reunion of Clinical Pharmacology, 1-3rd February Lisbon, Portugal. Ribeiro MJ, Sacramento JF, Gonzalez C, Guarino MP, Monteiro EC, Conde SV (2013). Carotid body is involved in the development of insulin resistance in Wistar rats: an effect mediated by sympathetic activation. XLIII Reunion of Portuguese Society of Pharmacology/XII Reunion of Clinical Pharmacology, 6-8th February Oporto, Portugal Poster Presentations: In International Congresses: Ribeiro MJ, Sacramento JF, Guarino MP, Conde SV (2013) Carotid body activity is increased in rat hypercaloric models of insulin resistance and hypertension". 37th Congress of the International Union of Physiological Sciences, 21-26th, Birmingham, United Kingdom. Ribeiro MJ, Sacramento JF, Guarino MP, Conde SV (2013) Can carotid sinus nerve resection be a therapeutic approach for the treatment of insulin resistance?" 49th European Association for the Study of Diabetes (EASD), 23-27th, Barcelona, Spain. Note: The results presented herein, in chapters III-V are formatted according to the style of the journal where the papers were published or submitted for publication, with minor modifications. Table of contents Abbreviations List.................................................................................................... I List of Figures.......................................................................................................... IV List of Tables............................................................................................................ VII Resumo..................................................................................................................... IX Abstract...................................................................................................................
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