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Rapport Activités Version26 06 09 Legend Scanning electron micrograph of a mouse Grueneberg ganglion cell. The cell body has been post-colorized in green, the axon in red and the sensory cilia, putative site of alarm pheromone recognition, in blue (Brechbühl et al. 2008). Rapport d’activités 2006-2008 Département de Pharmacologie et de Toxicologie TABLE DES MATIERES PREFACE 2 RECHERCHE 2 ENSEIGNEMENT 3 BUDGET 4 PERSONNEL 5 ENSEIGNEMENT 11 RECHERCHE 12 SODIUM AND CALCIUM HOMEOSTASIS AND THE RENAL SYSTEM 13 FIRSOV DMITRI 13 Maintaining salt and water balance by the kidney: role of circadian timing system 13 OLIVIER BONNY 15 Renal calcium reabsorption 15 EDITH HUMMLER 17 Molecular and functional characterization of the epithelial Na channel and its regulators in vivo 17 KÄTHI GEERING 22 FXYD proteins: New regulators of Na,K-ATPase 22 JEAN-DANIEL HORISBERGER 25 Structure-function relation of Na,K-ATPAse, regulation of the epithelial Na channel 25 BERNARD C. ROSSIER 27 Activation of the epithelial Na channel by membrane-bound proteases 27 OLIVIER STAUB 30 Role of intracellular protein-protein interaction in ion channel regulation 30 LAURENT SCHILD 34 Structure and function of the epithelial sodium channel 34 CARDIOVASCULAR SYSTEM AND ASSOCIATED PATHOLOGIES 37 DARIO DIVIANI 37 The Role of the A-kinase anchoring proteins signaling complexes in G protein-coupled receptor- induced cardiac remodeling 37 HUGUES ABRIEL 40 Molecular bases of cardiac arrhythmias 40 NEURONAL ION CHANNELS AND G-PROTEIN COUPLED RECEPTORS 43 SUSANNA COTECCHIA 43 Adrenergic receptors: molecular mechanisms of receptor function and physiological implications 43 STEPHAN KELLENBERGER 46 Acid-sensing ion channels (ASICs) : function in sensory neurons and structure-function relationship 46 MARIE-CHRISTINE BROILLET 49 Chemosensory systems: Ion channels and receptors involved in odor and pheromone transductions 49 PUBLICATIONS 52 Page 1 of 56 Rapport d’activités 2006-2008 Département de Pharmacologie et de Toxicologie Préface La pharmacologie occupe une place centrale dans la recherche biomédicale, compte tenu des nombreux efforts consentis actuellement dans le développement de nouveaux médicaments ; en thérapeutique médicale son rôle est également primordial, au vu de l’introduction et de l’utilisation constante de nouvelles entités pharmacologiques. Le Département de pharmacologie et toxicologie (DPT) de l’Université regroupe ses compétences autour de la pharmacologie fondamentale, tandis que l’aspect clinique de cette discipline dépend de la Division de pharmacologie et toxicologie clinique du Département de Médecine du CHUV. Les deux missions principales du DPT sont d’une part l’enseignement de la pharmacologie fondamentale aux étudiants en biologie et en médecine, d’autre part le développement d’une recherche relevante dans le domaine de la pharmacologie et de la thérapeutique en général. La période de 2006 à 2008 a vu de nombreux changements au sein du DPT avec pas moins de trois directeurs qui se sont succédés à la tête du Département. Le Professeur Bernard Rossier, nommé directeur en 1991, a pris sa retraite août 2006 ; la Professeure Susanna Cotecchia lui a succédé de 2006-2007. J’ai repris la direction du Département en 2007. Il convient également de relever le départ à la retraite de la Professeure K. Geering en 2008 ; la Prof. K. Geering, tout comme le Prof. B. Rossier, gardent des activités de recherche au sein du DPT, en tant que professeurs honoraires. Recherche La recherche en pharmacologie fondamentale a pour but de mieux comprendre les mécanismes d’actions des médicaments, leurs effets moléculaires et cellulaires, afin d’en améliorer leur usage. La recherche dans notre département s’intéresse essentiellement à la fonction et à la régulation de récepteurs pharmacologiques tels que les récepteurs liés aux protéines G, récepteurs nucléaires, les canaux et transporteurs ioniques ; cette recherche s’articule autour des thématiques suivantes: . L’homéostasie électrolytique du sodium potassium et calcium et ses implications dans les pathologies vasculaires, cardiaques, pulmonaires, cutanées, osseuses . La structure, les fonctions moléculaires, les mécanismes de signalisation des récepteurs liés aux protéines G, en particulier cardiaques . Les troubles de l’excitabilité cardiaque et arythmies . La neurophysiologie et la neuropharmacologie des récepteurs aux phéromones et des canaux senseurs de pH La qualité de la recherche du DPT est élevée comme l’attestent des publications parues dans les meilleurs journaux scientifiques à politique éditoriale tels que Science, The Proceedings of the National Academy of Sciences, EMBO Journal. En 2007, le DPT s’est vu décerner un important financement (6 millions € sur cinq ans) pour un programme de recherche transatlantique sur l’hypertension artérielle et sur son lien étroit avec l’homéostasie du sodium. Ce projet de recherche est financé par la Fondation Leducq et le coordinateur européen de ce projet est le Prof. B. Rossier. Les différents partenaires et collaborateurs de ce projet regroupent des chercheurs des Universités de Yale, de Mexico, du Collège de France, ainsi que plusieurs groupes du DPT impliqués dans une recherche sur la physiologie, la physiopathologie et la génétique de l’hypertension artérielle et des transports électrolytiques. Le DPT a accueilli en 2008 un nouveau groupe de recherche avec la venue du Dr O. Bonny, qui partage ses activités entre le Service de néphrologie de CHUV et son laboratoire de recherche au DPT. Il s’agit d’un premier engagement conjoint entre le CHUV et l’UNIL permettant à de jeunes médecins, destinés à une carrière académique, de garder une activité clinique conjointement à une activité de recherche Page 2 of 56 Rapport d’activités 2006-2008 Département de Pharmacologie et de Toxicologie Le DPT participe activement aux activités de recherche sur le site du Bugnon 27 grâce à ses collaborations avec le Département de Génétique Médicale (DGM), avec les groupes de recherche du CHUV (Prof. T. Pedrazzini, Prof. M. Burnier) et la plate-forme de transgenèse (TAF) de la FBM. En 2008, la plate-forme de phénotypage des rongeurs dans le domaine cardiovasculaire (CAF : Cardiovascular Assessment Facility) a débuté ses activités au Bugnon 27 sous la responsabilité du Prof. T. Pedrazzini. Enseignement Le DPT est fortement impliqué dans l’enseignement de la pharmacologie aux étudiants de l’Ecole de médecine (Faculté de Biologie et Médecine). Cet enseignement, centré sur la pharmacologie fondamentale, est donné en étroite collaboration avec la Division de Pharmacologie et Toxicologie cliniques du CHUV. Dans le cadre du Master en Biologie Médicale de l’Ecole de biologie, le DPT est responsable de l’enseignement de la pharmacologie. En ce qui concerne l’enseignement aux étudiants en médecine (Ecole de médecine), la période 2006-2008 a vu l’implantation du nouveau curriculum d’étude basé sur le modèle de ‘Bologne’ avec un baccalauréat (bachelor) de trois ans puis une maîtrise (Master) en médecine. La mise en place du baccalauréat avec ses trois années s’est terminée au cours de l’année académique 2007-2008. L’implantation du Master a débuté avec l’année académique 2008-09 et se terminera en 2011. Cette réforme a nécessité la mise en place d’un nouveau programme d’enseignement de la pharmacologie qui débute actuellement en 2e année et se poursuit jusqu’au Master. En outre le DPT est en charge de l’organisation d’un module (B2.6) pour les étudiants de 2e année du baccalauréat qui a pour thématique le rein et l’homéostasie hydro-électrolytique ; dans ce module, le DPT couvre l’enseignement de la pharmacologie et de la physiologie rénale. L’enseignement de la pharmacologie donné aux étudiants en biologie, dans le cadre de l’école de biologie, a été intégré dans la réforme des études de biologie, qui visait à l’introduction d’un bachelor pour la période 2006 – 2008. Ces travaux ont commencé en 2006 et ont débouché sur une mise en place graduelle des trois années réformées (1ère année en 2007, 2e en 2008, et la 3e en 2009). Plusieurs membres du DPT étaient activement impliqués dans cette réforme (Käthi Geering, Olivier Staub, Marie-Christine Broillet, Jean-Daniel Horisberger). Durant les années 2006 à 2009, le DPT a contribué à l’enseignement du bachelor en organisant le bloc option « Structures et fonctions cellulaires» qui est suivi par une quarantaine d’étudiants chaque année, et qui est très apprécié. Le DPT joue un rôle très actif dans le Master en biologie médicale (BM), qui était dirigé par Käthi Geering de 2004 à 2007 et depuis 2007 par Olivier Staub. Dans le cadre de ce Master, le DPT est en charge de la filière « Sciences pharmacologiques » (2e/3e semestre du Master, responsable Marie-Christine Broillet) pour les étudiants qui veulent se destiner à la recherche en pharmacologie dans un milieu académique ou industriel. Le DPT offre un cours de pharmacologie générale dans le cadre des programmes des Masters en « Bioingénierie et Biotechnologie » et « Sciences et technologie du vivant » à l’EPFL, ainsi qu’un cours d’introduction à la biologie cellulaire pour les étudiants en chimie (EPFL) et étudiants de sciences forensiques (UNIL) pendant la première année Bachelor. Le DPT vit actuellement une période de profonds changements tant dans ses activités d’enseignement que de recherche. L’enseignement de la pharmacologie aux étudiants en médecine et en biologie doit être repensé quant à ses objectifs de formation. Pour ce qui est de la recherche, le DPT est actuellement dans une phase de transition ; ces prochaines années seront
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