Objectif Many biologically active molecules signal via membrane-bound receptors coupled to heterotrimeric G proteins, and are therefore referred as G protein-coupled receptors (GPCR). They mediate various physiological functions such as vision, taste, calcium, glucose homeostasis and chemotaxis. Chemokines are secretory cytokines able to attract migratory cells. They bind to GPCRs and regulate immune defence, tumour growth, wound healing, allograft rejection, asthma and atherosclerosis. Mechanisms have evolved to fin e-tune and regulate receptor signalling.Desensitisation consists of inhibiting the response to continuous exposure to the same stimulus; it occurs by uncoupling and inactivation of G protein signalling. The b-arrestins bind to phosphorylated GPCR and physic ally uncouple them from their G proteins, resulting in termination of signalling. Regulators of G protein signalling (RGS) promote desensitisation by accelerating GTP hydrolysis by G proteins, inactivating the signal. Information on how arrestins and RGS act on chemokine receptors and signalling is scarce, and reports are incomplete and/or controversial.This project aims to study the desensitisation of the chemokine receptors CCR2 and CCR5 in hematopoietic cells using a multidisciplinary approach. We will characterize several receptor-interacting partners using proteomics and determine the temporal and spatial events that occur during CCR signalling and desensitisation by arrestins and RGS19, using total internal reflection microscopy (TIRFM). Using new methods, we will address the questions of how GPCR couple following their heterodimerization, and the functions of RGS in hematopoietic lines.These studies will provide new insights into the molecular mechanisms of how desensitisation and signalling occur, and will define potential targets for therapeutic intervention. This grant will give me the opportunity to return to the European community of scientists and promote my development as a European experimentalist. Champ scientifique sciences médicales et de la santémédecine fondamentalepharmacologie et pharmaciedécouverte de médicamentssciences médicales et de la santémédecine cliniquepneumologieasthmesciences médicales et de la santémédecine cliniquecardiologiemaladies cardiovasculairesartériosclérosesciences médicales et de la santémédecine fondamentalepathologiesciences médicales et de la santémédecine fondamentalephysiologiehoméostasie Mots‑clés GPCRs arrestin desensitization proteomics signaling Programme(s) FP6-MOBILITY - Human resources and Mobility in the specific programme for research, technological development and demonstration "Structuring the European Research Area" under the Sixth Framework Programme 2002-2006 Thème(s) MOBILITY-4.2 - Marie Curie International Reintegration Grants (IRG) Appel à propositions FP6-2004-MOBILITY-12 Voir d’autres projets de cet appel Régime de financement IRG - Marie Curie actions-International re-integration grants Coordinateur CONSEJO SUPERIOR DE INVESTIGACIONES CIENTÍFICAS Adresse Serrano 117 Madrid Espagne Voir sur la carte Liens Site web Opens in new window Contribution de l’UE Aucune donnée
