Objectif The study of immunodeficiency syndromes such as familial hemophagocytic lymphohistiocytosis (FHL) and Griscelli Syndrome type 2 (GS2) has revealed a crucial role for Munc13-4, Stx11, Munc18-2 and Rab27a – members of protein families that regulate vesicle trafficking and membrane fusion – in cytotoxic granule exocytosis. Loss-of-function mutations in these proteins result in loss of target cell killing by NK cells and CD8+ T cells, resulting in a life-threatening sepsis-like condition. The precise molecular role of these proteins in granule release remains, however, incompletely understood.The objective of this project is to elucidate presynaptic signaling cascades leading to NK cell exocytosis, and thus obtain a detailed map of the sub-cellular events leading to granule release. The project is divided into three specific aims. Post-translational modifications of the known regulators of exocytosis will be studied. In a second line of investigation, other, as yet unknown, proteins that might be involved in this process, like priming factors, and scaffold and adaptor proteins will be explored. This work will be facilitated by insights from the fields of neuroscience and hormone release; the mechanisms of which also share an exocytic pathway, and for which molecules important for this process have already been discovered. Additionally, to obtain a complete picture of the signaling pathways involved, spatiotemporal patterns of second messenger dynamics during granule release will be assessed. Importantly, primary, human NK cells will be employed throughout this study.In conclusion, this project aims to increase the understanding of the complex molecular mechanisms involved in NK cell cytotoxicity, thus broadening the spectrum of immunodeficiency syndromes and improving the clinical diagnosis and treatment of FHL patients. Champ scientifique natural sciencesbiological sciencesneurobiologynatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsnatural sciencesbiological sciencesgeneticsmutation Programme(s) FP7-PEOPLE - Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Thème(s) FP7-PEOPLE-2011-IIF - Marie Curie Action: "International Incoming Fellowships" Appel à propositions FP7-PEOPLE-2011-IIF Voir d’autres projets de cet appel Régime de financement MC-IIF - International Incoming Fellowships (IIF) Coordinateur KAROLINSKA INSTITUTET Contribution de l’UE € 181 418,40 Adresse Nobels Vag 5 17177 Stockholm Suède Voir sur la carte Région Östra Sverige Stockholm Stockholms län Type d’activité Higher or Secondary Education Establishments Contact administratif Klas Karlsson (Mr.) Liens Contacter l’organisation Opens in new window Site web Opens in new window Coût total Aucune donnée
