Objetivo 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. Ámbito científico natural sciencesbiological sciencesneurobiologynatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsnatural sciencesbiological sciencesgeneticsmutation Programa(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) Tema(s) FP7-PEOPLE-2011-IIF - Marie Curie Action: "International Incoming Fellowships" Convocatoria de propuestas FP7-PEOPLE-2011-IIF Consulte otros proyectos de esta convocatoria Régimen de financiación MC-IIF - International Incoming Fellowships (IIF) Coordinador KAROLINSKA INSTITUTET Aportación de la UE € 181 418,40 Dirección Nobels Vag 5 17177 Stockholm Suecia Ver en el mapa Región Östra Sverige Stockholm Stockholms län Tipo de actividad Higher or Secondary Education Establishments Contacto administrativo Klas Karlsson (Mr.) Enlaces Contactar con la organización Opens in new window Sitio web Opens in new window Coste total Sin datos