Cel 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. Dziedzina nauki natural sciencesbiological sciencesneurobiologynatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsnatural sciencesbiological sciencesgeneticsmutation Program(-y) FP7-PEOPLE - Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Temat(-y) FP7-PEOPLE-2011-IIF - Marie Curie Action: "International Incoming Fellowships" Zaproszenie do składania wniosków FP7-PEOPLE-2011-IIF Zobacz inne projekty w ramach tego zaproszenia System finansowania MC-IIF - International Incoming Fellowships (IIF) Koordynator KAROLINSKA INSTITUTET Wkład UE € 181 418,40 Adres Nobels Vag 5 17177 Stockholm Szwecja Zobacz na mapie Region Östra Sverige Stockholm Stockholms län Rodzaj działalności Higher or Secondary Education Establishments Kontakt administracyjny Klas Karlsson (Mr.) Linki Kontakt z organizacją Opens in new window Strona internetowa Opens in new window Koszt całkowity Brak danych
