Cel The lytic activity of cytotoxic T lymphocytes (CTL) plays a central role in the control of viral infection, cancer and homeostasis. The lethal hit of CTL is delivered to the target cell at the level of a highly organized synaptic structure (lytic synapse). How composition and organization of the lytic synapse contribute to the regulation of the lytic activity is largely unknown. The focus of this proposal is to study the lytic synapse of CTL isolated from patients affected by life-threatening primary immuno deficiencies (PID). CTL from patients with genetic mutations causing defects in cytolytic activity are unique natural knock-out models. The following PID will be considered: 1) Wiskott-Aldrich Syndrome due to WASP deficiency, 2) X-linked Lympho-Proliferati ve disease due to SAP deficiency, 3) Familial Hemophagocytic Lymphohistiocytosis due to perforin deficiency. This project will investigate the dynamics of molecular events that occur at the lytic synapse formed between CTL and antigen-loaded antigen-presen ting cells, using time-lapse video recording of the distribution of receptors and signalling components. Analysis of CTL activation and lytic activity will be performed in parallel. These approaches will be combined to lentiviral vector-mediated transfer o f untagged or GFP-tagged constructs encoding WASP, SAP and perforin, in order to visualize these proteins and to correct the lytic function of CTL from PID patients. In addition, a proteomics approach will be employed to identify novel proteins in healthy CTL that could complete our understanding of the lytic synapse architecture and function. This project will provide new insights in the mechanisms regulating CTL activity and in the physiopathology of severe PID. In addition, it will be instrumental for th e development of gene therapy for these severe PID and will have implications for the design of novel therapeutic approaches in which CTL mediated immunosurveillance plays a crucial role. Dziedzina nauki medical and health sciencesmedical biotechnologygenetic engineeringgene therapymedical and health sciencesbasic medicineimmunologynatural sciencesbiological sciencesgeneticsmutationmedical and health sciencesclinical medicineoncologymedical and health sciencesbasic medicinephysiologyhomeostasis Słowa kluczowe Cytolytic Gene Primary activity immunodeficiencies therapy Program(-y) 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 Temat(-y) MOBILITY-3.1 - Marie Curie Excellence Grants (EXT) Zaproszenie do składania wniosków FP6-2004-MOBILITY-8 Zobacz inne projekty w ramach tego zaproszenia System finansowania EIF - Marie Curie actions-Intra-European Fellowships Koordynator INSTITUT NATIONAL DE LA SANTÇ ET DE LA RECHERCHE MÈICALE Wkład UE Brak danych Adres Rue de Tolbiac 101 PARIS Francja Zobacz na mapie Linki Strona internetowa Opens in new window Koszt całkowity Brak danych
