Obiettivo The proposed project aims at investigating the molecular mechanisms that activate B cell antigen receptor (BCR) signalling in chronic lymphocytic leukaemia (CLL). While it is widely accepted that the unbroken BCR expression in CLL cells is indicative for a key role in disease development, the mechanisms that induce BCR activation and survival of malignant cells are still elusive. Using a unique reconstitution system, we have recently shown that CLL-derived BCRs possess the exceptional capacity for cell-autonomous signalling independent of external antigen. Crystallographic analyses confirmed our model that CLL-BCRs bind to intrinsic motifs in nearby BCRs on the very same cell. In addition to the BCR, several pathogenic factors influence the biological behaviour of CLL cells, but the functional hierarchy and the effect on BCR signalling are insufficiently understood. Here, we aim at investigating the structural cause of autonomous signalling as well as the characterization of important signalling pathways and their mechanistic action in CLL pathogenesis. By combining crystallography with the measurement of autonomous signalling of wild type and mutated receptors in our unique reconstitution system, we will generate a structure-function relationship for CLL-BCRs. By generating new animal models and by employing classical as well as cutting-edge approaches of biochemistry and molecular/cellular immunology, we will comprehensively characterize the signalling pathways that are activated by autonomous signalling and might be important for CLL pathogenesis.These systematic efforts are necessary to understand how various biological mechanisms operate and ultimately activate downstream pathways that result in a lymphoproliferative disease. In addition, a cohesive model of CLL pathogenesis, which elucidates the hierarchical order of pathogenic factors and their interaction with BCR signalling, may well lead to novel disease-specific preventive or therapeutic intervention. Campo scientifico engineering and technologycivil engineeringstructural engineeringstructural health monitoringnatural sciencesearth and related environmental sciencesgeologymineralogycrystallographymedical and health sciencesbasic medicineimmunologynatural scienceschemical sciencesorganic chemistryaminesmedical and health sciencesclinical medicineoncologyleukemia Programma(i) H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) Main Programme Argomento(i) ERC-ADG-2015 - ERC Advanced Grant Invito a presentare proposte ERC-2015-AdG Vedi altri progetti per questo bando Meccanismo di finanziamento ERC-ADG - Advanced Grant Istituzione ospitante UNIVERSITAET ULM Contribution nette de l'UE € 2 256 250,00 Indirizzo HELMHOLTZSTRASSE 16 89081 Ulm Germania Mostra sulla mappa Regione Baden-Württemberg Tübingen Ulm, Stadtkreis Tipo di attività Higher or Secondary Education Establishments Collegamenti Contatta l’organizzazione Opens in new window Sito web Opens in new window Partecipazione a programmi di R&I dell'UE Opens in new window Rete di collaborazione HORIZON Opens in new window Costo totale € 2 256 250,00 Beneficiari (1) Classifica in ordine alfabetico Classifica per Contributo netto dell'UE Espandi tutto Riduci tutto UNIVERSITAET ULM Germania Contribution nette de l'UE € 2 256 250,00 Indirizzo HELMHOLTZSTRASSE 16 89081 Ulm Mostra sulla mappa Regione Baden-Württemberg Tübingen Ulm, Stadtkreis Tipo di attività Higher or Secondary Education Establishments Collegamenti Contatta l’organizzazione Opens in new window Sito web Opens in new window Partecipazione a programmi di R&I dell'UE Opens in new window Rete di collaborazione HORIZON Opens in new window Costo totale € 2 256 250,00