Objectif The aim of this project is to try to understand the complex molecular mechanisms involved in DNA editing, repair and recombination during immunoglobulin class switch recombination (CSR) and somatic hypermutation (SHM). We have developed a series of PCR-based assays to study in vivo generated CSR junctions and the pattern of mutations introduced in the immunoglobulin variable region genes in human B cells, allowing us to characterize CSR and SHM in patients with immunodeficiency due to defect(s) in DNA repair/recombination. Novel in vitro CSR assays, based on GFP expression, allowing quantitative measurement of substrate recombination, are also being developed. In addition, we have initiated an evolutionary analysis of the function and structure of activation-induced deaminase, an essential molecule involved both in CSR and SHM, aiming to identify CSR specific-cofactor(s). Combining these approaches, we will be able to define the DNA repair pathways involved in CSR and SHM. The suggested project requires access to patients with various defects in the DNA repair pathways. Many of these diseases are exceedingly rare. However, through worldwide collaboration, we have obtained samples from a majority of the diagnosed patients. We are also refining the existing screening methods and developing novel methods, that will allow identification of additional patients both with recognized and new diseases caused by mutations in DNA repair pathways. Finally, we hope to be able to address the question whether illegitimate CSR events are associated with predisposition to lymphomagenesis in patients with immunodeficiency/DNA repair defect(s), by analyzing the CSR induced chromosomal breaks and translocations in these patients. A large-scale sequencing project is also planned to characterize the CSRnome in B-cell lymphoma samples. Champ scientifique engineering and technologycivil engineeringstructural engineeringstructural health monitoringnatural sciencesbiological sciencesgeneticsDNAnatural sciencesbiological sciencesgeneticsmutationmedical and health sciencesclinical medicineoncology Programme(s) FP7-IDEAS-ERC - Specific programme: "Ideas" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Thème(s) ERC-SG-LS6 - ERC Starting Grant - Immunity and infection Appel à propositions ERC-2009-StG Voir d’autres projets de cet appel Régime de financement ERC-SG - ERC Starting Grant Institution d’accueil KAROLINSKA INSTITUTET Contribution de l’UE € 1 888 166,00 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 Chercheur principal Qiang Pan Hammarström (Dr.) Contact administratif Kim Von Schoultz (Mr.) Liens Contacter l’organisation Opens in new window Site web Opens in new window Coût total Aucune donnée Bénéficiaires (1) Trier par ordre alphabétique Trier par contribution de l’UE Tout développer Tout réduire KAROLINSKA INSTITUTET Suède Contribution de l’UE € 1 888 166,00 Adresse Nobels Vag 5 17177 Stockholm Voir sur la carte Région Östra Sverige Stockholm Stockholms län Type d’activité Higher or Secondary Education Establishments Chercheur principal Qiang Pan Hammarström (Dr.) Contact administratif Kim Von Schoultz (Mr.) Liens Contacter l’organisation Opens in new window Site web Opens in new window Coût total Aucune donnée
