B cells distinguish themselves from all other cells, as they diversify their immunoglobulin (Ig) genes by hypermutation, gene conversion and switch recombination. All three processes required the expression of Activation Induced cytidine Deaminase (AID).
The project aims to resolve the long-standing question why hypermutations are targeted almost exclusively to the Ig loci. Using the chicken B cell line DT40 as a model the fellow's laboratory previously identified a 10 kb cis-acting regulatory sequence (DIVAC) within the Ig light chain locus which activates hypermutation. The first goal will be to define the functionally relevant parts and sequence motifs of DIVAC and to determine their optimal arrangement. The next objective will be to identify DIVAC binding factors which may interact with AID and recruit it to the Ig loci. The last goal will be to understand how the DIVAC binding factors coordinate the association of AID with the neighboring transcribed sequence.
This project will be developed in one of the best molecular immunology labs in Yale University and then transferred to the Centre for Chromosome Biology at the National University of Ireland, Galway. The outgoing host David Schatz has a long and excellent track record studying Ig gene diversification in mice and humans. The return host Noel Lowndes has extensive expertise in the analysis of protein-protein as well as DNA-protein interactions needed at the later stages of the project.
The fellowship will allow the fellow to resume his career as an experimental scientist after a paternity leave and acquire valuable new knowledge in bioinformatics, comparative biology and protein chemistry. He will also gain complementary skills by participating in student teaching programs.
The European community will benefit from the transfer of an excellent and competitive project , the establishment of long-term international collaborations and the eventual re-opening of the fellow's laboratory in Europe.
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