Understanding the spatiotemporal dynamics of B cell receptor signalling in chronic lymphocytic leukaemia
Description: Abnormal B-cell receptor (BCR) signalling is crucial to the pathogenesis of chronic lymphocytic leukaemia (CLL). Much of our understanding of BCR-s gnalling in CLL is based on classical models of B-cell activation. In contrast, it is now understood that the spatiotemporal dynamics of BCR- signalling are of critical importance,highlighting a pivotal role for cytoskeletaI regulation. The objective of this proposal is to translate these advances into CLL. Therefore, direct stochastic optical reconstruction microscopy and total internal reflection fluorescence microscopy will be used to investigate the diffusion dynamics/clustering of BCRs in resting CLL cells, along with BCR-microcluster formation and microsignalosome structure in activated CLL cells. These techniques will also be used to investigate cell spreading, contraction,antigen internalisation and motility of CLL cells. The impact of BCR-signalling inhibitors and immune modulatory drugs on these assays will also be assessed. We hypothesise that abnormalities in !he BCR and cytoskeleton of CLL cells will have a profound impact on this pathwa y,resulting in abnormal BCR-clustering and aberrant interactions between BCRs and signalling molecules within the membrane,resultingin the tonic signalling that drives this leukaemia. This project will provide an entirely new mechanistic understanding of this area with the aim of developing novel tarqeted therapies.
Funder: Wellcome Trust
Amount: £1,053,000
Funding type: fellowship
Funder scheme: Intermediate Clinical Fellowship
Start date: 2016-02-03
End date: 2021-12-02
Investigator: Dr John Riches
Institution: The Francis Crick Institute
Funded outputs count: 6
Funder award ID: 110020/Z/15/Z
OpenAlex ID: G3603399992