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Tailoring the tail of L-selectin (leukoselectin)
Date du début: 1 mai 2013, Date de fin: 30 avr. 2015 PROJET  TERMINÉ 

Leukocytes protect humans from pathogens. During episodes of infection, leukocytes leave the blood circulation and migrate to sites in the body where they mount a response against pathogens. In order for leukocytes to migrate, they must adhere to endothelial cells which cover blood vessels. Such adhesion allows them to migrate along the endothelial layer, pass though endothelial junctions, and reach tissues. Excessive migration of leukocytes is a characteristic of inflammatory and auto-immune diseases, and leads to tissue damage as leukocytes have destructive capacities. L-selectin is an adhesion receptor expressed in leukocytes. This receptor plays a critical role in the adhesion of leukocytes to endothelial cells. Interaction of proteins with the cytoplasmic tail of L-selectin controls the functions of L-selectin. As L-selectin tail contains only one serine residue at position 364, it was proposed but not proven that such phosphorylation may be essential for the recruitment of proteins to L-selectin tail and regulation of L-selectin functions. By using sophisticated proteomics, and by generating mice harbouring nonphosphorylatable serine-to-alanine knock-In substitution at position 364 of the L-selectin tail, we will get insights into the mechanisms by which L-selectin functions are regulated. Our objectives are:1- To identify new proteins interacting with L-selectin tail and identify which one are important for L-selectin functions2- To investigate whether serine phosphorylation of L-selectin tail regulates interaction with binding partners and L-selectin functions in vitro3- To investigate whether leukocytes from L-selectin tail serine-to-alanine knock-In mice exhibit impaired adhesion and migration in vivoIdentification of new proteins binding to L-selectin tail and understanding the mechanisms controlling this interaction is essential for the design of new therapeutic strategies for the treatment of inflammatory and auto-immune diseases.