Sphingosine-1-Phosphate Receptors in Human B Cells: Expression, Role and Signaling

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Studying the functions of sphingosine-1 phosphate (S1P) in human B cells we hope to contribute to the understanding of human B cell malignancies and to provide new tools and procedures for diagnosis, staging and treatment. Using primary human B cells, samples from B cell malignancies, human B cell lines, and humanized mouse models, we examine how S1P receptors elicit and modulate cellular responses to S1P, interfere with signals that regulate human B cell development, growth and differentiation. By comparing normal and malignant B cells we hope that we can characterize how S1P-dependent pathways contribute to lymphomagenesis. Fusion proteins between S1P receptors and fluorescence proteins like GFP are introduced into human B cell lines by lentiviral gene transfer to analyze the S1P receptor response to S1P binding, receptor internalization and compartmentalization in living cells. The results should reveal the functional differences between S1P receptors in B cells, define the critical residues and domains within the receptors and provide insight into the interactions between signals induced by S1P and essential B-lymphocyte specific receptors. Since new therapeutic approaches are based on the application of S1P analoga the projected outcome should help in understanding the beneficial and adverse effects of these therapies.