cAMP/PKA mediated signaling in B cell metabolism and function.

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Activated lymphocytes face considerable metabolic challenges and need to be able to adjust their metabolic activity in a dynamic manner. Increasing evidence suggests that nutrient acquisition and utilization is not simply a passive process in lymphocytes, but is tightly regulated by various intracellular signaling pathways. The goal of the proposed project is to systematically analyze how cAMP/PKA mediated signaling contributes to the regulation of B cell metabolism and function. cAMP is a ubiquitous signaling molecule known to activate protein kinase A (PKA). cAMP-dependent signaling has been implicated to regulate different aspects of cell function and metabolism, however surprisingly little is known about cAMP signaling in B cells. Our preliminary data suggest that PKA inhibition leads to impaired mitochondrial function and ultimately cell death in activated B cells. Surprisingly however, cAMP mediated PKA activation has profoundly different effects on B cell viability and proliferation depending on the signaling context. The goal of the project is to define PKA-dependent and independent signaling pathways downstream of cAMP in normal and malignant B cells and to elucidate the role of cAMP and PKA in regulating mitochondrial function and metabolic activity. Moreover, cell metabolism not only supports proliferation, but often guides cell fate decisions and effector functions. In our previous studies, we have shown that B cells are exposed to changes in their metabolic environment during the germinal center response and that appropriate responses to metabolic challenges are necessary to maintain B cell viability. Our aim is to analyze how nutrient and oxygen availability affect activation of the cAMP/PKA signaling pathway and how these environmental cues are integrated with cytokine induced signaling. In summary, this project will yield novel insights into the regulation of cell metabolism in normal and malignant B cells. A better understanding of metabolic adaptations in B cells is essential in order to identify metabolic vulnerabilities in cancer cells and novel avenues for immunomodulation.