The main focus of this laboratory is to elucidate the role of ATP and adenosine receptor signaling in immune cell activation. We have discovered that cellular ATP release and autocrine feedback via P2X-, P2Y-, and P1-type “purinergic” receptors regulate a wide range of immune cell functions (1). We are interested in defining the mechanisms by which these autocrine purinergic signaling systems control gradient sensing, polarization, and chemotaxis of neutrophils as well as activation of other immune cell types (2). Recent work has shown that pannexin-1-mediated ATP release and activation of P2X1 and P2X4 receptors at the immune synapse regulate T cell activation by facilitating TCR-mediated calcium entry, NFAT activation, and IL-2 transcription (3). We are interested in the structure of the purinergic signaling systems at the immune synapse, the role of ATP signaling in the intercellular communication between T cells and accessory cells, and the relationships between purinergic signaling mechanisms and other intracellular signaling pathways (4).
In order to be able to study the highly dynamic purinergic signaling mechanisms, we have been developing novel live cell imaging techniques that allow us to visualize local ATP concentrations using conventional as well as confocal microscopy. We have also established methods to reliably assess nucleotide concentrations in plasma and other complex biological fluids and we employ a wide range of additional molecular and cellular methods to study how purinergic signaling regulates immune cell responses in vitro and in vivo. Our laboratory has strong translational interests and therefore we are using our findings to develop novel therapeutic strategies that allow modulation of the cellular immune responses in inflammatory diseases. For such translational studies, we utilize transgenic mouse models of disease as well as clinical specimens from actual patients. In synergy with local, national, and international collaborators, we test some of our translational concepts in pre-clinical and clinical trials.
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