Signal transduction by extracellular nucleotides in inflammation and immunity
The ability to cells to sense local tissue damage or microbial invasion is critical to the proper regulation of inflammatory and innate immune responses in health and disease. Such biological stresses often induce the release of ATP and other nucleotides from intact or damaged cells. In turn, the released nucleotides stimulate so-called P2 receptors on nearby cells to rapidly induce adaptive responses such as vasodilation, hemostasis, and inflammation. My research group focuses on two fundamental aspects of nucleotide-based signal transduction:
1) the physiological and pathophysiological roles of extracellular nucleotides and P2 nucleotide receptors as regulators of inflammation, innate immunity, and cardiovascular function; and
2) the mechanisms by which ATP and other nucleotides are released into, and metabolized within, extracellular compartments.
Fifteen different nucleotide receptors including G protein-coupled receptors (P2Y class) and ATP-gated channel receptors (P2X class) have been identified in mammalian genomes. We are currently interested in the functions of the P2X7 receptor, an ATP-gated ion channel that is predominantly expressed in the effector leukocytes (macrophages and lymphocytes) that mediate many inflammatory and immune responses. We study natively expressed P2X7 receptors, recombinant P2X7 receptors ectopically expressed in various model cell types, and the inflammatory effector cells derived from normal or P2X7-knockout mice. A major focus is analysis of the signal transduction mechanisms that couple P2X7 receptors to the activation of caspase-family proteases involved in the maturation of inflammatory cytokines (interleukin-1 ? and interleukin-18) and induction of regulated cell death (apoptosis). In other projects we are analyzing how various cell types, including cardiac myocytes, endothelial cells, and leukocytes, release extracellular nucleotides under physiological and pathological conditions. Another focus is characterization of the ecto-nucleotidases that metabolize and interconvert extracellular nucleotides in cardiovascular and inflammatory tissue environments.
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