George R. Dubyak, PhD
Professor, Physiology and Biophysicsgxd3@case.edu 216.368.5523 (o) 216.368.5586,3 (f)
Signal transduction by extracellular nucleotides and inflammasomes in innate immunity and inflammation
The ability of 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. The released nucleotides stimulate P2 receptors on nearby cells to rapidly induce adaptive responses such as vasodilation, hemostasis, and inflammation. Released nucleotides belong to the larger group of so-called DAMPs (Danger-Associated Molecular Patterns) that include other host-derived molecules (e.g., some nuclear proteins, nucleic acids, and metabolites like uric acid) which entrain innate immune and inflammatory responses. A common theme of current studies is the interaction between P2 nucleotide signaling and inflammasome signaling. Inflammasomes are signaling platforms that recruit various adapter proteins which nucleate the oligomerization and activation of proinflammatory members of the caspase-family proteases. We study several proinflammatory signaling responses triggered by extracellular ATP and other DAMPs, predominantly in murine models including mice with genetic deletion of various P2 receptors and inflammasome proteins.