Our laboratory focuses on the molecular mechanisms that govern inflammasome assembly and activity, and the signaling pathways that modulate activation of caspases during cell death and inflammation using in vitro and whole animal model systems. In the past two decades our group was among the leading groups that contributed to the elucidation of the molecular pathways of apoptosis and inflammatory cell death (pyroptosis). We led the initial discovery of several apoptotic caspases, including caspase-3 (CPP32), caspase-9 (Mch6) and caspase-8 (Mch5), and the characterization of the mechanism of activation of the Apaf-1 apoptosome. We have also characterized through a series of high impact publications the role of the mitochondrial serine protease HtrA2/Omi in apoptosis and neurodegeneration, with the most recent work in mice implicating HtrA2/Omi in aging.  We have also been investigating the role of NOD-like receptors (NLRs) and non-NLR proteins in activation of caspase-1 in inflammatory cell death, inflammatory diseases and infection. This work led to the discovery of the Ipaf (NLRC4), pyrin, and AIM2 inflammasomes, and the ASC pyroptosome. Our recent work in AIM2-deficient mice demonstrated that AIM2 is uniquely involved in sensing cytosolic DNA released during infection with the intracellular bacteria Francisella tularensis and DNA viruses. Current efforts are focused on elucidating exactly how the NLR inflammasome NLRP3 is activated by diverse danger signals. Our latest findings that NLRP3 is activated by a posttranslational modification mechanism initiated by Toll-like receptor signaling (signal 1) and potassium efflux (signal 2) could explain how NLRP3 is activated by diverse danger signals. Further characterization of this activation mechanism and the understanding of the signaling pathways that activate and those that suppress the NLRP3 inflammasome should yield important fundamental insight into NLRP3 biology and provide new conceptual advances that significantly advance the field.  We are also interested in the role of the NLRP3 inflammasome in cancer development, metabolic diseases and aging because chronic inflammation has long been associated with increased predisposition to cancer and tumor progression, and increased inflammasome activation has been shown to occur during the aging process and during chronic inflammatory diseases.

PhD, Temple University School of Medicine - 1991