The innate immune system is the first line of defense against invading microorganisms. The focus of our studies is a recently described family of molecules called NLRs (NOD-like receptors) that are involved in the regulation of innate immune responses and cell death pathways. Some NLR family members promote the activation of pro-inflammatory caspases within multiprotein complexes called inflammasomes. Mutations within NALP3, a member of the NLR family, have been linked to a group of autoinflammatory disorders in humans collectively known as the Cryopyrin-associated periodic syndromes. IPAF, another NLR family member, has been shown to play a crucial role in response to infection with a number of Gram-negative bacteria. To understand the role of NLRs in coordinating the immune response we have used a gene-targeting approach utilizing mice deficient in specific inflammasome components. We are interested in three major areas of study. 1.Characterizing the signaling events involved in activation of the NALP3- and IPAF-inflammasomes. This entails determining the specific ligand for NALP3 and IPAF and identifying downstream events mediated by their activation. 2.Determining the role of NALP3 and IPAF in host the response to bacterial infection and identifying mechanisms pathogens use to evade these innate immune defenses. 3.Characterizing the role of NLRs in murine models of autoimmune and autoinflammatory disease and correlating this to disease pathogenesis in humans.