During the past 3.5 years of this Merit award, considerable progress has been made including the elucidation of a dual role of caspase-11 in regulating inflammation and apoptosis, identification of wedelolactone as an inhibitor of caspase-11 induction and salubrinal as a small molecule inhibitor of ER stress. The original Specific Aim 1 has been accomplished by providing definitive evidence for a role of caspase-11 in cell migration during inflammatory response. Furthermore caspase-11 was found to interact with Aip1, an actin interacting protein that can promote cofilin mediated actin depolymerization. Caspase-11 and Aip1 were found to cooperate with cofilin to mediate actin depolymerization and promote cell migration. This study provided an unexpected function of a caspase in regulating cell migration and a novel actin-mediated intracellular mechanism regulating cell migration during inflammatory responses. In this report, the experiments proposed concentrate on the original Specific Aim 2 to determine the molecular mechanism of caspase-11 activation and specification in regulating cytokine release, activated lymphocyte and macrophage migration and apoptosis and Specific Aim 3 to determine the molecular mechanism of caspase- 11 induction.
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