Neutrophil priming following trauma and sepsis is a key event implicated in causing Adult Respiratory Distress Syndrome (ARDS) and Multi-Organ Failure Syndrome (MOSF). Priming of the respiratory burst by cytokines following injury and sepsis results in excessive superoxide production by NADPH oxidase leading to auto-inflammatory tissue damage. Numerous studies have focused on details of how NADPH oxidase produces superoxide. A similar investigation into the mechanisms of priming has been relatively lacking. Our long-term goal is to develop a detailed molecular understanding of this priming phenomenon. Our previous studies and preliminary observations show that different signaling pathways activated by trauma and sepsis converge to phosphorylate two serine residues in a key protein of the NADPH oxidase, p47phox. We propose that through this phosphorylation, p47phox integrates upstream signaling events to control the level of NADPH oxidase activity by regulating protein-protein interactions within neutrophils. In the studies outlined in this proposal the consequences of priming-induced phosphorylation and the identity of proteins associating with NADPH oxidase components following priming will be investigated using neutrophil cell-biological and protein chemistry approaches. The results from these studies may assist in the development of novel therapies aimed at limiting the auto-inflammatory tissue damage patients suffer as a result of sepsis and trauma.
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