? Neutrophil priming and activation following trauma and sepsis is a key event implicated in causing Adult Respiratory Distress Syndrome (ARDS), Multi-Organ Failure Syndrome (MOSF), and ischemia-reperfusion injury. Priming of the respiratory burst by cytokines following injury and sepsis results in excessive superoxide production by the NADPH oxidase leading to auto-inflammatory tissue damage. Many of the molecular mechanisms involved in priming and activation of the NADPH oxidase, however, remain poorly defined. Our long-term goal is to develop a detailed molecular understanding of how protein kinase and lipid kinase signaling pathways, including the PI 3-kinase pathway, the p38MAPK pathway and the Erk1/2 pathways regulate the assembly, subcellular targeting, and activity of the neutrophil NADPH oxidase during priming and activation. Our previous work and preliminary observations identified PX domains in the p47phox and p40phox subunits as modular protein domains that bind to specific lipid products of PI 3-kinase, and showed that the priming agents PAF and TNFa induced the assembly of a p47phox:p67phox:p40phox heterotrimeric complex in the cytoplasm of primed but un-activated cells. In the studies outlined in this proposal we will investigate what roles the PX domains play in neutrophil priming and activation, and determine the protein kinase signaling pathways and molecular mechanisms involved in priming-induced heterotrimer formation. The results from these studies may assist in the development of novel diagnostic or therapeutic reagents aimed at limiting the auto-imflammatory tissue damage patients suffer as a result of sepsis and trauma. ? ?
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