The non-muscle myosin light chain kinase (MLCK) isoform contributes to the mechanism of increased vascular endothelial permeability in lipopolysaccharide (LPS) induced model of inflammatory lung injury, the primary cause of the acute respiratory distress syndrome (ARDS). However, the role of MLCK in the anti-microbial activity of neutrophils remains poorly understood. Based on our preliminary data, we will test the hypothesis that MLCK regulates neutrophil anti-microbial functions including cell attachment, motility, and oxidant generation. The proposed studies have the following specific aims: i) to dissect the myosin light chain (MLC) independent pathway of non-muscle MLCK that is required for the full activation of (2 integrins via the tyrosine kinases Src and Pyk2 and that in turn mediate neutrophil transmigration;ii) to determine the role of non-muscle MLCK in NADPH oxidase mediated oxidant production and to identify a potentially critical positive feedback loop between oxidant triggered Ca2+ signaling and MLCK activity;and iii) to address the role of LPS activated TLR4 signaling in the mechanism of MLCK activation via an ERK-dependent pathway. In these studies, we will identify the MLCK-regulated signaling pathways that mediate neutrophil transmigration and oxidant production, which in turn are crucial in the mechanism of acute lung injury. Our goal is to understand the molecular mechanisms of the non-muscle MLCK-mediated activation of neutrophils and its role in the genesis of the lung inflammatory response. We hope that through the understanding of the novel function of this MLCK isoform, more effective strategies will be developed for the prevention and treatment of lung inflammation and the resultant injury.
We propose to study the role of a protein kinase, non-muscle myosin light chain kinase (MLCK) in bacterial induced inflammatory lung injury, the primary cause of the acute respiratory distress syndrome (ARDS). We hope that through the understanding of the novel function of this MLCK isoform, more effective strategies will be developed for the prevention and treatment of lung inflammation and the resultant injury.
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