Calprotectin is released in neutrophil extracellular traps in response to infection and is central to CF lung inflammation. (360G-Wellcome-093767_Z_10_Z)

This research will elucidate a central role for calprotectin, and its release on NETS in the exagerated inflammatory response to persisting infection in the CF lung. Calprotectin may have a fundamental role in the pathophysiology of CF lung disease based on my previous findings that calprotectin is: 1. highly abundant in CF BALF and sputum; 2. a major constituent of NETs, and correlates with the levels of NETs in sputum; and 3. pro-inflammatory to primary human macrophages. I will now ans wer questions leading to a better understanding of inflammation in CF following infection and offer new therapeutic insights by utilising both clinical samples and animal models. Key Research Goals: 1. Assess NET production and calprotectin release following neutrophil interaction with bacteria in both CF and non-CF donor neutrophils, and demonstrate the pro-inflammatory potential of NETs containing calprotectin in-vitro. 2. Evaluate the induction of NET production and calprotectin release in wild type and CF models of infection. 3. Elucidate a central role for calprotectin in the inflammatory response in wild type and CF models of infection. 4. Intervene therapeutically in CF models by neutralising calprotectin (monoclonal antibody therapy) or increasing NET clearance (nebulised DNAse) and evaluate similar in clinically relevant samples.