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Software name: S7-PLCSIM V5 Sample: S7-PLCSIM V5 Sample: S7-PLCSIM Advanced MHJ MHJ Sample: WinSPS-S7.Lung disease caused by CFTR dysfunction is a major cause of morbidity and mortality. However, current therapy is only partially effective at ameliorating disease. Thus, there is a strong need for new approaches to treatment. The innate immune system is a well-recognized participant in the pathogenesis of lung disease. While neutrophils are a key element of immunity, their contribution is not always beneficial in the CF lung. A major consequence of neutrophil effector function is the production of neutrophil extracellular traps (NETs). NETs consist of a mesh-like structure composed of components of the neutrophil cytoplasm, including histone proteins, DNA and a variety of antimicrobial and inflammatory mediators. We have previously demonstrated that CFTR dysfunction results in neutrophil dysfunction, including increased production of NETs and reduced migration to chemokines. However, the impact of NETs in CF lung disease remains undefined. Moreover, our understanding of the neutrophil features that contribute to NETs formation or resolution, or therapeutic targets that may ameliorate NETs is also limited. In this proposal, we will test the hypothesis that NETs in the CF lung are a driving force in the pathogenesis of CF lung disease. This hypothesis is based on the following Specific Aims: 1) Define the contribution of NETs to CF disease, 2) Determine how NETs are generated and resolve, and 3) Determine
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