Background, knowledge gap and therapeutic value: Lung disease is the primary cause for the morbidity and mortality of patients with cystic fibrosis (CF). One of the major culprits of the CF airway diseases is chronic inflammation associated with dying neutrophils, accumulating DNA and colonizing Pseudomonas aeruginosa. However, the factors and pathways that regulate the pathological changes, particularly relevant to neutrophil death, in CF airways are unclear.
NETosis or the death of neutrophils by forming neutrophil extracellular traps (NETs) is a recently identified form of cell death. Our data strongly suggest that dysregulation of NETosis contributes to the accumulation of DNA and neutrophilic cytotoxic by-products in CF lung disease. We aim to inhibit this pathway to treat CF lung disease and to prevent the deterioration of lung health.
Overall objectives of our project are to identify the host and microbial factors that regulate NETosis in the inflamed lungs and to devise therapeutic strategies to suppress NETosis.
Specific aims and experimental approaches: (i) The first aim is to determine the key factors (host and microbial components) that regulate NETosis. We will use wildtype and mouse model with CF-like lung conditions to identify the host factors. To identify the bacterial factors, we will use clinical strains of bacteria and their components in NETosis assays. (ii) The second aim is to elucidate the relevance of these factors in CF lung disease and to suppress NETosis in CF-like mouse airways. We will use human (healthy, CF) blood, BAL and sputum samples and in vivo mouse models to achieve this aim.
Significance: Identifying molecules that suppress NETotic neutrophil death in the CF airways could help to devise novel therapeutics for treating CF lung disease.
University of Toronto
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