Investigating the effect of iron overload in a murine model of cystic fibrosis

Cystic fibrosis (CF) is a genetic disorder caused by mutations in the cystic fibrosis transmembrane regulator (CFTR) gene, which impairs chloride transport across cells and leads to the excessive secretion of sweat and mucus, particularly affecting the lungs. As a result, CF lungs are highly susceptible to chronic bacterial infections, which contribute to disease exacerbations. Elevated iron levels have been observed in the airways of CF patients, and this iron overload is associated with increased bacterial infections Iron is a biologically active metal required for normal physiological processes, but it can also produce damaging reactive oxygen species that may contribute to disease pathogenesis. We have a mouse model of CF (CftrG551D/G551D) that has been treated with iron dextran to mimic human disease. CF animals have also been crossed with Hemochromatosis mice, a genetic model of iron overload caused by mutations in the HFE gene, to determine how the presence of these mutations also contribute to disease phenotype.

1. Quantify iron and mediators of iron homeostasis in lung, liver and spleen tissue
2. Investigate immune responses to changes in iron levels
3. Investigate the microbiome and effect of iron and HFE mutations on the microbiome.

To achieve this aim, we have already collected tissues, serum, and bronchoalveolar lavage fluid (BALF) from G551D CFTR mutant mice and wild-type (WT) controls. These samples will undergo a range of analyses, including protein and gene expression studies, histology, immunohistochemistry, iron assays, and ICP-MS. Additionally, serum and BALF will be analysed for cytokine levels to assess inflammation and immune responses.

This project has significant potential to advance our understanding of iron dysregulation in CF. By investigating the mechanisms of iron overload in the G551D CFTR mouse model, the findings could reveal novel therapeutic targets to reduce oxidative damage and improve lung function in CF patients. Ultimately, the project has the potential to influence both CF treatment strategies and the broader understanding of iron-related pathologies in other diseases.