Project overview
Cystic fibrosis (CF) is an inherited genetic disorder affecting over 10,400 people in the UK, equivalent to 1:2500 newborns.1 Symptoms include recurrent respiratory infections with excessive inflammation, leading to progressive bronchiectasis, respiratory failure, and death. CF is caused by mutations in a single gene encoding an ion channel expressed predominantly in epithelial cells, the CF transmembrane regulator (CFTR). A link between CFTR dysfunction and changes in the lipid metabolism is established, resulting in altered levels of polyunsaturated fatty acids (PUFAs).2, 3 There is an imbalance in the ratio of ω-6/ω-3 PUFAs resulting in increased levels of arachidonic acid over docosahexaenoic acid in CF nasal epithelium.4 Metabolites of arachidonic acid, e.g. eicosanoids like prostaglandins, are important pro-inflammatory mediators contributing to an inflammatory status in the CF lung. However, there is a gap in knowledge about how altered lipid metabolism is mechanistically linked to respiratory bacterial infections in CF, e.g. colonisation and biofilm formation by Pseudomonas aeruginosa (PA). We hypothesise that an altered lipid profile in CF respiratory epithelial cells promotes PA colonisation and biofilm formation.
Study aims and Objectives:
We aim to investigate if an altered lipid profile diminishes antimicrobial defence mechanisms in CF airway epithelium, thereby promoting PA colonisation and biofilm formation. Using human primary respiratory epithelial cells from CF patients and healthy controls, we will:
1. Characterise the lipid membrane profile of ex vivo respiratory epithelial cells from CF patients and healthy controls
2. Recapitulate the in vivo lipid membrane profile in our in vitro CF model by supplementing cultures with PUFAs
3. Analyse PA colonisation and biofilm formation on differentiated respiratory CF epithelium with altered lipid membrane profile compared to normal control epithelium
4. Investigate whether PUFA induced modification of the CF epithelial lipid membrane profile can reduce PA colonisation and biofilm formation
Study aims and Objectives:
We aim to investigate if an altered lipid profile diminishes antimicrobial defence mechanisms in CF airway epithelium, thereby promoting PA colonisation and biofilm formation. Using human primary respiratory epithelial cells from CF patients and healthy controls, we will:
1. Characterise the lipid membrane profile of ex vivo respiratory epithelial cells from CF patients and healthy controls
2. Recapitulate the in vivo lipid membrane profile in our in vitro CF model by supplementing cultures with PUFAs
3. Analyse PA colonisation and biofilm formation on differentiated respiratory CF epithelium with altered lipid membrane profile compared to normal control epithelium
4. Investigate whether PUFA induced modification of the CF epithelial lipid membrane profile can reduce PA colonisation and biofilm formation
