MISSION · Metabolomics InveStigation of cyStic fIbrosis pulmOnary exacerbatioNs

Cystic fibrosis (CF) is a lethal genetic disease affecting 1 out of 2500 newborns. In CF patients, compromised innate immunity enhances the susceptibility to colonization of lower airways by different microbes, leading to long-term bacterial infections. Data suggests that the resulting host-pathogen interactions can shape the course of disease progression, but this relationship is still poorly understood. I propose to use CF patients' samples of exhaled breath condensate to investigate intra-microbial interactions and host-responses, especially during pulmonary exacerbations (PEx), which are recurrent episodes of acute worsening of respiratory symptoms, adversely influencing patients' quality of life.Metabolomics (i.e., the exploration of small molecules within a biological system under defined conditions) has been acknowledged to be the omics discipline closest to the actual phenotype. Thus, I plan to use an unbiased metabolomics approach based on liquid chromatography-mass spectrometry to investigate the chemical environment of CF lungs, with the aim of reducing interpatient variability, characteristic of CF, to increase the generalisability of the findings. I will combine this approach with clinical information and cell biology techniques to test the immune response modulation in vitro, and shed light on the important roles played by metabolites present in CF airways in the regulation of host immune responses.Targeting the main hurdles in finding a cure for CF patients, namely the interpatient variability and the elucidation of the immunopathogenesis of CF, the expected results will give a necessary contribution to the understanding of CF mechanisms, that are still largely unknown. This knowledge is in turn fundamental to guide personalised clinical decisions for early intervention and amelioration of PEx treatment. To the best of our knowledge, there are not yet studies proposing a similar methodology to achieve such an ambitious goal.