Pilot 1 – Becker

P30 CFRTC – Pilot 1

Macrophage and Dendritic Cell Pathways in Cystic Fibrosis

P.I.: Lev Becker, PhD
Assistant Professor
Department of Pediatrics
University of Chicago
P30 CFRTC Publications

Project Period: 2010 – 2013

Abstract: The clinical hallmark of cystic fibrosis (CF) is greatly increased susceptibility to infection with pathogenic bacteria like P. aeruginosa. Cystic fibrosis is primarily a disorder of electrolyte transport that results due to mutations in the CF transmembrane conductance regulator (CFTR) gene. One major unresolved issue in CF pathogenesis is how chloride dysregulation leads to the observed clinical manifestations. While it is well established that the lung epithelium contributes to this process, relatively little is known about the role of CFTR deficient alveolar macrophages (MΦ) and dendritic cells (DC).

We hypothesize that CFTR deficiency in MΦs and DCs influences their immune function thereby contributing to sustained bacterial infection and inflammation in CF. We intend to approach this unresolved issue from two angles. First, we will use a proteomics-based approach to identify plasma membrane-associated markers of differentially activated MΦs and DCs in humans and then use these markers to phenotype macrophages in normal and CF lungs. Second, by interrogating the plasma membrane proteomes of monocyte-derived MΦs and DCs from CF patients we will simultaneously address the effect of CFTR deficiency on cell differentiation and/or activation pathways and identify phenotype-specific effects of CFTR deficiency on protein expression. The functional significance of any CFTR-dependent changes in protein expression in MΦs/DCs will be determined by elucidating their effect on neutrophil function.

Collectively, the proposed studies should provide important insights into how CF monocyte derived immune cells contribute to the pathogenesis of cystic fibrosis.