The SCOR will focus on abnormal CF airway epithelial ion transport and the links between CF ion transport defects and persistent airways bacterial infection. The SCOR will attack these issues at two levels: 1) studies of regulation of airway apical membrane channel number and activity, including the epithelial Na+ channel (ENaC), CFTR, mutant CFTR, and CLC-3B; 2) studies of the downstream effects of abnormal ion transport, focusing on the effects of airway surface liquid (ASL) volume depletion on mucus stasis, accumulation, and infection in both well-differentiated (WD) human culture models and an in vivo mouse model. Project I (M.J. Stutts, Principal Investigator) will study the mechanisms for regulating ENaC activity, elucidating how signals from the ASL compartment control the activity of ENaC to fine-tune ENaC function in response to the volume requirements of the apical environment. Project II (J. Riordan, Principal Investigator ) will focus on the mechanisms that control the availability of CFTR and a second CI- channel, CLC-3B (a candidate for ORCC) at the plasma membrane. This Project will explore the hypothesis that critical interactions with PDZ proteins in the Golgi determine the availability of CFTR (including mutant CFTR) and CLC-3B at the plasma membrane, thus greatly affecting the cellular capacity to regulate ASL volume. Project Ill (R.C. Boucher, Principal Investigator ) will use WD human cultures to explore the ramifications of depleted ASL volume on mucus clearance by investigating the effects of ASL depletion on mucus adhesion to the cell surface, the effects of mucin concentration in the mucus layer on bacterial and neutrophil activities, and therapeutic strategies to detach mucus plaques from airway surfaces. Project IV (B.R. Grubb, Principal Investigator ) will test the hypothesis that an imbalance in ion transport created by ENaC overexpression and generation of Na+ hyperabsorption will deplete ASL volume, producing mucus stasis and a propensity to infection. This Project will explore this hypothesis in mice transgenically overexpressing ENaC sub-units in airway epithelia. The SCOR is supported by two Cores: Molecular Biology(A), and Imaging and Histology (B). The goal of the SCOR is to provide a comprehensive description of the pathogenesis of CF lung disease, in studies ranging from cell biology and biochemistry to whole animal models, so that novel and effective therapies for CF lung disease can be developed.
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