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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Specialized Center (P50)
Project #
5P50HL060280-07
Application #
6801422
Study Section
Special Emphasis Panel (ZHL1-CSR-P (M2))
Program Officer
Banks-Schlegel, Susan P
Project Start
1998-09-01
Project End
2008-08-31
Budget Start
2004-09-01
Budget End
2005-08-31
Support Year
7
Fiscal Year
2004
Total Cost
$1,777,614
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
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Livraghi-Butrico, A; Grubb, B R; Wilkinson, K J et al. (2017) Contribution of mucus concentration and secreted mucins Muc5ac and Muc5b to the pathogenesis of muco-obstructive lung disease. Mucosal Immunol 10:829
Livraghi-Butrico, Alessandra; Grubb, Barbara R; Wilkinson, Kristen J et al. (2017) Contribution of mucus concentration and secreted mucins Muc5ac and Muc5b to the pathogenesis of muco-obstructive lung disease. Mucosal Immunol 10:395-407
Saini, Yogesh; Wilkinson, Kristen J; Terrell, Kristy A et al. (2016) Neonatal Pulmonary Macrophage Depletion Coupled to Defective Mucus Clearance Increases Susceptibility to Pneumonia and Alters Pulmonary Immune Responses. Am J Respir Cell Mol Biol 54:210-21
Saini, Yogesh; Dang, Hong; Livraghi-Butrico, Alessandra et al. (2014) Gene expression in whole lung and pulmonary macrophages reflects the dynamic pathology associated with airway surface dehydration. BMC Genomics 15:726
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Livraghi-Butrico, Alessandra; Kelly, Elizabeth J; Wilkinson, Kristen J et al. (2013) Loss of Cftr function exacerbates the phenotype of Na(+) hyperabsorption in murine airways. Am J Physiol Lung Cell Mol Physiol 304:L469-80
Graeber, Simon Y; Zhou-Suckow, Zhe; Schatterny, Jolanthe et al. (2013) Hypertonic saline is effective in the prevention and treatment of mucus obstruction, but not airway inflammation, in mice with chronic obstructive lung disease. Am J Respir Cell Mol Biol 49:410-7
Livraghi-Butrico, A; Kelly, E J; Klem, E R et al. (2012) Mucus clearance, MyD88-dependent and MyD88-independent immunity modulate lung susceptibility to spontaneous bacterial infection and inflammation. Mucosal Immunol 5:397-408
Kreda, Silvia M; Davis, C William; Rose, Mary Callaghan (2012) CFTR, mucins, and mucus obstruction in cystic fibrosis. Cold Spring Harb Perspect Med 2:a009589

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