Cystic Fibrosis and Pulmonary Diseases Research and Treatment Center

The UNC Cystic Fibrosis/Pulmonary Research and Treatment Center (CF Center) has a rich tradition of collaboration. It exhibits a wide scope but “thin” coverage of the scientific areas relevant to CF. In brief, we typically have recruited only one or two experts in a given field, but have attempted to use our large numbers of investigators to cover a wide spectrum of scientific disciplines required to tackle CF research in a collaborative and efficient fashion.

There are many key areas of CF research that require such collaborative interactions (see Table 1). The Hooker UNC Proteomics gift ($25 M) has spurred an extra CF Center collaborative effort at UNC, termed the Virtual Lung Project (VLP). The VLP has allowed us to bring a unique group of physicists, applied mathematicians, and physical chemists into the world of CF research. One measure of the outcome of the collaborative efforts at UNC is the large number of multi-authored publications that can be observed in the overall UNC bibliography. Another measure of our collaborative efforts is the number of NIH multi investigator grants awared to the UNC CF Center, including a Program Project based in the CF Center [Pulmonary Epithelia in Health and Disease (HL34322)], a PPG shared between the UNC MLI and the Gene Therapy Center [Gene Therapy of Airways and Hematopoietic Diseases (HL51818, HL66973)], a Molecular Therapeutics Translational Core Grant (DK65988), a multi-investigator systems biology grant for the Virtual Lung Group (HL077546), collaborative R01s on gene modifiers between UNC and Case Western (HL68890) and UNC and Columbia University (DK66368), and on CFTR biogenesis, between UNC and Scripps (DK051870), and finally, a SCCOR focused on comparing host defence in CF vs. COPD subjects (HL084934).

An important facilitator of CF translational research at UNC is the Clinical and Translational Science Award. The CTSA provides not only the clinical translational facilities for CF translational research at UNC, but also >$2,000,000/year in Pilot Grant and Core Facility support. The CF Center Director is one of four co-P.I.s for the UNC CTSA.

In sum, collaborative efforts are certainly not unique to the UNC CF Center. However, we believe the UNC CF Center has recruited an extraordinarily broad scope of talented basic scientists from all basic science departments with research interests consistently focused on CF, who interrelate seamlessly with high-quality clinical translational researchers from both the Department of Pediatrics and Pulmonary Diseases and Critical Care Medicine.

Director: Richard C. Boucher, MD

Co-Director: Michael R. Knowles, MD

Internal Advisory Board: T Magnuson, RJ Samulski

UNC Cystic Fibrosis Center Structure


M Knowles
M Zariwala
F Zou

Virtual Lung

R Superfine
G Forest
S Mitterrand
R Camaso
R McLaughlin


CW Davis
C Ehre
D Hill

Cell Biology

S Randell
L Ostrowski
C Ribeiro
S Kreda
D Cyr


E Lazarowski
TK Harden
P Smith
T Elston


J Stutts
B Button
R Tarran
R Caldwell
R Coakley


S Donaldson
G Retsch-Bogart
C Esther
R Aris
W Bennett
K Zeman

CFTR Biochemistry

J Riordan
M Gentzsch
N Dokholyan

Animal Models

B Grubb
B Koller
S Tilley


M Wolfgang
P Gilligan
R Arnold
M Miller
P Cotter


J Lobo
T Egan
B Harthcock

Gene Therapy

RJ Samulski
R Pickles
T Kafri
R Kole













Future Goals

Accelerate Development/Translation of CFTR Correctors into the Clinic

Building on the basic science expertise of Drs. Riordan, Gentzsch, and Cyr, the Tissue Procurement and Cell Culture Core, the Molecular Biology Core, the Mouse Models Core, and the Michael Hooker Microscopy Core will make available in vitro HBE and animal models of ΔF508 CFTR for testing CFTR correctors and potentiators. Great efforts have now been expended into developing the biomarker capabilities to assess mutant CFTR correction in vivo, focused on NPD measurements, coupled with rectal biopsy measurements.

Study of CFTR-ENaC Interactions

This work is now, to our great satisfaction, finally becoming tractable. The basic biological studies are being performed by Drs. Gentzsch, Stutts, and co-workers. The Tissue Procurement and Cell Culture Core will to provide a spectrum of cell types, including alveolar Type II cells and sweat ductal cells, for these studies, and the Molecular Core will supply a large number of cDNA reagents. Of note, we believe that the biochemical assays of ENaC activation via endoproteolysis may serve as a good in vivo biomarker of restoration of CFTR-ENaC regulatory function, e.g., as observed with VTX770 in G551D patients.

Provide Basic Science/Concept Support for Modifier Gene Studies

It is clear that a translation must be made from candidate genes identified by a variety of genetic approaches to understand the biology of gene modifiers of the lung and liver. We are intent in linking genetic loci of interest to changes in gene expression/function, focusing on collaborations between the Molecular Core and the Tissue Procurement and Cell Culture Core to relate SNP and HapMap data to eQTL loci, RNA SEQ data, and epithelial function (ion transport, nucleotide release, mucin secretion rates), utilizing a systems biology approach in concert with the UNC Virtual Lung Group.

Expansion of Studies of Hypertonic Saline, Ion Transport Modulators, and Novel “Mucolytics” for the Therapy of CF Lung Disease

Again, the Tissue Procurement and Cell Culture Core, the Molecular Core, the Mouse Models Core, and the Michael Hooker Microscopy Core will provide the reagents and support for the in vitro cell culture models that are interfaced to our novel mucus adhesion and cavitation (to measure mucus cohesion) models for screening “mucolytic” candidates, and provide βENaC mice for in vivo testing of single “mucolytic” agents and candidate combinations with hydrating agents as effective therapies for treating the mucus adhesive aspects of CF lung disease. This program has particularly benefited from the Program Enhancement Core, which has brought in experts in materials sciences in conjunction with the Virtual Lung Group to help us understand the biochemical and biophysical bases of adhesion/cohesion.

Develop Novel Therapies for Specific Bacterial Pathogens in the CF Lung

We have greatly expanded our interest in specifically anaerobic bacteria in the CF lung and Burkholderia cepacia. Again, the Cell Culture Core will provide all the cellular reagents required to initiate the generation of hypoxic airway cells for testing the pathogenesis of candidate anaerobes in an airway luminal environment. In parallel, the Molecular/Mouse Core has provided both the βENaC mice and wild-type mice that have been used in the recently developed mucus simulant (low melting-point agarose) model to initiate both anaerobic infections and B. cepacia airways infections. These Core activities are complemented by a recently funded joint U.S.-Irish R01 to study the acquisition and role of anaerobes in CF lung disease, utilizing 454 pyrosequencing technologies overseen by Dr. Matthew Wolfgang in the UNC Microbiome Core.

Gene Therapy

Stubbornly, we continue to believe that there may be a future for gene therapy as a therapy for CF lung disease. Thus, the Cell Culture Core supplies large numbers of cells the Samulski lab for AAV gene shuffling approaches to develop novel vectors; to the Olsen lab, for testing novel pseudotyped EIAV vectors; and to the Pickles lab, for studies of paramyxovirus vectors. The Molecular Biology Core and the Mouse Models Core provide a variety of mouse models for these gene therapy studies, including CF mice for in vivo studies of AAV and EIAV gene transfer.

New Initiatives in Studies of Infant Pulmonary Therapies

Clearly, the field is moving to the concept of preventing CF lung disease, which requires studies in CF infants. We believe that MRI for structural information, combined with MRI-based imaging for perfusion information, will be a major research tool for the future. The Molecular Biology Core and the Mouse Models Core are providing variant mutant mice, e.g., CF mice and βENaC mice, for studies of MRI imaging as a means to verify the anatomic correlates of MRI-defined airways disease, including small airways induced parenchymal hypoperfusion. These studies are being paralleled by studies with Drs. Stephanie Davis of the Department of Pediatrics and Katherine Birchard of the Department of Radiology, in preparation of MRI imaging studies of infants with CF.