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The overarching goal of the Marsico Lung Institute is to provide support to the Core and Pilot & Feasibility for the purpose of galvanizing translational research in all areas of CF that may contribute to the overall CF U.S./international effort.

The areas on which we intend to focus these Core resources in the next 3-6 year period include:

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 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 to 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.