Twenty-five years after the discovery of the CFTR gene and identification of its functions, we lack answers to many crucial questions, current treatments are inadequate, and cystic fibrosis (CF) remains a life shortening, lethal disease. A major barrier to progress has been lack of a CF animal model other than the mouse. Project leaders in this PPG developed the ferret and pig models of CF to overcome this impediment. Remarkably, these models develop lung disease with many similarities to that of human babies with CF. In this Program four senior and highly accomplished investigators and their teams will seize the unique opportunity to use CF ferrets and pigs as tools to investigate novel episomal and integrating gene transfer vectors. They will test the efficacy of gene transfer in correcting key physiologic defects that arise from loss of CFTR function. Studies with gene transfer vectors will be complemented by novel transgenic ferret and pig models expressing CFTR in a cell type specific or inducible manner. Program scientists will use several novel surrogate endpoints developed in the PPG to probe relationships between CFTR function and correction of biological and pathophysiological endpoints to judge efficacy. They will be guided by how complementation of CFTR function modifies airway biology, including Cl- and HCO3 - transport, host defense and mucociliary transport. The Project Leaders have an outstanding track record of collaboration in CF research, and here they sharpen their focus to a common goal. Their research is highly creative and is supported by five cores that provide innovative services and infrastructure. Discoveries from this PPG will accelerate development of novel therapies for patients who suffer from this devastating disease.
- OVERALL PROGRAM The overarching goal of this program is to advance gene-based therapies to prevent or treat CF airway disease. To achieve this goal, project leaders will investigate episomal and integrating vector systems and develop new transgenic models with cell type specific expression of CF. They will be guided by how complementation of CFTR function modifies airway biology. The program employs novel CF ferret and pig models that develop lung disease with many similarities to CF in humans.
| Meyerholz, David K; Sieren, Jessica C; Beck, Amanda P et al. (2018) Approaches to Evaluate Lung Inflammation in Translational Research. Vet Pathol 55:42-52 |
| Rosen, Bradley H; Evans, T Idil Apak; Moll, Shashanna R et al. (2018) Infection Is Not Required for Mucoinflammatory Lung Disease in CFTR-Knockout Ferrets. Am J Respir Crit Care Med 197:1308-1318 |
| Mao, Suifang; Shah, Alok S; Moninger, Thomas O et al. (2018) Motile cilia of human airway epithelia contain hedgehog signaling components that mediate noncanonical hedgehog signaling. Proc Natl Acad Sci U S A 115:1370-1375 |
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| Lynch, Thomas J; Anderson, Preston J; Rotti, Pavana G et al. (2018) Submucosal Gland Myoepithelial Cells Are Reserve Stem Cells That Can Regenerate Mouse Tracheal Epithelium. Cell Stem Cell 22:653-667.e5 |
| Meyerholz, David K; Stoltz, David A; Gansemer, Nick D et al. (2018) Lack of cystic fibrosis transmembrane conductance regulator disrupts fetal airway development in pigs. Lab Invest 98:825-838 |
| Gray, Robert D; Hardisty, Gareth; Regan, Kate H et al. (2018) Delayed neutrophil apoptosis enhances NET formation in cystic fibrosis. Thorax 73:134-144 |
| Thornell, Ian M; Li, Xiaopeng; Tang, Xiao Xiao et al. (2018) Nominal carbonic anhydrase activity minimizes airway-surface liquid pH changes during breathing. Physiol Rep 6: |
| Reznikov, Leah R; Meyerholz, David K; Abou Alaiwa, Mahmoud et al. (2018) The vagal ganglia transcriptome identifies candidate therapeutics for airway hyperreactivity. Am J Physiol Lung Cell Mol Physiol 315:L133-L148 |
| Meyerholz, David K; Beck, Amanda P; Goeken, J Adam et al. (2018) Glycogen depletion can increase the specificity of mucin detection in airway tissues. BMC Res Notes 11:763 |
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