Progressive and chronic airway inflammation and infection are hallmarks of cystic fibrosis (CF) lung disease. A reduction of the host inflammatory response could favorably modify the disease phenotype. Indeed this has been the goal of clinical trials with steroids and non-steroidal anti-inflammatory drugs. Another approach to reduce inflammation is to silence pro-inflammatory mediators by RNA interference (RNAi). Here, we propose to use several novel methods to accomplish RNAi in the airways. In one approach, we hypothesize that virally expressed inhibitory RNAs can effectively transduce airway epithelia and inhibit expression of our target genes. We will use methods developed in our laboratories for optimal inhibitory RNA expression. In a second approach, we will use peptide-siRNA complexes. In these experiments, we will take advantage of peptides that bind to airway epithelia to direct siRNA uptake and target gene silencing. For both viral and nonviral experiments, we will first test the effectiveness in vitro using well differentiated airway epithelia. Once optimized in vitro, the tools will be tested in vivo in wild type, and then CF pigs. Importantly, the methods we develop to deliver RNAi and reduce geneexpression in vitro and in vivo will have direct relevance to other pro-inflammatory targets, and newly identified participants in CF ainway disease.
| O'Malley, Yunxia; Rotti, Pavana G; Thornell, Ian M et al. (2018) Development of a polarized pancreatic ductular cell epithelium for physiological studies. J Appl Physiol (1985) 125:97-106 |
| Rosen, Bradley H; Chanson, Marc; Gawenis, Lara R et al. (2018) Animal and model systems for studying cystic fibrosis. J Cyst Fibros 17:S28-S34 |
| 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 |
| Montoro, Daniel T; Haber, Adam L; Biton, Moshe et al. (2018) A revised airway epithelial hierarchy includes CFTR-expressing ionocytes. Nature 560:319-324 |
| 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: |
Showing the most recent 10 out of 184 publications
