Animal model for chronic obstructive pulmonary disease and cystic fibrosis
View Patent ↗A nonhuman transgenic mammal is described whose genome comprises a promoter construct operably linked to a heterologous DNA encoding an epithelial sodium channel β subunit, wherein said promoter construct directs expression of the epithelial sodium channel β subunit in lung epithelial cells of said animal, and wherein said transgenic mammal has increased lung mucus retention as compared to the corresponding wild-type mammal. The animal is useful in screening compounds for activity in treating lung diseases such as cystic fibrosis and chronic obstructive pulmonary disease.
1. A method of screening compounds for activity in treating lung disease, comprising:
providing a transgenic mouse whose genome comprises a mammalian lung epithelial promoter construct operably linked to a heterologous DNA encoding a mouse epithelial sodium channel β subunit, wherein said promoter construct directs expression of the mouse epithelial sodium channel β subunit in lung epithelial cells of said mouse, and wherein said transgenic mouse has increased lung mucus retention as compared to the corresponding wild-type mouse; and then
administering a test compound to said mouse subject, and
determining the effect of said test compound on susceptibility to airway disease in said mouse, a decrease in susceptibility to airway disease in said mouse indicating that said test compound may be useful in treating lung disease.
2. The method of claim 1 , wherein said lung disease is chronic obstructive pulmonary disease or cystic fibrosis.
3. The method of claim 1 , wherein said lung disease is chronic bronchitis.
4. The method of claim 1 , wherein said lung disease is asthma.
5. The method of claim 1 , wherein said test compound is an antibiotic.
6. The method of claim 1 , wherein said test compound is an osmolite.
7. The method of claim 1 , wherein said test compound is a sodium channel blocker.
8. The method of claim 1 , wherein said test compound is a P2Y 2 receptor agonist.
9. The method of claim 1 , wherein said test compound is an ENaC regulator.
10. The method of claim 1 , wherein said test compound is an anti-inflammatory agent.
11. The method of claim 1 , wherein said test compound is a mucolytic agent.
12. The method of claim 1 , wherein said promoter is selected from the group consisting of the CCSP promoter, the surfactant protein C promoter, the cytokeratin 18 promoter, and the human forkhead homologue 4 promoter.
13. The method of claim 1 , wherein said promoter is the CCSP promoter.
14. The method of claim 1 , wherein said mouse has increased lung mucus plugging and airway inflammation as compared to the corresponding wild-type mouse.
15. The method of claim 1 , wherein said mouse has increased mortality at 30 days of age as compared to the corresponding wild-type mouse.