Claims
- 1. A recombinant nucleic acid comprising a promoter operably linked to a heterologous nucleic acid encoding an epithelial sodium channel β subunit, wherein said promoter construct directs expression of the epithelial sodium channel β subunit in lung epithelial cells.
- 2. The recombinant nucleic acid according to 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.
- 3. The recombinant nucleic acid according to claim 1, wherein said promoter is the CCSP promoter.
- 4. A host cell containing a recombinant nucleic acid according to claim 1.
- 5. A nonhuman transgenic mammal whose genome comprises a promoter construct operably linked to a heterologous nucleic acid 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.
- 6. The nonhuman transgenic mammal of claim 5, 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.
- 7. The nonhuman transgenic mammal of claim 5, wherein the genome of said mammal further comprises a promoter construct operably linked to a heterologous nucleic acid encoding an epithelial sodium channel α subunit, wherein said promoter construct directs expression of the epithelial sodium channel α subunit in lung epithelial cells of said animal.
- 8. The nonhuman transgenic mammal of claim 5, wherein the genome of said mammal further comprises a promoter construct operably linked to a heterologous nucleic acid encoding an epithelial sodium channel γ subunit, wherein said promoter construct directs expression of the epithelial sodium channel γ subunit in lung epithelial cells of said animal.
- 9. The nonhuman transgenic mammal of claim 5, wherein said mammal is selected from the group consisting of mice, rats, pigs, and monkeys.
- 10. The nonhuman transgenic mammal of claim 5, wherein said mammal is a mouse.
- 11. The nonhuman transgenic mammal of claim 5, wherein said mammal has increased lung mucus plugging and airway inflammation as compared to the corresponding wild-type mammal.
- 12. The nonhuman transgenic mammal of claim 5, wherein said transgenic mammal has increased mortality at 30 days of age as compared to the corresponding wild-type mammal.
- 13. The nonhuman transgenic mammal of claim 5, wherein said transgenic mammal exhibits a cystic fibrosis or chronic obstructive pulmonary disease phenotype not exhibited by the corresponding wild-type mammal.
- 14. A method of screening compounds for activity in treating lung disease, comprising:
providing a nonhuman transgenic mammal 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; and then administering a test compound to said subject, and determining the effect of said test compound on susceptibility to airway disease in said animal, a decrease in susceptibility to airway disease in said animal indicating that said test compound may be useful in treating lung disease.
- 15. The method of claim 14, wherein said lung disease is chronic obstructive pulmonary disease or cystic fibrosis.
- 16. The method of claim 14, wherein said lung disease is chronic bronchitis.
- 17. The method of claim 14, wherein said lung disease is asthma.
- 18. The method of claim 14, wherein said test compound is an antibiotic.
- 19. The method of claim 14, wherein said test compound is an osmolite.
- 20. The method of claim 14, wherein said test compound is a sodium channel blocker.
- 21. The method of claim 14, wherein said test Compound is a P2Y2 receptor agonist.
- 22. The method of claim 14, wherein said test compound is an ENaC regulator.
- 23. The method of claim 14, wherein said test Compound is an anti-inflammatory agent.
- 24. The method of claim 14, wherein said test compound is a mucolytic agent.
STATEMENT OF FEDERAL SUPPORT
[0001] This invention was made with Government support under grant number HL 34322 from the National Institutes of Health. The Government has certain rights to this invention.