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1 Pediatrics, Washington University School of Medicine, St. Louis, Missouri, United States
2 Medicine, Washington University School of Medicine, St. Louis, Missouri, United States
3 Biological Sciences, University of Missouri, Columbia, Missouri, United States
4 Roche Center for Medical Genomics, Basel, Switzerland
5 Roche, Palo Alto, California, United States
6 Medicine, Washington University School of Medicine, St. Louis, Missouri, United States; Cell Biology, Washington University School of Medicine, St. Louis, Missouri, United States
* To whom correspondence should be addressed. E-mail: holtzman{at}im.wustl.edu.
Complex airway diseases such as asthma and COPD exhibit stereotyped traits (especially airway hyperreactivity and mucous cell metaplasia) that are variably expressed in each patient. Here we use a mouse model for virus-induced long-term expression of these traits to determine whether individual traits can be genetically segregated and thereby linked to separate determinants. We show that an F2 intercross population derived from susceptible and non-susceptible mouse strains can manifest individual phenotypic extremes that exhibit one or the other disease trait. Functional genomic analysis of these extremes further indicated that a member of the chloride channel calcium-activated (CLCA) gene family designated mClca3 was inducible with mucous cell metaplasia but not airway hyperreactivity. In confirmation of this finding, we found that mClca3 gene transfer to mouse airway epithelium was sufficient to induce mucous cell metaplasia but not airway hyperreactivity. However, newly-developed mClca3-/- mice exhibited the same degree of mucous cell metaplasia and airway hyperreactivity as wild-type mice. Bioinformatic analysis of the Clca locus led to the identification of mClca5, and gene transfer indicated that mClca5 also selectively drives mucous cell metaplasia. Thus, in addition to the capacity of CLCA family members to exhibit diverse functional activities, there is also preserved function so that more than one family member mediates mucous cell metaplasia. Nonetheless, Clca expression appears to be a selective determinant of mucous cell metaplasia so that shared homologies between CLCA family members may still represent a useful target for focused therapeutic intervention in hypersecretory airway disease.
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