Chronic airway diseases like asthma, chronic bronchitis and cystic fibrosis belong to the most frequent chronic diseases in Europe. Progress in the understanding of the pathophysiology and development of effective treatments for these diseases has been ham pered by the lack of good animal models, i.e. even "knock-out" mice for the monogenic disease cystic fibrosis lacked a lung disease phenotype. We have recently developed a novel transgenic mouse model with airway-specific overexpression of epithelial sodiu m channels (ENaC) and demonstrated that a dysbalance of airway ion transport causes a severe spontaneous lung disease that shares common features with human chronic airway diseases, including mucus obstruction, goblet cell metaplasia and inflammation (Mall M et al, Nat. Med. 2004). The overall goal of this project is to exploit and further develop this animal model for studies on the pathogenesis and the development of novel treatments for chronic airway diseases. We will test the therapeutic in vivo effect s of ion channel modulators, and novel inhibitors of inflammation and mucus hypersecretion. Furthermore, we will identify novel genes that modify disease severity in bENaC overexpressing mice by a microarray approach. Finally, we will establish a novel mou se model with an inducible chronic bronchitis phenotype to circumvent early pulmonary mortality associated with constitutive bENaC overexpression. We will use this regulated model for studies on the role of chronic exposure to allergens and pathogens, and endogenous lung repair mechanisms acting once the bENaC transgene is switched off. The success of this project will build upon the high level of expertise of the team leader and host in the proposed tasks. It will result in the establishment of an interdis ciplinary research team that will significantly contribute to a better understanding of the pathogenesis and development of more effective therapies for chronic airway diseases at a high level of excellence.
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