The airway epithelium expresses a considerable H+ conductance localized in the apical membrane where it contributes to acid release into the airway surface liquid. In April 2006 a H+ channel gene (HVCN1) was identified. Our preliminary data suggest that HVCN1 is the H+ channel found in the airways. This application explores the contribution of HVCN1 to the airway H+ conductance and its physiological function. Both our preliminary data and the described function of the H+ channel in phagocytes suggest that the H+ channel in the airways supports the NADPH oxidase DUOX1, and is thus part of airway defenses. Our general hypothesis is that HVCN1 codes for the airway epithelial H+ channel and HVCN1 supports the NADPH oxidase DUOX1.
Our specific aims are to 1) molecularly identify, express, and functionally characterize the HVCN1 H+ channel of the human airway epithelium, and 2) determine the role of the HVCN1 H+ channel in DUOX1 function.
These aims test a model in which HVCN1 is necessary for the DUOX1-based airway defenses. The proposed studies will be done by a combination of molecular biology approaches, cell culture techniques, and electrophysiological and fluorescence microscopy methods. This study will result in information about the identity of the airway H+ channel, its function, and its proposed role in airway defense. The results of this study will have public health relevance because ineffective bacterial defenses are commonly found in airway diseases.
. The innate defenses of the airways are crucial to prevent infection of the lungs with airborne pathogens, which is an important area of public health. This project will investigate a novel mechanism of airway defenses focused on the function of the proton channel of the airways, which may in the long-term lead to therapeutic applications in inflammatory airway diseases, such as cystic fibrosis or asthma.
| Fischer, Horst (2012) Function of Proton Channels in Lung Epithelia. Wiley Interdiscip Rev Membr Transp Signal 1:247-258 |
| Cho, Do-Yeon; Hwang, Peter H; Illek, Beate et al. (2011) Acid and base secretion in freshly excised nasal tissue from cystic fibrosis patients with ?F508 mutation. Int Forum Allergy Rhinol 1:123-7 |
| Iovannisci, David; Illek, Beate; Fischer, Horst (2010) Function of the HVCN1 proton channel in airway epithelia and a naturally occurring mutation, M91T. J Gen Physiol 136:35-46 |
| Fischer, Horst (2009) Mechanisms and function of DUOX in epithelia of the lung. Antioxid Redox Signal 11:2453-65 |
| Cho, D-Y; Hajighasemi, M; Hwang, P H et al. (2009) Proton secretion in freshly excised sinonasal mucosa from asthma and sinusitis patients. Am J Rhinol Allergy : |
| Fischer, Horst; Illek, Beate (2008) Activation of the CFTR Cl- channel by trimethoxyflavone in vitro and in vivo. Cell Physiol Biochem 22:685-92 |
