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Physiological function and transport mode of the anion transporter SLC26A9 in the gastric and alveolar epithelium

Subject Area Anatomy and Physiology
Term since 2024
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 426950122
 
The anion transporter SLC26A9 is strongly expressed in the epithelia of the airways and the stomach and to a lesser degree in the upper intestine, pancreas, and kidney. Polymorphisms in Slc26a9 are associated with worse clinical outcomes in the intestinal, pancreatic and respiratory tract of patients with cystic fibrosis. Slc26a9-deleted mice also develop respiratory, small intestinal and pancreatic functional deficits, but the most prominent features in slc26a9-/- mice is a very high mortality of the neonates, possibly due to an inability to effectively clear the lung alveoli of fluid, and a loss the ability to secrete gastric acid during adolescence, with consecutive rapid development of gastric neoplasias. SLC26A9 is the first mammalian member of the SLC26 family whose molecular structure was elucidated by cryo-electron microscopy. It has been characterized as a fast-gating Cl- uniporter with a potential to also operate in a channel mode. Despite this advance, the physiological transport function of SLC26A9, its cellular location, the interaction partners, and the regulation of its transport rate in the native epithelia has remained unclear. This project therefore has three objectives: 1. We aim to elucidate the exact cellular localization of SLC26A9 in murine and human gastric, airway, pancreatic and intestinal epithelia. 2. We will generate human gastric organoids, knock out SLC26A9 by Crispr/Cas9 technology, express flag-tagged SLC26A9 in these KO organoids, and study SLC26A9 transport function and its regulation by comparison of control, SLC26A9-deleted and flag-tagged SLC26A9 organoid-derived epithelial monolayers, using electrophysiological, fluorometric, biochemical and confocal techniques, 3. We will establish alveolar monolayer cultures from murine or human lung and clarify the function of Slc26A9 in the alveoli. The overall result of the project will be an understanding of the cellular expression and physiolog-ical function of endogenous SLC26A9 in the epithelia with the highest endogenous SLC26A9 expression levels.
DFG Programme Research Units
 
 

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