The overall goal of this research is to provide, for basic scientists and clinicians, a complete understanding of the mechanism of HCl secretion by the stomach. The proposed studies specifically examine interactions between plasma membranes and the cytoskeleton elements that support and promote the dynamic apical surface structure associated with secretory activity. The gastric parietal cell is the principal experimental model, with special emphasis on mechanisms regulating and effecting the enormous membrane recruitment and recycling processes associated with acid secretion, and which are now recognized as the means for cycling specific transport proteins in all cells. Though the parietal cell is the principal model (because its extensive surface remodeling), comparative studies will examine other epithelial systems (e.g., renal tubules, intestinal villi). The stability and turnover of actin microfilaments, and accessory bundling and capping proteins in parietal cells, will be characterized throughout the course of apical membrane expansion associated with the onset of secretion, and the reverse of this process as the cells return to rest. The functional activity of an essential membrane-cytoskeleton linker protein, ezrin, potentially provides the most important factor in these surface interactions, and proposed experiments will test the nature of its bivalent linking activity. Specific questions address: i) The role of phosphorylation, the number of phosphorylation sites, and the turnover of phosphorylation within the concept of actin binding specificity and flexibility. ii) Relative functional differences between membrane binding and actin binding domains during the secretory cycle in the parietal cell. iii) The basis for differences in actin/ezrin interactions in highly flexible, functionally variable, parietal cell microvilli, and the highly regular brush borders of intestinal and proximal tubular cells.
A complete understanding of gastric secretory mechanisms, and the application of these principles to all secretory and epithelia, has been and continues to be an important objective for NIDDK. Past discoveries led to the development and application of drugs that control acidity by receptor intervention or by directly targeting essential acid pump proteins. Aggravated conditions such as dyspepsia, ulcers, and GERD can be alleviated, and cured, by the efficacious use of these drugs. While there is a certain level of comprehension, more complete understanding will offer further insight for pathological analysis and new targets for pharmacological intervention.
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