EXCEED THE SPACE PROVIDED. Our goal is to understand the functions of ion transporters in both secretion/absorption of ions and mucosal protection in the Gl tract and in renal control of acid/base and electrolyte homeostasis. In working toward this goal, we have developed and analyzed a dozen mouse models with mutations in epithelial Na/H exchangers (NHEs), H,K-ATPases, CI/HCO3 exchangers (AEs), ion cotransporters, and channels.
Aim 1 is to develop new models, for Slc4a bicarbonate transporters (NBC1 Na/HCO3 cotransporter, AE4, Slc4a10, and Slc4a11) and the KVLQT1 K channel.
In Aim 2, transport mechanisms underlying gastric acid secretion and mucosal protection will be analyzed. We will test the hypothesis that KVLQT1 is essential for acid secretion and that AE4, NHE2, and NHE4 function in mucosal protection. NHE knockout mice with transgenic rescue of NHE expression in parietal cells, which should restore acid secretion, will be used to assess the mucosal protection role of each NHE in mucous cells.
In Aim 3, the intestinal absorptive and secretory functions of AEs and NBCs of the Slc4a family, and of NHE1, will be analyzed to determine which NBC works in concert with AE2 to support anion secretion, whether NHE1 supports secretion, whether an alternative Na absorptive mechanism in the NHES knockout is due to NHE2 or one of the NBCs, and whether apical AE4 is needed for absorption and/or mucosal protection.
Aim 4 will include studies of the general roles and relative importance of the Slc4a transporters in renal function, NHE2 in renal HCO3 excretion, ROMK in electrolyte recovery, and the colonic and gastric H,K-ATPases in K recovery during dietary K depletion coupled with excess HCO3 delivery to the collecting duct. A proximal tubule absorptive defect is predicted for the NBC1 KO, reduced tubular HCO3 secretion in alkali-loaded AE4 and NHE2 KOs, and K-wasting in the HKA mutants. These studies will substantially expand our understanding of the specific functions of individual transporters and how they work together to mediate transepithelial ion transport and mucosal protection in vivo. PERFORMANCE SITE ========================================Section End===========================================
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