Our objective is to understand the functions and coupling modes of bicarbonate and proton transporters in transepithelial ion transport. HCO 3 and H are generated from H2 O and CO2 via carbonic anhydrase activity and coupled to transport of other ions by Na/H exchangers (NHE1-4), Cl/HCO exchangers (AE1-4, PAT1, DRA), Na- HCO3 cotransporters (NBCe1, NBCe2), H,K-ATPases, and others. In coupled systems, they mediate gastric acid secretion;maintain fluidity and pH of lumenal contents in intestine;recover ions and water in colon;and control acid-base, electrolyte, and fluid excretion by the kidney. To study these issues, we are utilizing mice with genetic ablation of various acid-base transporters.
In Aim 1, the mechanisms of HCl secretion in stomach and maintenance of parietal cell (PC) viability will be analyzed by testing the hypotheses that AE2 is the major basolateral Cl/HCO3 exchanger that balances HCl secretion;that AE2 is coupled with the basolateral NHE4 Na/ H exchanger for volume loading;that NHE4 and NHE2 are required for PC viability;and that CLIC intracellular Cl channels are required for acid secretion.
Aim 2 will test the hypotheses that reductions in apical NaCl absorption in the intestinal tract involving coupled Cl/HCO (PAT1, DRA) and Na/H (NHE3) exchange can correct perturbations of lumenal fluidity and pH in Cystic Fibrosis (CF) and lessen the severity of CF intestinal disease;and that basolateral AE2 in concert with apical NHE3 and/or colonic H,K-ATPase mediates Na-HCO3 and K-HCO3 absorption in the intestinal tract.
Aim 3 will test the hypotheses that NBCe1 and the AE4 Cl/HCO exchanger, each a component of coupled systems in different segments of the kidney, contribute to Na-HCO absorption;that NBCe2 mediates a unique Na-HCO secretory function in the collecting duct;and that the colonic H,K-ATPase contributes to K-HCO3 absorption in the collecting duct. These studies will expand our understanding of the coupling modes that allow these transporters to mediate both absorptive and secretory functions. They have clinical relevance to gastroesophageal reflux and other diseases involving acid secretion;diarrheas;cystic fibrosis intestinal disease;and renal mechanisms for recovery from disorders of systemic acid-base, electrolyte, and fluid-volume homeostasis caused by gastrointestinal and other diseases.

Public Health Relevance

The goal of this project is to understand the functions and interactions of proteins that transport acid (protons) and base (bicarbonate) across cell membranes in the gastrointestinal tract and kidney. To do this we are analyzing mouse models in which these proteins have been mutated. These studies will expand our understanding of the role of these transporters in absorptive and secretory functions, and have clinical relevance to gastroesophageal reflux disease;diarrheas;cystic fibrosis intestinal disease;and renal mechanisms for recovery from disorders of acid-base, electrolyte, and fluid-volume homeostasis caused by gastrointestinal and other diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK050594-17
Application #
8249143
Study Section
Clinical, Integrative and Molecular Gastroenterology Study Section (CIMG)
Program Officer
Rasooly, Rebekah S
Project Start
1996-03-01
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
17
Fiscal Year
2012
Total Cost
$458,304
Indirect Cost
$166,390
Name
University of Cincinnati
Department
Genetics
Type
Schools of Medicine
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
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Schultheis, Patrick J; Fleming, Sheila M; Clippinger, Amy K et al. (2013) Atp13a2-deficient mice exhibit neuronal ceroid lipofuscinosis, limited ?-synuclein accumulation and age-dependent sensorimotor deficits. Hum Mol Genet 22:2067-82
Coury, Fabienne; Zenger, Serhan; Stewart, Andrew K et al. (2013) SLC4A2-mediated Cl-/HCO3- exchange activity is essential for calpain-dependent regulation of the actin cytoskeleton in osteoclasts. Proc Natl Acad Sci U S A 110:2163-8
Prasad, Vikram; Lorenz, John N; Miller, Marian L et al. (2013) Loss of NHE1 activity leads to reduced oxidative stress in heart and mitigates high-fat diet-induced myocardial stress. J Mol Cell Cardiol 65:33-42
Engevik, Melinda A; Aihara, Eitaro; Montrose, Marshall H et al. (2013) Loss of NHE3 alters gut microbiota composition and influences Bacteroides thetaiotaomicron growth. Am J Physiol Gastrointest Liver Physiol 305:G697-711
Pan, Wanling; Borovac, Jelena; Spicer, Zachary et al. (2012) The epithelial sodium/proton exchanger, NHE3, is necessary for renal and intestinal calcium (re)absorption. Am J Physiol Renal Physiol 302:F943-56
Miller, Marian L; Andringa, Anastasia; Schultheis, Patrick J et al. (2011) Loss of the NHE2 Na+/H+ exchanger in mice results in dilation of folliculo-stellate cell canaliculi. J Biomed Biotechnol 2011:510827
Lorenz, John N; Lasko, Valerie M; Nieman, Michelle L et al. (2011) Renovascular hypertension using a modified two-kidney, one-clip approach in mice is not dependent on the *1 or *2 Na-K-ATPase ouabain-binding site. Am J Physiol Renal Physiol 301:F615-21
Xue, Lin; Aihara, Eitaro; Wang, Timothy C et al. (2011) Trefoil factor 2 requires Na/H exchanger 2 activity to enhance mouse gastric epithelial repair. J Biol Chem 286:38375-82
Ruminot, Iván; Gutiérrez, Robin; Peña-Münzenmayer, Gaspar et al. (2011) NBCe1 mediates the acute stimulation of astrocytic glycolysis by extracellular K+. J Neurosci 31:14264-71

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