This is a competing renewal application designed to continue our studies on NHE8 (Na+/H+ exchanger isoform 8;SLC9A8), the newest member of a family of transport proteins involved in many cellular functions regulated through electroneutral Na+/H+ exchange. NHE8 is expressed in many tissues including the apical membrane of the epithelial cells in the intestine and the kidney. During the last funding period, we cloned NHE8 from the intestine and characterized its regulation during development. Furthermore, we showed that NHE8 plays a major role in apical Na+/H+ exchange during early life, and it compensates for the loss of NHE2 and NHE3 in NHE2-/-xNHE3-/- mice. We have developed a novel animal model of NHE8 deficiency and plan, in this renewal, to characterize the role of NHE8 in the gastrointestinal tract and the male reproductive system. Our central hypothesis is that NHE8 is essential for optimal HCO3- transport as evidenced by the down- regulation of DRA (down-regulated in adenoma;SLC26A3) and PAT1 (putative anion transporter 1, SLC26A6) in NHE8-/- mice. Because HCO3- is the byproduct of mitochondrial respiration and is essential for accelerating CO2 waste disposal, down regulation of HCO3- transport results in loss of control of cellular and systemic acid- base balance. Dysfunctional HCO3- transport is the basis of and a consequence of a variety of maladies. Based on the preliminary data obtained from phenotypic analysis of NHE8-/- mice, we have planned three specific aims to investigate the role of NHE8, the consequence of its loss on gastrointestinal and reproductive system development. The three specific aims are: 1) Phenotypic characterization of NHE8-/- mouse during development;2) Characterization of the role of NHE8 in the gastrointestinal tract and in response to epithelial injury;and 3) Characterization of the role of NHE8 in testicular function. The studies are novel and will yield new insight into the role of NHE8 to include regulation of ion fluxes in epithelial cells in general.

Public Health Relevance

This proposed research is relevant to public health because determining the physiological role of NHE8 and studying its mechanism of regulating bicarbonate transport will enhance our understanding of epithelial transport.

National Institute of Health (NIH)
Research Project (R01)
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Clinical, Integrative and Molecular Gastroenterology Study Section (CIMG)
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Grey, Michael J
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University of Arizona
Schools of Medicine
United States
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Ghishan, Fayez K; Kiela, Pawel R (2014) Epithelial transport in inflammatory bowel diseases. Inflamm Bowel Dis 20:1099-109
Johansson, Malin E V; Gustafsson, Jenny K; Holmen-Larsson, Jessica et al. (2014) Bacteria penetrate the normally impenetrable inner colon mucus layer in both murine colitis models and patients with ulcerative colitis. Gut 63:281-91
Xu, Hua; Li, Jing; Chen, Huacong et al. (2013) NHE8 plays important roles in gastric mucosal protection. Am J Physiol Gastrointest Liver Physiol 304:G257-61
Liu, Chang; Xu, Hua; Zhang, Bo et al. (2013) NHE8 plays an important role in mucosal protection via its effect on bacterial adhesion. Am J Physiol Cell Physiol 305:C121-8
Wang, Chunhui; Xu, Hua; Chen, Huacong et al. (2011) Somatostatin stimulates intestinal NHE8 expression via p38 MAPK pathway. Am J Physiol Cell Physiol 300:C375-82
Xu, Hua; Li, Jing; Chen, Rongji et al. (2011) NHE2X3 DKO mice exhibit gender-specific NHE8 compensation. Am J Physiol Gastrointest Liver Physiol 300:G647-53
Xu, Hua; Zhang, Bo; Li, Jing et al. (2010) Transcriptional inhibition of intestinal NHE8 expression by glucocorticoids involves Pax5. Am J Physiol Gastrointest Liver Physiol 299:G921-7
Xu, Hua; Zhang, Bo; Li, Jing et al. (2010) Epidermal growth factor inhibits intestinal NHE8 expression via reducing its basal transcription. Am J Physiol Cell Physiol 299:C51-7
Xu, Hua; Chen, Huacong; Dong, Jiali et al. (2009) Tumor necrosis factor-{alpha} downregulates intestinal NHE8 expression by reducing basal promoter activity. Am J Physiol Cell Physiol 296:C489-97
Xu, Hua; Chen, Huacong; Dong, Jiali et al. (2008) Gastrointestinal distribution and kinetic characterization of the sodium-hydrogen exchanger isoform 8 (NHE8). Cell Physiol Biochem 21:109-16