The gastrointestinal tract undergoes significant morphological and functional changes during maturation to meet the increasing demands for nutrient transport. The major function of the gastrointestinal tract is to transport nutrients and fluids to maintain adequate electrolyte homeostasis. The gastrointestinal tract of a 1- year-old infant handles approximately 3 liters of fluid per day, resulting in only 50 grams of daily stool output, indicating the complex transport capacity of the gastrointestinal tract during early life. Our previous studies have shown that expression of the intestinal sodium/hydrogen exchangers (NHE2 and NHE3) is low during early life, and increases significantly with maturation. Moreover, the phenotypes of knockout mouse models of NHE2 and NHE3 show minimal perturbations in fluid and electrolyte balance, indicating the presence of another NHE(s) during this period of maturation. Our study demonstrates that NHE8 is expressed in the apical membrane of epithelial cells in the gastrointestinal tract, at high levels during early life, and decreasing into adulthood. This localization is similar to the finding that NHE8 is expressed apically in the renal epithelium. Therefore, the proposed studies are designed to test the hypothesis that NHE8 represents a unique, novel NHE, which is important in electrolyte homeostasis during the suckling and weaning periods of development. We plan to explore five specific aims to determine the physiological role of NHE8 and its regulation in physiological and pathological conditions.
Specific Aim 1 is designed to characterize functional and pharmacological properties of NHE8. Our second Specific Aim is designed to determine NHE8 expression along the cephalo-caudal and crypt-villus axes in the rat intestine and in NHE2/3 knock-out mice. We will also seek to further strengthen our supposition that NHE8 is expressed on the brush-border membrane of intestinal epithelial cells.
In Specific Aim 3, we plan to investigate the transcriptional mechanisms of NHE8 regulation under basal conditions and as regulated by EGF and glucocorticoids. Our preliminary data show that NHE8 gene expression is regulated by these physiological effectors. EGF and glucocorticoids are important for functional maturation of the gastrointestinal tract, and have been shown to regulate intestinal NHEs. Furthermore, known intestinal NHEs are regulated during inflammation and we plan to follow up on our preliminary observation that NHE8 is regulated during endotoxemia (e.g. LPS administration) and by TNFa exposure. Therefore our Specific Aim 4 is designed to determine the mechanism responsible for acute and chronic effects of TNFa on NHES protein and gene expression.
Specific Aim 5 is designed to define the mechanisms involved in the acute regulation of NHES by second messengers (cyclic nucleotides and intracellular calcium). Overall, the proposed studies are likely to have a significant impact on our understanding of the molecular mechanisms controlling electroneutral NaCI absorption in early life and its relationship to various perturbations of intestinal homeostasis. ? ? ?

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Clinical and Integrative Gastrointestinal Pathobiology Study Section (CIGP)
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May, Michael K
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University of Arizona
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Xu, Hua; Li, Qingtian; Zhao, Yang et al. (2016) Intestinal NHE8 is highly expressed in goblet cells and its expression is subject to TNF-? regulation. Am J Physiol Gastrointest Liver Physiol 310:G64-9
Li, Xiao; Cai, Lin; Xu, Hua et al. (2016) Somatostatin regulates NHE8 protein expression via the ERK1/2 MAPK pathway in DSS-induced colitis mice. Am J Physiol Gastrointest Liver Physiol 311:G954-G963
Wang, Aiping; Li, Jing; Zhao, Yang et al. (2015) Loss of NHE8 expression impairs intestinal mucosal integrity. Am J Physiol Gastrointest Liver Physiol 309:G855-64
Xu, Hua; McCoy, Anthony; Li, Jing et al. (2015) Sodium butyrate stimulates NHE8 expression via its role on activating NHE8 basal promoter activity. Am J Physiol Gastrointest Liver Physiol 309:G500-5
Xu, Hua; Chen, Huacong; Li, Jing et al. (2015) Disruption of NHE8 expression impairs Leydig cell function in the testes. Am J Physiol Cell Physiol 308:C330-8
Xu, Hua; Zhao, Yang; Li, Jing et al. (2015) Loss of NHE8 expression impairs ocular surface function in mice. Am J Physiol Cell Physiol 308:C79-87
Johansson, Malin E V; Gustafsson, Jenny K; Holmén-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
Ghishan, Fayez K; Kiela, Pawel R (2014) Epithelial transport in inflammatory bowel diseases. Inflamm Bowel Dis 20:1099-109
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

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