The mammalian gastrointestinal tract undergoes morphological, biochemical, and functional changes during maturation. The P.I.'s interests have focused over the last decade on the ontogenic changes in electrolyte transport across the intestinal epithelium to achieve a better understanding of gastrointestinal disorders in early life. The P.I. initially demonstrated ontogenic changes in the activity of the Na+/H+ exchanger (NHE) in isolated intestinal brush-border membrane vesicles. In order to investigate the molecular basis of these observations, the P.I. subsequently cloned the human and rat apical Na+/H+ exchanger isoform (NHE-2). Presently there are 2 known apical isoforms, NHE-2 and NHE-3. The primary objective of the proposed studies is to determine the molecular mechanisms responsible for ontogenic changes in apical NHE gene expression in epithelial cells of the intestinal tract. Several reagents have been developed for study of NHE-2 and NHE-3, such as probes for northern blot analysis that do not cross-hybridize with other NHE isoforms, and specific polyclonal antiserum for both isoforms. The P.I. hypothesizes that apical NHEs are regulated during mammalian ontogeny to meet the changing physiological needs of the developing animal. To test this hypothesis, the P.I. will investigate six specific aims: 1) determine the pattern of spatial and temporal NHE-2 and NHE-3 gene expression during ontogenic development; 2) characterize the transcriptional and post-transcriptional mechanisms that regulate ontogenic expression of intestinal NHE-2; 3) characterize the transcriptional and post-transcriptional mechanisms that regulate ontogenic expression of intestinal NHE-3; 4) clone and characterize the NHE-2 promoter, and identify cis-acting regulatory elements; 5) determine the role that trans-acting protein factors play in regulating intestinal NHE-2 gene transcription during development, and 6) determine the role that corticosteroids and epidermal growth factors play in regulating ontogenic expression of NHE-2 and NHE-3. The proposed studies are likely to yield significant new knowledge regarding the mechanism responsible for differential expression of intestinal apical NHE's during ontogeny, and will have clinical implications for pediatric intestinal disorders.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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General Medicine A Subcommittee 2 (GMA)
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May, Michael K
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University of Arizona
Schools of Medicine
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Harrison, Christy A; Laubitz, Daniel; Ohland, Christina L et al. (2018) Microbial dysbiosis associated with impaired intestinal Na+/H+ exchange accelerates and exacerbates colitis in ex-germ free mice. Mucosal Immunol 11:1329-1341
Gurney, Michael A; Laubitz, Daniel; Ghishan, Fayez K et al. (2017) Pathophysiology of Intestinal Na+/H+ exchange. Cell Mol Gastroenterol Hepatol 3:27-40
Ghishan, Fayez K; Kiela, Pawel R (2017) Vitamins and Minerals in Inflammatory Bowel Disease. Gastroenterol Clin North Am 46:797-808
Laubitz, Daniel; Harrison, Christy A; Midura-Kiela, Monica T et al. (2016) Reduced Epithelial Na+/H+ Exchange Drives Gut Microbial Dysbiosis and Promotes Inflammatory Response in T Cell-Mediated Murine Colitis. PLoS One 11:e0152044
Kiela, Pawel R; Ghishan, Fayez K (2016) Physiology of Intestinal Absorption and Secretion. Best Pract Res Clin Gastroenterol 30:145-59
Wang, Aiping; Ling, Zongxin; Yang, Zhixiang et al. (2015) Gut microbial dysbiosis may predict diarrhea and fatigue in patients undergoing pelvic cancer radiotherapy: a pilot study. PLoS One 10:e0126312
Larmonier, C B; Shehab, K W; Ghishan, F K et al. (2015) T Lymphocyte Dynamics in Inflammatory Bowel Diseases: Role of the Microbiome. Biomed Res Int 2015:504638
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
Larmonier, Claire B; Laubitz, Daniel; Hill, Faihza M et al. (2013) Reduced colonic microbial diversity is associated with colitis in NHE3-deficient mice. Am J Physiol Gastrointest Liver Physiol 305:G667-77

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