Eugene Chang, M.D.

Intestinal Adaptation Mechanism for Nutrient and Electrolyte Absorption in Disease and Hormonal Regulation of Intestinal Absorption and Secretion

Research Summary

We have two major research interests:

1. Characterization of expression and function of Na-H exchange isoforms (NHE)

Although NHE isoforms are structurally similar and have similar transport characteristics, they markedly differ in tissue expression, regulation, and functional activation in a physiological setting. To study the structure-function properties of NHE isoforms, we are employing a combined approach of site-directed mutagenesis, cassette swapping, and chimeric constructions with physiological measurements in epithelial and mesenchymal cell expression systems. We are also characterizing the physiological determinants of tissue-specific NHE isoform expression. Specific transcriptional and post-translational mechanisms mediating alterations in expression are being studied. Finally, using chimeric constructs, mutational analysis, and natural mRNA splicing variants of NHE, we are trying to identify the determinants of NHE protein sorting and/or membrane stabilization in stable transfectants of epithelial cell lines. Membrane trafficking is followed biochemically and by laser scanning confocal microscopy.

2. The role of heat shock protein in mucosal cytoprotection

Heat shock proteins (HSPs) are a highly conserved family of molecules which are essential for numerous esesntial cellular functions. Although many types are constitutively expressed, some, such as HSP 70, are rapidly induced and preferentially synthesized under conditions of cellular stress and injury. In epithelial cells, their induction protects against toxic, oxidant, and thermal injury. Our laboratory, therefore, is investigating cellular and molecular mechanisms that mediate their cytoprotective effects in the context of mucosal inflammation. These studies involve correlations of molecular and biochemical techniques with physiological findings and imaging analysis.

Selected Papers

Arvans D, Vavricka SR, Ren H, Musch MW, Kang L, Rocha F, Lucioni A, Turner J, Alverdy J, Chang EB. Luminal bacterial flora determines physiological expression of intestinal epithelial cytoprotective heat shock proteins, Hsp 25 and Hsp72. Am J Physiol 288: G696-G704, 2005

Shiue H, Yingman W, Musch MW, Chang EB, Turner JR.  Akt2 phosphorylates ezrin to trigger NHE3 translocation and activation. J Bio Chem  280(2):1688-1695, 2005

Sun J, Hobert M, Duan Y, Rao A, He TC, Chang EB, Madara JL.  Crosstalk between NF-kB and beta-catenin pathways in bacterial-colonized intestinal epithelial cells.  Am J Physiol  Mar.24, 289: G129-G137,  2005

Ropeleski MJ, Riehm J, Baer KA, Musch MW, Chang EB.  Anti-apoptotic effects of L-Glutamine mediated transcriptional modulation of the Heat Shock Protein 72 during heat shock. Gastroenterol 129:170-84, 2005

Wu L, Estrada O, Zaborina O, Bains M, Le S, Kohler JE, Patel N,  Musch MW, Chang EB, Fu Y, Jacobs MA, Nishimura MI, Hancock REW,  Turner JR, Alverdy JC.  Recognition of host immune activation by Pseudomonas aeruginosa.   Science   309: 774-777, 2005

Vavricka SR, Musch MW, Fujiya M, Kles KA, Chang L, Elorante J, Kullak-Ublick GA, Drabik K, Merlin D,  Chang EB. TNF-α and IFN-γ induce hPepT1 expression and activity in the human colon carcinoma cell line Caco2/bbe cells and in mouse intestine.  Pflugers Arch- Eur J Physiol 452: 71-80, 2006

Musch MW, Walsh-Reitz MM and Chang EB.  Roles of ZO-1, Occludin and Actin  in oxidant-induced barrier disruption. Am J Physiol 290:G222-231, 2006

Wu L, Kohler JE, Zaborina O, Akash G, Musch MW, Chang EB, and Alverdy JC. Chronic acid water feeding protects mice against lethal gut-derived sepsis due to Pseudomonas aeruginosa. Curr Issues Intest Microbiol. 7(1):19-28, 2006

Tao Y, Drabik KA, Waypa TS, Musch MW, Alverdy J,  Schneewind O, Chang EB, and Petrof EO.  Soluble factors from the probiotic Lactobacillus GG activate MAP kinase and induce cyto-  protective heat shock proteins in intestinal epithelial cells. Am J Physiol . 290: C1018-1030,  2006

Phanvihitsiri K, Musch MW, Ropeleski MJ, Chang EB. Heat-Induction of Heat Shock Protein 25 Requires Cellular Glutamine in Intestinal Epithelial Cells. Am J Physiol  291(2):C290-C299, 2006

Carlson RM, Vavricka SR, Eloranta JJ, Mushc MW, Arvans DL, Kles KA, Walsh-Reitz MM, Kullak-Ublick G and Chang EB.  fMLP induces hsp27 expression, Attenuates NFkB activation and confers intestinal epithelial cell protection.  Am J Physiol , 292(4):G1070-G1078, 2007

Musch MW, Arvans, D, Walsh-Reitz M, Uchiyama K, Fukuda M and Chang EB.  Synaptotagmin I binds intestinal epithelial NHE3 and mediates cAMP-and Ca2+-induced endocytosis by recruitment of AP2 and clathrin. Am J Physiol, 292(6):G1549-G1558, 2007

Fujiya M, Musch MW, Nakagawa Y, Hu S, Alverdy J, Kohgo Y, Schneewind O, Jabri B, Chang EB. The Bacillus subtilis quorum-sensing molecule CSF contributes to  intestinal homeostasis via OCTN2, a host cell membrane transpoter. Cell Host and Microbe,  1(4) 299-308, 2007

Hu S, Ciancio MJ, Lahav M, Fujiya M, Lichtenstein L, Anant S, Musch MW, Chang EB. Translational inhibition of colonic epithelial heat shock proteins by interferon –gamma and TNF-alpha in IBD. Gastroenterology   133:1893-1904 , 2007

Petrof EO, Musch MW, Ciancio MJ,  Sun J, Hobert ME, Claud EC, Gewirtz A, and Chang EB.  Flagellin is required for Salmonella-induced expression of heat shock protein Hsp25 in intestinal epithelium.  Am J Physiol,  294: G808-G818 2008

Musch MW, Lucioni A and Chang EB. Aldosterone regulation of intestinal Na absorption involves SGK-mediated changes in NHE3 and Na+ pump activity.  Am J Physiol Gastrointest Liver Physiol. 2008 Sep 18