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

Musch MW, Bookstein C, Rocha F, Lucioni A, Ren H, Daniel J, Xie Y, McSwine R, Rao MC, Alverdy J, and Chang EB. (2002). Region-specfic adaptation of apical Na+/H+ exchanges after extensive proximal small bowel resection. Am J Physiol. 283: G975-G985.

Musch MW, Clarke LL, Mamah D, Gawenis LR, Zhang Z, Ellsworth W, Shalowitz D, Mittal N, Efthimiou P, Alnadjim Z, Hurst SD, Chang EB, and Barrett TA. (2002). T-cell activation causes diarrhea by increasing intestinal Na/K ATPase. J Clin Invest 110: 1739-1747.

Ropeleski M, Tang J, Walsh-Reitz M, Musch M, Larson R, Chang EB. (2003). Interleukin-11 induces heat shock protein25 confers intestinal epithelial-specific cytoprotection from oxidant stress. Gastroenterol 124:1358-68.

Kojima K, Musch M, Ren H, Boone D, Hendrickson B, Ma A, Chang EB. (2003). Enteric flora and lymphocyte-devived cytokines determine expression of Hsp in mouse colonic epithelial cells. Gastroenterol 124:1395-07.

Toback FG, Walsh-Reitz MM, Musch MW, Chang EB, DelValle J, Ren H, Huang E, Martin T. (2003). Peptide fragments of AMP-18, a novel secreted gastric antrum mucosal protein, are mitogenic anf motogenic. Am J Physiol. 285:344-53.

Wu L, Holbrook C, Zaborine O, Ploplys E, Rocha F, Pelham D, Chang EB, Musch M, Alverdy J. (2003). Pseudomonas aeruginosa express a lethal virulence determinant, the PA-I lectin/adhesion, in the intestinal tract of a stressed host: the role of epithelia cell contact and molecules of the Quorum Sensing Signaling System, Ann Surg 238:754-64.

Musch MW, Kapil A, Chang EB. (2004). Heat shock protein72 binds and protects dihydrofolate reductase against oxidative injury. Biochim Biophys Res Com 313:185-192.

Vavricka SR, Musch MW, Chang JE, Nakagawa Y, Phanvijhitsiri K, Waypa TS, Merlin D, Schneewind O, Chang EB. (2004). hPepT1 transports muramyl dipeptide, activating NF-kappaB and stimulating IL-8 secretion in human colonic Caco2/bbe cells. Gastroenterology. 127(5):1401-9.

Petrof EO, Kojima K, Ropeleski MJ, Musch MW, Tao Y, De Simone C, Chang EB. (2004). Probiotics inhibit nuclear factor-kappaB and induce heat shock proteins in colonic epithelial cells through proteasome inhibition. Gastroenterology.127(5):1474-87.

Arvans DL, Vavricka SR, Ren H, Musch MW, Kang L, Rocha FG, Lucioni A, Turner JR, Alverdy J, Chang EB. (2004). Luminal Bacterial Flora Determines Physiological Expression of Intestinal Epithelial Cytoprotective Heat Shock Proteins, Hsp 25 and Hsp 72. Am J Physiol Gastrointest Liver Physiol. [Epub ahead of print]