Terrence Barrett, MD Associate Professor Medicine and Microbiology-Immunology Chief, Division of Gastroenterology Beta catenin signaling in intestinal stem cells Curricula: Immunology and Microbial Pathogenesis Cancer Biology E-mail:   tabarrett@northwestern.edu

Studies in the Barrett lab have revealed that intestinal epithelial stem cells are activated by acute and chronic levels of inflammation as found in human Crohn’s disease and ulcerative colitis.  Furthermore, stem cell activation increases during the transition from chronic inflammation to intestinal dysplasia and cancer.  In recent studies, we found that Akt phosphorylation of the C-terminus of ß catenin leads to activation of beta catenin signaling in intestinal stem cells in both mice and human.  Using a phospho specific antibody, we find activation of stem cells at sites of crypt branching and crypt fission which are both clearly increased in dysplasia and colitis induced cancer as well as sporadic colorectal cancer.  These studies have led the lab into exploring both mechanisms for activating ß catenin signaling in intestinal stem cells as well as designing approaches for chemoprevention to inhibit phosphoinositol 3 kinase (PI3K) signaling in patients with chronic colitis and dysplasia.  The novel association of PI3K signaling and ß catenin activation in epithelial and cancer stem cells will be the major focus of the Barrett lab in the next 5 to 10 years.  Other areas of active research related to our focus on stem cells in cancer include: 1) The application of molecular probes (fluorescent probes cleaved by cellular cathepsins) for identifying early dysplasia in patients with Barrett’s esophagus, colitis-induced dysplasia, anal dysplasia in AIDS and bronchodysplasia in smokers, and 2) The application of inositol feeding to patients with dysplasia to examine if inositol can prevent PI3K signaling and reverse dysplasia by inhibiting stem cell activation.

Publications:

Lee, Ho, Ian, LJ, Hurst, SD, Miller, SD and TA Barrett. Interferon-g mediates oral tolerance by decreasing T-cell migration to peripheral sites of inflammation. Gastroenterology. 119 (July issue), 2000.

Hurst, SD, Cooper, CJ, Sitterding, SM, Choi, J, Jump, RL Levine, AD and TA Barrett. The differentiated state of lamina propria CD4+ T cells results in altered cytokine production, activation threshold and costimulatory requirements. J. Immunol. 163:5937-5945, 1999.

Hurst, SD, Sitterding, SM, Ji, S and TA Barrett. Functional differentiation of intestinal T cells in TCR transgenic mice. Proc Natl Acad Sci USA . 94: 3920-3925, 1997.