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Research at Mass General
Emiko Mizoguchi, M.D., Ph.D. Principal Investigator Assistant Professor of Medicine, Harvard Medical School Assistant Immunologist, Department of Medicine, Massachusetts General Hospital Investigator, Center for the Study of Inflammatory Bowel Disease at Massachusetts General Hospital
Gastrointestinal Unit, GRJ 825D55 Fruit Street, Boston, MA 02114Lab Phone: (617) 723-1736Office Phone: (617) 726-7892Fax: (617) 726-3673E-mail: email@example.com
We investigate the basic cellular and molecular mechanisms involved in the functional modulation of colonic epithelial cells (CEC) during the development of inflammatory bowel disease (IBD). Our primary study includes identifying key molecules which regulate CEC/microorganism interaction, CEC/lamina propria cell interaction and intestinal epithelial cell barrier function.
Current Lab Members
Renuka Subramaniam, DVM, Ph.D.
Rita Kumari, Ph.D.
Arianna DeGruttola, B.S.
Barbara Steele - Grant Manager
Former Lab Members
Daren Low, Ph.D. (A*STAR Graduate Academy, Singapore)
In-Ah Lee, Ph.D. (JINIS Biopharmaceutical Co., Wanju, South Korea)
Tsuyoshi Mishiro, M.D. Ph.D. (Shimane Medical University, Simane, Japan)
Our research group has utilized experimental models of IBD to understand the mechanisms in the pathogenesis of chronic colitis, which include T cell receptor alpha chain knockout (KO) mice, CD45RBhi cell transfer mice, IL-10 KO mice, IL-2 KO mice, and dextran sulfate sodium induced colitis models (Inflamm Bowel Dis, 2003; J Gastroenterol, 2008; Curr Opin Pharmacol, 2010 in press).
My laboratory currently focuses on studying the functional role of the Chitinase 3-like-1 (CHI3L1) molecule in the colonic mucosa (mainly expressed in CEC and macrophages). Our studies have demonstrated that CHI3L1 upregulation is a common factor in intestinal inflammation as indicated by the upregulation of this molecule in acute and chronic colitis models as well as human IBD. The CHI3L1 molecule was upregulated after pro-inflammatory cytokine stimulation and enhanced the adhesion and internalization of intracellular bacteria in epithelial cells. Most importantly, in vivo neutralization of CHI3L1 activity significantly suppressed the development of acute colitis by dramatically decreasing bacterial invasion of the intestinal mucosa. Our present study provides a novel insight into the physiological role of mammalian chitinases in host/microbial interactions (Gastroenterology, 2006; Immunologic Research, 2007; Lab Invest, 2008). We will expand our study of CHI3L1 and other members of mammalian chitinases (e.g., acidic mammalian chitinase and chitotriosidase) in relation to acute and chronic colitis in animal models as well as human IBD.
Furthermore, we propose to test the hypothesis that oral administration of low doses of chitin micro-particles ameliorates intestinal inflammation in both acute and chronic colitis. Chitinase-like molecules are most likely a potential therapeutic target that can be manipulated to control IBD and other forms of inflammatory disorders. Furthermore, it has been reported that CHI3L1 is not synthesized by healthy individuals but shows significantly increased production in the serum of patients with IBD as well as colon cancer (World J Gastroenterol 2009). Utilizing colonic samples obtained from patients with colitis-associated cancer (CAC), a mouse model of CAC and an in vivo experimental system, we are now analyzing the biological function of CHI3L1 in the pathogenesis of IBD and following CAC.
In addition to this major project, our laboratory focuses on the biological function of tumor necrosis factor receptor type-I (TNFR1) and type-II (TNFR2) associated with CEC in colitis. TNFR1 protein is constitutively expressed on wide variety of cell types, but TNFR2 is only expressed on highly activated cells. It has been well characterized that the dual signaling pathways (cell death and cell proliferation) are stimulated by TNFR1 and TNFR2 in T cells. Recently, we have identified that TNFR2 expression is induced on the surface of CEC under inflammatory conditions seen in human IBD as well as several murine models of colitis (Gastroenterology, 2002). Recently, we identified that TNFR1-signaling cascade in colonic myeloid lineage cells contributes to the suppression of acute damage associated mortality by controlling CEC homeostasis (Gastroenterology, 2008). Although it is clear that TNF/TNFRs interactions in T cells play a crucial pathogenic role in colitis, the effects of TNF/TNFRs interactions on CEC function have not been fully defined yet. Our studies will help clarify the distinct roles of TNFRs in the pathogenesis of colitis and providing new therapeutic approach based on the modification of TNF/TNFRs interactions in human IBD.
We strongly believe that our studies will provide novel insight into the mechanisms by which a previously undescribed host/microbial interaction regulates intestinal inflammation.
Selected from 71 original articles and 12 review articles:
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