Inflammatory bowel diseases (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), are a group of chronic inflammatory disorders that affect individuals throughout life. Several studies have indicated that dysregulated host/enteric bacterial interactions are required for the development of chronic intestinal inflammation. However, the exact mechanisms underlining the initial host/microbial interaction in triggering colitis and the following steps for exacerbating colitis have not been fully defined. We have recently identified a novel, intestinal inflammation-associated inducible molecule Chitinase 3-like-1 (CHI3L1) that is produced by colonic epithelial cells (CECs) and lamina propria cells. CHI3L1 may be involved in the pathogenesis of colitis by enhancing intracellular bacterial adhesion and internalization on/into CECs. A major goal of this study is to define the biological significance of CHI3L1 in the pathogenesis of colitis.
In Aim -I, we will examine the in vivo biological function of CHI3L1 in the pathogenesis of murine models of acute and chronic colitis actively in vivo through administration of the specific antibody.
In Aim -II, we will test the interaction between microorganism-derived chitin-binding proteins and CEC-derived CHI3L1 in the adhesion and invasion of microorganisms to CECs.
In Aim -III, we will define a prophylactic effect of orally administered chitin, a polymer of N-acetylglucosamine and substrate for CHI3L1, in animal models of acute and chronic colitis. These studies will help clarify the critical role of CHI3L1 in inflammation and provide a rationale for the development of novel anti- CHI3L1 based immuno-therapeutics, as well as chitin sensitization-based prophylactic approaches in IBD. We believe that the data obtained from this study would provide an important clue for understanding the role of CHI3L1 in the pathogenesis of IBD.

Public Health Relevance

The specific aims of this proposal are designed to define the biological function of chitinase 3-like-1 and chitin in the pathogenesis of IBD. These studies will provide important information for developing therapeutic and prophylactic approaches in human IBD in the near future.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
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Grey, Michael J
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Massachusetts General Hospital
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Tran, Hoa T; Lee, In-Ah; Low, Daren et al. (2014) Chitinase 3-like 1 synergistically activates IL6-mediated STAT3 phosphorylation in intestinal epithelial cells in murine models of infectious colitis. Inflamm Bowel Dis 20:835-46
Lee, In-Ah; Kamba, Alan; Low, Daren et al. (2014) Novel methylxanthine derivative-mediated anti-inflammatory effects in inflammatory bowel disease. World J Gastroenterol 20:1127-38
Low, Daren; Mino-Kenudson, Mari; Mizoguchi, Emiko (2014) Recent advancement in understanding colitis-associated tumorigenesis. Inflamm Bowel Dis 20:2115-23
Lee, In-Ah; Low, Daren; Kamba, Alan et al. (2014) Oral caffeine administration ameliorates acute colitis by suppressing chitinase 3-like 1 expression in intestinal epithelial cells. J Gastroenterol 49:1206-16
Low, Daren; Tran, Hoa T; Lee, In-Ah et al. (2013) Chitin-binding domains of Escherichia coli ChiA mediate interactions with intestinal epithelial cells in mice with colitis. Gastroenterology 145:602-12.e9
Low, Daren; Mizoguchi, Atsushi; Mizoguchi, Emiko (2013) DNA methylation in inflammatory bowel disease and beyond. World J Gastroenterol 19:5238-49
Yamamoto, Shuji; Nakase, Hiroshi; Matsuura, Minoru et al. (2013) Heparan sulfate on intestinal epithelial cells plays a critical role in intestinal crypt homeostasis via Wnt/*-catenin signaling. Am J Physiol Gastrointest Liver Physiol 305:G241-9
Low, Daren; Nguyen, Deanna D; Mizoguchi, Emiko (2013) Animal models of ulcerative colitis and their application in drug research. Drug Des Devel Ther 7:1341-57
Kawada, M; Seno, H; Kanda, K et al. (2012) Chitinase 3-like 1 promotes macrophage recruitment and angiogenesis in colorectal cancer. Oncogene 31:3111-23
Nishida, Atsushi; Lau, Cindy W; Zhang, Mei et al. (2012) The membrane-bound mucin Muc1 regulates T helper 17-cell responses and colitis in mice. Gastroenterology 142:865-874.e2

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