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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK080070-01A2
Application #
7654571
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Hamilton, Frank A
Project Start
2009-04-01
Project End
2014-03-31
Budget Start
2009-04-01
Budget End
2010-03-31
Support Year
1
Fiscal Year
2009
Total Cost
$338,880
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Subramaniam, Renuka; Mizoguchi, Atsushi; Mizoguchi, Emiko (2016) Mechanistic roles of epithelial and immune cell signaling during the development of colitis-associated cancer. Cancer Res Front 2:1-21
DeGruttola, Arianna K; Low, Daren; Mizoguchi, Atsushi et al. (2016) Current Understanding of Dysbiosis in Disease in Human and Animal Models. Inflamm Bowel Dis 22:1137-50
Legarda, Diana; Justus, Scott J; Ang, Rosalind L et al. (2016) CYLD Proteolysis Protects Macrophages from TNF-Mediated Auto-necroptosis Induced by LPS and Licensed by Type I IFN. Cell Rep 15:2449-61
Low, Daren; DeGruttola, Arianna K; Poltrak, Alexander et al. (2015) High Endogenous Expression of Chitinase 3-Like 1 and Excessive Epithelial Proliferation with Colonic Tumor Formation in MOLF/EiJ Mice. PLoS One 10:e0139149
Low, Daren; Subramaniam, Renuka; Lin, Li et al. (2015) Chitinase 3-like 1 induces survival and proliferation of intestinal epithelial cells during chronic inflammation and colitis-associated cancer by regulating S100A9. Oncotarget 6:36535-50
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; Mino-Kenudson, Mari; Mizoguchi, Emiko (2014) Recent advancement in understanding colitis-associated tumorigenesis. Inflamm Bowel Dis 20:2115-23
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; 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

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