Tumor necrosis factor-alpha (TNFalpha) induces multiple physiological effects through distinct signaling cascades associated with TNF receptor-type I (TNFR1) and -type II (TNFR2). TNFalpha plays an important role in the pathogenesis of inflammatory bowel disease (IBD) and neutralization of TNFalpha is effective in the treatment of Crohn's disease (CD). TNFR2 can be expressed by inflammatory cells including lymphocytes and macrophages as well as colonic epithelial cells (CEC) under inflammatory conditions, and the induction of TNFR2 expression on CEC is associated with the development of IBD. TNFR1 which is constitutively expressed on the CEC seems to be involved in the regulation of TNFR2 expression. The experiments in the proposal are designed to test the hypothesis that TNFalpha/TNFRs interactions on CEC play functionally distinct roles from those on immune cells in the development of colitis. We also hypothesize that the TNFRs mediate different responses in T helper type 1 (Th1)- and T helper type 2 (Th2)-dominant chronic colitis.
In Aim I, we plan to define the cooperative effect of TNFR1 and TNFR2 on the CEC proliferation in the context of experimental inflammation.
In Aim II, we plan to define the role of TNFR2 on CEC and macrophages in the development of Th1-mediated colitis.
In Aim III, we plan to define the role of TNFRs on CEC in the pathogenesis of Th2-mediated chronic colitis. These studies will help clarify the functional role of TNF/TNFRs interaction on CEC in the pathogenesis of IBD. This application is for a Mentored Clinical Scientist Development Award to an applicant who has completed training in internal medicine, and has received pre-and post-doctoral training in Immunology and immunopathology. The applicant's long term goals are to establish and direct her own independent basic research program in studies to link epithelial biology in inflammatory bowel disease. Accordingly, these studies are sponsored by Dr. Daniel K. Podolsky from the Division of Gastroenterology and by Dr. Atul K. Bhan from the Immunopathology Unit, both at Massachusetts General Hospital and Harvard Medical School.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08DK064289-05
Application #
7214069
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Podskalny, Judith M,
Project Start
2003-07-01
Project End
2008-08-31
Budget Start
2007-04-01
Budget End
2008-08-31
Support Year
5
Fiscal Year
2007
Total Cost
$129,870
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
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
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
Kamba, A; Lee, I-A; Mizoguchi, E (2013) Potential association between TLR4 and chitinase 3-like 1 (CHI3L1/YKL-40) signaling on colonic epithelial cells in inflammatory bowel disease and colitis-associated cancer. Curr Mol Med 13:1110-21
Low, Daren; Mizoguchi, Atsushi; Mizoguchi, Emiko (2013) DNA methylation in inflammatory bowel disease and beyond. World J Gastroenterol 19:5238-49
Nagatani, Katsuya; Wang, Sen; Llado, Victoria et al. (2012) Chitin microparticles for the control of intestinal inflammation. Inflamm Bowel Dis 18:1698-710
Kanneganti, Manasa; Mino-Kenudson, Mari; Mizoguchi, Emiko (2011) Animal models of colitis-associated carcinogenesis. J Biomed Biotechnol 2011:342637
Chen, Chun-Chuan; Pekow, Joel; Llado, Victoria et al. (2011) Chitinase 3-like-1 expression in colonic epithelial cells as a potentially novel marker for colitis-associated neoplasia. Am J Pathol 179:1494-503
Chen, Chun-Chuan; Llado, Victoria; Eurich, Katrin et al. (2011) Carbohydrate-binding motif in chitinase 3-like 1 (CHI3L1/YKL-40) specifically activates Akt signaling pathway in colonic epithelial cells. Clin Immunol 140:268-75
Tran, H T; Barnich, N; Mizoguchi, E (2011) Potential role of chitinases and chitin-binding proteins in host-microbial interactions during the development of intestinal inflammation. Histol Histopathol 26:1453-64

Showing the most recent 10 out of 27 publications