Scientific Abstract

Proposal No.  IBD-0048
Principal Investigator:  Emiko Mizoguchi, M.D., Ph.D.
Applicant Organization:  Massachusetts General Hospital (Boston, U.S.A.)
Project Title:  Role of tumor necrosis factor receptors of colonic epithelial cells in inflammatory bowel disease
Period of Award:  March 1, 2003 - May 31, 2005

Tumor necrosis factor-alpha (TNFα) induces multiple physiological effects through distinct signaling cascades associated with TNF receptor-type I (TNFR1) and -type II (TNFR2).  TNFα plays an important role in the pathogenesis of inflammatory bowel disease (IBD) and neutralization of TNFα is effective in the treatment of Crohn’s disease (CD).  TNFR2 can be expressed by various cell types including lymphocytes and macrophages as well as colonic epithelial cells (CEC) under inflammatory conditions.  TNFR1, which is constitutively expressed on the CEC, has been demonstrated to counter-regulate the TNFR2 expression.

The experiments in this proposal are designed to test the hypothesis that TNFα/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 and in human colonic epithelial cells obtained from UC or CD patient after surgery.  In Aim II, we plan to define the role of TNFR2 on the CEC and macrophages in the development of Th1-mediated experimental colitis model for human CD.  In Aim III, we plan to define the role of TNFRs on CEC in the pathogenesis of Th2-mediated experimental colitis model for human UC.
 
These studies will help clarify the functional role of TNF/TNFRs interaction on CEC in the pathogenesis of IBD.