Scientific Abstract

Proposal No.  IBD-0020R
Principal Investigator:  Giovanni Monteleone, M.D., Ph.D.   
Applicant Organization:  University Tor Vergata of Rome (Italy)  
Project Title:  Role of Smad7, an inhibitor of TGF-β1 signaling, in chronic intestinal inflammation
Period of Award: September 1, 2002 - November 30, 2004

There is little doubt that TGF-β1 plays a key role in maintaining intestinal homeostasis and controlling inflammation.  Defective TGF-β1 activity promotes and/or exacerbates chronic intestinal inflammation such as Crohn's disease.  We have recently shown that Smad7, an inhibitor of TGF-β1 signaling, is upregulated in inflammatory bowel disease (IBD) mucosa, and that this results in hyporesponsiveness of mucosal cells to TGF-β1 and perhaps promotes inflammation.

In the present project, we plan to elucidate some mechanisms underlying the ability of TGF-β1 to maintain intestinal homeostasis.  We also plan to further characterize the involvement of Smad7 in the pathogenesis of IBD, first by drawing attention to the factors/mechanisms which regulate Smad7 production in IBD mucosal cells, and then considering the role of this protein in specific inflammatory pathways, including NF-κB activation and resistance of T cells to apoptotic stimuli.  Results from the proposed experiments will shed light on the interaction between Smad7 and other signaling pathways in IBD and establish if blocking Smad7 can decrease intestinal inflammation, and thus improve therapy of patients with IBD.