Scientific Abstract

Proposal No. IBD-0226R
Principal Investigator: Shanthi V. Sitaraman, M.D., Ph.D.
Applicant Organization: Emory University (Atlanta, Georgia, U.S.A.)
Project Title: Prohibitin: a novel antioxidant based treatment for inflammatory bowel disease
Period of Award: January 1, 2009 – March 31, 2010

Oxidative stress as a result of increased production of pro-oxidants and reduced antioxidant defenses has been well recognized to play pathophysiologic role in IBD. In this application, we will evaluate the role of prohibitin as a novel antioxidant that acts upstream to turn on a number of antioxidants and antioxidant defense enzymes. Prohibitin is a 32 kDa evolutionarily conserved and ubiquitously expressed protein that is implicated in diverse cellular processes. The function of prohibitin in the intestine is not known. We recently demonstrated the expression and function of prohibitin in intestinal epithelial cells (FASEB J, 2007, J. Biol. Chem. 2007). Our data demonstrate: i) prohibitin is expressed by native human colonic epithelia as well as model intestinal epithelial cells, ii) prohibitin is down-regulated during oxidant stress, during active human inflammatory bowel disease (IBD) and experimental colitis, iii) prohibitin induces the expression array of antioxidant genes and restores oxidant-induced glutathione depletion through the activation of Nrf-2, a master transcription factor that activates a battery of antioxidant defense enzymes, v) overexpression of prohibitin prevents oxidant-induced NF-κB activation and barrier dysfunction and vi) Prohibitin transgenic mice are protected from DSS-induced colitis. These data uncover a previously unrecognized antioxidant role of prohibitin. Based on these data, the central hypothesis of the proposal is that decreased level of prohibitin in IBD contributes to oxidant-mediated tissue injury and inflammation and that restoration of prohibitin levels in IBD will protect from oxidative stress and tissue damage. The overall objective of this proposal, therefore, is to establish an antioxidant role for prohibitin in human IBD (specific aim 1) and provide evidence for the use of prohibitin as a therapeutic target in IBD (specific aim 2).

The completion of this proposal will not only advance our understanding of the pathophysiological role of prohibitin in IBD, but also open avenues for novel therapeutic targets to treat active flares of IBD.