Prohibitin is a highly conserved protein that has pleiotropic functions depending on the cell and tissue type in which it is expressed. Little is known regarding the expression and function of prohibitin in the intestine. During my postdoctoral fellowship I demonstrated that 1) prohibitin is expressed by native human colonic epithelia as well as model intestinal epithelial cells, 2) in resting intestinal epithelial cells, prohibitin localizes to the mitochondria and protects against oxidative stress, 3) prohibitin is downregulated during oxidant stress, during active human inflammatory bowel disease (IBD) and experimental colitis, and 4) prohibitin transgenic mice are protected from DSS- and Salmonella typhimurium-induced colitis and oxidative stress. In assessing the mechanism by which prohibitin modulates inflammation, our preliminary data demonstrate that prohibitin is a potent activator of Nrf2, a master transcriptional regulator that activates a battery of anti-oxidant genes. In addition, our recent in vitro data demonstrate that prohibitin inhibits TNF(-induced NF-(B activation and barrier dysfunction. Based on these data, the central hypothesis of this proposal is that prohibitin functions as an epithelial defense against oxidative stress and inflammation-induced barrier dysfunction and decreased levels of prohibitin in IBD contribute to tissue injury and inflammation. The overall objective of the proposal is to determine the mechanism underlying the protective role of prohibitin in colitis. Our interrelated yet independently achievable aims based on our hypothesis and supported by preliminary data are i) to determine the role and mechanism by which prohibitin modulates Nrf2, ii) to address the mechanism of prohibitin in inhibiting NF-(B signaling and its downstream effects, and iii) to determine the in vivo mechanism by which prohibitin ameliorates colitis Together, these studies will elucidate the function and mechanism of action of prohibitin as an activator of anti-oxidants and as an anti-inflammatory molecule in intestinal epithelial cells. The training in protein biochemistry and electrophysiology the candidate will learn from executing the proposed studies will improve potential for transition to an independent IBD researcher.
This study proposes to define the function and mechanism of prohibitin in protecting against oxidative stress, NF-(B activation and barrier dysfunction, which are hallmarks of intestinal inflammation. These studies are designed to provide evidence for prohibitin as a potential therapeutic target to prevent the consequences of intestinal inflammation.
