Grant: CAG/CCFC/CIHR Summer Studentship for Research in Gastroenterology

Clostridium difficile (Cdf)-associated diarrhea (CDAD) is a severe medical condition with increasing incidence and mortality rates worldwide. Even with optimal medical care patients can develop toxic megacolon, sepsis, and death. In the USA and Canada, nearly 30,000 deaths were attributable to advanced CDAD in 2005, a number which is almost double the current annual number of HIF-related deaths. After assessing what was known of how Cdf toxins caused intestinal injury, we looked for innate protective agents or pathways that could counteract the damaging actions of C. difficile. The hypoxia inducible factor-1 (HIF-1) is a key regulatory molecule that can protect the intestine from severe inflammation. Thus, we have hypothesized that HIF-1 plays an important role in Cdif toxin-induced intestinal injury. Our studies have progressed so that we can now state that Cdf toxins directly induce HIF-1 activity and that HIF-1 plays a critical innate protective role in Cdf-induced intestinal injury. Since we now know that HIF-1 is protective in Cdif toxin-induced injury, we would predict that those patients that fail to adequately induce HIF-1 activity or have altered signaling downstream of HIF-1 may be more likely to develop severe CDAD. In this project, we wish to determine specifically how Cdif toxin and/or CDAD-associated injury and inflammation up-regulates HIF-1 protein abundance and protective activity. We will employ biochemical as well as physiological experimentation to examine whether a molecule (nitric oxide, NO) that is released during intestinal inflammation acts to modify the HIF-1 protein and prevent its degradation within the cell. We have preliminary data to suggest that this mechanism may increase the HIF-1 protective capacity within the intestine during CDAD. In summary, we believe that our studies suggest that HIF-1 may be employed as a new therapeutic tool in this devastating disease.