Injury to the small intestinal epithelium is a major adverse effect of abdominal radiation therapy. Ionizing radiation (IR) induces apoptosis of epithelial cells in the crypts of the small intestine. Above a critical threshold of exposure, IR kills clonogenic stem cells leading to crypt death. This results in widespread mucosal injury and causes the acute post-IR gastrointestinal (GI) syndrome, which leads to malnourishment, sepsis and death. The long-term goal of this project is to characterize the molecular regulation of IR-induced intestinal injury. Our studies to date have revealed a previously unrecognized endogenous mechanism of protection against IR-induced apoptosis in intestinal epithelial cells: activation of the DNA damage- responsive transcription factor NF-kappa B. In the proposed research, we will determine the role of intestinal epithelial cell NF-kappa B in protection against the post-IR GI syndrome. Our central hypothesis is that intestinal epithelial cell NF-kappa B decreases the severity of the post-IR GI syndrome by inhibiting crypt death.
In specific aim 1, determine the amount of IR required for NF-kappa B activation in the small intestine, the cell types that activate it and whether it is activated during crypt regeneration.
In specific aim 2, we will determine if NF-kappa B affects the death or proliferative potential of crypt clonogenic stem cells, thereby affecting the development of post-IR GI syndrome. These results will provide mechanistic insight into an important medically relevant problem, amd will point the way towards novel therapies to prevent radiation injury to the intestines.
