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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Small Research Grants (R03)
Project #
5R03DK069915-02
Application #
6951961
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Podskalny, Judith M,
Project Start
2004-09-30
Project End
2006-01-31
Budget Start
2005-08-01
Budget End
2006-01-31
Support Year
2
Fiscal Year
2005
Total Cost
$73,750
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905