With funding from a pilot project from the Harvard Center for Medical Countermeasures against Radiation, we have utilized sophisticated mouse genetics to determine the role of the intrinsic pathway of apoptosis in the acute radiation syndrome. Through these studies, we have dissected the cellular target of radiation in the GI syndrome and these data suggest that mitotic death (rather than apoptotic death) of GI crypt epithelial cells causes crypt destruction that leads to the GI Syndrome. In this application, we will test this model using a combination of mouse genetics and small molecule inhibitors to block mitotic death. These studies will help define the mechanism of action of a novel medical countermeasure, which we have shown protects mice from the GI Syndrome. The overall goal of this application is to understand the mechanism of action of this countermeasure and to define the pharmacokinetics and pharmacodynamics of this product, so that it can be developed into a safe and effective agent to help minimize damage and restore GI function after radiation exposure. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
NIH Challenge Grants and Partnerships Program (RC1)
Project #
1RC1AI078521-01
Application #
7472909
Study Section
Special Emphasis Panel (ZAI1-MP-I (S3))
Program Officer
Dicarlo-Cohen, Andrea L
Project Start
2007-09-01
Project End
2010-02-28
Budget Start
2007-09-01
Budget End
2010-02-28
Support Year
1
Fiscal Year
2007
Total Cost
$999,964
Indirect Cost
Name
Duke University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Sullivan, Julie M; Jeffords, Laura B; Lee, Chang-Lung et al. (2012) p21 protects ""Super p53"" mice from the radiation-induced gastrointestinal syndrome. Radiat Res 177:307-10
Kirsch, David G (2011) Using genetically engineered mice for radiation research. Radiat Res 176:275-9
Kirsch, David G; Santiago, Philip M; di Tomaso, Emmanuelle et al. (2010) p53 controls radiation-induced gastrointestinal syndrome in mice independent of apoptosis. Science 327:593-6