Mitigating the Gastrointestinal Acute Radiation Syndrome by Blocking Calcium/Calmodulin-Dependent Protein Kinase Kinase 2
Abstract
Exposure of the gastrointestinal (GI) tract to ionizing radiation can cause acute injury of GI epithelial cells and death from the gastrointestinal acute radiation syndrome (GI-ARS). GI dysfunction after abdominal irradiation is a complicated process that includes enterocyte depletion, shortening of villi, and a loss of crypts that results in mucosal barrier breakdown, bacterial translocation, and sepsis. Because the survival from the GI-ARS is only possible if the GI epithelium can be successfully regenerated, there is an urgent need to develop medical countermeasures that mitigate this fatal syndrome by facilitating regeneration of the GI epithelium. Here, we propose to study a crucial gene that regulates the regeneration of the GI epithelium after radiation injury called calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2). Using genetically engineered mice, we showed that deletion of CaMKK2 markedly ameliorate the GI-ARS and improved the recovery of body weight. In this Discovery Award, we will use sophisticated genetically engineered mice to study the reason that blocking CaMKK2 ameliorates the GI-ARS. Also, we will develop STO-609, a small molecule inhibitor of CaMKK2, as a medical countermeasure that mitigates the GI-ARS. Together, our research will identify CaMKK2 as a novel target to improve the regeneration of the GI epithelium and reduce the risk of developing the GI-ARS.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910170
Entities
People
- Chang-Lung Lee
Organizations
- Duke University
- United States Army