Mitigating the Gastrointestinal Acute Radiation Syndrome by Blocking Calcium/Calmodulin-Dependent Protein Kinase Kinase 2
Abstract
The gastrointestinal acute radiation syndrome (GI-ARS) occurs after high dose total-body or abdominal radiation exposure, which inducesextensive damage to crypt stem cells of the small intestines. Severe damage to intestinal stem cells impairs regeneration of the intestinalepithelium, which can result in atrophy of the villi, loss of mucosal barrier, and sepsis. With growing concern over a mass casualty scenariocaused by a nuclear attack, it is imperative to develop novel medical countermeasures that mitigate the GI-ARS. Therefore, this project is highly relevant to the health care needs of military service members because currently there is no FDA-approved drug to mitigate the gastrointestinal syndrome induced by accidental exposure to ionizing radiation. Our preliminary data suggested that deletion of calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) markedly protected mice from the GI-ARS induced by partial body irradiation. The overall goal of this study is to define cellular mechanisms by which CaMKK2 regulates the GI-ARS and evaluate the effects of a small molecule CaMKK2 inhibitor STO-609 on mitigating the GI-ARS when administered after radiation exposure. Together, we anticipate that the outcomes from this Discovery Award will provide a foundation that we can build upon to develop a full research program that defines molecular mechanisms by which CaMKK2 functions to regulate the regeneration of the GI epithelium after radiation injury.
Document Details
- Document Type
- Technical Report
- Publication Date
- Feb 01, 2021
- Accession Number
- AD1134752
Entities
People
- Chang-Lung Lee
Organizations
- Duke University