Mitigation of Gastrointestinal Damage

Columbia University Health Sciences, New York NY

Investigators

Abstract

MERIE PROJECT 1: SUMMARY/ABSTRACT Drugs are being developed to help people survive the effects of radiation from a large-scale event, such as detonation of an improvised nuclear device (IND). While several agents are already approved to treat hematopoietic acute radiation syndrome (H-ARS), which occurs at the lowest lethal radiation dose, there is still a need for mitigator drugs to treat injuries that occur at higher doses in other organ systems, such as the gut, lung, kidney and heart. Most mitigators are only tested with conventional dose rate x-rays, however, and not with the radiation types that would actually be produced in such a detonation. Some drugs that work for x-rays either don't work or can cause even more injury when exposure is from a radiation source that models actual exposures from an IND. This project will test MIIST305, a drug that protects the gut from conventional x-ray damage, to test the hypothesis that it will also work against gastro-intestinal (GI) damage caused by the types of radiation (IND-spectrum neutrons and ultra-high dose rate (UHDR) radiation) that are actually produced by a nuclear bomb. Both the survival of rats and the damage to their gut tissue will be compared for the different radiation types with and without treatment with MIIST305. Biomarkers that indicate gut damage and inflammation will be measured in samples of serum and feces. Sharing animals and samples with Projects 2 and 3 will allow the efficient study of possible MIIST305 effects on delayed radiation injuries in the gut, lung, kidney, and heart. Shared samples from Projects 2 and 3 will also be used to see if drugs designed to protect the lung, kidney, and heart from radiation injury can also reduce damage to the gut both through measurement of biomarkers in serum and feces, and through examination of the GI tissue from animals that are euthanized during the study. Together these studies will test the hypothesis that radiation mitigators developed for a specific organ system can also reduce injury in other organs following IND-neutron or UHDR exposure. Finally, a collaboration between all three Projects will combine the mitigators being developed by each project. Because radiation injury does not happen to individual organs in isolation, a real-world exposure would cause damage throughout the body. This study will test the hypothesis that combining treatments developed to individually target each of the major early and late-occurring sites of radiation injury will have an overall beneficial effect, reducing all-cause mortality as well as improving the health status of the survivors of IND- neutron and UHDR exposure. Biomarkers of GI functional integrity and inflammation will be measured in feces and serum of rats exposed to conventional dose rate x rays, IND-spectrum neutrons, or UHDR followed by combined treatment with the three mitigating agents or a treatment control.