Mitigator Efficacies after Realistic Improvised Nuclear Device (IND) Exposure: MERIE - The need for improved radiation effect mitigators stems from the significant probability of the detonation of an Improvised Nuclear Device (IND). Typically pharmaceutical radiation countermeasures have been tested against x rays delivered over a few minutes. In practice, however, 1) the majority of the IND-related radiation dose will be delivered by “direct” radiation from the IND, over a time period of less than a microsecond, and 2) A significant component (10 - 50%) of the biological effect from a ground-burst IND will be from fission neutrons. The biological effects and associated mechanisms from these IND-specific radiations are typically quite different as compared with the corresponding effects and mechanisms associated with conventional x rays delivered over a few minutes. In addition there is evidence that mitigator performance is different for these IND- specific radiation types. It is therefore important to understand whether radiation countermeasures that have been developed and tested against x rays delivered over time periods of a few minutes will also be effective in these more realistic IND exposure scenarios. At Columbia University unique radiation sources are available to simulate each of these IND-specific exposures. These tools will allow each of the Research Projects to address the same common research themes: 1. Are radiation mitigators that were developed and tested with x rays irradiated over a few minutes, also effective against a) very short, very high dose rate radiation exposures, b) IND-specific neutrons? 2. Using these realistic IND exposures, can mitigators developed for specific endpoints have utility for other key radiobiological endpoints? 3. Using these realistic IND exposures, can combining multiple mitigators that were each designed for specific endpoints, have increased overall utility if given in combination (“polypharmacy”)? In this highly synergistic proposal, the Projects and Cores are tightly linked by common research themes and hypotheses, by a shared animal model, and by shared samples and data. The WAG/RijCmcr rats that will be used sequentially manifest our radiation endpoints of interest, allowing the sequential study in the same irradiated animals of GI-ARS (Project 1), lung and kidney damage (Project 2) and cardiovascular damage (Project 3). Each Project also features state-of-the-art pharmaceutical mitigators that have already been designed and tested by the relevant project team, using conventional x rays for their respective endpoint. The Proposal also features three strong central Research Cores (Radiation, Biomarker and Statistics), unifying the Research Program. The 7 Project and Core Teams already have a strong track record of working together, with >260 Team-Team interactions in publications, and >50 Team-Team interactions in grants - largely from NIAID RNCP grants. Finally a highly experienced Administrative Core will provide fiscal management support and will organize an annual 1.5-day retreat, coupled with a full-day training session targeting junior radiation scientists.
