Development of a minimally invasive biomarker assay to detect delayed radiation injury

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PROJECT SUMMARY/ABSTRACT The general population continues to be at risk of exposure to ionizing radiation because of nuclear warfare, terrorism, or radiological accidents. Some countermeasures of the acute radiation syndrome (ARS) have been placed in the national stockpile, increasing the chance of survival in a radiation emergency. However, individuals who survive the ARS may develop delayed effects of acute radiation exposure (DEARE) within months to years after irradiation. Currently, no system is available for the early identification of individuals who are at risk for DEARE and in which particular organ systems late radiation injuries will occur. Therefore, to personalize the clinical management of radiation victims, research is required to develop minimally invasive assays that predict organ-specific DEARE. However, although ~25% of the total population is pediatric, to our knowledge, no research has been performed in predictive biomarker assays of DEARE in victims who have been exposed at a young age. The main goal of the NIAID funded grant U01 AI148308 “Development of a minimally invasive biomarker assay to detect delayed radiation injury” is to develop urine and plasma biomarker assays of radiation injury to major organ systems at risk. In this parent project, the initial identification of urine and plasma biomarkers is performed with untargeted high-resolution mass spectrometry-based metabolomics in adult male and female WAG/RijCmcr rats (11-12 weeks of age) exposed to X-rays (0, 6, 9.5 and 13 Gy) with one hind-leg shielded from radiation to assure long-term survival of the animals. In years 1 and 2 of the parent U01 grant, we received supplements to perform studies in a juvenile rat model of leg-out X-ray exposure, to identify early biomarker panels that predict the development of lung, kidney and heart radiation injury. We exposed 41-44 days old male and female WAG/RijCmcr rats to a single dose of 12 Gy, 13 Gy (males), or 13.5 Gy (females). These radiation exposures resulted in radiation pneumonitis and kidney dysfunction within the first 160 days after irradiation. However, long-term kidney and heart injury could not be studied. Therefore, in this supplement application, we propose to expose female WAG/RijCmcr rats at the age of 41-44 days to 9.5 Gy leg-out X-rays. Based on our experience with adult rats, we expect that all animals will survive long-term, which will allow us to examine both kidney and cardiac dysfunction. This radiation dose will then complete a dose response study of DEARE in our juvenile rat model. Moreover, we propose to treat a subcohort of rats with the FDA-approved radiation countermeasure Neulasta, to examine its effects on DEARE as well as predictive biomarkers. We will use the same rat strain and metabolomics/lipidomics approaches as in the parent U01, which will enable us to make comparisons of biomarker panels in juvenile and adult rats.