Biomarkers to identify regional exposure to radiation

PROJECT SUMMARY
The overall objective of this application, set within the context of radiation exposure during a public health
emergency, is to develop a panel of biomarkers to discriminate between exposure of upper- and lower-body
organs to radiation that will predict health outcomes. Currently, there is a marked gap in knowledge in the
radiation effects community in that biomarkers are not available to identify individual organs exposed to radiation.
To predict clinical outcomes after a radiation emergency, it is essential to know whether total- or partial body
exposures occurred. Detonation of an improvised nuclear device will result in heterogeneous patterns of partial-
body irradiation, whereas nuclear accidents will predominantly result in total body exposure. We will evaluate
microRNAs early after radiation exposure as biomarkers that can identity the individual organ irradiated to
develop an assay to assess late injury to kidney and heart. The study aims to reveal microRNA expression
changes in blood samples. MicroRNAs present in blood serve as early biomarkers of exposure to total body
radiation. However, the changes reported are not specific to individual organs. Innovative studies are proposed
that will overcome these limitations by determining organ-specific changes in microRNA following exposure to
radiation. Establishing an accurate, integrated microRNA signature that can be developed for biodosimetry
requires an understanding of the factors that cause differences in radiation responses across the general
population. The research proposed will allow us to detect whether exposure of the lower body, containing the
kidneys, or exposure of the upper body, containing the heart, releases microRNAs specific to these organs into
the blood to predict whether kidney and heart will become injured. We will utilize the well-established and
validated WAG/RijCmcr rat model to assess single-fraction total body vs. upper vs. lower body effects
consequent to X-radiation. The total body (95% body exposed), lower body (50% body exposed) and upper body
(50% body exposed) of adult male and female WAG/RijCmcr rats will be exposed to X-radiation. It is
hypothesized that microRNAs in blood can be developed as organ-specific biomarkers to discriminate between
exposure of upper- and lower-body organs to radiation. Two aims are proposed. Aim 1 will determine the latency,
incidence, severity, and progression/duration of respective sequelae for delayed effects of acute radiation
exposure for kidney and heart injury after total-, lower- and upper-body exposure to radiation. Aim 2 will
determine the levels of microRNA in blood after irradiation of the total, upper- and lower body. MicroRNA levels
in blood will be correlated with heart and kidney histopathology. This study will contribute to the development of
a novel diagnostic approach for assessing multi-organ injury from exposure to radiation that will permit future
biodosimetry studies. The outcomes will close the knowledge gap relative to organ-specific responses that can
yield novel insights into radiation-dependent injury and may uncover potential therapeutic targets for mitigating
radiation-induced tissue injury and allow microRNAs to be developed for organ-specific biodosimetry.

Grant Number: 1R21AI193636-01
NIH Institute/Center: NIH
Principal Investigator: JOHN BAKER