Organ-specific NRF2-mediated protein signatures of radiation exposure & tissue da

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DESCRIPTION (provided by applicant): The overall rational of this proposal is to develop a blood test for individuals exposed to ionizing radiation (IR) to provide a personal molecular signature of exposure and exposure-related organ damage, for guidance of treatment options, and potentially for feedback of efficacy of treatment. We will perform hypothesis-driven targeted proteomics experiments that focus upon NRF2-mediated responses to IR in mice. The experiments will address a range of mouse strains, of varying age and sex, and will investigate targeted organ IR exposure. NRF2-mediated response proteins were chosen because we previously showed that single doses of ionizing radiation from 2 to 8 Gy activated antioxidant response element (ARE)-dependent transcription (via NRF2) in breast cancer cells in a dose-dependent manner, but only after delays of a day or more. Late onset and long- lived responses are especially useful for the intended biomarker rational. Our initial experiments will focus on organs and enriched sub-fractions of blood from IR-exposed mice, to provide a panel of potential tissue- specific biomarkers, for subsequent investigation of their specific presence in blood plasma. Thus our experiments will address three general hypotheses; that there are a number of NRF2-modulated proteins that will change in tissues in a dose-dependent manner in response to IR; that the patterns of damage will provide molecular signatures that report severity of overall radiation exposure, and specific individual organ stress/damage; and that some of these potential biomarkers will leak into the blood stream and persist so that they can be measured in plasma, toward human blood tests. While our experiments focus upon IR dose- dependent responses, we note that by targeting stress proteins specific to individual organs we may find biomarkers that report individual health/distress, regardless of dose, thereby accommodating individuals with unusual sensitivity.