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Identification and Validation of Biodosimetry Markers in Multiple Models of Radiation Exposure
EPA Grant Number: FP916948Title: Identification and Validation of Biodosimetry Markers in Multiple Models of Radiation Exposure
Investigators: Upton, Ashley N.
Institution: University of Alabama at Birmingham
EPA Project Officer: Thompson, Delores
Project Period: September 1, 2008 through August 31, 2011
RFA: STAR Graduate Fellowships (2008)
Research Category: Academic Fellowships
Description:
Objective:In the event of an ecological (industrial) or terrorism related radiation exposure, emergency radiation dose assessment will be necessary to reduce mortality through early medical intervention. Retrospective radiation dose assessment is limited to monitoring clinical symptoms, cytogenetic analysis and, when available, physical dosimetry badges. Unfortunately, rapid, minimally invasive and reliable biodosimetry assays remain to be developed. The identification and validation of biomarkers capable of both qualitative (yes/no) and quantitative (dose) radiation dose assessment through the analysis of biological information stored in the human body would facilitate rationally directed medical treatment.
The ultimate goal of this project is to identify and validate biodosimetry markers capable of radiation dose assessment in multiple models of radiation exposure.
Approach:Studies being conducted at Children’s Hospital and the Comprehensive Cancer Center at the University of Alabama at Birmingham include obtaining whole blood from patients undergoing myeloablative therapy with total body irradiation (TBI) administered over 3 days divided into 2 daily doses of 2 Gy each (total=12 Gy). Preliminary studies examined changes in gene expression at 5 and 23 hours post-irradiation using Taqman low density array (TLDA). Results identified 17 potential radiation-responsive genes. Following these initial studies, we conducted a comprehensive literature search which revealed 29 potential biodosimetry genes identified by other investigators in multiple models including mice, lymphoid cell lines, ex vivo whole blood, peripheral blood lymphocytes, and TBI patients. In future studies, we will expand our research to examine the 17 genes identified in our preliminary data, together with the 29 genes identified by other investigators (total = 46 genes) in patients receiving TBI. Gene expression will be measured before TBI (baseline) and at multiple time points after each 2 Gy fraction. Potential biodosimetry markers will also be examined in immortalized B lymphocytes and in mouse models to determine the effects of radiation dose and cellular microenvironment. Linear and higher-order polynomial regression analyses will be used to identify mathematical models defining time- and dose-dependent changes in gene expression. Additional studies will focus on determining the molecular basis of radiation induced changes in gene expression through analysis of mRNA half-life and/or changes in gene transcription.
Expected Results:Identification of molecular biomarkers is a sensitive new tool that can be utilized for the development of robust assays capable of radiation dose assessment. The proposed studies will expand upon preliminary data and are expected to ultimately identify and validate radiation-responsive genes. Preliminary data suggests that sentinel (yes/no), early (<24 hours), and late (>24 hours) biodosimetry genes will be identified. Taken collectively, these genes may be important components of a genetic profile capable of determining extent of exposure, allowing for stratification of individuals requiring immediate medical intervention following an accidental or terrorist-related radiological event.
Supplemental Keywords:Radiation, Total Body Irradiation, Biodosimetry,