Development of a multiomic biodosimetry panel for use during sepsis and antibiotic treatment - Program Director/Principal Investigator (Last, First, Middle): Pannkuk, Evan Lacy Project Summary Potential exposures to ionizing radiation (IR) in large populations exist from both intentional (terrorist actions) and accidental (nuclear power plant accidents) sources. Novel biodosimetry assays are needed for rapid screening (e.g. above or below 2 Gy) to separate the “worried well” from individuals needing medical care. In addition, assays are needed within the first week to provide more accurate dose reconstruction past this initial screening after patients have been transported to a medical care facility. These assays should provide accurate measurements between 2 – 10 Gy in a high-throughput manner, identifying the level of medical intervention required as well as those with a low probability of survival. Modern mass spectrometry (MS) platforms provide tools for high-throughput biodosimetry as they rapidly measure quantitative metabolite concentrations that can be used as a proxy for radiation injury. Metabolite panels can also be combined with other biomarkers, such as transcripts, to increase assay sensitivity. Following a nuclear emergency, initial care will be restricted to antibiotic (Abx) administration, decontamination, and supportive care; however, combined injuries and infections will be inextricably linked to radiation injury. Bacterial infections of the blood (bacteremia and septicemia) and lung (pneumonia) will be of the highest concern. As both infections and Abx treatment will alter the host microbiome, there is a need to determine how established biodosimetry panels will be affected in these events. Here, we propose to develop a multiomic biodosimetry panel (metabolomic and gene expression) with increased sensitivity and specificity during dynamic microbiome changes following IR exposure. Our objectives include refining our metabolomic profile in biofluids during sepsis and Abx administration using a murine model and incorporating an established gene panel to improve dose reconstruction. To achieve these goals, we will first use an established murine model of sepsis, that utilizes intraperitoneal live pathogen injections of Klebsiella pneumonia in IR exposed BALB/c mice. This model will more closely recapitulate a microbial infection than our previous lipopolysaccharide (LPS) model and allow us to measure changes in metabolite and transcript levels. A cohort of mice will also be treated with an enrofloxacin and amoxicillin cocktail after infection to determine how the altering microbiome during sepsis and treatment affects biomarker levels. Our team is highly qualified to achieve the below aims, which is exemplified through multiple peer-reviewed publications on radiation metabolomics/lipidomics, bioinformatics, development of targeted MS methodologies, and toxicogenomics. These studies are needed to complement current biomarker panels developed for biodosimetry and the variable microbiota associated with human populations. Continuation Format Page
