Wartime Radiation Exposure: Epigenetic Regulation of the CNS Response
Abstract
Among the hazards faced by warfighters is exposure to ionizing radiation. One potential health risk of particular concern that is associated with such exposures is the persistent radiation induced impairment of cognitive capabilities. We hypothesize that radiation exposure induces changes in neuronal signaling, synaptic plasticity, neurodegeneration and cognition that are driven by epigenetic changes involving DNA methylation. In the brain, 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) can regulate gene expression that maintains homeostasis and central nervous system (CNS) functionality. In this project we will determine whether 5mC and 5hmC DNA methylation regulate the expression of genes key to normal neuronal function and how irradiation induces aberrant methylation patterns that impact the neurocognitive side effects of exposure. Preliminary data from our laboratory indicate that radiation induced cognitive decline is associated with compromised neuronal structure, imbalance in synaptic integrity and elevated inflammation in the brain. These data provide the fundamental basis of our approach for pursuing the mechanisms by which epigenetic changes regulate the radiation response of the brain. In this proof-of-principle driven series of studies, we will use established behavioral testing platforms to define radiation induced cognitive deficits in mice exposed to low dose radiation. These studies will be followed by immunohistochemical staining to define the global 5mC and 5hmC levels in discrete regions of the brain and molecular studies of the microdissected brain to define the DNA methylation status and mRNA levels for specific genes involved in synaptic plasticity and neuronal function. Our data will define critical CNS radiation response pathways from the epigenetic to the functional level, and will elucidate the molecular pathways disrupted by radiation exposure that adversely impact cognition. Overall, this project will provide an in depth understanding of the epigenetic mechanisms that regulate biological responses to potential battlefield radiation exposures, and will provide a platform useful for the development of medical countermeasures.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- May 26, 2016
- Source ID
- HDTRA11610022
Entities
People
- Janet Baulch
Organizations
- Defense Threat Reduction Agency
- Naval Information Warfare Center Pacific