Exosomes - novel mediators of direct and bystander radiation effects on the brain

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The overarching goal of my NSERC program is to understand how organisms (mammals) respond to low-dose ionising radiation on a molecular level and to determine the role of small vesicles (exosomes) in radiation responses, with a focus on mammalian brain radiation responses.Background: The program is based on our most recent fundamental studies that have shifted the paradigm of radiation biology and proved that the brain is highly sensitive to low dose radiation (LDR) exposure. Recently, we reported that head LDR exposure induced DNA damage and affected gene expression in the prefrontal cortex of irradiated animals. We also proved that bystander effects exist in the brain after liver irradiation. Both head and liver irradiation reduced spine density, dendritic complexity and dendritic length and altered behavior. Moreover, fractionated LDR exposure also caused DNA damage, altered global genomic methylation and induced behavioral changes.While the occurrence of direct and bystander LDR effects in the brain was reported, the molecular mechanisms of this phenomenon are under-investigated. Cells release a wide array of microvesicles, including nanoparticles (50100 nm) called exosomes, into the extracellular space. Exosomes may be important in a wide array of brain side effects of radiation exposure.Theory and Hypotheses: Here, we hypothesise that exosomes may be involved in direct and bystander radiation effects in vivo and propose a new exosomal theory of the LDR brain phenomenon, whereby the mechanisms that underlie the LDR's effects on the brain are mediated via exosomal signaling.The following hypotheses are proposed to test our theory:1. Direct and bystander LDR exposures affect exosome profiles in the brain and blood and influence exosome cargo.2. Exosome signaling is implicated in LDR effects in vivo on the brain and exosomes constitute bona fide bystander signals.3. Environmental enrichment will at least partly reverse the LDR-induced exosome-mediated effects.I will engage a team of trainees who we will for the first time analyse exosomes in the brains and serum of LDR-exposed rats and compare them with the exosomes of untreated animals. Together, we will analyse DNA, RNA, small RNA and protein content of the exosomes, and will attempt to mitigate the effects of LDR on the brain by applying novel environmental enrichment techniques to positively alter exosome patterns.Expected outcomes: This research and training program is devoted to fundamental studies on the biological effects of LDR on the brain. It will address a fundamentally important issue: are small doses of LDR dangerous for living organisms, do they affect the brain, and are organisms capable of adapting to environmental LDR exposures? Understanding the molecular changes that occur in exposed cells and organisms may assist in the development of measures to prevent the deleterious effects of LDR.