Biomarkers of radiation exposure are useful both to indicate a recent exposure, such as in the case of a nuclear accident and for assessing exposures after a long time, for instance to improve dose reconstruction in retrospective epidemiological studies. Nowadays, with growing threats of nuclear terrorism, as acknowledged during the Nuclear Security Summit in Washington last April, the identification of efficient biomarkers for radiation exposure for the purpose of a fast initial screening (triage) of exposed individuals in need of extra medical attention is becoming increasingly important. Current golden standard methods for biological dosimetry such as cytogenetics assays fall short in several aspects related to emergency situations, in that their analysis is very laborious, time-consuming and expensive and therefore not amenable for fast screening of large cohorts. The last decade, gene expression signatures have emerged as potential interesting biomarkers that could be useful for the abovementioned purposes1–6. We have recently taken this research a step further with the identification of exon expression signatures as robust radiation biomarkers7. We could furthermore show that these exon signatures are more sensitive than gene signatures, and therefore more suitable in the case of low-dose exposures.
Beside biomarkers for exposure, also biomarkers for radiation sensitivity are important for a number of reasons. Current radiotherapy treatment plans are adjusted to the most sensitive individuals in such a way that only about 5% of the patients will develop severe side effects on the healthy tissue. On the other hand, also cancer cells can display differences in radiation sensitivity. In both cases, this may lead to treatments being suboptimal. Thus, identifying biomarkers of sensitivity can play a major role in maximizing tumor control, while minimizing radiation toxicity8.
Circular RNAs (circRNAs) are a recently described class of non-coding RNA molecules that are generated by the canonical splicing machinery in a process called "back-splicing", resulting in a covalently closed circular RNA molecule, which lacks a poly-A tail9,10. CircRNAs are widely expressed, and their expression profiles can vary according to the cell/tissue-type and developmental timing11–16. Many circRNAs are conserved between worms, flies, and mammals13,16–18. One of the main disadvantages of classical mRNA biomarkers is their inherent instability. This is especially problematic for radiation exposure biomarkers for retrospective dosimetry, in which the biomarker should reflect a past event, rather than a physiological state. Due to their covalently closed circular structure, circRNAs are resistant to exonuclease degradation, and therefore remarkably stable17. This, together with observations that circRNAs are highly abundant in blood cells19 and furthermore enriched in exosomes from human serum20 makes them a species of RNA molecules with a very high potential as biomarkers in general, and radiation biomarkers in particular. Hence, in this PhD project, we will identify circRNA biomarkers for radiation exposure and radiosensitivity and furthermore characterize the functions of some of the most promising ones.
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