Cross-species conserved miRNA as biomarker of radiation injury and to predict fatality risk
Multiple accidents in nuclear power plants and growing concerns in misuse of radiation exposure in warfare have called for rapid determination of radiation exposure and the chances to survive. Latest findings about circulating microRNA (miRNAs) using several animal models revealed considerable promises, although translating this knowledge to clinics remains a major challenge. To address this issue, we randomly divided 36 non-human primates (NHPs) into six equal groups and each group was exposed to six radiation doses from 6 Gy to 8.5 Gy with 0.5 Gy incremental order. Serum samples were collected pre-total body irradiation (TBI) and three timepoints afterwards namely, day 1, 2 and 6 post-TBI. Global microRNA (miRNA) reads were generated from deep sequencing platform and to increase the translational potential, we diligently aligned the miRNA sequences and functional responses of NHPs to human following an in silico routine. Those miRNAs, which were sequentially and functionally conserved between human and NHPs were curated to meet two primary objectives. First to find the molecular dynamics correlated to radiation dosimetry and second to find putative markers to predict the risk to radiation-induced fatality (RRiF). Multi-variate differential analysis identified dosimetry-miRNA markers that consistently regulated with increasing dose but independent of the time since irradiation (TSI). Likewise, a set of potential TSI-markers were identified that consistently shifted their regulations with increasing TSI, but independent of dosimetry. Functional analysis found a considerable gender bias in low range of dosimetry, but at high dose, when the RRiF increased, the bionetworks across the sexes operated in sync. Bionetworks linked to cell quantity and cell invasion significantly altered between the survived and decedent cohort. Proprietary algorithm identified candidate models with a few miRNAs that can predict RRiF with >80% AUC. An assay could be conceptualized from this putative RRiF panel supplemented with the dose-/TSI-markers to predict RRiF with high confidence. Overall design: Non Human Primates were exposed to different doses of radiation, and serum samples were collected at different timepoints for each organism.