Project description:Development of biomarkers capable of estimating absorbed dose is critical for effective triage of affected individuals after radiological events. Levels of cell-free circulating miRNAs in plasma were compared for dose-response analysis in non-human primates (NHP) exposed to lethal (6.5 Gy) and sub-lethal (1 and 3 Gy) doses over a 7 day period. The doses and test time points were selected to mimic triage needs in the event of a mass casualty radiological event. Changes in miRNA abundance in irradiated animals were compared to a non-irradiated cohort and a cohort experiencing acute inflammation response from exposure to lipopolysaccharide (LPS). An amplification-free, hybridization-based direct digital counting method was used for evaluation of changes in microRNAs in plasma from all animals. Consistent with previous murine studies, circulating levels of miR-150-5p exhibited a dose- and time-dependent decrease in plasma. Furthermore, plasma miR-150-5p levels were found to correlate well with lymphocyte and neutrophil depletion kinetics. Additionally, plasma levels of several other evolutionarily and functionally conserved miRNAs were found altered as a function of dose and time. Interestingly, miR-574-5p exhibited a distinct, dose-dependent increase 24 h post irradiation in NHPs with lethal versus sub-lethal exposure before returning to the baseline level by day 3. This particular miRNA response was not detected in previous murine studies but was observed in animals exposed to LPS, indicating distinct molecular and inflammatory responses. Furthermore, an increase in low-abundant miR-126, miR-144, and miR-21 as well as high-abundant miR-1-3p and miR-206 was observed in irradiated animals on day 3 and/or day 7. The data from this study could be used to develop a multi-marker panel with known tissue-specific origin that could be used for developing rapid assays for dose assessment and evaluation of radiation injury on multiple organs. Furthermore this approach may be utilized to screen for tissue toxicity in patients who receive myeloablative and therapeutic radiation.
Project description:Aging is a major risk factor for various forms of disease. An enhanced understanding of the physiological mechanisms related to aging is urgently needed. Nonhuman primates (NHPs) have the closest genetic relationship to humans, making them an ideal model to explore the complicated aging process. Multiomics analysis of NHP peripheral blood offers a promising approach to evaluate new therapies and biomarkers. Here, we explored the mechanisms of aging using proteomics (serum and serum-derived exosomes [SDEs]) in rhesus monkey (Macaca mulatta) blood.
Project description:MicroRNAs are small non-coding RNAs that are critical in post-transcriptional regulation. According to the latest miRBase (v22), there are 617 annotated pre-miRNAs in Macaca mulatta, which is much less than 1917 in human, although both of these two species are primates. To improve the annotation of miRNAs in Macaca mulatta, we generated 12 small RNA profiles from 8 tissues and perform comprehensive analysis of these profiles. We identified 613 conserved pre-miRNAs that have not been reported in Macaca mulatta and 25 novel miRNAs. Furthermore, we identified 996 editing sites with significant editing levels from 250 pre-miRNAs after analyzing the 12 self-generated and 58 additional published sRNA-seq profiles from different types of organs or tissues. Our results show that the distribution of different miRNA editing types in Macaca mulatta is different from that in human brains. Particularly, there are much more small indel events in miRNAs of Macaca mulatta than in human brains. These results significantly increase our understanding of miRNAs and their editing events in Macaca mulatta.
Project description:Aging is a major risk factor for various forms of disease. An enhanced understanding of the physiological mechanisms related to aging is urgently needed. Nonhuman primates (NHPs) have the closest genetic relationship to humans, making them an ideal model to explore the complicated aging process. Multiomics analysis of NHP peripheral blood offers a promising approach to evaluate new therapies and biomarkers. Here, we explored the mechanisms of aging using proteomics (serum) in rhesus monkey (Macaca mulatta) blood.
Project description:Abstract Purpose: There is a recognised need to develop new methods of high throughput, rapid and minimally invasive individual dose assessment for radiation exposure. The aim of this work is to establish a panel of highly radiation responsive genes suitable for biological dosimetry and to explore inter-individual variation in response to ionising radiation exposure.Materials and method: Analysis of gene expression in response to radiation was carried out using three independent techniques (microarray, Multiplex Quantitative RT-PCR and nCounter Analysis System) in human lymphocytes in culture and circulating blood exposed ex vivo from the same donors. Results: Variations in transcriptional response to exposure to ionising radiation analysed by microarray allowed the identification of genes which can be validated and measured accurately as biomarkers of radiation exposure using other techniques. We have identified genes which are consistently up-regulated following exposure at different time points to either 2 or 4 Gy of X-rays, for all individuals in blood and cultured lymphocytes. Most down-regulated genes including cyclins, centromeric and mitotic checkpoints proteins, particularly those associated with chromosome instability and cancer can only be detected in dividing cells. Conclusions: The data provides evidence that there are a number of genes which seem suitable for biological dosimetry, like SESN1, GADD45A, CDKN1A, CCNG1, FDXR, BBC3 and MDM2. ÊThese biomarkers could potentially be used for triage after large-scale radiological incidents. Variations in transcriptional response accurately measured by MQRT-PCRæ may allow the identification of biomarkers of radiation sensitivity and individual susceptibility and therefore being useful in radiation oncology.