Identification of miRNA Associated with Reduced Survival after Whole-Thorax Lung Irradiation in Non-Human Primates

Rogers, Claude J.; Kyubwa, Espoir M.; Lukaszewicz, Agnès; Yamada-Hanff, Jason; Starbird, Mark A.; Miller, Tim; Phelps, Asa A.; Wallack, Seth; Mahendra, Saikanth; Thrall, Karla D.; Menon, Naresh

doi:10.1667/rade-20-00031.1

Cited by 11 publications

(13 citation statements)

References 62 publications

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“…This dose-dependent response is consistent with our previous findings(6). NHPs exposed to 9.8 or 10.7 Gy WTLI did not develop severe neutropenia by day 7(25).…”

supporting

confidence: 93%

“…2). These outcomes have been previously described in independent studies in NHPs (6,25), mice (7), and other species. Thus, the outcomes described here are consistent with the well-described response to these types of radiation exposures.…”

Section: Discussionsupporting

confidence: 71%

“…This pathway is associated with changes in lipid homeostasis (43) which has been shown to occur after irradiation (44). In a WTLI study in mice, we have shown that miRNAs are linked to lipid metabolism using KEGG pathway analysis (7,25). Many of the other most significantly enriched GO terms are associated with regulation of transcription from RNA polymerase II in response to stress and were common to both types of radiation injury.…”

Section: Discussionmentioning

confidence: 96%

“…This suggests that these pathways are not selective for WTLI survival. TGF-b and BMP signaling were highly specific to WTLI and have a well-established mechanistic relationship with radiation-induced pulmonary fibrosis (50-54), as observed by histology at the study endpoint (25). miRNA linked to these pathways were also identified in mice after WTLI (7).…”

Section: Discussionmentioning

confidence: 98%

“…Circulating miRNA were isolated from plasma taken before the onset of symptoms, at day 2 post-TBI and day 15 post-WTLI. NHP exposed to TBI developed severe neutropenia (neutrophil counts , 500 lL À1 ) by day 7 and NHP exposed to WTLI developed radiation-induced lung diseases (including pneumonitis and fibrosis), that resulted in reduced aerated lung volume by day 60 by computed tomography (CT), increased collagen deposits in the lung tissue by histochemistry, and reduced survival (25). Circulating miRNA that correlated with the onset of post-TBI neutropenia and post-WTLI survival were identified.…”

Section: Introductionmentioning

confidence: 99%

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Observation of Unique Circulating miRNA Signatures in Non-Human Primates Exposed to Total-Body vs. Whole Thorax Lung Irradiation

et al. 2021

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A radiological/nuclear (RAD-NUC) incident, especially in an urban setting, results in diverse radiation-induced injuries due to heterogeneities in dose, the extent of partial-body shielding, human biodiversity and pre-existing health conditions. For example, acute radiation syndrome (ARS) can result in death within days to weeks of exposure to 0.7–10 Gy doses and is associated with destruction of the bone marrow, known as hematopoietic ARS (H-ARS). However, partial-body shielding that spares a portion of the bone marrow from exposure can significantly reduce the occurrence of H-ARS, but delayed effects of acute radiation exposure (DEARE) can still occur within months or years after exposure depending on the individual. In a mass casualty event, ideal triage must be able to pre-symptomatically identify individuals likely to develop radiation-induced injuries and provide an appropriate treatment plan. Today, while there are FDA approved treatments for hematopoietic ARS, there are no approved diagnosis for radiation injury and no approved treatments for the broad spectra of injuries associated with radiation. This has resulted in a major capability gap in the nations preparedness to a potentially catastrophic RAD-NUC event. Circulating microRNA (miRNA) are a promising class of biomarkers for this application because the molecules are accessible via a routine blood draw and are excreted by various tissues throughout the body. To test if miRNA can be used to predict distinct tissue-specific radiation-induced injuries, we compared the changes to the circulating miRNA profiles after total-body irradiation (TBI) and whole thorax lung irradiation (WTLI) in non-human primates at doses designed to induce ARS (day 2 postirradiation; 2–6.5 Gy) and DEARE (day 15 postirradiation; 9.8 or 10.7 Gy), respectively. In both models, miRNA sequences were identified that correlated with the onset of severe neutropenia (counts <500 μL–1; TBI) or survival (WTLI). This method identified panels of eleven miRNA for both model and assigned functional roles for the panel members using gene ontology enrichment analysis. A common signature of radiation-induced injury was observed in both models: apoptosis, DNA damage repair, p53 signaling, pro-inflammatory response, and growth factor/cytokine signaling pathways were predicted to be disrupted. In addition, injury-specific pathways were identified. In TBI, pathways associated with ubiquitination, specifically of histone H2A, were enriched, suggesting more impact to DNA damage repair mechanisms and apoptosis. In WTLI, pro-fibrotic pathways including transforming growth factor (TGF-β) and bone morphogenetic protein (BMP) signaling pathways were enriched, consistent with the onset of late lung injury. These results suggest that miRNA may indeed be able to predict the onset of distinct types of radiation-induced injuries.

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“…This dose-dependent response is consistent with our previous findings(6). NHPs exposed to 9.8 or 10.7 Gy WTLI did not develop severe neutropenia by day 7(25).…”

supporting

confidence: 93%

Section: Discussionsupporting

confidence: 71%

Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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Observation of Unique Circulating miRNA Signatures in Non-Human Primates Exposed to Total-Body vs. Whole Thorax Lung Irradiation

et al. 2021

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Circulating miRNA profiles in COVID-19 patients and meta-analysis: implications for disease progression and prognosis

Gao,

Kyubwa,

Starbird

et al. 2023

Sci Rep

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We compared circulating miRNA profiles of hospitalized COVID-positive patients (n = 104), 27 with acute respiratory distress syndrome (ARDS) and age- and sex-matched healthy controls (n = 18) to identify miRNA signatures associated with COVID and COVID-induced ARDS. Meta-analysis incorporating data from published studies and our data was performed to identify a set of differentially expressed miRNAs in (1) COVID-positive patients versus healthy controls as well as (2) severe (ARDS+) COVID vs moderate COVID. Gene ontology enrichment analysis of the genes these miRNAs interact with identified terms associated with immune response, such as interferon and interleukin signaling, as well as viral genome activities associated with COVID disease and severity. Additionally, we observed downregulation of a cluster of miRNAs located on chromosome 14 (14q32) among all COVID patients. To predict COVID disease and severity, we developed machine learning models that achieved AUC scores between 0.81–0.93 for predicting disease, and between 0.71–0.81 for predicting severity, even across diverse studies with different sample types (plasma versus serum), collection methods, and library preparations. Our findings provide network and top miRNA feature insights into COVID disease progression and contribute to the development of tools for disease prognosis and management.

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Serum microRNA profile of rhesus macaques following ionizing radiation exposure and treatment with a medical countermeasure, Ex-Rad

Russ,

Fatanmi,

Wise

et al. 2024

Sci Rep

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Exposure to ionizing radiation (IR) presents a formidable clinical challenge. Total-body or significant partial-body exposure at a high dose and dose rate leads to acute radiation syndrome (ARS), the complex pathologic effects that arise following IR exposure over a short period of time. Early and accurate diagnosis of ARS is critical for assessing the exposure dose and determining the proper treatment. Serum microRNAs (miRNAs) may effectively predict the impact of irradiation and assess cell viability/senescence changes and inflammation. We used a nonhuman primate (NHP) model—rhesus macaques (Macaca mulatta)—to identify the serum miRNA landscape 96 h prior to and following 7.2 Gy total-body irradiation (TBI) at four timepoints: 24, 36, 48, and 96 h. To assess whether the miRNA profile reflects the therapeutic effect of a small molecule ON01210, commonly known as Ex-Rad, that has demonstrated radioprotective efficacy in a rodent model, we administered Ex-Rad at two different schedules of NHPs; either 36 and 48 h post-irradiation or 48 and 60 h post-irradiation. Results of this study corroborated our previous findings obtained using a qPCR array for several miRNAs and their modulation in response to irradiation: some miRNAs demonstrated a temporary increased serum concentration within the first 24–36 h (miR-375, miR-185-5p), whereas others displayed either a prolonged decline (miR-423-5p) or a long-term increase (miR-30a-5p, miR-27b-3p). In agreement with these time-dependent changes, hierarchical clustering of differentially expressed miRNAs showed that the profiles of the top six miRNA that most strongly correlated with radiation exposure were inconsistent between the 24 and 96 h timepoints following exposure, suggesting that different biodosimetry miRNA markers might be required depending on the time that has elapsed. Finally, Ex-Rad treatment restored the level of several miRNAs whose expression was significantly changed after radiation exposure, including miR-16-2, an miRNA previously associated with radiation survival. Taken together, our findings support the use of miRNA expression as an indicator of radiation exposure and the use of Ex-Rad as a potential radioprotectant.

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Identification of miRNA Associated with Reduced Survival after Whole-Thorax Lung Irradiation in Non-Human Primates

Cited by 11 publications

References 62 publications

Observation of Unique Circulating miRNA Signatures in Non-Human Primates Exposed to Total-Body vs. Whole Thorax Lung Irradiation

Observation of Unique Circulating miRNA Signatures in Non-Human Primates Exposed to Total-Body vs. Whole Thorax Lung Irradiation

Circulating miRNA profiles in COVID-19 patients and meta-analysis: implications for disease progression and prognosis

Serum microRNA profile of rhesus macaques following ionizing radiation exposure and treatment with a medical countermeasure, Ex-Rad

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