Plasma microRNAs as prognostic biomarkers for development of severe epilepsy after experimental traumatic brain injury - EpiBioS4Rx Project 1 study
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ABSTRACT:
PROVIDER: PRJNA1174225 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31033967.fastq.gz | Fastqsanger.gz | |||
| SRR31033968.fastq.gz | Fastqsanger.gz | |||
| SRR31033969.fastq.gz | Fastqsanger.gz | |||
| SRR31033970.fastq.gz | Fastqsanger.gz | |||
| SRR31033971.fastq.gz | Fastqsanger.gz |
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Project description:Purpose: Post-traumatic epilepsy (PTE) is an epilepsy that develops after traumatic brain injury (TBI), and it comprises 10-20% of structural epilepsies and 5% of all epilepsies. The lack of prognostic biomarkers for PTE hinders the development of anti-epileptogenic treatments. In this preclinical multicenter study, plasma samples collected from a rat model of PTE were analyzed by small RNA sequencing to reveal the post-TBI expression profile of circulating microRNAs and to identify potential miRNA biomarkers for PTE development. Methods: The animal experiments were conducted at 3 different study sites: University of Eastern Finland (Finland), Monash University (Australia), and University of California, Los Angeles (USA). Severe TBI was induced in adult male Sprague-Dawley rats by the lateral fluid-percussion injury (LFPI) method. Rats that developed PTE were identified by video-EEG monitoring during the 7th post-injury month (TBI rats with epilepsy, TBIE; TBI rats without epilepsy, TBIN). Small RNA sequencing was conducted with plasma samples collected 48 hours after TBI or sham operation (craniotomy). Following the primary quantification, DESeq2 (v. 1.42.0) was used to identify differentially expressed miRNAs between the experiment groups. Results were further validated in a larger sample cohort by droplet digital PCR (ddPCR). Results: Small RNA sequencing detected a total of 754 miRNAs that were expressed in at least one sample. DESeq2 detected 23 differentially expressed (DE) miRNAs between the TBI and sham groups, 12 between the TBIE and sham groups, and 5 between the TBIN and sham groups. In contrast, no DE miRNAs were detected between the TBIE and TBIN groups. From the list of 23 DE miRNAs between the TBI and sham groups, 3 upregulated miRNAs (rno-miR-183-5p, rno-miR-323-3p, and miR-434-3p) were selected for further ddPCR validation. The list of miRNAs for validation was further complemented by 4 miRNAs (rno-miR-9a-3p, rno-miR-124-3p, rno-miR-132-3p, and rno-miR-212-3p), which were not differentially expressed in the DESeq2 analysis, but which we have previously detected to be acutely upregulated in TBI rat plasma. The validation was conducted with samples from the entire EpiBioS4Rx cohort [26 baseline samples, 45 sham, 164 TBI (32 TBIE, 132 TBIN)]. DdPCR analysis revealed that all 7 investigated miRNAs were upregulated in the TBI rats compared with the sham controls. No differences were detected between the rats with (TBIE) or without epilepsy (TBIN). In contrast, TBIE rats that had seizure clusters (severe PTE) had lower levels of plasma miR-212-3p compared with other TBI rats. Furthermore, elastic net regularized logistic regression (glmnet) analysis identified miR-212-3p and miR-132-3p as the optimal set to differentiate TBIE rats with seizure clusters from other TBI rats. Conclusions: The profile of circulating plasma microRNAs differed between TBI rats and sham controls. MiR-212-3p alone or in combination with miR-132-3p showed potential as prognostic biomarkers for development of severe PTE.
2024-12-12 | GSE279767 | GEO
Project description:Purpose: Traumatic brain injury (TBI) causes 10%–20% of structural epilepsies and 5% of all epilepsies. The lack of prognostic biomarkers for post-traumatic epilepsy (PTE) is a major obstacle to the development of anti-epileptogenic treatments. In this study, we conducted high throughput small RNA-Seq analysis from tail-vein plasma samples collected from a rat model of PTE to discover miRNA biomarker candidates that could serve as prognostic biomarkers for brain damage severity and the development of PTE. Methods: Epileptogenesis was induced in adult male Sprague-Dawley rats by the lateral fluid-percussion-induced TBI. Epilepsy was defined as the occurrence of at least 1 unprovoked seizure during continuous 1-month video-electroencephalography monitoring in the sixth post-TBI month. Small RNA-seq was performed from tail-vein plasma samples collected from a subset of 20 animals (4 sham-operated controls, 7 TBI rats with epilepsy, 9 TBI rats without epilepsy) at 2 days and 9 days post-TBI. RNA was extracted from 200 μl plasma using an miRNeasy Mini Kit. Small RNA-Seq was conducted by GenomeScan (Leiden, the Netherlands). Small RNA library preparation was performed using the Illumina TruSeq Small RNA Sample Prep Kit. Single-end sequencing was performed on the Illumina HiSeq 4000.
2023-02-10 | GSE222801 | GEO
Project description:ObjectiveTo test a hypothesis that acutely regulated plasma microRNAs (miRNAs) can serve as prognostic biomarkers for the development of post-traumatic epilepsy (PTE).MethodsAdult male Sprague-Dawley rats (n = 245) were randomized to lateral fluid-percussion-induced traumatic brain injury (TBI) or sham operation at three study sites (Finland, Australia, United States). Video-electroencephalography (vEEG) was performed on the seventh post-injury month to detect spontaneous seizures. Tail vein plasma collected 48 h after TBI for miRNA analysis was available from 209 vEEG monitored animals (45 sham, 164 TBI [32 with epilepsy]). Based on small RNA sequencing and previous data, the seven most promising brain enriched miRNAs (miR-183-5p, miR-323-3p, miR-434-3p, miR-9a-3p, miR-124-3p, miR-132-3p, and miR-212-3p) were validated by droplet digital polymerase chain reaction (ddPCR).ResultsAll seven plasma miRNAs differentiated between TBI and sham-operated rats. None of the seven miRNAs differentiated TBI rats that did and did not develop epilepsy (p > .05), or rats with ≥3 vs <3 seizures in a month (p > .05). However, miR-212-3p differentiated rats that developed epilepsy with seizure clusters (i.e., ≥3 seizures within 24 h) from those without seizure clusters (.34 ± .14 vs .60 ± .34, adj. p < .05) with an area under the curve (AUC) of .81 (95% confidence interval [CI] .65-.97, p < .01, 64% sensitivity, 95% specificity). Lack of elevation in miR-212-3p also differentiated rats that developed epilepsy with seizure clusters from all other TBI rats (n = 146, .34 ± .14 vs .55 ± .31, p < .01) with an AUC of .74 (95% CI .61-.87, p < .01, 82% sensitivity, 62% specificity). Glmnet analysis identified a combination of miR-212-3p and miR-132-3p as an optimal set to differentiate TBI rats with vs without seizure clusters (cross-validated AUC .75, 95% CI .47-.92, p < .05).SignificancemiR-212-3p alone or in combination with miR-132-3p shows promise as a translational prognostic biomarker for the development of severe PTE with seizure clusters.
| S-EPMC11908664 | biostudies-literature
Project description:Epilepsy frequently develops as a result of brain insult, for example brain injury or stroke. Currently there are no tools allowing us to predict which trauma patients will eventually develop epilepsy. There is evidence that microRNAs levels are altered in plasma, making them attractive candidates for peripheral biomarkers of epilepsy. We analyzed miRNA levels in plasma samples using Affymetrix microarrays 4.1 and performed comparative analysis of samples. We performed 3 comparisons: i) control animals vs. Status epilepticus animals, ii) animals which developed first spontaneous seizure around 7 days post stimulation (EARLY), or later after 21days post stimulation (LATE), iii) animals that had developed seizures at given timepoint (EPI) and animals that did not experience seizures by given timepoint (NONEPI).
2023-12-10 | GSE241756 | GEO
Project description:Plasma miRNAs as biomarkers of epilepsy
| PRJNA1009812 | ENA
Project description:Pediatric epilepsy is a neurological condition that causes repeated and unprovoked seizures and is more common in 1–5-year-old children. Drug resistance has been indicated as a key challenge in improving the clinical outcomes of patients with pediatric epilepsy. In the present study, we aimed to identify serum small extracellular vesicles (sEVs) derived microRNAs (miRNAs) from the serum samples of children for predicting the prognosis in patients with epilepsy and drug-resistant epilepsy
2022-01-20 | GSE193842 | GEO
Project description:The diagnosis of epilepsy is complex and challenging and would benefit from the availability of molecular biomarkers, ideally measurable in a biofluid such as blood. Experimental and human epilepsy are associated with altered brain and blood levels of various microRNAs (miRNAs). Evidence is lacking, however, as to whether any of the circulating pool of miRNAs originates from the brain. To explore the link between circulating miRNAs and the pathophysiology of epilepsy, we first sequenced Ago2-bound miRNAs in plasma samples collected from mice subject to status epilepticus (SE) induced by intraamygdala microinjection of kainic acid. This identified time-dependent changes in plasma levels of miRNAs with known neuronal and microglial-cell origins. To explore whether the circulating miRNAs had originated from the brain, we generated mice expressing FLAG-Ago2 in neurons or microglia using tamoxifen-inducible Thy1 or Cx3cr1 promoters, respectively. FLAG immunoprecipitates from the plasma of these mice after seizures contained miRNAs, including let-7i-5p and miR-19b-3p. Taken together, these studies confirm that a portion of the circulating pool of miRNAs in experimental epilepsy originates from the brain, increasing support for miRNAs as mechanistic biomarkers of epilepsy.
2023-09-13 | GSE233890 | GEO
Project description:Explore DNA methylation in traumatic brain injury model of epilepsy and its relationship to gene expression. Examination of methylation changes in stimulated rats compared to sham operated animals in traumatic brain injury model of epilepsy.
2016-09-06 | E-GEOD-75119 | biostudies-arrayexpress
Project description:Traumatic brain injury (TBI) remains a leading cause of post traumatic epilepsy (PTE). Blast TBI (bTBI) found in Veterans presents cognitive and behavioral disturbance such as PTE, however, the underlying mechanisms that drive the long-term sequelae are not well understood. Using an unbiased proteomics approach in a murine model of repeated bTBI (rbTBI), this study addresses this gap in knowledge. Following rbTBI, mice underwent 24/7 EEG recording for four months before collecting the cortex and hippocampus of PTE+, PTE- and sham mice. Hundreds of differentially expressed proteins were identified in the cortex and hippocampus of PTE+ and PTE- relative to sham. Focusing on protein pathways unique to PTE+ animals revealed mitochondrial function, post translational modifications, and protein transport proteins were disrupted. Computational metabolic modeling using dysregulated protein expression predicted mitochondrial proton pump dysregulation, suggesting electron transport chain dysregulation in epileptic tissue relative to PTE- and sham. Finally, data mining enabled the identification of several novel and previously validated TBI and epilepsy biomarkers in our data set, many of which were found to already be targeted by drugs in various phases of clinical testing. These findings highlight novel proteins and protein pathways that may drive the chronic PTE sequala following rbTBI.
2024-06-22 | PXD048228 | Pride
Project description:Explore DNA methylation in traumatic brain injury model of epilepsy and its relationship to gene expression. Examination of expression changes in stimulated rats compared to sham operated animals in traumatic brain injury model of epilepsy.
2016-09-06 | E-GEOD-75120 | biostudies-arrayexpress