Comparison of serum and saliva miRNAs for identification and characterization of mild Traumatic Brain Injury (mTBI) in adult mixed martial arts fighters
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE123336 | GEO | 2018/12/05
REPOSITORIES: GEO
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Project description:Traumatic brain injury (TBI) is a global problem reaching near epidemic numbers that manifests clinically with cognitive problems that decades later may result in dementias like Alzheimer’s disease (AD). Presently, little can be done to prevent ensuing neurological dysfunctions by pharmacological means. Recently, it has become apparent that several CNS diseases share common terminal features of neuronal cell death. The effects of exendin-4 (Ex-4), a neuroprotective agent delivered via a subcutaneous micro-osmotic pump, were examined in the setting of mild TBI (mTBI). Utilizing a model of mTBI, where cognitive disturbances occur over time, animals were subjected to four treatments: sham; Ex-4; mTBI and Ex-4/mTBI. mTBI mice displayed deficits in novel object recognition, while Ex-4/mTBI mice performed similar to sham. Hippocampal gene expression, assessed by gene array methods, showed significant differences with little overlap in co-regulated genes between groups. Importantly, changes in gene expression induced by mTBI, including genes associated with AD were largely prevented by Ex-4. These data suggest a strong beneficial action of Ex-4 in managing secondary events induced by a traumatic brain injury.
2012-10-17 | GSE41345 | GEO
Project description:The etiology of mild traumatic brain injury (mTBI) remains elusive due to the tissue and cellular heterogeneity of the affected brain regions that underlie cognitive impairments and subsequent neurological disorders. This complexity is further exacerbated by disrupted circuits within and between cell populations across brain regions and the periphery, which occur at different timescales and in spatial domains. We profiled three tissues (hippocampus, frontal cortex, and blood leukocytes) at the acute (24hr) and chronic (7days) phases of mTBI at single cell resolution and demonstrated that the coordinated gene expression patterns across cell types were disrupted and re-organized by TBI at different timescales with distinct regional and cellular patterns. Gene expression-based network modeling identified astrocytes as a key regulator of the cell-cell coordination following mTBI in both hippocampus and frontal cortex across timepoints, and mt-Rnr2, which encodes the mitochondrial peptide humanin, as a potential target for intervention based on its broad regional and dynamic dysregulation following mTBI. Treatment of a murine mTBI model with humanin reversed cognitive impairment caused by mTBI through the restoration of metabolic pathways within astrocytes. Our results offer a systems-level understanding of the dynamic and spatial regulation of gene programs by mTBI and pinpoint key target genes, pathways, and cell circuits that are amenable to therapeutics.
2022-08-17 | GSE180862 | GEO
Project description:Accurate assessment of treatment response and residual disease is indispensable for the evaluation of cancer treatment efficacy. However, performing tissue biopsies for longitudinal follow-up poses a major challenge in the management of solid tumours like neuroblastoma. In the present study, we evaluated whether circulating miRNAs are suitable to monitor neuroblastoma tumour burden and whether treatment-induced changes of miRNA abundance in the tumour are detectable in serum. We performed small RNA sequencing on longitudinally collected serum samples from mice carrying orthotopic neuroblastoma xenografts that were exposed to treatment with idasanutlin or temsirolimus. We identified 57 serum miRNAs to be differentially expressed upon xenograft tumour manifestation, out of which 21 were also found specifically expressed in the serum of human high-risk neuroblastoma patients. The murine serum levels of these 57 miRNAs correlated with tumour tissue expression and tumour volume, suggesting potential utility for monitoring tumour burden. In addition, we describe serum miRNAs that dynamically respond to p53 activation following treatment of engrafted mice with idasanutlin. We identified idasanutlin-induced serum miRNA expression changes upon one day and 11 days of treatment. By limiting to miRNAs with a tumour-related induction, we put forward hsa-miR-34a-5p as a potential pharmacodynamic biomarker of p53 activation in serum.
| EGAS00001006678 | EGA
Project description:Analysis of hybridisation performance and utility in identifying differentially expressed miRNAs of six miRNA microarray platforms using three biological samples in quadruplicate.
2010-02-24 | E-MTAB-96 | biostudies-arrayexpress
Project description:Purpose: High throughput small RNA-Seq analysis from circulating biofluids is crucial in driving the discovery of non-invasive miRNA biomarkers for TBI. In this study, we focused our analysis on acute post-TBI alterations in plasma miRNA profiles in adult, male Sprague-Dawley rats. We compared the plasma miRNA profiles from naive, sham-operated controls and rats with mild and severe TBI. The aim was to identify a miRNA signature that would distinguish the rats with mTBI from the naive and sham-operated controls. Next, we compared the rats with mild and severe TBIs to investigate if a dose-dependent increase would occur in the plasma miRNA levels with corresponding increase in injury severities. Finally, we analysed if the sham surgery itself results in alterations in circulating miRNA profiles, by comparing the naive and sham-operated controls. Methods: TBI was induced with the lateral fluid percussion injury (FPI) model. Tail-vein plasma was collected at 2 days post-TBI from 31 adult male, Sprague-Dawley rats (5 naive, 8 sham-operated controls, 10 mTBI and 8 sTBI) under inhalation of isoflurane anesthesia. Small RNA-Seq was performed from plasma samples of a subset of 20 rats (5 cases each from naive, sham-operated controls, mTBI and sTBI groups). For each case, RNA was isolated from 200 µL plasma using the miRNeasy serum/plasma kit. The extracted RNA was subjected to qPCR-based quality control (QC). Small RNA library preparation was performed with the QIASeq miRNA library kit for Illumina NGS systems. Single-end sequencing of 75 bp reads was performed at a depth of 12M, with one sample/lane in the Illumina NextSeq 550. One naive plasma sample failed at the library preparation step. Hence, small RNA-Seq was succesful for 19/20 cases. The raw fastq files obtained from small RNA-Seq were first manually inspected with FastQC (v0.11.3) to check the overall quality of the sequencing data. For primary quantification of read counts, the fastq files were then uploaded to the Qiagen Geneglobe Data analysis center (DAC), a freely available web resource to analyze data from Qiagen’s QIASeq NGS library kits (https://geneglobe.qiagen.com/in/analyze/). Mapping was performed in the DAC portal with bowtie, using the rat reference genome RGSC Rnor_6.0. Annotation of miRNAs was performed with miRBase v21. Following primary quantification, differential expression analysis for miRNAs was performed with DESeq2 (v1.22.2) in R environment (v3.5.3). Logistic regression (LR) with feature selection utilizing nested leave-one-out cross-validation was also performed to identify miRNAs (“features”) contributing most to groupwise differences (differences between naïve, sham, mTBI, sTBI, sTBI + mTBI and naïve + sham). Results: A total of 748 miRNAs were detected across all samples, out of which 723 (97%) were expressed in all the four groups (naive, sham-operated, mTBI and sTBI). Based on the differential expression and logistic regression analyses, we identified five miRNA candidates that contributed most to the seperation between the mTBI and naive groups: rno-miR-9a-3p, rno-miR-153-3p, rno-miR-15a-3p, rno-miR-136-3p and rno-miR-434-3p. We validated the small RNA-Seq data for these miRNA candidates with miRCURY reverse transcriptase quantitative PCR (RT-qPCR). We could succesfully validate elevated levels of miR-9a-3p, miR-136-3p and miR-434-3p in the mTBI group in comparison to naive. When analysed from the whole cohort, the elevated levels of these miRNAs were consistently observed in the mTBI group compared to the naive, both with RT-qPCR and droplet digital PCR (ddPCR). Further, all the three miRNAs revealed elevated plasma levels in the sTBI group in comparison to the mTBI. Conclusions: Elevated plasma miRNA signature of miR-9a-3p, miR-136-3p and miR-434-3p distinguishes rats with mTBI from the naive, in the lateral FPI model of TBI. Further, all these miRNAs exhibit a dose-dependent increase in plasma levels with increase in injury severities.
2021-03-03 | GSE159011 | GEO
Project description:Background/Aim: We investigated alterations in the expression of serum exosomal miRNAs with the progression of liver fibrosis and evaluated their clinical applicability as biomarkers. Methods: This study prospectively enrolled 71 patients who underwent liver biopsy at an academic hospital in Korea. Exosomes were extracted from serum samples, followed by next-generation sequencing (NGS) of miRNAs and targeted real-time quantitative polymerase chain reaction. A model was derived to discriminate advanced fibrosis based on miRNA levels and the performance of this model was evaluated. Validation of the effect of miRNA on liver fibrosis in vitro was followed. Methods: This study prospectively enrolled 71 patients who underwent liver biopsy at an academic hospital in Korea. Exosomes were extracted from serum samples, followed by next-generation sequencing (NGS) of miRNAs and targeted real-time quantitative polymerase chain reaction. A model was derived to discriminate advanced fibrosis based on miRNA levels and the performance of this model was evaluated. Validation of the effect of miRNA on liver fibrosis in vitro was followed. Results: NGS data revealed that exosomal miR-660-5p, miR-125a-5p, and miR-122 expression were changed significantly with the progression of liver fibrosis, of which miR-122 exhibited high read counts enough to be used as a biomarker. The level of exosomal miR-122 decreased as the pathologic fibrosis grade progressed and patients with biopsy-proven advanced fibrosis had significantly lower levels of exosomal miR-122 (P < 0.001) than those without advanced fibrosis. Exosomal miR-122 exhibited a fair performance in discriminating advanced fibrosis especially in combination with fibrosis-4 score and transient elastography. In a subgroup of patients with a non-viral etiology of liver disease, the performance of exosomal miR-122 as a biomarker was greatly improved. Inhibition of miR-122 expression increased the proliferation of the human hepatic stellate cell line, LX-2, and upregulated the expression of various fibrosis related proteins. Conclusion: Exosomal miR-122 may serve as a useful non-invasive biomarker for liver fibrosis, especially in patients with non-viral etiologies of chronic liver disease.
2021-07-15 | GSE179961 | GEO
Project description:Repetitive mild traumatic brain injury (mTBI) in children and adolescents leads to acute and chronic neurological sequelae and is linked by epidemiological data to later life neurodegenerative disease. However, the biological mechanisms connecting early life mTBI to neurodegeneration remain unknown. Using an adolescent mouse repetitive closed head injury (CHI) model that induces progressive cognitive impairment in the absence of overt histopathology, we examined transcriptional and translational changes in neurons isolated from sham and injured brain in the chronic phase after injury. At 14 months, single nuclei RNA sequencing of cortical brain tissue identified disruption of genes associated with neuronal proteostasis in injured mice. Western blot analysis of neurons isolated by immunopanning showed evidence of inflammasome activation, accumulation of misfolded, hyperphosphorylated Tau, and changes in expression of proteins suggestive of impaired translation. Compared to injured wild type, injured interleukin-1 receptor 1 knockout mice, which are protected from post-injury cognitive deficits, had reduced microgliosis and decreased accumulation of pro-interleukin-1 beta and misfolded tau in cortex and cerebellum at six months. Taken together, our findings provide evidence for neuronal inflammasome activation and impaired proteostasis as key mechanisms linking repetitive mTBI in adolescence to later life neurological dysfunction and neurodegeneration.
2021-05-01 | GSE167942 | GEO
Project description:Traumatic brain injury (TBI) is a global problem reaching near epidemic numbers that manifests clinically with cognitive problems that decades later may result in dementias like Alzheimer’s disease (AD). Presently, little can be done to prevent ensuing neurological dysfunctions by pharmacological means. Recently, it has become apparent that several CNS diseases share common terminal features of neuronal cell death. The effects of exendin-4 (Ex-4), a neuroprotective agent delivered via a subcutaneous micro-osmotic pump, were examined in the setting of mild TBI (mTBI). Utilizing a model of mTBI, where cognitive disturbances occur over time, animals were subjected to four treatments: sham; Ex-4; mTBI and Ex-4/mTBI. mTBI mice displayed deficits in novel object recognition, while Ex-4/mTBI mice performed similar to sham. Hippocampal gene expression, assessed by gene array methods, showed significant differences with little overlap in co-regulated genes between groups. Importantly, changes in gene expression induced by mTBI, including genes associated with AD were largely prevented by Ex-4. These data suggest a strong beneficial action of Ex-4 in managing secondary events induced by a traumatic brain injury. Male ICR mice weighing 30–40 g were kept five per cage under a constant 12-h light/dark cycle, at room temperature (23°C). Food (Purina rodent chow) and water were available ad libitum. Each mouse was used for one experiment and for one time point only. The Ethics Committee of the Sackler Faculty of Medicine approved the experimental protocol (M-09-055), in compliance with the guidelines for animal experimentation of the National Institutes of Health (DHEW publication 85–23, revised, 1995). A minimal number of mice were used for the study and all efforts were made to minimize suffering. All experimental manipulations were conducted during the light phase of the cycle. Experimental mTBI was induced using the concussive head trauma device described previously (Milman et al. 2005; Zohar et al. 2003). Briefly, mice were lightly anesthetized (Isoflurane) and placed under the weight-drop concussive head trauma instrument. The device consists of a metal tube (inner diameter 13 mm), placed vertically over the mouse head. A metal weight (30 g) was dropped from the top of the tube (80 cm) and struck the skull at the temporal right side between the corner of the eye and the ear. A sponge supported the head, allowing some antero-posterior motion without any rotational head movement at the moment of the impact. Immediately after the injury, mice were placed back in their cages for recovery. The effect of the injury upon behavior and cognition was studied from 7 days following the trauma. Sham treated mouse groups were treated identically only the weight was not dropped. The peptide Ex-4 was obtained from Bachem (Torrance, CA). In order to obtain a constant steady-state concentration of Ex-4 in mice prior to injury; Ex-4 was delivered by use of micro-osmotic pumps (7 day infusion duration), 2 days prior to the induction of mTBI. For the Ex-4 treated animals the peptide was dissolved in an equal volume of saline and dimethyl sulfoxide (DMSO) mixture and delivered from a subcutaneously implanted ALZET Micro-osmotic pump (Model 1007D, Alzet, Cupertino, CA) at a rate of 3.5 pM/kg/min. In drug treatment control groups, saline and DMSO pumps were implanted in each animal following the same surgical procedure as used for the Ex-4 treatment animals. In all animals, pumps were placed, posterior to the scapulae. Pump implantation was performed under anesthesia (ketamine/xylazine) utilizing sterile procedures. Mini pumps were implanted 48 hours prior to the weight drop injury. The number of animals from each treatment group that went on to microarray analysis were as follows, Sham, n = 5; mTBI, n = 4; Ex-4, n = 5; Ex-4/ mTBI, n = 4. Mouse cognition was assessed using the novel object recognition paradigm. After the completion of the novel object behavioral assessment, animals were euthanized and the hippocampus dissected for total RNA isolation. Total RNA was prepared using the Qiagen RNeasy Mini Kit (Qiagen, Inc. Valencia CA) following the manufacturer's specifications. Quantity and quality of the RNA was assessed using the Agilent 2100 Bioanalyzer with RNA 6000 Nano Chips. The total RNA (500 ng) was used to generate biotin-labeled cRNA using the Illumina TotalPrep RNA Amplification Kit (Ambion; Austin, TX, cat # IL1791). In short, 500 ng of total RNA was first converted into single-stranded cDNA with reverse transcriptase using an oligo-dT primer containing the T7 RNA polymerase promoter site and then copied to produce double-stranded cDNA molecules. The double stranded cDNA was cleaned and concentrated with the supplied columns and used in an overnight in vitro transcription reaction where single-stranded RNA (cRNA) was generated and labeled by incorporation of biotin-16-UTP. This cRNA was used in the hybridization reaction. Briefly, a total of 750 ng of biotin-labeled cRNA was hybridized at 58oC for 16 hours to Illumina's SentrixMouse Ref-8, v2 Expression BeadChips (Illumina, San Diego, CA). Each BeadChip has ~24,000 well-annotated RefSeq transcripts with an approximately 30-fold redundancy. The arrays were washed, blocked and the biotin labeled cRNA was detected by staining with streptavidin-Cy3. Arrays were scanned at a resolution of 0.8 m using the Beadstation 500 X from Illumina, data was extracted from the image using Illumina BeadStudio software, v3.4.0.
2012-10-17 | E-GEOD-41345 | biostudies-arrayexpress
Project description:The relationship between repetitive mild traumatic brain injury (r-mTBI) and Alzheimer’s disease (AD) is well-recognized. However, the precise nature of how r-mTBI leads to or precipitates AD pathogenesis is currently not understood. Part A: Plasma biomarkers potentially provide non-invasive tools for detecting neurological changes in the brain, and can reveal overlaps between long-term consequences of r-mTBI and AD. In this study we address this by generating time-dependent molecular profiles of response to r-mTBI and AD pathogenesis in mouse models using unbiased proteomic analyses. To model AD, we used the well-validated hTau and PSAPP(APP/PS1) mouse models that develop age-related tau and amyloid pathological features respectively, and our well-established model of r-mTBI in C57BL/6 mice. Plasma were collected at different ages (3, 9, and 15 months-old for hTau and PSAPP mice), encompassing pre-, peri- and post-“onset” of the cognitive and neuropathological phenotypes, or at different timepoints after r-mTBI (24hrs, 3, 6, 9 and 12 months post-injury). Liquid chromatography/mass spectrometry (LC-MS) approaches coupled with Tandem Mass Tag labeling technology were applied to develop molecular profiles of protein species that were significantly differentially expressed as a consequence of mTBI or AD. Mixed model ANOVA after Benjamini-Hochberg correction, and a stringent cut-off identified 31 proteins significantly changing in r-mTBI groups over time and, when compared with changes over time in sham mice, 13 of these were unique to the injured mice. The canonical pathways predicted to be modulated by these changes were LXR/RXR activation, production of nitric oxide and reactive oxygen species and complement systems. We identified 18 proteins significantly changing in PSAPP mice and 19 proteins in hTau mice compared to their wildtype littermates with ageing. Six proteins were found to be significantly regulated in all three models i.e. r-mTBI, hTau and PSAPP mice compared to their controls. The top canonical pathways coincidently changing in all three models were LXR/RXR activation, and production of nitric oxide and reactive oxygen species. This work suggests potential biomarkers for TBI and AD pathogenesis and for the overlap between these two, and warrant targeted investigation in human populations. Part B: In this study we also address the aformention gap in the field by utilizing our unbiased proteomic approach to generate detailed time-dependent brain molecular profiles of response to repetitive mTBI and AD pathogenesis in established mouse models. Methods: We used the well-validated hTau and PSAPP(APP/PS1) mouse models that develops age-related tau and amyloid pathological features respectively, and our well-established model of repetitive-mTBI in C57BL/6 mice. Brain tissue from these animals were collected at different time points after repetitive mTBI (24hrs -12 months post-injury) and at different ages (3-15 months-old for hTau and PSAPP mice), encompassing pre-, peri- and post-“onset” of the cognitive and neuropathological phenotypes previously described in all models. Liquid chromatography/mass spectrometry (LC-MS) approach coupled with Tandem Mass Tag labeling technology were applied to reveal molecular profiles of proteins and pathways that are significantly altered as a consequence of AD or repetitive mTBI. Results: Mixed model ANOVA after Benjamin Hochberg correction identified 30 and 47 proteins that were specifically unique and changing in the hippocampus and cortex, respectively, within the r-mTBI group alone when compared with changes overtime in sham mice. PI3K/AKT signaling, Protein Kinase A signaling and PPAR/RXR activation in the hippocampus, and Protein Kinase A signaling, GNRH signaling and B cell receptor signaling in the cortex were the top canonical systems significantly altered in injury groups compared to sham mice. Mixed model AONVA identified 19 proteins significantly changing in the cortex of PSAPP mice and 7 proteins in hTau mice compared to their relative wildtype littermates respectively. In addition to the heterogeneous changes observed in the TBI and AD mouse models, there was a notable convergence and coincidental change in 6 unique proteins identified in the repetitive mTBI model and the hTau and PSAPP model. These proteins ostensibly indicate significant common pathobiological responses involving alterations in mitochondrial bioenergetics and energy metabolism, aberrant cytoskeletal reorganization and alterations in intracellular signaling transduction cascades. Conclusion: We believe that this work could help identify the common molecular substrates responsible for the precipitation of AD pathogenesis following repetitive mTBI, and also help to identify novel biological targets for therapeutic modulation in mTBI and AD.
2022-02-22 | PXD010602 | Pride
Project description:During blood feeding haematophagous arthropods inject into their hosts a cocktail of salivary proteins whose main role is to counteract host haemostasis, inflammation and immunity. However, animal body fluids are known to also carry miRNAs. To get insights into saliva and salivary gland miRNA repertoires of the African malaria vector Anopheles coluzzii we used small RNA-Seq and identified 214 miRNAs, including tissue-enriched, sex-biased and putative novel anopheline miRNAs. Noteworthy, miRNAs were asymmetrically distributed between saliva and salivary glands, suggesting that selected miRNAs may be preferentially directed toward mosquito saliva. The evolutionary conservation of a subset of saliva miRNAs in Anopheles and Aedes mosquitoes, and in the tick Ixodes ricinus, supports the idea of a non-random occurrence pointing to their possible physiological role in blood feeding by arthropods. Strikingly, eleven of the most abundant An. coluzzi saliva miRNAs mimicked human miRNAs. Prediction analysis and search for experimentally validated targets indicated that miRNAs from An. coluzzii saliva may act on host mRNAs involved in immune and inflammatory responses. Overall, this study raises the intriguing hypothesis that miRNAs injected into vertebrates with vector saliva may contribute to host manipulation with possible implication for vector-host interaction and pathogen transmission.
2019-02-22 | GSE120658 | GEO